2023 ESMO 摘要集 (LBA+O+MO+POSTER)

其他综合与多学科· 未分类与其他 · 2023

European Society for Medical Oncology (ESMO)

ESMO Executive Board

European Society for Medical Oncology (ESMO)

ESMO is the leading professional organisation for medical oncology. With more than 30,000 members representing oncology professionals from 168 countries worldwide, ESMO is the society of reference for oncology education and information. Driven by a shared determination to secure the best possible outcomes for patients, ESMO is committed to standing by those who care about cancer through addressing the diverse needs of #ONEoncologycommunity,offering #educationforLIFE, and advocating for #accessiblecancerCARE.

Drawing on more than 45 years of experience, ESMO serves its members and the oncology community by:

providing networking and professional growth opportunities: through ESMO, oncologists can engage in projects, committeesand working groups aiming to promote science and foster improvements in the oncology practice; providing training, resources and tools which enable oncologists to stay up-to-date with the latest scientiﬁc advances andcontinue to deliver the best possible care to cancer patients; representing and advocating for the oncology community at the highest political levels, ensuring that the needs of bothpatients and doctors are properly taken care of.

Cancer care becomes more integrated and more specialised every day; whether their ﬁeld is research, diagnosis,treatment, care, or advocacy, oncology professionals need to both build their specialist knowledge and connect with the best practitioners in other disciplines worldwide. ESMO membership makes this possible.

www.esmo.org

ESMO Executive Board

President

Andrés Cervantes, Valencia, Spain

President-Elect

Fabrice André, Villejuif, France

Past-President

Solange Peters, Lausanne, Switzerland

Director of Education

Nadia Harbeck, Munich, Germany

Director of Membership

Evandro de Azambuja, Brussels, Belgium

Director of Public Policy

Jean-Yves Blay, Lyon, France

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ONC。

European Oncology Nursing Society (EONS)

The European Oncology Nursing Society (EONS) is a pan-European membership organisation for cancer nurses e the largest group of healthcare workers in the oncology workforce.

EONS provides leadership in all areas of cancer nursing: research, practice, continuing education, communications and advocacy for better recognition of cancer nursing across Europe.

Vision

Our vision is that cancer nursing will be recognised by the cancer community, national and European level policy makers, as a profession with specialised training and qualiﬁcations available across the continent. Working conditions for cancer nurses will be optimal, providing a commensurate ﬁnancial income as well as protecting and promoting individual well-being.We anticipate that this will produce a relatable improvement in the health and clinical outcomes for people affected by cancer. Finally, we envisage that all our members will become conﬁdent and empowered cancer nurses operating as leaders in research, practice and education within multi-professional teams.

Strategic goals

All strategic goals are equal and assume no hierarchy. EONS aims to achieve the following:

1. Cancer nursing is recognised across Europe for its positive impact on the lives of people affected by cancer through C.A.R.E. e Communication, Advocacy, Research and Education.

2. All cancer nurses have access to specialised education that is aligned with the EONS Cancer Nursing Education Framework.

3. All cancer nurses gain ofﬁcial recognition, reward and respect as a result of the RECaN and advocacy campaigns.

4. All cancer nurses are connected in order to exchange and share information and support for their work.

5. EONS facilitates, leads and promotes collaborative cancer nursing research across Europe.

6. EONS leads EU-wide advocacy initiatives at EU policy level.

7. EONS provides evidence-based advice to people and organisations affected by cancer on healthy lifestyles and cancer prevention.

EONS has prepared an update strategy for 2024-2028.

Read more about this at https://cancernurse.eu/about-eons/strategy/

EONS Board as of June 2023

|President |Virpi Sulosaari, Turku, Finland | |---|---|

|Past-President |Johan de Munter, Ghent, Belgium |

|President-Elect |Helena Ullgren, Stockholm, Sweden |

|Treasurer |Matthew Fowler, Birmingham, UK |

|Board member |Gülcan Bagcivan, Istanbul, Turkey|

|Board member |Merel van Klinken, Haarlem, Netherland |

|Board member |Amanda Drury, Dublin, Ireland |

|Board member |Wendy McInally, Edinburgh, UK |

|Board member |Nikolina Dodlek, Osijek, Croatia |

ESMO Congress 2023 Congress Ofﬁcers

Congress President

Scientiﬁc Chair

Silke Gillessen, Bellinzona, Switzerland

Educational Chair

Karin Jordan, Potsdam, Germany

Press Ofﬁcer

Angela Lamarca, Madrid, Spain

Scientiﬁc Committee

Basic science & translational research

Chair: Federica Di Nicolantonio, Candiolo, Italy

Christina Curtis, Stanford, CA, USA

Stefan Fröhling, Heidelberg, Germany Elin Gray, Perth, WA, Australia

Göran Jönsson, Lund, Sweden

Madelon Maurice, Utrecht, Netherlands Fatima Mechta-Grigoriou, Paris, France Katerina Politi, New York, NY, USA

Caetano Reis e Sousa, London, UK

John Stagg, Montreal, QC, Canada

Naureen Starling, London, UK

Marc Vooijs, Maastricht, Netherlands

Breast cancer, early stage

Chair: Stephen Johnston, London, UK

Thomas Bachelot, Lyon, France

Boon Chua, Randwick, NSW, Australia

Evandro De Azambuja, Brussels, Belgium Richard De Boer, Melbourne, VIC, Australia Carsten Denkert, Marburg, Germany

Valentina Guarneri, Padua, Italy

Seock-Ah Im, Seoul, Republic of Korea Ava Kwong, Hong Kong, China

Shani Paluch-Shimon, Jerusalem, Israel Ann Partridge, Boston, MA, USA

Peter Schmid, London, UK

Breast cancer, metastatic

Chair: Hervé Bonnefoi, Bordeaux, France

Giampaolo Bianchini, Milan, Italy

Lisa Carey, Chapel Hill, NC, USA

Eva Ciruelos, Madrid, Spain

Giuseppe Curigliano, Milan, Italy

Suzette Delaloge, Paris, France

Karen Gelmon, Vancouver, BC, Canada Sung-Bae Kim, Seoul, Republic of Korea Ian Krop, New Haven, CT, USA

Christoph Thomssen, Halle, Germany Constanta Timcheva, Soﬁa, Bulgaria Janice Tsang, Hong Kong, China

Andrew Tutt, London, UK

CNS tumours

Chair: Roger Stupp, Chicago, IL, USA

Anna Sophie Berghoff, Vienna, Austria Dieta Brandsma, Amsterdam, Netherlands Filip De Vos, Utrecht, Netherlands

Evanthia Galanis, Rochester, MN, USA Jens Gempt, Munich, Germany

Monika Hegi, Lausanne, Switzerland

Matthias Holdhoff, Baltimore, MD, USA Slavka Lukacova, Aarhus, Denmark

Giuseppe Minniti, Siena, Italy

Sabine Mueller, Zurich, Switzerland

Ho-Keung Ng, Hong Kong, China

Emeline Tabouret, Marseille, France

Developmental therapeutics

Chair: Lillian Siu, Toronto, ON, Canada

Alex A. Adjei, Cleveland, OH, USA

Philippe Cassier, Lyon, France

Maja de Jonge, Rotterdam, Netherlands Alex Drilon, New York, NY, USA

Steven Gallinger, Toronto, ON, Canada Elena Garralda, Barcelona, Spain

Kevin Harrington, London, UK

Fernanda Herrera, Lausanne, Switzerland Ulrik Lassen, Copenhagen, Denmark

Chia-Chi Lin, Taipei, Taiwan

Ruth Plummer, Newcastle Upon Tyne, UK Ignacio Wistuba, Houston, TX, USA

Gastrointestinal tumours, lower digestive Chair: Chiara Cremolini, Pisa, Italy

Guillem Argiles Martinez, New York, NY, USA Myriam Chalabi, Amsterdam, Netherlands Su Pin Choo, Singapore

Rodrigo Dienstmann, São Paulo, Brazil

Gunnar Folprecht, Dresden, Germany

Thomas Gruenberger, Vienna, Austria

Karin Haustermans, Leuven, Belgium

Dominik Modest, Berlin, Germany

Clara Montagut, Barcelona, Spain

Hans Prenen, Antwerp, Belgium

Jenny Seligmann, Leeds, UK

Julien Taieb, Paris, France

Gastrointestinal tumours, upper digestive Chair: Elizabeth Smyth, Cambridge, UK

Stephen Chan, Hong Kong, China

Laura Dawson, Toronto, ON, Canada

Tania Fleitas, Valencia, Spain

Yelena Janjigian, New York, NY, USA

Andrew Ko, San Francisco, CA, USA

Angela Lamarca, Manchester, UK

Florian Lordick, Leipzig, Germany

Sylvie Lorenzen, Munich, Germany

Magnus Nilsson, Stockholm, Sweden

Radka Obermannova, Brno, Czech Republic

Lorenza Rimassa, Milan, Italy

Kohei Shitara, Kashiwa, Japan

Hanneke Van Laarhoven, Amsterdam, Netherlands

Genitourinary tumours, prostate Chair: Karim Fizazi, Villejuif, France

Gerhardt Attard, London, UK

Himisha Beltran, Boston, MA, USA

Elena Castro, Malaga, Spain

Marco Gizzi, Charleroi, Belgium

Gwenaelle Gravis, Marseille, France

Boris Hadaschik, Essen, Germany

Daniel Heinrich, Lorenskog, Norway

Nicholas James, London, UK

Niven Mehra, Nijmegen, Netherlands

Dana Rathkopf, New York, NY, USA

Shahneen Sandhu, Melbourne, VIC, Australia Bertrand Tombal, Woluwe-Saint-Lambert,Belgium

Genitourinary tumours, non-prostate

Chair: Michiel van der Heijden, Amsterdam, Netherlands

Laurence Albiges, Villejuif, France

Axel Bex, London, UK

Toni Choueiri, Boston, MA, USA

Maria De Santis, Berlin, Germany

Petros Grivas, Seattle, WA, USA

Robert Huddart, Sutton, UK

Andrea Necchi, Milan, Italy

Elisabeth Plimack, Philadelphia, PA, USA Thomas Powles, London, UK

Manuela Schmidinger, Vienna, Austria Srikala Sridhar, Toronto, ON, Canada Cristina Suárez, Barcelona, Spain

Gynaecological cancers Chair: David Tan, Singapore

Susana Banerjee, London, UK

Nicoletta Colombo, Milan, Italy

Stephanie de Boer, Leiden, Netherlands Antonio González-Martin, Madrid, Spain Charlie Gourley, Edinburgh, UK

Alexandra Leary, Villejuif, France

Sven Mahner, Munich, Germany

Vicky Makker, New York, NY, USA

Ana Oaknin, Barcelona, Spain

Isabelle Ray-Coquard, Lyon, France

Clare Scott, Melbourne, VIC, Australia

Haematological malignancies

Chair: Davide Rossi, Bellinzona, Switzerland

Elias Campo, Barcelona, Spain

Olivier Casasnovas, Dijon, France

Barbara Eichhorst, Cologne, Germany Ramon Garcia-Sanz, Salamanca, Spain Nicola Gökbuget, Frankfurt, Germany Claire N. Harrison, London, UK

Ulrich Jaeger, Vienna, Austria

Won Seog Kim, Seoul, Republic of Korea Marco Ladetto, Alessandria, Italy

Catherine Thieblemont, Paris, France Elena Zamagni, Bologna, Italy

Thorsten Zenz, Zurich, Switzerland

Head and neck cancer

Chair: Paolo Bossi, Rozzano, Italy

Pierluigi Bonomo, Florence, Italy

Irene Brana, Barcelona, Spain

Anthony TC Chan, Hong Kong, China Robert Ferris, Pittsburgh, PA, USA

Jens Peter Klussmann, Cologne, Germany Senada Koljenovic, Antwerp, Belgium Lisa Licitra, Milan, Italy

Brigette Ma, Hong Kong, China

Jean-Pascal Machiels, Brussels, Belgium Sjoukje Oosting, Groningen, Netherlands Amanda Psyrri, Athens, Greece

Petr Szturz, Lausanne, Switzerland

Investigational immunotherapy

Chair: Inge Marie Svane, Herlev, Denmark

Victoria Atkinson, Woolloongabba, QLD, Australia Alessandra Curioni-Fontecedro, Fribourg, Switzerland Tanja de Gruijl, Amsterdam, Netherlands

John Haanen, Amsterdam, Netherlands

Jessica Hassel, Heidelberg, Germany

Lana Kandalaft, Lausanne, Switzerland

Sebastian Kobold, Munich, Germany

Nicholas McGranahan, London, UK

Ignacio Melero, Pamplona, Spain

Gary Middleton, Birmingham, UK

Antoni Ribas, San Francisco, CA, USA

Licia Rivoltini, Milan, Italy

Melanoma and other skin tumours

Chair: Teresa Amaral, Tubingen, Germany

Boris C. Bastian, San Francisco, CA, USA Reinhard Dummer, Zurich, Switzerland

Omid Hamid, Los Angeles, CA, USA

Mathilde Jalving, Groningen, Netherlands Georgina V. Long, Sydney, NSW, Australia Ivan Marquez-Rodas, Madrid, Spain

Teresa Petrella, Toronto, ON, Canada

Inês Pires da Silva, Sydney, NSW, Australia Caroline Robert, Paris, France

Dirk Schadendorf, Essen, Germany

Ryan Sullivan, Boston, MA, USA

Alexander van Akkooi, Wollstonecraft, NSW,Australia

NETs and endocrine tumours

Chair: Jaume Capdevila, Barcelona, Spain

Eric Baudin, Paris, France

Emily Bergsland, San Francisco, CA, USA

Alfredo Berruti, Brescia, Italy

Sara De Dosso, Bellinzona, Switzerland

Christelle de la Fouchardiere, Marseille, France Nicola Fazio, Milan, Italy

Grigorios Kaltsas, Athens, Greece

Stefano Partelli, Milan, Italy

Marianne Pavel, Erlangen, Germany

Rachel Riechelmann, São Paulo, Brazil

Margot Tesselaar, Amsterdam, Netherlands

Non-metastatic NSCLC and other thoracic malignancies

Chair: Rafal Dziadziuszko, Gdansk, Poland

Nicolas Girard, Paris, France

Matthias Guckenberger, Zurich, Switzerland Jarushka Naidoo, Dublin, Ireland

Silvia Novello, Turin, Italy

Kersti Oselin, Tallin, Estonia

Luis Paz-Ares, Madrid, Spain

Zoﬁa Piotrowska, Boston, MA, USA

Sanjay Popat, London, UK

Gaetano Rocco, New York, NY, USA

Johan Vansteenkiste, Leuven, Belgium

Heather Wakelee, Stanford, CA, USA

Yasushi Yatabe, Tokyo, Japan

NSCLC, metastatic

Chair: Marina Garassino, Chicago, IL, USA

Fiona Blackhall, Manchester, UK

Eddie Garon, Santa Monica, CA, USA Cecile Le Pechoux, Paris, France

Jessica Lin, Boston, MA, USA

Tetsuya Mitsudomi, Osaka, Japan Giulia Pasello, Padua, Italy

Martin Reck, Grosshansdorf, Germany Noemi Reguart, Barcelona, Spain

Christian Rolfo, New York, NY, USA Ross Soo, Singapore

Giulia Veronesi, Milan, Italy

Yi-Long Wu, Guangzhou, China

Policy and preventive strategies

Chair: Jose Maria Martin-Moreno, Valencia,Spain

Tit Albreht, Ljubljana, Slovenia

Melanie Bertram, Geneva, Switzerland Nathan Cherny, Jerusalem, Israel

Elizabeth De Vries, Groningen, Netherlands Rudolf Fehrmann, Groningen, Netherlands Mary Gospodarowicz, Toronto, ON, Canada Margaret Hutka, Peterborough, UK

James McKay, Lyon, France

Gilberto Morgan, Lund, Sweden

Manju Sengar, Mumbai, India

Tanja Spanic, Ljubljana, Slovenia

Wendy Yared, Brussels, Belgium

Sarcoma

Chair: Silvia Stacchiotti, Milan, Italy

Sebastian Bauer, Essen, Germany Sylvie Bonvalot, Paris, France

Kjetil Boye, Oslo, Norway

Dario Callegaro, Milan, Italy

Tom Wei-Wu Chen, Taipei, Taiwan Bernd Kasper, Mannheim, Germany Aisha Miah, London, UK

Piotr Rutkowski, Warsaw, Poland Marta Sbaraglia, Padua, Italy

Sandra Strauss, London, UK

Claudia Valverde, Barcelona, Spain Breelyn Wilky, Aurora, CO, USA

Supportive and palliative care

Chair: Christina Ruhlmann, Odense,Denmark

Snezana Bosnjak, Belgrade, Serbia

Tanja Fusi, Lugano, Switzerland

Jørn Herrstedt, Roskilde, Denmark

David Hui, Houston, TX, USA

Dorothy Keefe, Surry Hills, NSW, Australia Gudrun Kreye, Krems, Austria

Anne Letsch, Kiel, Germany

Mitsue Saito, Tokyo, Japan

Anton Snegovoy, Moscow, Russia

Ines Vaz Luis, Villejuif, France

Jayne Wood, London, UK

Camilla Zimmermann, Toronto, ON, Canada

EONS16 Scientiﬁc Committee

Virpi Sulosaari, Turku, Finland, Co-Chair, EONS President Elect

Amanda Drury, Dublin, Ireland, Co-Chair, in place for EONS Past President

Johan de Munter, Ghent, Belgium, Senior advisor, EONS President

Constantina Cloconi, Limassol, Cyprus, Communication Working Group representative

Gianluca Catania, Genoa, Italy, Advocacy Working Group representative

Eva Pape, Ghent, Belgium, Research Working Group representative

Tugba Pehlivan, Istanbul, Turkey, Education Working Group representative

Bethany Maynard, Southampton, UK, Young Cancer Nurses representative

Julio César de la Torre Montero, Madrid, Spain, local representative

Jorgina Serra, Spain, Barcelona, local representative

Paz Fernandez Ortega, Barcelona, Spain, local representative

Richard G Kelly, Brussels, Belgium, EONS COO

The European Society for Medical Oncology and the European Oncology Nursing Society wish to express their appreciation and gratitude to all of the above experts for their major effort in reviewing and selecting the content of this Abstract Book.

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CircIGF1R_0001 mediates platinum resistance in ovarian cancer that sensitive to PARP inhibitors via promoting PARP1 binding to DNA damage sites

L. Ruilin1, Q. Li2, H. Yao3

1Department of Gynecologic Oncology, Second Afﬁliated Hospital/Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, China; 2Medical Oncology, The Second Afﬁliated Hospital of Sun Yat-Sen University, Guangzhou, China; 3Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regu, Second Afﬁliated Hospital of Sun Yat-Sen University, Guangzhou, China

Background: Clinical research indicated that some platinum-resistant ovarian cancer patients are sensitive to Poly (ADP-ribose) polymerase inhibitors(PARPi) and it is associated with high Poly(ADP-ribosyl)lation (PARylation) activity of PARP1. However,the speciﬁc mechanism remains unclear.

Methods: Key functional circRNAs that promote platinum resistance in epithelial ovarian cancer（EOC）were screened and identiﬁed through next-generation sequencing, quantitative real-time polymerase chain reaction (qRT-PCR), and comet assay methods. Experiments such as RNA immunoprecipitation (RIP), RNA pull-down,laser micro-irradiation, and ﬂuorescence colonization were used to identify the proteins and domains that interact with target circRNA. The recruitment and trapping of PARP1 at DNA damage sites were detected through Chromatin extract isolation and Biotin-tagged Nicked DNA pulled down.

Results: The circIGF1R_0001 is highly expressed in some platinum-resistant tissues and cell lines, and its overexpression enhances DNA repair and platinum resistance in ovarian cancer cells. The circIGF1R_0001 binds to the DNA binding domain of PARP1 and can be recruited together to DNA damage sites. Silencing circIGF1R_0001 signiﬁcantly reduces the PARylation of PARP1, weakens the recruitment of PARP1 at DNA damage sites, and inhibits the activation of downstream DNA liag3. Furthermore,EOC patients and cell lines with platinum resistance that overexpressing circIGF1R_0001 are more sensitive to PARP inhibitors; silencing circIGF1R_0001 increases the resistance to PARPi while weakening the DNA trapping effect of PARP1.

Conclusions: 1. Overexpression of circIGF1R_0001 promotes platinum resistance but also promotes sensitivity to PARPi in ovarian cancer. 2. The circIGF1R_ 0001 binds to and regulates the DBD domain of PARP1 to promote its PARylation and enhance its recruitment to DNA damage sites then enhanced the base excision repair pathway.

Importantly, circIGF1R_ 0001 also enhances the DNA trapping of PARP1 by PARPi. 3.

The circIGF1R_ 0001 acts as a potential biomarker for platinum resistance in ovarian cancer and a marker for screening patients who can beneﬁt from PARPi after platinum resistance.

Legal entity responsible for the study: The authors.

Funding: Has not received any funding.

Disclosure: All authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1504

2O PD-1 deﬁnes a distinct, functional, tissue-adapted state in

V-delta-1+ T cells with implications for cancer

immunotherapy

Y. Wu1, D. Davies1, S. Kamdar1, R. Woolf2, I. Zlatareva2, M.L. Iannito1, C. Morton3,Y. Haque2, H. Martin4, O. O’Neill5, O. Nussbaumer2, A. Hayday2

1Centre for Inﬂammation Biology and Cancer Immunology, King’s College London,London, UK; 2Peter Gorer Department of Immunobiology, King’s College London,London, UK; 3Department of Oncology, Guy’s and St Thomas’ NHS Foundation Trust,London, UK; 4Immunosurveillance Lab, The Francis Crick Institute, London, UK;5Advanced Sequencing Facility, The Francis Crick Institute, London, UK

Background: Checkpoint inhibition (CPI), particularly that targeting the inhibitory coreceptor, programmed cell death protein (PD-1), has transformed cancer care.

Although CPI can de-repress cancer antigen-speciﬁc ab T cells that ordinarily show PD-1-dependent exhaustion, it can also be efﬁcacious against cancers evading ab T cell recognition through loss of MHC or low mutational burdens. In such settings,tissue-associated Vd1+ gd T cells have been implicated as these cells are not classically peptide-MHC dependent. Despite some evidence for association of Vd1+ T cells to CPI response, the immunological signiﬁcance of PD-1 expression by human Vd1+ T cells remains uncharacterised.

Methods: As Vd1+ T can operate independent of neoantigen load, we looked for a transcriptomic signature of Vd1+ T cells in a public dataset of patients with melanoma receiving anti-PD-1 therapy and correlated this signature to response in the context of neoantigen load. Alongside this, we developed a protocol which enabled the

e 34 - Issue S2 - 2023

extraction of substantial numbers of human skin gd T cells to permit transcriptomic and functional studies of these rare cells. Skin-derived PD-1+and PD-1-Vd1+ T cells were sorted and analysed by NanoString using the nCounter Immune Exhaustion Panel. The cells were also activated in vitro both in the presence and absence of recombinant PD-L1 +/- atezolizumab and assayed for cytotoxic degranulation and production of effector cytokines.

Results: We found that a transcriptional signature of intratumoral Vd1+ T cells predicts response to anti-PD-1 in patients with melanoma, particularly in the context of low neoantigen load. Moreover, we found that skin-derived PD-1+Vd1+ T cells display a transcriptomic programme of tissue-residence, survival/self-renewal, and functional competence distinct from the canonical exhaustion programme of co-located PD-1+CD8+ ab T cells. Indeed, PD-1+Vd1+ T cells retained effector responses to T cell receptor signalling that were inhibitable by PD-1 engagement and partially derepressed by CPI.

Conclusions: Our formal demonstration that Vd1+ T cells can be suppressed by PD-1 engagement and de-repressed by anti-PD-(L)1 CPI therapy supports their utility as a predictive biomarker for therapy.

Funding: Wellcome Trust, Francis Crick Institute, Takeda Pharmaceutical Company.

Disclosure: Y. Wu: Non-Financial Interests, Personal and Institutional, Research Grant: Wellcome Trust; Financial Interests, Personal, Advisory Board: PersonGen Biotherapeutics. A. Hayday: NonFinancial Interests, Personal and Institutional, Funding: Takeda Pharmaceutical Company; Financial Interests, Personal, Advisory Board: eGenesis, Prokarium. All other authors have declared no con-ﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1505

3O IGSF8 is an innate immune checkpoint and cancer

immunotherapy target

K. Benhadji1, Y. Li2, X. Wu2, H. Liu2, X. Xiao2, H. Liu2, Q. Ding2, B. Xie2, C. Sheng2,R. Zheng2, Q. Yu2, X. Hu3, X.S. Liu4, T. Xiao2

1Clinical Department, GV20 Therapeutics, Cambridge, MA, USA; 2Biology, GV20 Therapeutics, Shanghai, China; 3Bioinformatics, GV20 Therapeutics, Cambridge, MA,USA; 4GV20 Therapeutics, Cambridge, MA, USA

Background: Loss of MHC-I antigen presentation is often associated with T cell excluded tumors, and represents a common mechanism of both primary and acquired resistance to immune checkpoint blockade (ICB) treatment. MHC-I normally acts as a marker of “self” and cells that lack MHC-I are recognized and killed by innate immunity. A major puzzle in cancer immunology remains as to how T cell excluded tumors with MHC-I antigen presentation defects evade innate immune killing.

Methods: Integrating functional genomics, big data, and artiﬁcial intelligence, we discovered that IGSF8 expressed on cancer cells is a conserved innate immune checkpoint. IGSF8 is normally expressed in neuronal tissues and is not essential in vitro or in vivo. However, knockout of IGSF8 in B16-F10 melanoma cell line decreased tumor growth in vivo. For clinical relevance of IGSF8 in tumor immunity, we analyzed genomics, transcriptomics, and clinical data from The Cancer Genome Atlas (TCGA).

We developed an antibody (GV20-0251) against IGSF8 and tested its function to induce immune cell killing of cancer cells in vitro and inhibit tumor growth in vivo.

Results: IGSF8 has receptors on both natural killer (NK) cells and dendritic cells (DC)to strongly suppress NK cytotoxicity and antigen presentation. In many cancer types across TCGA, IGSF8 is frequently DNA copy number ampliﬁed and overexpressed, and IGSF8 expression is associated with low antigen presentation, low immune inﬁltration, and worse overall survival in patients with low MHC class I expression. We developed a cross-species reactive antibody against IGSF8 (GV20-0251) which blocks IGSF8 interaction with NK and DC. This antibody enhances NK killing of cancer cells in vitro and increases antigen presentation, NK-mediated cytotoxicity, and T cell signaling in vivo. In multiple syngeneic tumor models (B16-F10, CT26, LLC and EMT6),anti-IGSF8 shows single-agent efﬁcacy and is synergistic with anti-PD1 in controlling tumor growth.

Conclusions: IGSF8 is a novel innate immune checkpoint and cancer immunotherapy target. Given the ability for anti-IGSF8 to activate innate immunity, a phase 1 study has been initiated to explore the IGSF8 inhibitor GV20-0251 in patients with advanced or metastatic solid tumors (NCT05669430).

Legal entity responsible for the study: GV20 Therapeutics.

Funding: GV20 Therapeutics.

Disclosure: K. Benhadji: Financial Interests, Personal, Ofﬁcer: GV20 Therapeutics; Financial Interests, Personal, Stocks/Shares: Lilly; Other, Employment: Taiho Oncology. Y. Li, H. Liu, X. Xiao, H.

Liu: Financial Interests, Personal, Full or part-time Employment, Stock options: GV20 Therapeutics. X.

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Wu, B. Xie, R. Zheng, Q.Yu: Financial Interests, Personal, Full or part-time Employment: GV20 Therapeutics. Q. Ding: Financial Interests, Personal, Full or part-time Employment, Stock Ownership:GV20 Therapeutics. C. Sheng: Financial Interests, Personal, Financially compensated role, Stock options: GV20 Therapeutics; Financial Interests, Personal, Full or part-time Employment: Novartis. X.

Hu: Financial Interests, Personal, Ofﬁcer, Stock Options: GV20 Therapeutics. X.S. Liu, T.Xiao: Financial Interests, Personal, Ofﬁcer, Director, Stock ownership: GV20 Therapeutics.

https://doi.org/10.1016/j.annonc.2023.09.1506

Spatially resolved transcriptome elucidates bidirectional tertiary lymphoid structure interacts with tumor

microenvironment of non-small cell lung cancer

X. Zhao1, B. Zhang2, S. Qiao1, S. Cao1, L. Dian1, Y. Xu1, D. Yue3

1Cancer Research Center, BGI-Shenzhen - Headquarters, Shenzhen, China; 2Department Of Lung Cancer, Tianjin Medical University Cancer Institute & Hospital, Tianjin,China; 3Lung Cancer Dept, Tianjin Medical University Cancer Institute & Hospital,Tianjin, China

Background: The presence of tertiary lymphoid structure has a signiﬁcant correlation with the lung cancer patient’s response to immune checkpoint inhibitors. Nonetheless, the developmental characteristics of TLS and their surrounding tumor microenvironmental features in the primary tumor have not been elucidated comprehensively.

Methods:We utilized spatially resolved transcriptome and single-cell RNA sequencing to examine the molecular signatures and the essential cell types of TLS during its maturation process in the tumor microenvironment. Additionally, multiplex immunoﬂuorescence staining and whole transcriptome sequencing were performed for validation.

Results: We categorized 406 potential TLSs into four states: pre-TLS, primary TLS,mature TLS, and aging TLS - based on their spatial molecular characteristics. The high expression of FDCSP in follicular DCs is a novel marker to promote TLS maturation by speciﬁcally binding to activated B cells. Three types of receptor-ligand interactions in mature and aging TLS could predict the prognosis in early-stage LUAD. Interestingly,aging TLS with signiﬁcantly upregulated FOXP3 and TOX2 could limit anti-tumor immunity. Additionally, the molecular characteristics of aging TLS showed a lower expression of a group of CC chemokine ligands compared to mature TLS, which could potentially lead to a weaker anti-tumor response. We also observed an increase in tumor proliferation activity in the periphery of the aging TLS region. One approach to reverse the anti-tumor activity of aging TLS to that of mature TLS could be to increase the concentration of environmental chemokines while simultaneously blocking the upregulation of TIGIT in aging TLS.

Conclusions: Those results demonstrated that the condition of TLS was inﬂuenced by the neighboring tumor microenvironment in the early-stage LUAD. And the conventional mature TLS would eventually reach a biologically aged state in the same tumor microenvironment. By regulating chemokine signaling in the aging TLS’s surrounding environment, it could potentially serve as an adjuvant therapy to enhance the antitumor activity of immune elements in resectable LUAD patients.

Legal entity responsible for the study: TJMUCH and BGI.

https://doi.org/10.1016/j.annonc.2023.09.1507

5P Tertiary lymphoid structures (TLS) presence and stromal

blood vessels heterogeneity differentially inﬂuence

recurrence, lymphovascular, and perineural invasion in

breast cancer molecular subtypes

A.A. Cosma1, A.C. Barb1, S.M. Negru2, M.M. Pasca Fenesan2, A.M. Cimpean1

1Department of Microscopic Morphology/Histology, UMFT - University of Medicine and Pharmacy Victor Babes, Timisoara, Romania; 2Oncology Department, OncoHelp Oncology Center Timisoara, Timisoara, Romania

Background: Tertiary Lymphoid Structures (TLS) mediate local antitumor immunity.

Since cancer immunotherapy, TLS interests grown considerably. We examined TLS and tumor stromal blood vessels for BC molecular subtypes associated with recurrence,lymphovascu-lar (LIV), and perineural invasion (PnI).

Methods: CD34/SMA double immunostaining revealed TLS high endothelial venules and BC tumor stromal immature and mature blood vessels. Statistical study linked microscopic data to recurrence, LIV, and PnI.

Results: TLS- subgroups have higher LIV, PnI, and recurrence (p<0.001), except for Luminal A type. LIV and PnI rise in HER2+/TLS- subgroups (p<0.001). TNBC/TLS- had the highest recurrence and invasion risks. TNBC/TLS- subgroup recurrence is related to tumor grade and LIV/PnI (p<0.001), unlike other TLS- subgroups. PnI but not LVI are related with TNBC/TLS+ subgroup recurrence (p<0.001).

Conclusions: TLS affect BC molecular subtype recurrence, LVI, and PnI differently. Its antitumor immunity mediator seems closely associated to tumor aggressiveness and stromal blood vessels.

https://doi.org/10.1016/j.annonc.2023.09.1508

6P Combined single-cell and spatially resolved mapping of the

human lymph node ecosystem reveals fundamental

principles of lymphoma tissue organization

D. Hübschmann1, L. Jopp-Saile2, F. Czernilofsky3, A. Mathioudaki3, R. Lutz4,

D. Vonﬁcht5, X. Wang3, M.A. Baertsch4, H. Vöhringer3, T. Roider3, J. Mammen3,D. Ordoñez-Rueda6, C. Pabst4, W. Huber3, A. Trumpp7, C. Müller-Tidow4, G. Nolan8,J. Zaugg3, S. Haas9, S. Dietrich10

1Computational Oncology Group, Molecular Precision Oncology Program, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany; 2Pattern Recognition and Digital Medicine, HI-STEM -Heidelberg Institute for Stem Cell Technology and Experimental Medicine, Heidelberg,Germany; 3Molecular Medicine Partnership Unit, EMBL - European Molecular Biology Laboratory - Heidelberg, Heidelberg, Germany; 4Department of Internal Medicine V,Heidelberg University Hospital, Heidelberg, Germany; 5Stem Cells at the Interface of Hematopoiesis, Immunity and Cancer, HI-STEM - Heidelberg Institute for Stem Cell Technology and Experimental Medicine, Heidelberg, Germany; 6Flow Cytometry Core Facility, EMBL - European Molecular Biology Laboratory - Heidelberg, Heidelberg,Germany; 7Stem Cells and Cancer, German Cancer Research Center, Heidelberg, Germany; 8Cancer Institute, Stanford Medical, Stanford, CA, USA; 9Berlin Institute of Health, Charité - Universitätsmedizin Berlin, Berlin, Germany; 10Hematology, Oncology and Clinical Immunology, UKD - Universitätsklinikum Düsseldorf, Düsseldorf, Germany

Background: Lymph nodes (LN) act as central hubs for the orchestration of adaptive immune responses. A network of lymph node stromal cells (LNSC), including mesenchymal and endothelial cells, build a 3D network for immune cells to migrate and home to distinct niches in the LN.Within B cell non-Hodgkin lymphomas, indolent follicular lymphomas (FL) are characterized by subtle structural changes while the compartmentalization of the tissue remains present. In contrast, aggressive diffuse large B cell lymphomas (DLBCL) are deﬁned by a complete loss of tissue organization indicating a potential role of LNSCs in tumorigenesis. While the morphological differences are well-known, the underlying molecular and cellular mechanisms remain poorly understood.

Methods: Here, we dissect the mechanisms underlying loss of structure in lymphomagenesis using combined single-cell transcriptome and spatially-resolved mapping approaches of LNSCs and immune cells.

Background: Metastasis accounts for 90% of cancer related deaths and blocking of metastatic cascade has critical clinical impact. However, the clinical drug development for cancer treatment, including cancer immunotherapies, is evaluated largely depending on their ability to cause tumour shrinkage and ignores the effect on metastasis as it has proven challenging to target. Therefore, there is an urgent need for novel therapeutic strategies and agents targeting metastasis. Using an attenuated Salmonella typhimurium strain YB1 engineered by our lab, we have found a potent suppressive effect of attenuated Salmonella on cancer metastasis, regardless of cancer types and genetic background, by evoking strong anti-metastatic immune response.

Methods: Mutant mice and antibody-mediated cell depletion were used to identify the host genetic and cellular requirement for the bacterial supression of cancer cell metastasis. CyTOF (mass cytometry or cytometry by time of ﬂight) was used to investigate the the innate immune responses after Salmonella treatment.

Results: Our studies showed that suppression of cancer metastasis by attenuated Salmonella only requires the innate immune response. Among the many induced cytokines, IFN-g was identiﬁed as an indispensable factor for inhibiting cancer metastasis. CyTOF and antibody-mediated cell depletion analysis of the innate immune responses after Salmonella treatment, revealed that NK cells are the major factor involved in Salmonella-provoked metastasis suppression.

Conclusions: We found that IFN-g was mainly produced by NK cells during early Salmonella infection, and in turn, IFN-g promoted the accumulation, activation and cytotoxicity of NK cells. The IFN-g-dependent NK cells directly eliminated newly accumulated cancer cells in the lung to block the cancer metastasis cascade in response to the Salmonella treatment.

Legal entity responsible for the study: The author.

Funding: This work was supported by grants from the Shenzhen Peacock Team Project (KQTD2015033117210153) and Shenzhen Science and Technology Innovation Committee Basic Science Research Grant (JCYJ20170413154523577).

https://doi.org/10.1016/j.annonc.2023.09.1510

8P Modulating tumor microenvironment using a VEGF active

immunotherapeutic approach in gastrointestinal tumors:

Beyond angiogenesis modulation

M. Bequet-Romero1, Y. Morera2, F. Hernández-Bernal3, C. Canaan-Haden1,

K-H. Selman-Housein3, I. González-Moya1, J. Sanchez-Ramirez1, Y. Martín-Bauta3,A. de la Torre-Santos4, M. Ayala3

1Biomedical Research, Center for Genetic Engineering and Biotechnology, Havana,Cuba; 2Cancer Immunotherapy, Center for Genetic Engineering and Biotechnology,Havana, Cuba; 3Clinical Research, Center for Genetic Engineering and Biotechnology,Havana, Cuba; 4Oncology, General Hospital Celestino Hernández, Havana, Cuba

Background: Targeting of the vascular endothelial growth factor (VEGF) is known for going beyond mere modiﬁcation of angiogenesis, and extends to the systemic and intratumoral regulation of immune cells activation state. In this study, we aim to explore the effect of a VEGF active immunotherapy based on a recombinant antigen named CIGB-247, in the systemic and tumor compartments in preclinical settings for mice, and in a subset of 22 patients with advanced gastrointestinal cancer (GIC) from phase I clinical trials (RPCEC00000102 and RPCEC00000155).

Methods: BALB/c mice were immunized with CIGB-247, and challenged with CT26 colon carcinoma cells subcutaneously. A week after the last immunization mice were euthanized and the tumor and the systemic compartment, were analyzed by ELISA,ﬂow cytometry, and RT-QPCR assays. GIC patients’ serum and leukocyte samples were evaluated for cytokines, speciﬁc VEGF antibody titers, and VEGFR2 neutralization using ELISA, while the cellular response was assessed by ELISPOT.

Results: The vaccine signiﬁcantly boosted the inﬁltration of activated CD3+ cells and caused a decrease in the number of MDSCs and Tregs in analyzed compartments. The levels of VEGF, PLGF, and CXCL1 were signiﬁcantly reduced in the tumor lysates, while the concentration of CD8 activation-related molecules like IFN-g, and GRZ-B were induced. Finally, we analyzed GIC cases within the two phase I clinical trials after stratiﬁcation between responders and non-responders. The evaluations indicate a signiﬁcant increase in the VEGF-speciﬁc humoral and cellular response parallel to a reduction in VEGF that relates signiﬁcantly to increased survival. Within this small cohort, reduction or stabilization of other proangiogenic factors was also detected.

Conclusions: CIGB-247 antigen-based vaccine increased tumor-inﬁltrating lymphocytes and reversed the immunosuppressive effect of the tumor microenvironment in the CT26 mouse model. Such results were corroborated in a GIC patient cohort indicating that the strategy might be a successful treatment option for such patients

me 34 - Issue S2 - 2023

by modifying systemic and tumor microenvironment beyond angiogenesis modulation.

Clinical trial identiﬁcation: RPCEC00000102, RPCEC00000155.

Legal entity responsible for the study: Center for Genetic Engineering and Biotechnology.

Funding: HEBERBiotec.

https://doi.org/10.1016/j.annonc.2023.09.1511

9P Identiﬁcation of a mCT-based radiomic signature of CD8+

tumour inﬁltrating lymphocytes in an orthotopic murine

model

G. Mazzaschi1, M. Dos Santos2, P. Bergeron3, L. Sitterle3, M. Gérbé de Thoré3,W. Liu3, C. Clémenson3, L. Meziani3, O. Bawa4, A. Leroy3, R. Sun5,

L. Moron Dalla Tor1, F. Quaini1, M. Tiseo1, F. Milliat2, C. Robert3, M. Mondini3,E. Deutsch5

1Department of Medicine and Surgery, University Hospital of Parma, Parma, Italy;2Department of Radiobiology and Regenerative Medicine (SERAMED), Laboratory of Medical Radiobiology (LRMed), Institute for Radiological Protection and Nuclear Safety (IRSN), Paris, France; 3INSERM U1030, Université Paris-Saclay, Gustave Roussy,Villejuif, France; 4Plateforme de Pathologie Expérimentale et Translationnelle, UMS AMMICA, 94805, Gustave Roussy, Villejuif, France; 5Radiation Oncology Dept., Institut Gustave Roussy, Villejuif, France

Background: In the era of immunotherapy (IT), radiomics emerged as a non-invasive tool to decode tumor immune microenvironment (TIME) and predict IT response.

Intrinsic patient and tumor variability challenging the explainability of radiomic readouts might be overcome in preclinical settings. Thus, we aimed to develop a mCT radiomic platform in a CD8 T cell functionally manipulated orthotopic murine model,closely mimicking human head and neck cancer, to validate the biological reality of radiomics in assessing tumor inﬁltrating lymphocytes (TILs).

Methods: Set-up, training and validation experiments (N Tot ¼ 50 C57BL/6 mice)were conducted as follows: submucosal injection of 0.5 x 106TC1-luc cells in the right inner lip and generation of an orthotopic model of head and neck cancer (day [D] -7);tailored treatment consisting of irradiation D0] ± anti-CD8 antibody [D3] to selec-[D0] anti-CD8 antibody [D3] to selec-tively enrich or deplete CD8+ TILs; in vivo preclinical imaging through Quantum FX mCT technology [D3, D4]; mice euthanasia and tumor sampling [D4], followed by immunohistochemical staining for CD8; mCT image pre-processing (voxel resampling,image discretization and delineation of the volume of interest) and radiomic features(RFs) extraction (pyradiomics).

Results:We developed and optimized an efﬁcient quantitative mCT imaging approach.

Overall, 106 mCT RFs (shape, ﬁrst- and second- order) were extracted and correlated with distinct TIME. Following redundant feature elimination (Spearman correlation,cut-off ¼ 0.99) and Z-score standardization, we identiﬁed 12 mCT-RFs differentiallyregulated in T CD8 enriched vs depleted TIME (P < 0.05, Mann Whitney). The statistical performance of our CD8 signature, documented in both training and validation sets, was further implemented when pooled data were analysed (P< 0.01). Finally, by applying a reconstruction algorithm, we obtained a 3D map of CD8+ TILs, which enabled us to correlate the spatial distribution of immune cells with mCT textural parameters.

Conclusions: Our results document the feasibility and accuracy of radiomics to detect dramatic changes in T cells within the TIME, thus providing effective radio-immune signatures potentially translatable into clinical practice.

Legal entity responsible for the study: Institut Gustave Roussy.

Funding: ESMO (Translational Research Fellowship; Recipient: Dr. Giulia Mazzaschi).

https://doi.org/10.1016/j.annonc.2023.09.1512

S189

10P

Cancer cells induce intracellular gap formation in sinusoidal endothelial cells to produce liver metastasis through proinﬂammatory paracrine mechanisms

H.H. Truong1, M. Sato-Mátubara2, T. Matsubara2, H. Yuasa2, T. Le Thi Thanh3,J. Gracia-Sancho4, N. Kawada5

1Department of Pain Management and Palliative Care, 108 Military Central Hospital,Hanoi, Vietnam; 2Department of Anatomy and Regenerative Biology, Osaka Metropolitan University, Asahi-machi, Japan; 3Department of Hepatology, Osaka Metropolitan University, Asahi-machi, Japan; 4Liver Vascular Biology Research Group,IDIBAPS Biomedical Research Institute, CIBEREHD, Barcelona, Spain; 5Department of Hepatology, Osaka City University Medical School, Osaka, Japan

Background: Engraftment of cancer cells to liver pre-metastatic niches requires complex interaction with liver sinusoidal endothelial cells (LSECs). Intracellular gap(iGap) formation in LSECs is caused by the destruction of fenestrae and appears under pathological conditions. Here, we aimed to explore the novel role of LSECs-iGap in liver metastasis of cancer cells.

Methods: Mouse models using acetaminophen (APAP) or thioacetamide (TAA) followed by intrasplenic injection of hepatocellular carcinoma (HCC) cell line, Hepa1-6 cells, to assess the LSECs-iGap formation. Functional effects of LSECs-iGap on cancer cells were analyzed using MMPs inducer, monocrotaline and inhibitor, doxycycline and MMP2/9 inhibitor. Morphological and molecular features of LSECs-iGap were examined using in vivo mouse models and in vitro co-culture system with electron microscopy, 3 dimensions tomographic reconstruction image (3D-TRI), RNAsequencing, cytokine array and endothelial trans-endothelial migration assay. Biopsy specimens from 98 patients with HCC were statistically evaluated.

Results: APAP-induced liver injury and TAA-induced ﬁbrotic liver resulted in LSECsiGap formation, which positively correlated with increased numbers of metastatic foci after Hepa1-6 cells injection. In addition, Hepa1-6 cells induced IL-23-dependent TNFa secretion by LSECs and triggered LSECs-iGap formation, toward which their processes protruded to transmigrate into the liver parenchyma. TNF-a caused depolymerization of F-actin and increased MMP9, ICAM1, and CXCLs expression in LSECs.

Moreover, high expression of ICAM1 and MMP9 was signiﬁcantly associated with intrahepatic metastasis and overall survival of patients with HCC. Blocking MMP9 activity by doxycycline or MMP-2/9 inhibitor eliminated LSECs-iGap formation and attenuated liver metastasis of Hepa1-6 cells.

Conclusions: This study revealed that cancer cells induced LSEC-iGap formation via pro-inﬂammatory paracrine mechanisms and proposed MMP9 as a novel target for blocking cancer cell metastasis to the liver.

Legal entity responsible for the study: H.H. Truong.

Funding: Japan Agency for Medical Research and Development.

https://doi.org/10.1016/j.annonc.2023.09.1513

11P Targeting stromal cells to reverse immune suppression in triple-negative breast cancer

J. Chen1, T. Ruan1, S. Wu2, E. Lim1, A. Swarbrick1

1Cancer Ecosystem Program, Garvan Institute of Medical Research, Darlinghurst, NSW,Australia; 2Turley Lab, Immunology Discovery & Oncology Bioinformatics, Genentech,South San Francisco, CA, USA

Background: Although there have been some positive results, the success of immune checkpoint inhibition in triple-negative breast cancer (TNBC) to date remains rather limited. A better understanding of mechanisms of immune evasion other than via PD1/PD-L1 axes and how to overcome these is therefore much needed to improve the efﬁcacy of immunotherapy in this poor prognosis disease. Recent studies of the tumour microenvironment (TME) have elucidated the heterogeneity of stromal cells and suggested that stromal subsets play an important role in regulating anti-tumour immunity. Here we investigate how stromal cells contribute to the immunosuppressive TME and as a potential therapeutic target to overcome this.

Methods: Using co-culture models of patient-derived TNBC cancer-associated ﬁbroblasts (CAFs) and peripheral blood mononuclear cells (PBMCs) from healthy donors,we applied ﬂow cytometry and single-cell RNA sequencing (scRNAseq) to assess stromal-immune interactions in vitro. A high throughput drug screen was performed to identify novel stromal-targeting drug candidates which could reverse stromalinduced immunosuppression in our coculture models.

Results: TNBC CAFs suppress the proliferative capability of both CD4 and CD8 T cells in vitro. scRNAseq of these co-culture models demonstrate that CAF-cocultured T cells are driven into LAG3+ exhausted state enriched for canonical pathways of immunosuppressive cytokine signalling. Drug screen identiﬁed Talabostat as a novel candidate which shifts stromal subtype composition from aSMA-positive to aSMA-negative phenotypes. Talabostat treatment in the co-culture models reverses CAF-induced suppression of T cell proliferation.

Conclusions: Talabostat reverses stromal-mediated T cell suppression and is a potential therapeutic strategy to elicit a more effective immune response.

Funding: US Department of Defense grant.

Disclosure: E. Lim: Financial Interests, Institutional, Advisory Board: Gilead, Novartis, Pﬁzer, Roche,AstraZeneca, MSD, Lilly; Financial Interests, Institutional, Invited Speaker: Roche, Gilead, Novartis,Lilly, AstraZeneca; Financial Interests, Institutional, Research Grant: Pﬁzer, Novartis; Financial Interests, Institutional, Steering Committee Member: Roche, Lilly, AstraZeneca; Financial Interests,Institutional, Local PI: Novartis, Gilead; Non-Financial Interests, Leadership Role, Scientiﬁc Advisory Committee: Breast Cancer Trials Australia; Non-Financial Interests, Leadership Role, Principal Cancer Theme Lead, Faculty of Medicine: University of New South Wales; Non-Financial Interests, Leadership Role, Faculty: Garvan Institute of Medical Research; Non-Financial Interests, Leadership Role,Director Cancer Research: St Vincent’s Hospital Sydeny. A. Swarbrick: Financial Interests, Personal and Institutional, Financially Compensated Role, Paid Consultant: Phenomic AI. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1514

12P Immuno-suppressive role of tumour-derived GDF-15 on myeloid cells

C. Schuberth-Wagner1, I. Giese1, M. Kist1, N. Vashist1, S. Genßler1, B. Haack2,J. Weigandt1, M. Auer3, J. Wischhusen2, K. Klar3, E. Leo4, M. Haake1

1Research, CatalYm GmbH, Planegg-Martinsried, Germany; 2Obstetrics and Gynecology, University of Würzburg, Würzburg, Germany; 3Translational Research, CatalYm GmbH, Planegg-Martinsried, Germany; 4Clinical Research, CatalYm GmbH, PlaneggMartinsried, Germany

Background: Growth and differentiation factor 15 (GDF-15), a divergent member of the TGF-b superfamily, shows high expression during pregnancy. Beyond that, GDF-15 is induced in stressed and damaged tissues limiting inﬂammation. GDF-15 also functions as a prognostic marker in numerous cancers and was shown to be a key inhibitor of T-cell inﬁltration in solid tumors. However, the impact of GDF-15 on other immune cells in the tumor microenvironment (TME) is still poorly understood.

Methods: M1 and M2 macrophages were derived from either the human monocytic THP-1 cell line or monocytes from healthy donors by incubation with IFNg and LPS(M1) or IL-4 and IL-13 (M2) in combination with or without GDF-15. Analysis was performed by Western Blot, ﬂow cytometry and RT-qPCR. To investigate the role of GDF-15 in vivo we inoculated NOG mice subcutaneously with SK-Mel5 GDF15-/- cells.

On day 35/36 tumors were assessed on myeloid immune cell subpopulations by ﬂow cytometry.

Results: Our initial studies have shown that monocytes are sensitive to GDF-15 mediated inhibition of tumor inﬁltration. Now we wanted to understand how GDF-15 affects the myeloid compartment beyond inﬁltration. In primary cells, GDF-15 exposure of monocytes during IFNg or LPS induced M1 polarization led to a reduction of activation marker expression such as HLA-DR, CD80 and CD86 and an altered cytokine secretion proﬁle. M2 macrophages did not show differences in their activation pattern. This effect was transferable to THP-1 derived M1 macrophages. TGF-ß was not able to exert this biologic effect. Activation was restored by addition of a GDF-15 neutralizing antibody. In vivo, GDF-15 had no direct effect on tumor growth,yet we observed that loss of GDF-15 altered the TME and led to an increase of activated myeloid cells such as M1 macrophages and dendritic cells.

Conclusions: GDF-15 secretion helps tumors to generate a TME that is poorly inﬁltrated by anti-tumoral immune cells. GDF-15 counteracts myeloid activation in the TME, a hallmark of initiation of antitumoral immune responses. By inducing a more pro-inﬂammatory tumor phenotype, anti-GDF-15 antibodies may synergize with other immunotherapeutic agents. A clinical phase 2 trial combining anti-GDF-15 (CTL-002)with anti-PD-1 (NCT04725474) is ongoing.

Legal entity responsible for the study: CatalYm GmbH.

Funding: CatalYm GmbH.

Disclosure: C. Schuberth-Wagner: Financial Interests, Personal, Full or part-time Employment:CatalYm GmbH; Financial Interests, Personal, Stocks/Shares: CatalYm GmbH, Merck & Co; Financial Interests, Personal, ,Royalties: Rigontec GmbH; Non-Financial Interests, Advisory Role: RNHale GmbH.

I. Giese, M. Kist, N. Vashist, S. Genßler, M. Auer, K. Klar: Financial Interests, Personal, Full or part-time Employment: CatalYm GmbH. J. Weigandt: Financial Interests, Personal, Full or part-time Employment, Scientist Role: Catalym; Financial Interests, Personal, Stocks/Shares, small number of shares held privately: AstraZeneca, Moderna. J. Wischhusen: Financial Interests, Personal, Advisory Board:CatalYm; Financial Interests, Personal, Stocks/Shares: CatalYm; Financial Interests, Personal, Advisory Board, Fees received via University of Würzburg as compensation for inventorship: CatalYm;Financial Interests, Institutional, Funding: CatalYm. E. Leo: Financial Interests, Personal, Advisory Board, Advisory role: T-knife GmbH; Financial Interests, Personal, Full or part-time Employment,CMO: CatalYm GmbH; Financial Interests, Personal, Stocks/Shares, Share options: CatalYm GmbH, Tknife GmbH. M. Haake: Financial Interests, Personal, Full or part-time Employment: CatalYm GmbH;Financial Interests, Personal, Stocks/Shares, Co-Founder: CatalYm GmbH; Financial Interests, Personal, Advisory Board: CatalYm GmbH; Non-Financial Interests, Other, Co-founder: CatalYm GmbH.

All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1515

13P

Disrupting the immunosuppressive tumor

microenvironment using genetically engineered

macrophages for triple-negative breast cancer therapy

S. Traxel, C. Beerli, F. Schmidt, V. Dinh-Van, R.F. Speck, S. Bredl

Division of Infectious Diseases and Hospital Epidemiology, USZ - University Hospital Zürich, Zurich, Switzerland

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer and accounts for 40% of breast cancer deaths. Currently, surgery and chemotherapy are standard therapy in TNBC, whereas immunotherapies often fail due to a cold tumor microenvironment (TME), which is mainly generated by tumor associated macrophages (TAMs). Importantly, immunosuppressive M2-like TAMs are associated with worse outcome in TNBC patients. Cytokines like IL-10 and TGFb induce M2-like TAMs, which inhibit the adaptive immune response and promote tumor growth, migration, and vascularization. In contrast, M1-like macrophages induce an anti-tumor immune response and tumor cell death. Thus, we aim to develop an adoptive cell therapy employing macrophages that are polarized towards a M1-like phenotype by the immunosuppressive cytokines, which will generate an inﬂamed TME.

Methods: To achieve M1 polarization in a M2-inducing TME, we genetically modiﬁed macrophages to express a chimeric cytokine receptor (ChCR), which will induce an M1 signaling upon stimulation with M2 inducing cytokines. Here, we evaluated two ChCR variants activated by IL-10 and TGFb, respectively. We transduced monocytes to express the ChCR using lentiviruses. Upon differentiation to macrophages, we assessed M1 polarization by analyzing surface marker expression and the secretome. Moreover, we assessed their effect on TNBC cell line viability.

Results: We could successfully transduce macrophages at 80% and conﬁrmed ChCR expression and M1 signaling. Furthermore, we could show that stimulation of ChCR macrophages by IL-10 or TGFb switches them towards an M1-like phenotype, as analyzed by surface marker expression and IP-10 secretion. Moreover, we found that the viability of TNBC cell lines was reduced upon treatment with supernatants of TGFb or IL-10 stimulated ChCR macrophages.

Conclusions:We could show that we can engineer macrophages to switch towards an M1-like phenotype in an M2-inducing environment. Thus, ChCR macrophages represent a promising strategy to disrupt the immunosuppressive TME. Currently, we are assessing the effect of ChCR macrophages on immune activation in vitro and their phenotype in TNBC co-cultures.

Funding: Gebauer Stiftung, Lotte und Adolf Hotz-Sprenger-Stiftung, Claudia von Schilling, Foundation for Breast Cancer Research, OPO-Stiftung, Stiftung zur Krebsbekämpfung, Alfred und Anneliese Sutter-Stöttner Stiftung, Dr. Arnold U. und Susanne, Huggenberger-Bischoff Stiftung, Novartis Foundation for Medical-Biological Research, UZH Bio & MedTech Entrepreneur Fellowship, UZH Postdoc Grant.

Disclosure: R.F. Speck: Other, Personal and Institutional, Other, Inventor of pending patent EP 22/215498 related to project: University of Zurich. S. Bredl: Financial Interests, Personal and Institutional, Other, Inventor of pending patent EP 22/215498 related to project: University of Zurich. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1516

14P Peripheral immune kinetics in survival prediction of small cell lung cancer patients treated with immune checkpoint blockade therapy

M.A. Galindo Campos1, M. Hardy-Werbin2, J. Gibert3, A. Ríos-Hoyo4, A. Rossell2,S. Gonzalez2, P. Rocha2, R. Del Rey-Vergara2, A. Rovira2, E. Arriola4

1IMIM - Institut Hospital del Mar d’Investigacions Mediques, Barcelona, Spain;2Cancer Research Programme, IMIM - Institut Hospital del Mar d’Investigacions Mediques, Barcelona, Spain; 3Pathology, Hospital del Mar - Parc de Salut Mar, Barcelona, Spain; 4Medical Oncology Department, Hospital del Mar - Parc de Salut Mar,Barcelona, Spain

Background: Small cell lung cancer (SCLC) is a lethal neoplasia. Chemotherapy (Ct)plus immune checkpoint blockade therapy (ICBt) is now the standard of care although limited survival beneﬁt. Lack of biomarkers of response leads to suboptimal patient selection, distorting results of clinical trials. Deciphering the ICBt-driven peripheral immune events may recognize those patients who beneﬁt the most. Here, we characterize early peripheral immune kinetics in SCLC patients treated with Ct + ICBt with improved survival.

Methods: SCLC patients from 8 centers were prospectively recruited into 3 cohorts.

Cohort 1 include patients treated with Ct (n¼24). Cohort 2 (n¼37) comprise patientstreated with Ct + anti-CTLA-4, and cohort 3 (n¼20) patients treated with Ct + anti-PD-1/PD-L1. Peripheral blood mononuclear cells were obtained prior to treatment and after the ﬁrst dose of ICBt. Variation in proliferation, senescence, adhesion, immunosuppression, and checkpoints markers was assessed by FACS. KaplaneMeier and log-rank test were used for survival analysis. MaxStat was used to calculate cut points.

A p-value <0.05 was considered statistically signiﬁcant.

Results: We found 6 independent cellular subsets which modulation right after the start of ICBt identify patients with improved survival. An increase in CD8+CD103+Ki67+ cells identify survival beneﬁt in cohorts 1 and 3 (p¼0.043; 0.0033).An upregulation of Ki67 in total CD4+ (p¼0.012; 0.0027) and CD4+PD-1+ T cells(p¼0.026; 0.027), predicts long survival in ICBt cohorts 2 and 3, while a down-regulation of CD4+ICOS+ T cells (p¼0.025; 0.011) identiﬁed survival beneﬁt in theseICBt cohorts. Expansion of Ki67+ and ICOS+ (p¼0.0024; 0.0074) CD8+ T cells was alsoobserved in CD8+ T cells from long survivors exclusively from cohort 2.

Conclusions: Expansion of CD8+CD103+Ki67+, CD4+Ki67+, and CD4+PD-1+Ki67+, or a reduction in CD4+ICOS+ circulating T cells subsets identify long survival patients treated with anti-CTLA-4 or anti-PD-1/PD-L1, while an increase in CD8+Ki67+ or CD8+ICOS+ cells predicts beneﬁt only in patients treated with anti-CTLA-4. Assessment of the immune kinetics of these peripheral cellular subsets identify patients who beneﬁt the most from ICBt in SCLC.

Results: Using ultra-high plex immunoﬂuorescence imaging, we characterized how lymph node cells organize into spatially distinct cellular neighborhoods, the disruption of which was congruent with lymphoma-induced remodeling. Using single-cell transcriptome data, we investigated the molecular programs driving this loss of organization. In DLBCL, chemokines relevant for immune cell organization were downregulated, while chemokines contributing to inﬂammation were upregulated,suggesting a phenotypic switch from a structural organized to an inﬂammatory andﬁbrotic state. In silico cell-cell interaction analysis indicated that besides the loss of mesenchyme-derived chemokine gradients, inﬂammatory immune cells outside of follicles turn into ectopic sources of these chemokines, an effect which likely contributes to the diffuse growth pattern of aggressive lymphomas. High expression of organizing chemokines was associated with better overall survival, this association being signiﬁcant in FL and a trend in DLBCL.

Conclusions: Collectively, these data suggest that a reprogramming of the LN microenvironment triggers an imbalance in chemokine gradients, which underlies loss of tissue organization in aggressive lymphomas.

https://doi.org/10.1016/j.annonc.2023.09.1509

Volu

Engineered salmonella blocks cancer metastasis by activating NK cells in an IFN-g-dependent manner

J. Huang

School Of Biomedical Sciences, The University of Hong Kong, Hong Kong, China

Funding: Fundació Amics de l’Hospital del Mar.

Disclosure: E. Arriola: Financial Interests, Personal and Institutional, Advisory Role, Speaker,Institutional funding, Travel and educational expenses: BMS, MSD; Financial Interests, Personal and Institutional, Advisory Role, Speaker, Institutional and Research funding, Travel and educational expenses: Roche; Financial Interests, Personal and Institutional, Advisory Role, Speaker, Institutional and Research funding: Pﬁzer; Financial Interests, Personal, Advisory Role, Speaker, Travel and educational expenses: Lilly; Financial Interests, Personal and Institutional, Advisory Role, Speaker,Institutional funding: AstraZeneca; Financial Interests, Personal, Advisory Role, Speaker: Boehringer Ingelheim, Takeda; Other, Personal, Member of Board of Directors, Co-founder: TrialingHealth. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1517

15P CBL E3 ubiquitin ligases are key inhibitory regulators in PD-1/LAG-3 co-signaling in human cancers, targeted through bispeciﬁc co-blockade

L. Chocarro1, L. Fernández-Rubio1, M.J. Garcia Granda1, E. Blanco Palmeiro1,

A.I. Bocanegra Gondan1, M. Echaide1, M. Garnica1, M. Zuazo1, C. Johnston2,

C.J. Edwards2, J. Leggs2, A. Pierce2, H. Arasanz3, R. Vera3, K. Ausin4, E. Santamaría4,J. Fernández-Irigoyen4, G. Kochan1, D. Escors1

Funding: This research was supported by: The Spanish Association against Cancer(AECC), PROYE16001ESCO; Instituto de Salud Carlos III (ISCIII)-FEDER Project grants FIS PI20/00010, COV20/00000, and TRANSPOCART ICI19/00069; Biomedicine Project Grant from the Department of Health of the Government of Navarre-FEDER funds(BMED 050-2019, 51-2021); Strategic projects from the Department of Industry,Government of Navarre (AGATA, Ref. 0011-1411-2020-000013; LINTERNA, Ref. 0011-1411-2020-000033; DESCARTHES, 0011-1411-2019-000058); European Union Horizon 2020 ISOLDA project, under grant agreement ID: 848166. L.C. is ﬁnanced by Instituto de Salud Carlos III (ISCIII), co-ﬁnanced by FEDER funds, "Contratos PFIS: contratos predoctorales de formación en investigación en salud" (FI21/00080); M.E. is ﬁnanced by the Navarrabiomed- Fundación Miguel Servet predoctoral contract.

Disclosure: C.J. Edwards: Other, Personal, Other, Declares to be inventor of the Humabody CB213(WO/2019/158942. 603 Crescendo Biologics Ltd.): Crescendo Biologics. J. Leggs: Other, Declares to

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be e inventor of the Humabody CB213 (WO/2019/158942. 603 Crescendo Biologics Ltd.): Crescendo Biologics. D. Escors: Other, Declares to be e inventor of the Humabody CB213 (WO/2019/158942.

603 Crescendo Biologics Ltd.): Navarrabiomed. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1518

16P

Terminally exhausted CD8+ T cells and increased

immunosuppressive soluble factors in malignant ascites of patients with gastric cancer with peritoneal metastasis

H.S. Han1, H. Kim1, M. Kwon2, S.K. Lee1, S-M. Son3, H.K. Kim1, Y. Yang1, K.H. Lee1

1Internal Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea; 2Ajou University Hospital School of Medicine, Suwon, Republic of Korea; 3Pathology, Chungbuk National University Hospital, Cheongju, Republic of Korea

Background: Peritoneal metastasis is a relatively common manifestation of poor prognosis and resistance to immune checkpoint blockades in patients with gastric cancer (GC). In the present study, we aimed to investigate the exhaustion status of CD8+T cells and immunosuppressive soluble factors in malignant ascites from patients with GC and peritoneal metastasis.

Methods: We obtained pathologically conﬁrmed malignant ascites samples along with peripheral blood from 27 patients with GC peritoneal metastasis and examined the exhaustion status of CD8+T cells using multicolor ﬂow cytometry. A multiplex enzyme-linked immunosorbent assay for immunosuppressive soluble factors,including matrix metalloproteinase-2 (MMP-2), MMP-7, transforming growth factor beta (TGF-b), hepatocyte growth factor (HGF), vascular endothelial growth factor(VEGF), E-cadherin, and angiopoietin-2, was performed on 45 cell-free ﬂuid samples(15 paired malignant ascites and plasma of patients with GC and 15 benign ascites of liver cirrhosis patients).

Results: CD8+ T cells in the malignant ascites of GC showed signiﬁcantly increased expression of PD-1, TIGIT, and TIM-3 compared with peripheral blood CD8+T cells.

CD8+T-cells in malignant ascites had more terminally differentiated phenotypes (TbetlowEomeshigh) and tumor antigen reactivity (CD39+CD103+) than peripheral blood CD8+T cells. The expression levels of immunosuppressive soluble factors, including MMP-2, MMP-7, TGF-b, HGF, VEGF, E-cadherin, and angiopoietin-2, were signiﬁcantly higher in the malignant ascites than in the plasma of patients with GC or in the benign ascites of liver cirrhosis patients.

Conclusions: We found that CD8+T cells in the malignant ascites of GC are terminally exhausted and tumor antigen-reactive T cells. Furthermore, immunosuppressive soluble factors were signiﬁcantly increased in cell-free ﬂuid of malignant ascites of GC. Thus, the present ﬁndings suggest that the co-blockade of immune checkpoints and immunosuppressive soluble factors may be a feasible therapeutic option for patients GC with peritoneal metastasis.

https://doi.org/10.1016/j.annonc.2023.09.1519

17P Continued expansion of long-lived effect CD8+ T cells associates with durable response post-PD-1 blockade

R.A. Watson1, O. Tong1, B. Sun2, C. Taylor1, E. Jungkurth1, S. Sijbesma1, C. Ye1,F. Matos Santo1, M.R. Middleton3, B.P. Fairfax4

1Department of Oncology, The MRC Weatherall Institute of Molecular Medicine Oxford, Oxford, UK; 2Nufﬁeld Department of Clinical Neuroscience, John Radcliffe Hospital University of Oxford, Oxford, UK; 3Oncology Department, Churchill Hospital,Oxford, UK; 4Oncology Department, University of Oxford, Oxford, UK

Background: Early CD8+T cell responses to PD-1 blockade are well-characterised.

However, an understanding of the long-term clonal and transcriptomic signatures of complete response (CR) to Immune Checkpoint Blockade (ICB) is currently lacking. We aimed to identify and describe CD8+T cell clonal and transcriptomic changes post complete response to PD-1 blockade in metastatic melanoma (MM).

Methods: We performed single-cell RNA sequencing (scRNAseq) of both the T cell receptor (TCR) and transcriptomes of PBMCs and sorted peripheral CD8+T cells in patients with MM with a complete response to PD-1 blockade (n¼10), patients withprogressive disease (PD, n¼6) and healthy donors (HD, n¼2). Blood was sampled atmultiple time points, including a median of 3.2 years following cessation of PD-1 blockade for CR.

Results: Following a CR and cessation of ICB, there is increased abundance of a subtype of CD8+T cell characterised by high expression of NK-associated genes,termed a killer-like subset. Using the top 25 genes upregulated by this subset to generate a ‘Killer Score’, we show that patients with CR to anti-PD-1 demonstrate a broad increase in killer gene expression over time absent in those with PD and HDs.

By tracking key clones through TCR usage, we identify those which are stable/expanding from pre-treatment to post treatment, occupy >0.5% of the repertoire and

are persistent post-cessation of ICB, terming these large expanding persistent clones.

These clones have a predominantly cytotoxic, effector, gene expression proﬁle and display surface markers consistent with a recently-described ‘Long-lived Effector Cell’subtype.

Conclusions: CR to PD-1 blockade is associated with persistence of highly-cytotoxic effector CD8+T cells that circulate years after cessation of treatment. Whilst similar subsets have been implicated with chronic viral infection, these observations are novel in the cancer setting and have important implications for mechanisms of durable disease control.

Funding: The Wellcome Trust, Cancer Research UK, National Institute for Health Research.

https://doi.org/10.1016/j.annonc.2023.09.1520

18P Exposure of calreticulin is required for vitamin C immunomediated cancer surveillance

A. Cavaliere1, M. Macagno2, F. Maione1, V. Amodio3, R. Chilà3, S. Lamba2,

P.P. Vitiello1, V. Pessei2, N. Congiusta1, A. Lorenzato1, G. Germano1, A. Bardelli1,F. Di Nicolantonio4

1Dipartimento di Oncologia, University of Turin, Candiolo, Italy; 2Department of Oncology, Istituto di Candiolo - Fondazione del Piemonte per l’Oncologia - IRCCS,Candiolo, Italy; 3Genomics of Cancer and Targeted Therapies, IFOM ETS - The AIRC Institute of Molecular Oncology, Milan, Italy; 4Dipartimento di Oncologia, University of Turin, Candiolo, Italy

Background: Vitamin C (VitC) was shown to synergize with immune checkpoint blockade in tumor bearing immunocompetent mice, which provided the rationale for the ongoing ALFEO trial in colorectal cancer patients (Clinical Trial Registration Number 2022-502101-15-00). In this work, we aimed to elucidate the molecular mechanisms underlying these preclinical observations. We hypothesized that VitC could strain cancer cells, which react by emitting danger signal molecules, which in turn could stimulate an immune mediated anticancer response.

Methods: We assessed expression of the oxidative stress marker hydroxyguanosine(8-OHG) and danger signal molecules (calreticulin and HMGB1) in breast and colon murine tumors treated with VitC. A calreticulin blocking antibody was given in combination with VitC to functionally ascertain the role of this stress signal protein.

Results: Pharmacological doses of VitC were able to strongly induce oxidative stress as indicated by strong 8-OHG staining in tumor sections. VitC-stressed tumor cells mobilized the danger molecules calreticulin and HMGB1. Although the induction of these danger markers was seen in tumors grown both in immunocompromised and immunocompetent VitC treated mice, its anticancer activity was evident only in the presence of an intact immune system. In vivo, a calreticulin blocking antibody effectively prevented its translocation and inhibited HMGB1 release in murine tumors. Notably, preventing calreticulin exposure abrogated the immunomediated anticancer effect of VitC. VitC enhanced the inﬁltration of natural killers, activated CD8+ T lymphocytes, while it decreased the number of Tregs. Calreticulin blockade impaired the modulation of the immune tumor microenvironment induced by VitC.

Conclusions: We unveil that VitC is able to mobilize calreticulin and HMGB1, which are among the established markers of immunogenic cell death. These results,alongside the observation that VitC exerts its maximal antitumor activity only in immunocompetent mice are clues that VitC could act as immunogenic cell death inducer when given at pharmacological doses. Our ﬁndings have implications for cancer patients enrolled in clinical trials based on VitC containing regimens

Funding: AIRC.

Disclosure: P.P. Vitiello: Financial Interests, Personal, Speaker, Consultant, Advisor: Biocartis,Merck. G. Germano: Other, Personal, Advisory Board: NeoPhore. A. Bardelli: Financial Interests,Personal, Advisory Role: Illumina, Inivata; Financial Interests, Personal, Advisory Board: NeoPhore. F.

Di Nicolantonio: Financial Interests, Personal, Speaker, Consultant, Advisor: Illumina, Pierre Fabre. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1521

19P

Preclinical and clinical signiﬁcance of VEGF deprivation in ovarian cancer through a speciﬁc active immunotherapy

Y. Morera1, M. Bequet-Romero2, F. Hernández-Bernal3, I. González-Moya2,

K-H. Selman-Housein3, C. Canaan-Haden2, J. Sanchez-Ramirez2, Y. Martín-Bauta3,A. de la Torre-Santos4, M. Ayala3

1Cancer Immunotherapy, Center for Genetic Engineering and Biotechnology, Havana,Cuba; 2Biomedical Research, Center for Genetic Engineering and Biotechnology, Havana, Cuba; 3Clinical Research, Center for Genetic Engineering and Biotechnology,Havana, Cuba; 4Oncology, General Hospital Celestino Hernández, Havana, Cuba

Conclusions: PMC-309 enhanced both T-cell activation and monocyte activation.

PMC-309 increased the number of T cell inﬁltration while a decrease of MDSCs in the TME. PMC-309 in combination with chemotherapy or other IO drugs could address the high medical unmet needs of patients with drug resistance to currently available IO treatment options.

Legal entity responsible for the study: PharmAbcine Inc.

https://doi.org/10.1016/j.annonc.2023.09.1526

24P Single cell transcriptomics of the immune cells during chemotherapy in triple-negative breast cancer patients

A. Frolova1, T.S. Gerashchenko2, M. Patysheva1, A.A. Fedorov2, O. Bragina3,E. Garbukov4, N. Cherdyntseva1, V.Y. Korobeynikov2

1Laboratory of Molecular Oncology and Immunology, Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russian Federation; 2Laboratory of Cancer Progression Biology, Cancer Research Institute,Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk,Russian Federation; 3Department of Radionuclide Therapy and Diagnostics, Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russian Federation; 4Department of General Oncology, Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russian Federation

Background: Chemotherapy is the mainstay of systemic treatment for patients with triple-negative breast cancer (TNBC) due to the lack of targets for targeted therapy(HER2/neu; ER; PR). Components of the immune system are known to be involved in the response to chemotherapeutic treatment. Here we aimed to study the dynamics of changes in immune cell composition during neoadjuvant chemotherapy (NACT).

Methods: The immune cells were puriﬁed from peripheral blood and biopsy samples of 5 TNBC patients before NACT and 21st days of ﬁrst course of NACT (AC regimen).

Total cell concentration and viability (Calcein/DRAQ7) were assessed by ﬂow cytometry (Cytoﬂex, Beckman Coulter). Single cells were sequenced on a Genolab M platform (GeneMind Biosciences) using 10x Genomics technology for ﬁxed multiplexed samples. Data were analyzed using Seurat and SingleR.

Results: Sequencing revealed a variety of immune cell populations including: B cells,DC cells, NK cells, CD4+, CD8+ and T regulatory lymphocytes, classical and non-classical monocytes, granulocytes and others. In the blood, the pool of classical monocytes and NK cells were depleted up to day 21 after the ﬁrst NACT cycle, while naive CD4+, CD8+ T cells and end effector CD8+ T cells, were increased by day 21. In the populations of monocytes and NK cells overexpression of RGS2, ANXA1, FGL2, MX1,IFI6 genes were observed, involved in induction apoptosis. CD8+T-cells, as well as Th1 and Th-2 CD4+ T-cells were characterized by increased expression of NFKBIA, JUN,FOS, involved in T cell differentiation. In the tumor microenvironment, depletion of CD4+ T cells, CD8+ T cells and memory B cells and an increase in T-regulatory cells and plasma cells were observed. DUSP4, LCK, CXCR4, LTB, TNFRSF18, IL2RB and PTPN7 genes were overexpressed and involved in the regulation of cytokine secretion and inhibition of TCR signaling in CD4+ and CD8+ T cells; chemotaxis-mediated inﬂammation in memory B cells; T cells differentiation, and induction of invasion/migration of tumor cells in T-regulatory cells and plasma cells.

Conclusions: The ﬁrst cycle of NACT induced renewal of the immune cells’ composition in the blood and tumor microenvironment skewing towards to immune disfunction.

Legal entity responsible for the study: Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russian Federation.

Funding: Russian Science Foundation (grant #22-75-10128).

https://doi.org/10.1016/j.annonc.2023.09.1527

25P Role of AXL activation on adaptive resistance to KRAS-G12C inhibitors in KRAS-G12C-mutated non-small cell lung cancer

T. Yamada1, K. Morimoto1, S. Hirai1, Y. Katayama1, K. Kunimasa2, T. Sasaki3,M. Nishida4, S. Watanabe5, S. Shiotsu6, H. Uehara7, K. Takayama1

1Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan;2Thoracic Oncology Department, OICI - Osaka International Cancer Institute, Osaka,Japan; 3Medical Oncology Department, AMU - Asahikawa Medical Univercity Hospital,Asahikawa, Japan; 4Internal Medicine, St. Marianna University School of Medicine,Kawasaki, Japan; 5Department of Respiratory Medicine and Infectious Diseases, Niigata University Medical and Dental Hospital, Niigata, Japan; 6Oncology, Kyoto First Red Cross Hospital (Kyoto Daiichi Sekijyuji Byoin), Kyoto, Japan; 7Pathology and Laboratory Medicine, Tokushima University Graduate School, Tokushima, Japan

Background: KRAS is the most frequent targetable oncogene in non-small cell lung cancer (NSCLC). Recently, novel KRAS inhibitor have been clinically developed for treatment of KRAS G12C-mutated NSCLC patients. However, it is difﬁcult to achieve complete remission of tumor. Therefore, the optimal combined therapeutic intervention with KRAS G12C inhibitors has a potentially crucial role in the clinical outcomes of patients. In this study, we focused on the mechanisms underlying adaptive resistance to KRAS G12C inhibitors and therapeutic strategies required to overcome them.

Methods: We used KRAS G12C-mutated NSCLC cell lines to evaluate the adaptive response to KRAS G12C inhibitors in vitro and in vivo. We also investigated the correlation between AXL expression in pre-treated tumors and clinical outcomes with sotorasib for KRAS G12C-mutated NSCLC patients.

Results: We reveal that AXL signaling was caused to the adaptive resistance to KRAS G12C inhibitors in KRAS-G12C mutated NSCLC, activation of which was induced by GAS6 production via transcriptional coactivator YAP. AXL inhibition reduced the viability of AXL-overexpressing KRAS G12C-mutated lung cancer cells by enhancing KRAS G12C inhibition-induced apoptosis. In xenograft models of AXL-overexpressing KRAS G12C-mutated lung cancer treated with KRAS G12C inhibitors, initial combination therapy with AXL inhibitor markedly regressed tumors and delayed tumor regrowth compared with KRAS G12C inhibitor alone or the combination after acquired resistance to KRAS G12C inhibitor. AXL was highly expressed in clinical specimens of KRAS G12C-mutated lung cancers and its high expression was associated with a low response rate to sotorasib.

Conclusions: These results indicated pivotal roles for AXL activation and its inhibition in the intrinsic resistance to KRAS G12C inhibitor.

Disclosure: T. Yamada: Financial Interests, Personal, Funding: Janssen Pharmaceutical K.K., Ono Pharmaceutical Company Limited, AstraZeneca, Takeda Pharmaceutical Company Limited; Financial Interests, Personal, Invited Speaker: Eli Lilly. K. Kunimasa: Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai pharmaceutical, Nippon Boehringer Ingelheim, Eli Lilly Japan, Roche Diagnostics, Daiichi Sankyo, Novartis, Pﬁzer, Merk, Bristol Myers Squibb, Nippon Kayaku; Financial Interests, Institutional, Funding: Taiho Pharmaceutical Co., LTD., AbbVie. S. Watanabe: Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai Pharmaceutical. K. Takayama: Financial Interests, Personal, Funding: Chugai-Roche; Financial Interests, Personal, Funding, Invited speaker:Ono Pharmaceutical; Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, Eli Lilly,Boehringer Ingelheim, Daiichi Sankyo. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1528

26P

Pre-clinical modelling and treatment of BRAF mutated colorectal cancer

M.White1, T. Lannagan2, L. McGarry3, L. Carlin3, M. Mills1, A.S. Yazgili1, R. Ridgway1,R. Jackstadt4, A.D. Campbell2, R.H. Wilson5, O.J. Sansom1

1Colorectal Cancer and Wnt Signalling Laboratory, CRUK - Cancer Research UK Beatson Institute, Glasgow, UK; 2Colorectal cancer and Wnt Signalling, CRUK - Cancer Research UK Beatson Institute, Glasgow, UK; 3BAIR, CRUK - Cancer Research UK Beatson Institute, Glasgow, UK; 4Cancer Progression and Metastasis, HI-STEM - Heidelberg Institute for Stem Cell Technology and Experimental Medicine, Heidelberg,Germany; 5Wolfson Wohl Cancer Research Centre - Institute of Cancer Science -University of Glasgow, Glasgow, UK

Background: 10% of colorectal cancers (CRC) have a BRAF mutation (BM). This is a poor prognostic group with distinct clinical characteristics. Robust preclinical models that reﬂect this CRC subtype are currently lacking. We have developed a novel,aggressive, immune competent, genetically engineered mouse model (GEMM) that aligns well with human BM CRC.

Methods: 4 genes were targeted with the villinCreER: activating BrafV600E/+ (B),deletion of Trp53ﬂ/ﬂ(P), deletion of ALK5ﬂ/ﬂand NOTCH1 intracellular domain expression Rosa26N1icd/+ (N). This generated BPNA mice. Mice were induced and aged until clinical endpoint. Clinically relevant treatments were benchmarked, including BRAFi (Dabrafenib) combined with EGFRi (Erlotinib). Mouse tumour organoids were derived and high throughput drug screening was performed.

Results: BPNA mice developed endpoint tumours in the proximal colon in a short time period (37 DPI). Mice had high rates of T4 disease (57%) and, despite short latency, developed peritoneal metastasis in 5/27 mice (19%). Primary tumours had proﬁcient mismatch repair (pMMR). Tumours classiﬁed as CMS4, aligned with the BM1 transcriptional subtype and displayed regenerative cancer stem cell markers.

Therapeutic interventions based on the BEACON CRC (BRAFi+EGFRi) combinations were tested. Both BRAFi and EGFRi as monotherapies had no signiﬁcant survival advantage (OS) in vivo. However in combination, mice lived twice as long with median OS of the combination group 66 DPI vs 32 DPI in the vehicle control (log-rank p<0.001). DUSP6 was only signiﬁcantly suppressed in the BRAF/EGFRi arm suggesting effective MAPK targeting requires combination therapy. Through organoid drug screening, 28/166 compounds were identiﬁed as hits of which 3/5 top hits were proteasome inhibitors.

Conclusions: The BPNA GEMM aligns with human disease in terms of primary tumour characteristics and metastatic pattern. Mice also respond to standard of care therapeutics similarly to humans creating a good benchmark for further investigation.

Organoid drug screens have highlighted a potentially novel drug class for BM CRC treatment. Future work will utilize these mice to test therapeutics enabling robust pre-clinical evidence to de-risk future novel early phase trials for BM CRC.

Funding: Cancer Research UK.

Disclosure: O.J. Sansom: Financial Interests, Institutional, Funding: Novartis, Cancer Research Technology, Redx. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1529

27P Extending a classiﬁcation system for atypical BRAF mutations to improve targeted therapies in colorectal cancer cells

A.B. Madduri1, Y. Liu2, B.G. Nelson1, K.E. Sanders1, D. Wang1, N. Hornstein3,J.P.Y.C. Shen3

1GI Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA; 2TMP, MD Anderson Cancer Center, Houston, TX, USA; 3GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Background: Unlike other types of cancer that are sensitive to single-target agents,such as lung cancer and chronic myeloid leukemia, colorectal cancer (CRC) involves a complex network of interactions between activating oncogenes and is thus more likely to respond to multi-target therapy. Approximately 10% of CRC mutations are within the BRAF gene, the most frequent being BRAFV600E. While this mutation can be targeted with relatively high efﬁcacy by single-target therapies, there exists a cohort of atypical BRAF mutations that confer higher resistance to currently available treatments. Furthermore, a large proportion of these atypical BRAF mutations are poorly understood.

Methods: We used principal component analysis and semi-supervised clustering learning methods to classify mutants unassigned by the previous BRAF classiﬁcation system. By leveraging previously established protein-protein networks, we overlaid them with gene essentiality data to successfully classify 84 new BRAF mutations. We then evaluated the oncogenic potential of the newly classiﬁed atypical class-2 or -3 BRAF mutations compared to wild-type and class-1 BRAF mutations to validate that our extended system was consistent with the previously established BRAF classes. We also performed a network analysis to determine which genes were co-mutated for each BRAF class.

Results: Cell viability analysis of the BRAF-mutant Ba/F3 cells yielded no signiﬁcant differences in the median AUC values between the new and old classiﬁcation systems.

Several key genes (including PIK3CA, EGFR, and MEK) were identiﬁed as potential drug targets (IC 50: 0.1 mM) for cell lines with class-2 and -3 atypical BRAF mutations.

We found that atypical BRAF mutations have signiﬁcantly more positive CERES scores than class-1 mutations and thus need to partner with other oncogenes to drive oncogenesis due to their lower oncogenic potential.

Conclusions: In conclusion, we extended the previous Yao classiﬁcation system to establish a more comprehensive BRAF-mutant classiﬁcation system, Yao Classiﬁcation System Plus, that encompasses more atypical BRAF mutations. This allows for greater therapeutic options to target cells carrying these previously uncharacterized mutations.

Legal entity responsible for the study: University of Texas MD Anderson Cancer Center.

Funding: National Cancer Institute , the Cancer Center Support Grant, and the Cancer Prevention & Research Institute of Texas.

https://doi.org/10.1016/j.annonc.2023.09.1530

28P Xanthine oxidase as a prognostic factor in colorectal cancer metastatic disease

A.A. Burlaka1, A. Burlaka2, V. Rozhkova1, S.V. Zemskov3, I.I. Lisnyy4

1Department of Minimally Invasive and Endoscopic Surgery, Interventional Radiology,National Cancer Institute of the Ministry of Health of Ukraine, Kiev, Ukraine;2Department of Modiﬁers of Antitumor Therapy, R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS, Kiev, Ukraine; 3University Administration, NMU - National Medical University, Kiev, Ukraine; 4National Cancer Institute of the Ministry of Health of Ukraine, Kiev, Ukraine

Background: Obesity and related diseases, namely, diabetes and metabolic syndrome,are associated with chronic inﬂammation and colorectal cancer (CRC). In CRC liver metastases (mCRC) and adjacent liver tissue defects are formed in the mitochondrial electron transport chain that causes mitochondrial dysfunction, activation of redoxmolecules (SR, NO) generation sources and MMP-2, -9 activity. Radical oxygen species take a part in the regulation of gelatinases (MMP-2 and -9) and the xanthine/xanthine oxidase reaction is widely used as a source of exogenous ROS in considering of MMPs.

The aim of the study was to determine the state of XO, SR and MMPs in liver tissue and CRC liver metastases (MT) and set the clinical signiﬁcance of obtained results.

Methods: The prospective study on 37 mCRC patients who underwent the liver resection due metastatic disease has been performed. The rate of SR generation of neutrophils and in the tissue samples, the rate of XO and the activity of matrix metalloproteinases in the tissue samples was measured accordingly study design.

Results: The highest level of XO in mCRC patients was detected in metastatic tissue(1.470.18 a.u.). The level of XO enzyme in the adjacent tissue (AT) and distant (1.47±0.18 a.u.).The level of XO enzyme in the adjacent tissue (AT) and distant tissuetissue(DT) were 0.380.10 a.u. (p<0.05) and 0.190.008 a.u. (r<0,05) respectively. (DT) were 0.38±0.10 a.u. (p<0.05) and 0.19±0.008 a.u. (p<0,05) respectively. AAcorrelation was found between the BMI and amount of XO in DTof the liver r2 ¼ 0,64.The total activity of gelatinases in subgroup of mCRC patients with BMI 25 The total activity of gelatinases in subgroup of mCRC patients with BMl ≥ 25 waswasfound to be signiﬁcantly higher than in normal body weight patients withing the DT(1.52; p<0.001), as well as in the AT (1.28 times; p<0.001). High XO levels (HR (95%CI) ¼ 0,002 (2,63 to 15.05) P ¼ 0,002) and SR generation levels (HR (95% CI) ¼ 0,01(2,4 to 10,37) P ¼ 0,01) in adjusted liver tissue to metastatic lesions had a negativeimpact on overall overall survival rates.

Conclusions: Xanthine oxidase and superoxide radicals can be a new metastatic disease prognostic factors for colorectal cancer patients, the latter requiring further randomized trials.

https://doi.org/10.1016/j.annonc.2023.09.1531

29P The effect of cancer associated ﬁbroblast-derived activin A on colorectal cancer progression

S. Stang1, L. Armborst1, S. Hilberath1, E. Koncina2, M. Macia-Guardado1,M. Hengstschläger1, E. Letellier2, H. Dolznig1

1Institute of Medical Genetics, MedUni Wien - Medical University of Vienna, Vienna,Austria; 2Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg

Background: Colorectal cancer (CRC) is one of the most common cancers worldwide.

In particular, the yearly mortality emphasizes the limited spectrum of treatment possibilities. The tumor microenvironment with its relevant inﬂuence on malignant tumor initiation, progression and chemoresistance represents a promising target for

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cancer therapeutics. Especially cancer-associated ﬁbroblasts (CAFs) are of importance in carcinogenesis as they are involved in tumorigenesis, metastasis, inﬂammatory responses, and extracellular matrix changes. Based on preliminary data, we found upregulated expression of INHBA, a gene encoding for the bA subunit of the TGFb superfamily members Activin A, Activin AB and Inhibin A, in the stromal compartment of human CRC. Therefore, we wanted to investigate the autocrine and paracrine functional consequences of CAF-secreted Activin A in CRC.

Methods:We knocked down INHBA in primary patient-derived CAFs and used in vitro 3D collagen gel assays, ﬂow cytometry, immunoﬂuorescence, secretome analysis and Western blotting to check the autocrine effects of Activin A on CAFs. Regarding the paracrine impact on tumor cells and immune cells, we employed 3D co- and tripleculture collagen gel assays to determine the impact of CAF-derived Activin A. Here,we focused on proliferation, apoptosis and invasion levels of tumor cells as well as on monocyte differentiation, myeloid cell plasticity and T-cell activation.

Results: Our data demonstrate that CAFs expressing INHBA show a pro-proliferative,pro-motile and pro-contractile phenotype. Furthermore, the secretome and plasticity of CAFs were notably modiﬁed by the INHBA knockdown. Additionally, CAF-derived Activin A seems to inﬂuence various aspects of tumor progression and the plasticity of immune cells.

Conclusions: Together, our results indicate key functions of CAF-derived Activin A in CRC progression suggesting a potential novel therapeutic target.

Funding: Austrian Academy of Sciences.

https://doi.org/10.1016/j.annonc.2023.09.1532

30P

Prostaglandin signaling in tumour stroma interaction in colorectal cancer and its impact on the secretome and functional relevance

M. Macia-Guardado1, M. Ertl1, V. Lutz1, E. Ebner1, E. Koncina2, S. Stang1,M. Hengstschläger1, E. Letellier2, J. Schüler3, H. Dolznig1

1Institute of Medical Genetics, MedUni Wien - Medical University of Vienna, Vienna,Austria; 2Life Sciences Research Unit, University of Luxembourg, Belvaux, Luxembourg;3Discovery Services, Charles River Discovery Research Services Germany GmbH, Freiburg Im Breisgau, Germany

Background: One of the risk factors to develop colorectal cancer (CRC), which is one of the deadliest types of cancer, is inﬂammation. Among the factors involved in the inﬂammatory response, prostaglandins (PGs) seem to play an important role. The tumor microenvironment (TME) inﬂuences the development of the tumor and within the TME, cancer associated ﬁbroblasts (CAFs) represent the major compartment.

Despite the importance of the TME, there is limited evidence on the secretomedependent communication of CRC cells with CAFs and myeloid cells with respect to PG signaling. In this project we mainly focus on PGE2 and PGF2a, that we have previously found are secreted by CAFs.

Methods: By using in vitro 3D cocultures secreted molecules induced by increased or decreased PGE2 and PGF2a expression were identiﬁed. The levels of both PGs were measured by ELISA, whereas the expression of the production enzymes was analyzed by Western Blot. Phenotypic analysis and functional assays were carried out using siRNA or speciﬁc inhibitors to analyze the effect on angiogenesis and contractility of CAFs, their proliferation, motility, and apoptosis levels. Finally, preliminary in vivo experiments were performed and, additionally, parafﬁn tissue sections from patientderived xenografts (PDX) models were stained to prove the stroma expression of the PGs speciﬁc synthases.

Results: We demonstrate that a combination of proinﬂammatory cytokines can increase the expression of COX-2 and mPGES-1 while IL-4 decreases it. Knocking down the speciﬁc synthases of PGE2 and PGF2a in the CAFs also leads to a decrease in their proliferation, contractiliy, motility and angiogenesis capacity, but did not induce apoptosis. In vivo, knocking down of the PGs speciﬁc synthases seems to lead to a worse survival capacity, and some of these enzymes seem to be only expressed in the stromal cells of PDX models.

Conclusions: More information about the link between cancer and its TME would help us to achieve a higher degree of accuracy in the development of potential future therapies. Here we have proved that the action of PGs, especially PGF2a and PGE2, is involved in tumor development in 2D and 3D suggesting a possible therapeutic target.

Funding: Marie Skłodowska-Curie Actions - PhD Research Fellowship. European Commission (Horizon 2020).

https://doi.org/10.1016/j.annonc.2023.09.1533

31P Cell-free tumor microRNA as early biomarkers of high-grade cervical intraepithelial neoplasia using liquid biopsy

S. Calfa1, A.J.A. de Freitas2, T.T. Komoto1, C.R. Nunes3, J.C.P. Resende4, R. dos Reis5,R.M. Reis2, M.M.C. Marques2

1Molecular Oncology Research Center, Hospital de Amor (Hospital De Cancer De Barretos) - Fundacao Pio XII, Barretos, Brazil; 2Molecular Oncology Research Center,Barretos Cancer Hospital, Barretos, Brazil; 3Centro de Oncologia Molecular, Barretos Cancer Hospital, Barretos, Brazil; 4Department of Prevention, Hospital de Amor(Hospital De Cancer De Barretos) - Fundacao Pio XII, Barretos, Brazil; 5Department of Gynecological Oncology, MD Anderson Cancer Center, Houston, TX, USA

Background: Cervical cancer (CC) is the fourth most common type of cancer among women worldwide. Considering that the early diagnosis of cervical intraepithelial neoplasia (CIN) is the main strategy to improve the prognosis of patients, new methodologies based on molecular analyzes performed on liquid biopsy samples,represent promising alternatives for minimally invasive biomarkers. miRNAs have been shown their role as non-invasive biomarkers, providing a wide perspective for personalized treatment and early diagnosis of cervical cancer through liquid-based cytology (LBC). However, more research is under way to identify miRNA signatures that can be implemented in clinical practice specially for early detection. In this study,we aimed to identify molecular signatures of miRNAs in cervical precursor lesions (CIN 2 and CIN 3) from LBC and their interaction with molecular pathways related to CC in a prospective study.

Methods: We analyzed 96 LBC cervical samples, that were divided into two groups:the case group was composed of women diagnosed with CIN 2 and CIN3 (n ¼ 48); thecontrol group corresponded to women without cervical precursor lesions (n ¼ 48).We We performed miRNA expression profiling using the nCounter® miRNA Expressionperformed miRNA expression proﬁling using the nCounter miRNA Expression Assay (NanoString Technology), which evaluated 800 targets. A functional analysis in silico was performed by mirDIP and enrichment were performed using Cytoscape with the Reactome plugin.

Results: We identiﬁed 54 miRNAs that were differentially expressed between case and control groups (p 0.05). Using logistic regression analysis, we identiﬁed and control groups (p ≤0.05). Using logistic regression analysis, we identified aasignature composed of ﬁve miRNAs, with a fold change 1.5 and FDR-corrected signature composed of five miRNAs, with a fold change ≥ 1.5 and FDR-corrected p-p-value of 0.05, of which two were up-regulated and three were down-regulated. value of≤ 0.05, of which two were up-regulated and three were down-regulated.TheThesignature had a predictive value with an AUC of 0.90. Furthermore, we found 26 miRNA target genes for four of the ﬁve identiﬁed miRNAs, mainly related to pathways in cancer, RNA Polymerase II Transcription, RhoA signaling pathway, and PI3K-Akt signaling pathway.

Conclusions: This study demonstrated that those miRNAs could be used as noninvasive biomarkers in LBC samples, once they were able to distinguish CIN 2 and CIN3 patients from healthy women and regulate important molecular pathways of onset carcinogenesis.

Legal entity responsible for the study: Barretos Cancer Hospital.

Funding: Programa Nacional de Apoio à Atenção Oncológica.

https://doi.org/10.1016/j.annonc.2023.09.1534

32P Epigenetic reprogramming induced prostaglandin E2

accumulation via overactivated arachidonic acid metabolism during trastuzumab resistance formation of HER2-positive breast cancer

Y. Yin, N. Duan, Y. Hua

Oncology Department, Jiangsu Province Hospital/The First Afﬁliated Hospital of Nanjing Medical University, Nanjing, China

Background: Secondary trastuzumab resistance seriously affects HER2-positive breast cancer treatment. However, we still lack knowledge about changes in tumor cells and their interaction with tumor microenvironment (TME) components during resistance formation. This study aimed to uncover metabolism pathway changes during trastuzumab resistance formation and potential epigenetic variations that are relevant to these processes.

Methods: Induced secondary trastuzumab-resistant SKBR3_HR cell line together with the original trastuzumab-sensitive SKBR3 cell line were applied in this study. Total RNA was collected for transcriptome analysis. Anti-H3K4me3, K27me3 and K27ac antibodies were chosen for CUT&Tag sequencing library preparation. Total genome DNA was prepared for Micro-C sequencing library preparation. Activity score of metabolism pathway was calculated as relative gene expression value averaged over all genes in this pathway in certain cell types. Extracellular prostaglandin E2 (PGE2) was measured by ELISA.

Results: SKBR3_HR cells showed higher trastuzumab tolerance than SKBR3 cells.

Upregulation of arachidonic acid metabolism, which was characterized by two overexpressed genes, PTGS1 and PTGES, was observed in SKBR3_HR cells, resulting in PGE2 accumulation in culture medium. Variations of 1519 H3K27me3 peaks and 256 H3K4me3 peaks at promoters were observed during resistance formation. Little H3K27me3 but considerable raised H3K4me3 levels at PTGS1 and PTGES gene promoters may stimulate their transcription.692 altered active enhancers were measured

during resistance formation. Meanwhile, 2741 and 7007 DNA loops were lost and gained. New DNA loops formation between PTGS1 gene promoter and enhancers nearby, indicating a positive synergy regulatory on PTGS1 gene expression together with promoter modiﬁcations.

Conclusions: During trastuzumab resistance formation, promoter H3K4me3, active enhancers and DNA loops together regulate PTGS1 and PTGES expression, activate arachidonic acid metabolism, and eventually stimulate PGE2 accumulation.

Funding: National Natural Science Foundation of China (81972484), National Natural Science Foundation of China (82203488).

https://doi.org/10.1016/j.annonc.2023.09.1535

33P

Visualizing trastuzumab-deruxtecan action in HER2+ breast cancer cells at nanoscale

K. Cortese1, O. Garrone2, M.C. Gagliani1, G. Bellese1, P. Arnaldi1, A. Abbona3,M. Paccagnella4, F. Ruatta5, M.C. Merlano6, P. Castagnola7

1Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genoa,Italy; 2Medical Oncology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico,Milan, Italy; 3Fondazione ARCO - Cuneo, Fondazione ARCO - Cuneo, Cuneo, Italy;4Azienda Ospedaliera St. Croce e Carle, Azienda Ospedaliera St. Croce e Carle, Cuneo,Italy; 5Astellas Pharma S.p.A., Assago, Italy; 6Clinical Oncology Dept., Candiolo Cancer Institute, Candiolo, Italy; 7Bioterapie, IRCCS Policlinico San Martino, Genoa, Italy

Background: Breast cancers that test positive for the human epidermal growth factor receptor 2 (HER2+) are known to be highly aggressive and hold poor survival rates.

However, advances in therapies targeting HER2 have led to anti-HER2 antibodies like Trastuzumab and tyrosine kinase inhibitors. Trastuzumab-deruxtecan (Tz-Dxd) is an antibody-drug conjugate that has shown remarkable results in both HER2+ and HER2-low BCa. By promoting its internalization and trafﬁcking to lysosomes through HER2 binding, Tz-Dxd has great potential to revolutionize cancer treatment.

Methods: This study aimed to investigate the effects of Tz-Dxd on HER2+ breast cancer cell lines at the nanoscale level using high-resolution light and electron microscopy techniques, biochemistry and ﬂow cytometry analysis.

Background: Vascular endothelial Growth factor (VEGF) has an important role in the physiology of normal ovaries and is a major player in the pathogenesis of OvCan. We have designed HEBERSaVax which is an active immunotherapy approach based on the use of a functionally deﬁcient VEGF 121 isoform as antigen combined with an adjuvant. On immunocompetent mice, the ID8 model resembles the advanced stages of human OvCan and intervention results offer data potentially translatable to the clinical setting. Two sequential phase I clinical trials with single HEBERSaVax treatment have been concluded in patients with advanced solid tumors including subjects with advanced OvCan. A phase II clinical trial in this oncologic setting was recentlyﬁnished. Herein we present data on HEBERSaVax effects on tumor development and reshaping of the microenvironment in OvCan.

Methods: C57BL/6 mouse tumor ID8 model was used to evaluate the vaccine effects in cancer growth control and tumor microenvironment remodeling. Immune response and cytokines concentrations were assessed by ELISA. Ascitic leukocytes were characterized by ﬂow cytometry. Serum and leukocyte samples from selected OvCan patients (n¼9) from the phase I clinical trials (RPCEC00000102 and RPCEC00000155)were also analyzed. Human anti-VEGF antibodies and cytokines were determined by ELISA. The cellular response was evaluated by IFN-g ELISPOT.

Results: HEBERSaVax-based treatment increases the survival of ID8 tumor-bearing mice by reducing the ascites loads. An increase in VEGF-speciﬁc antibodies were detected in mice ascitic ﬂuids, in parallel to a reduction of VEGF levels. The numbers of T lymphocytes and the expression of MHCII in macrophages were increased in the ascitic ﬂuid. Data analyses from OvCan patients in clinical trials revealed that decreased or stabilized VEGF serum levels, positive anti-VEGF titers, and cellular responses, were related to an increase in survival. Processing of phase II clinical trial(RPCEC00000246) immune variables evaluations is ongoing (n¼38, ﬁnal data: ESMO).

Conclusions: Our ﬁndings indicate that HEBERSavax’s impact on preclinical ID8 settings might be translatable to a positive outcome in advanced OvCan patients.

Clinical trial identiﬁcation: RPCEC00000102, RPCEC00000155 and RPCEC00000246.

https://doi.org/10.1016/j.annonc.2023.09.1522

20P The essential role of DNA repair in the pharmacological activities of AST-3424

F. Meng1, T. Qi1, X. Liu1, Y. Wang1, J. Yu2, Z. Lu3, X. Cai2, A. Li3, J. Duan3

1Pharmacology, Ascentawits Pharmaceuticals, Shenzhen, China; 2CMC, Ascentawits Pharmaceuticals, Shenzhen, China; 3Discovery, Ascentawits Pharmaceuticals, Shenzhen, China

Background: AST-3424 is an AKR1C3-activated prodrug and releases a toxic bisalkylating moiety after activation by tumor-speciﬁc AKR1C3. AST-3424 is currently being investigated in multiple phase I/II clinical trials for the treatment of various cancers.Wild-type p53 cells have checkpoint redundancy via G1/S checkpoint and G2/M checkpoint while p53-mutant tumor cells are solely dependent on G2/M checkpoint to arrest the cell cycle after DNA damage and allow DNA repair before progressing. Here, we have explored the essential role of DNA repair in AST-3424-mediated pharmacological activities in vitro and in vivo.

Methods: We employed in vitro cytotoxicity, DNA damage, apoptosis, cell cycle and cellular signaling assays in both p53-proﬁcient H460 and p53-deﬁcient HT29 cells as well as in vivo xenograft models to investigate the essential role of DNA repair in AST3424-mediated pharmacological activities.

Results: AST-3424 induced cytotoxicity, DNA damage, apoptosis and cell cycle arrest at G2 phase in a dose- and AKR1C3-dependent manner in both p53-proﬁcient H460 and p53-deﬁcient HT29 cells. However, enhancement of AST-3424 cytotoxicity by G2 arrest inhibitors, including adavosertib, AZD7762 and ceralasertib was only observed in HT29 but not in H460 cells. Similarly, AST-3424-induced gH2AX and apoptosis were also enhanced in HT29 upon the addition of G2 arrest inhibitors. The enhanced activity of AST-3424 in HT29 cells by G2 arrest inhibitors was due to the attenuation of cell cycle G2 arrest, as evidenced by decreased phosphorylation of Cdc2-Y15 and increased phosphorylation of histone H3, as well as reduced expression of RAD51,resulting in impaired DNA repair capacity. To further examine the essential role of DNA repair in AST-3424 anti-tumor activity, we utilized two PDX models with BRCA

deleterious mutations lacking capacity of double-strand DNA repair. The results showed that AST-3424 exhibited excellent anti-tumor activity in two pancreatic PDX models with BRCA deleterious mutations and high expression of AKR1C3.

Conclusions: DNA repair plays an essential role in AST-3424-mediated in vitro biological activities and in vivo anti-tumor activity. The preclinical data presented in this study support a new approach for cancer treatment.

Legal entity responsible for the study: Ascentawits Pharmaceuticals, Ltd.

Funding: The Development and Reform Commission of Shenzhen Municipality,Guangdong Province, P.R.C (XMHT20220104029, XMHT20220104047).

https://doi.org/10.1016/j.annonc.2023.09.1523

21P Implications of KMT2C knockdown for DNA damage repair in breast cancer

P. Bredin1, S. Toomey2, E. Tinsley3, G. Dowling2, N. Cosgrove3, S. Furney3,B. Hennessy1

1Medical Oncology Department, Beaumont RCSI Cancer Centre, Dublin, Ireland;2Department of Molecular Medicine, RCSI Molecular Medicine Laboratories, Dublin,Ireland; 3Genomic Oncology Research Group, RCSI - Royal College of Surgeons in Ireland, Dublin, Ireland

Background: Pathogenic mutations in the epigenetic modulator histone-lysine Nmethyltransferase 2C (KMT2C) occur in up to 1 in every 6 breast cancers and KMT2C likely functions as a tumour suppressor. Despite this high frequency, therapeutic implications of deleterious KMT2C mutations are poorly understood and detailed preclinical work is still needed. DNA damage repair pathways may be affected by KMT2C mutations according to published preclinical data. The aim of this study is to identify the effects of KMT2C knockdown in vitro in breast cancer cells as a basis for identifying potential synthetic lethality drug targets.

Methods: MCF-7 (ER+ breast cancer) cells were cultured and 500,000 cells per well were plated on 6-well plates. KMT2C siRNA was transfected via Lipofectamine as per protocol in three wells, with universal control siRNA in three wells. Total RNA was extracted and sent for sequencing. RNA expression was quantiﬁed by RT-qPCR.

Results: RNA-seq conﬁrmed reduction in expression of KMT2C in KMT2C siRNAtreated cells vs controls. RT-qPCR showed a reduction in expression of DNA damage repair genes including BRCA1 (RQ ¼ 0.36), BRCA2 (RQ ¼ 0.37), RAD51 (RQ ¼ 0.36),RAD54L (RQ ¼ 0.28) and POLD3 (RQ ¼ 0.47).

Conclusions: KMT2C loss-of-function in breast cancer may impact DNA damage response pathways including homologous recombination and therefore be implicated in response to established treatments such as PARP-inhibitors. Further study including mapping of co-dependencies by whole genome siRNA screens in KMT2C-mutant breast cancer cells to identify synthetic lethality targets, as well as cell toxicity assays,are being performed in light of these results.

Legal entity responsible for the study: Beaumont RCSI Cancer Centre.

https://doi.org/10.1016/j.annonc.2023.09.1524

22P Clinical signiﬁcance of DNA damage response mutations in early stage NSCLC

H. Zhang

Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Dongcheng, China

Background: DNA damage response (DDR) pathways are essential to sustain genomic stability and play a critical role in cancer development and progression. Here, we investigated DDR genes mutations proﬁle in early-stage non-small cell lung cancer(NSCLC) and their prognostic values.

Methods: We ﬁrst examined 74 DDR genes involved in seven DDR pathways and then focused on six speciﬁc genes: ATM, BRCA1/2, CHEK1, BARD1, BRIP1. A total of 179 stage I and IIIa NSCLC patients who received curative resection in Peking Union Medical College Hospital and their corresponding samples were collected for DNA sequencing, immunohistochemistry and survival analysis.

Results: A total of 167 eligible patients were ﬁnally analyzed. Mutation frequencies were 82% and 26.3% for the selected 74 genes and 6 genes, respectively. No association was found between DDR gene status and PD-L1 expression, CD8 positive lymphocyte and tumor-associated macrophage (TAM) inﬁltration in tumor area.

Numbers of gene mutations was signiﬁcantly increased among patients with DDR alterations. Deleterious mutations in ATM, BRCA1/2, CHEK1, BARD1 and BRIP1 were independent prognostic indicators of signiﬁcantly longer disease-free survival.

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Conclusions: Deleterious mutations of these six genes were common in early-stage NSCLC and may serve as prognostic biomarkers.

Funding: National High Level Hospital Clinical Research Funding (to MW), Grant/Award Number:2022-PUMCH-B-106.

https://doi.org/10.1016/j.annonc.2023.09.1525

23P

PMC-309: A highly selective anti-VISTA antibody reverses immunosuppressive TME to immune-supportive

C.H. Park, K. Kim, H. Han, W.S. Lee

R&D Center, PharmAbcine, Inc., Daejeon, Republic of Korea

Background: PMC-309 is a novel human monoclonal IgG1 antibody (mAb). It binds with human VISTA, an immune checkpoint protein, with the effect of regulating the immunological activity of myeloid cells such as MDSC or myeloid-derived immune cells, thereby improving the antitumor activities of immune cells. In addition to being a novel drug substance, PMC309 will be the ﬁrst IgG1 monoclonal antibody to act synergistically with other immunotherapies to improve treatment efﬁcacy.

Methods: In vitro T cell activity: human PBMC was employed for the evaluation of T cell activity, and was stimulated with or w/o PMC-309 in the presence of anti-CD3/28 Antibody. In vivo study: MC38-bearing human VISTA knock-in (KI) mice were employed for the assessment of the anti-tumor activity of PMC-309. The tumor inﬁltrated immune cells: Immune cells in the TME were evaluated by immunohistochemistry (IHC) or ﬂow cytometry (FACS) analysis.

Results: PMC-309 binding to VISTA-expressing cells is highly selective and the selectivity is maintained even in the low pH conditions that mimic TME. PMC-309 enhances the secretion of IFN-gamma, TNF-alpha, and IL-2 in Mixed Lymphocyte Reaction (MLR) settings. In addition, PMC-309 promoted monocyte differentiation into M1 macrophage which stimulates proinﬂammatory cytokine secretion of T cells.

For the in vivo study, PMC-309 was intravenously administrated in VISTA-KI mice. The tumor growth rate was suppressed accompanied by a synergistic effect with an antiPD1 antibody. The anti-tumor activity was associated with enhanced T cell activation,increased secretion of pro-inﬂammatory cytokines, and increased penetration of cytotoxic T cells, but lowing immune-suppressive MDSC cells into TME as demonstrated with IHC analysis.

1Onco-Immunology Unit, Navarrabiomed-Fundación Miguel Servet, Universidad Pública de Navarra (UPNA), Hospital Universitario de Navarra (HUN), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; 2Crescendo Biologics Ltd,Cambridge, UK; 3Medical Oncology Unit, University Hospital of Navarra, Pamplona,Spain; 4Proteomics Platform, Proteored-ISCIII, Navarrabiomed-Fundación Miguel Servet, Universidad Pública de Navarra (UPNA), Hospital Universitario de Navarra (HUN),Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain

Background: A signiﬁcant number of cancer patients do not beneﬁt from PD-L1/PD-1 blockade immunotherapies. PD-1 and LAG-3 co-upregulation in T-cells is one of the major mechanisms of resistance by establishing a highly dysfunctional state in T-cells.

Methods: A high-throughput screening was performed of PD-1/LAG-3 multiomic expression proﬁles in public databases of human cancer biopsies, to establish relationships between inﬁltrating tumor-inﬁltrating PD-1/LAG-3 T cells with biomarkers both in T cells and within the tumour microenvironment. These results were validated in engineered T-cell lines with constitutively active PD-1, LAG-3 pathways, and their combination, analysed by high-throughput quantitative proteomics and validated by conventional molecular techniques on primary T cells from NSCLC patients.

Results: The high-throughput multiomic human cancers screening and the experimental proteomic T cell lines uncovered a strong PD-1/LAG-3 dysfunctionality signature that was found which regulated immune, proteomic, metabolic, genetic,and epigenetic pathways. These mainly relied on differential regulation of E3 ubiquitin ligases CBL-B and C-CBL. Notably, LAG-3 expression has never been associated to CBL ubiquitin ligases before.

Conclusions: PD-1/LAG-3 co-signaling proﬁle uncovers a highly dysfunctional regulated programme. Co-blockade with a bispeciﬁc drug but not with a combination of anti-PD-1/anti-LAG-3 antibodies achieved both CBL-B and C-CBL inhibition, reverting T-cell dysfunctionality in lung cancer patients resistant to PD-L1/PD- 1 blockade. These results will help identifying the mechanisms of intrinsic resistance to PD-1 blockade mediated by LAG-3 co-signaling.

Legal entity responsible for the study: Navarrabiomed.

Results: We found that after 2 hours, Tz-Dxd induced ERBB2 phosphorylation and downstream signaling activation without signiﬁcant internalization of the receptor.

However, the receptor was internalized towards lysosomes at later stages (72 hours),but only in a limited fraction of cells. Nonetheless, Tz-Dxd induced apoptosis in more than 50% of cells after 72 hours of treatment, even in cells where ERBB2/Tz-Dxd was not internalized. This suggests that deruxtecan was efﬁciently released from Tz in lysosomes reaching by diffusion surrounding cells. In addition to apoptotic cells, we observed a consistent fraction of cells displaying suggestive hallmarks of senescence.

In particular, we detected dramatic cell ﬂattening, increased nuclear size, chromatin reorganization, nuclear envelope ruptures and expansion of the lysosomal compartment. Cells also displayed alterations of the mitochondrial network dynamics and induction of autophagy; indicative of an elevated energy demand to sustain autophagy and senescence.

Conclusions: These results suggest that Tz-Dxd has potent anti-tumor activity in vitro but might also induce cellular senescence, which would merit further investigation due to its uncertain role in cancer progression in the long run.

Legal entity responsible for the study: Academic group.

Disclosure: O. Garrone: Financial Interests, Institutional, Advisory Board: Eisai, MSD, Daiichi Sankyo, Gilead; Financial Interests, Personal, Financially compensated role: Novartis, Pﬁzer, Lilly. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1536

35P SAT-122: A potential ﬁrst-in-class, potent, small-molecule disruptor of RAD51-BRCA2, attenuates RAD51 foci formation and tumor progression in preclinical models

S. Patra1, M. Pothuganti1, V. Sankeshi1, G. K1, H. Pathange1, R. S1, K. Soumyajit2,S. Viswanadha1

1Biology, Satya Pharma Innovations, Hyderabad, India; 2Biochemistry, SDU - University of Southern Denmark - Medical Biotechnology Center, Odense, Denmark

Background: The DNA damage repair pathway plays a crucial role in signalling for effective DNA repair and cell cycle progression. DNA double-strand breaks (DSBs) are primarily repaired by homologous recombination. Acting downstream of ATR, ATM and PARP, RAD51 is a central recombinase in HR-mediated DDR pathway that participates in DSB repair via interaction with BRCA2, followed by its nuclear translocation. RAD51:BRCA2 interaction disruptors represent a ﬁrst-in-class anticancer target with therapeutic potential in refractory solid tumors.

Methods: Binding of SAT-122 to RAD51 and its interaction with BRC4 was determined using Surface Plasmon Resonance (SPR) and pull-down of the RAD51:BRC4 complex,respectively. Downstream modulation of RAD51 and gamma H2AX foci, along with effect on cell cycle was studied. Antiproliferative effects of SAT-122 was evaluated in a panel of multiple solid tumor cell lines. Selectivity was evaluated in a kinase panel.

Nanostring based evaluation of pathway-related genes following incubation of cells with SAT-122 was conducted. In Vivo efﬁcacy was evaluated in NCI-H358 and MDAMB-231 xenograft models.

Results: SAT-122 binds to RAD51 and disrupts RAD51:BRCA2 interaction with an IC50 of 20 nM. Fluorescent microscopy studies indicated a dose dependent reduction of RAD51 foci, and an increase in g-H2AX foci at 500 nM. FACS analysis demonstrated arrest at late S and G2 phase with subsequent apoptosis. SAT-122 inhibited proliferation of over 30 different cancer cell lines at IC50ranging from 150-800 nM.

Biochemical selectivity was established against a 345-kinase panel. RNA seq studies suggested modulation of multiple genes in the homologous recombination repair(HRR) pathway in line with the mechanism. In vivo translation was conﬁrmed in NCIH358 and MDA-MB-231 xenograft models with TGI of >70% and 50%, respectively.

Pharmacokinetic studies and tolerability studies in rodents, revealed sufﬁcient exposures, along with a wide therapeutic window.

Conclusions: SAT-122 is a novel and potent disruptor of RAD51:BRCA2 with potential to be used in the DDR context, in solid tumors. IND-enabling studies are ongoing with clinical trials planned in H1 2024.

Legal entity responsible for the study: Satyarx Pharma Innovations Pvt Ltd.

https://doi.org/10.1016/j.annonc.2023.09.1537

36P Molecular assessment of clinical antitumour therapeutics utilising established pancreatic ductal adenocarcinoma patient-derived models

Y-A. Suh

CMI, Seoul National University Hospital, Seoul, Republic of Korea

Background: Our proteogenomic analysis using pancreatic ductal adenocarcinoma(PDAC) tissues provides signiﬁcantly mutated genes/biomarkers, cell signaling pathways and cell types as potential therapeutic targets to improve stratiﬁcation of PDAC patients (Nat. Can., 2023). The current study aimed to evaluate clinical chemotherapeutics to validate targeting molecules and signaling pathways based on previous results, using patient-derived primary cells and tumor organoids.

Methods: The sensitivity on drugs was also evaluated on established primary PDAC cells and tumor organoids. To explore the mechanistic molecular changes for the development of drug resistance, we established resistant-cells on gemcitabine combined with radiation through long term treatment of the combination and selection procedure. Signaling pathways, EMT and cancer were explored at protein as well as RNA levels, and metabolomics were performed

Results: PDAC cells and organoids showed growth inhibition when treated with inhibitors against RhoA phosphorylation, HIF1A, or gemcitabine combined with radiation, ,respectively. Each chemotherapeutics showed reduced tumor growth through cell cycle arrest, apoptosis or autophagy. Biochemical analyses showed that drugtreated cells showed reduced expressions of phosphorylated ERK, phosphorylated Akt, or phosphorylated RhoA. HIF1A together with HK2 genes was overexpressed in resistant cells. Metabolomics showed differential glycolysis patterns among parental and resistant primary PDAC cells.

Conclusions: The results suggest that the targeting molecules associated with squamous PDAC malignancy discovered in our previous study would provide signiﬁcant therapeutic advantage. Additionally, hypoxic tumor microenvironment (TME) plays a critical role for chemotherapeutics sensitivity, according to the metabolomics analysis.

Importantly, the study implicates the critical role of patient-derived models, especially tumor organoids, for precise evaluation of drug sensitivity, and to validate functional mechanism of drug resistance on individual PDAC patients.

Funding: Korea Foundation for the Advancement of Science and Creativity.

https://doi.org/10.1016/j.annonc.2023.09.1538

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37P

|Table: 38P Study groups |Table: 38P Study groups |Table: 38P Study groups | |---|---|---|

|||Antiemetic Agent(s) |

|Group (n¼4, each study) |Emesis Agent |Study 1 Study 2 |

|1 e Normal |Saline IV |— |

|2 e Control |Zolbetuximab |— |

||1 mg/kg IV ||

|3 e DEX |3 e DEX |DEX 20 mg/kg IV |

|4 e OND |4 e OND |OND 3 mg/kg IV |

|5 e FOS |5 e FOS |FOS 3 mg/kg IV |

|6 e OLA |6 e OLA |OLA 0.03 mg/kg IM |

|7 e Combination |7 e Combination |DEX+OND+FOS+OLA |

Nischarin can be a target for stromal normalisation in pancreatic ductal adenocarcinoma

DEX, dexamethasone; FOS, fosaprepitant; IM, intramuscular; IV, intravenous; OLA,olanzapine; OND, ondansetron.

J. J.Grahovac1, K. Zivic2, D. Galun2Grahovac1, K. Zivic1, D. Galun2

1Experimental Oncology, Institute for Oncology and Radiology of Serbia, Belgrade,Serbia; 2HBP Unit, Clinical Center of Serbia, Belgrade, Serbia

Background: Nischarin (NISCH) is a scaffolding protein involved in the control of cytoskeletal dynamics. Its tumor suppressive role has been demonstrated in breast cancer; and high expression in tumor tissue was reported as a positive prognostic marker in breast and ovarian cancers. Of interest, there are several approved nischarin agonists used in treatment of hypertension. We have previously found that NISCH is expressed in both tumor cells and cancer-associated ﬁbroblasts (CAFs) in pancreatic ductal adenocarcinoma (PDAC) and that nischarin agonist rilmenidine can limit cancer cell invasion. As the dense tumor stroma makes up to 80% of the bulk tumor tissue in PDAC, and is one of the causes of current treatment failure, the aim of this study was to examine the effects of nischarin agonists on the phenotype of cancer-associated stroma in PDAC.

Methods: NISCH expression and co-localization with CAF markers were examined by immunohistochemistry in PDAC tissue microarray. CAFs were isolated from fresh tumor tissue by the outgrowth method. MTT test was used to evaluate cytotoxicity of nischarin agonist rilmenidine on patient-derived CAFs. Immunoblotting, immunocytochemistry, ELISA and qRT-PCR were used to examine the effects of rilmenidine treatment on the extracellular matrix deposition and cytokine and growth factor production in CAFs and ex vivo cultures of PDAC tumor tissue.

Results: Nischarin was expressed in both aSMA+and FAP+cells in the tumor tissue.

Patient-derived CAFs were a heterogeneous population, positive for aSMA+FAP+,collagen I and ﬁbronectin. Rilmenidine treatment of patient-derived CAFs in vitro was not cytotoxic at concentrations achievable in the human plasma. Nevertheless, rilmenidine treatment decreased fractions of both aSMA+and FAP+cells in vitro and decreased the production of pro-inﬂammatory cytokines IL-6, IL-8 and CCL-2. Treatment of ex vivo PDAC tumor cultures for 72h remodeled the extracellular matrix.

Conclusions: Our results imply that rilmenidine treatment in vitro and ex vivo shows a potential for normalizing PDAC tumor-derived CAFs and may be a good candidate for drug repurposing.

Funding: European Research Executive Agency; Science Fund of the Republic of Serbia.

https://doi.org/10.1016/j.annonc.2023.09.1539

38P Effects of antiemetics on zolbetuximab-induced gastric injury and emesis frequency in ferrets

J. Weng1, F. Kinugasa2, S. Kajikawa3, Y. Yamanaka4, T. Ugawa5, H. Fushiki6,S. Akuzawa7

1Astellas Pharma Inc., Tsukuba, Japan; 2Drug Discovery Research, Astellas Pharma Inc.,Tsukuba, Japan; 3Veterinary, The University of Tokyo, Meguro-ku, Japan; 4Applied Drug Metabolism & Pharmacokinetics-Non-Clinical Regulatory Science, Astellas Pharma Inc., Tsukuba, Japan; 5Nonclinical Regulatory Science, Astellas Pharma Inc., Tsukuba,Japan; 6Research Program Management, Astellas Pharma Inc., Tsukuba, Japan;7Applied Pharmacology, Astellas Pharma Inc., Tsukuba, Japan

Background: Claudin 18.2 (CLDN18.2) is expressed in normal gastric tissue and gastric cancers. Zolbetuximab is a chimeric IgG1 monoclonal antibody that selectively targets CLDN18.2, inducing antibody- and complement-dependent cytotoxicity and cancer cell lysis. In phase 3 studies of zolbetuximab for HER2-negative, advanced gastric/gastroesophageal junction adenocarcinomas (SPOTLIGHT, GLOW), the most frequent adverse events were nausea and vomiting (N/V). We investigated the mechanism of zolbetuximab-induced N/V and effects of antiemetic agents on gastric injury and emesis frequency in ferrets.

Methods: Ferrets were administered zolbetuximab with/without single or combination antiemetic treatment (Table). Retching/vomiting were monitored for 6 hours,after which gastric tissues were sampled for histopathologic assessment. The study was conducted twice.

Results: Zolbetuximab induced emesis within 30 minutes of administration. Singly,dexamethasone (DEX), ondansetron (OND), and fosaprepitant (FOS) signiﬁcantly reduced emesis vs control (no antiemetic) in Study 1; olanzapine (OLA) did not. In Study 2, FOS alone (but not DEX, OND, or OLA) almost completely suppressed emesis.

Further, both combination regimens containing FOS reduced emesis. Histopathologic analysis indicated that zolbetuximab induced gastric injury, evidenced by submucosal inﬂammation in the corpus and pylorus. DEX alone and the DEX-based combination regimen showed a tendency to alleviate submucosal inﬂammation in the corpus and pylorus, although the other antiemetics did not show any clear suppression of gastric mucosal damage. The combination of OND+FOS also tended to alleviate gastric mucosal abnormalities.

Conclusions: These ﬁndings in ferrets demonstrate that zolbetuximab-induced emesis may be associated with gastric mucosal damage. Further, antiemetics may have the potential to mitigate N/V in patients treated with zolbetuximab.

Editorial acknowledgement: This study is funded by Astellas Pharma, Inc. Medical writing/editorial support was provided by Sandra Westra, PharmD, Pamela Barendt,PhD, and Cheryl Casterline, MA, from Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, USA, and funded by the study sponsor.

Legal entity responsible for the study: Astellas Pharma, Inc.

Funding: Astellas Pharma, Inc.

https://doi.org/10.1016/j.annonc.2023.09.1540

39P Casein kinase 2 modulates epithelialemesenchymal transition through helicobacter pylori CagA-dependent pathway in gastric cancer cells

S. Lee

Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea

Background: Helicobacter pylori is the most important carcinogen in human gastric cancer. However, the pathogenic molecular mechanism which underlies the carcinogenesis in gastric cancer by H. pylori remains largely unknown. In this study, we understand that molecular biological mechanism related to gastric carcinogenesis by investigating the role of CK2 in EMT. Casein kinase 2 is a serine/threonine protein kinase and consists of two catalytic subunits (a or a’) and regulatory subunits (b). CK2 regulates many substrates and its involved in cell growth, proliferation, invasion. EMT is involved in many signaling pathways, but the key regulatory kinases in this process have not been clearly identiﬁed. Although the role of CK2 catalytic subunits has remained largely uncharacterized, several studies have recently focused on regulator subunits in EMT.

Methods: AGS and MKN74 cells as human gastric epithelial cells and H. pylori strains,H. pylori 60190 (CagA+) and H. pylori DCagA (CagA-) were used. Protein and mRNA levels of CK2 were tested by Western blot and RT-PCR in AGS cells infected with H.

pylori 60190. We also examined in vivo assay through tumor weight and size by xenograft mouse model. Expression levels of CK2 were analyzed in 54 gastric tissues from patients with gastric carcinoma by immunohistochemistry.

Results: Although CK2a protein expression remained unchanged during H. pylori infection, we found that CK2a kinase activity was increased in gastric epithelial cells.

We also found that the CK2b protein level decreased in H. pylori-infected gastric cancer cells in CagA-dependent manner and demonstrated that CagA induced CK2b degradation via HDM2. We observed that CagA induced HDM2 protein phosphorylation and that p53 levels were decreased in H. pylori-infected gastric cancer cells. We also found that the downregulation of CK2b triggered the upregulation of Snail levels in gastric cancer cells. Furthermore, our in vivo experiments and functional assays of migration suggest that CK2b downregulation is a major factor responsible for the EMT in gastric cancer.

Conclusions: In summary, we have shown that the downregulation of CK2b in H.

pylori-infected gastric cancer cells promotes the EMT in CagA-dependent manner.

Legal entity responsible for the study: Yonsei University College of Medicine.

Funding: National Research Foundation Of Korea.

https://doi.org/10.1016/j.annonc.2023.09.1541

40P

Bioinformatic evaluation of the transcriptomic and immunologic proﬁle of prostate tumors with high expression of kallikrein-2

I. Moreno Candilejo1, L. Paniagua Herranz2, B. Doger de Spéville3, C. Diaz-Tejeiro4,C. Nieto-Jimenez4, A. Sanvicente4, J. Ramon5, V. Moreno Garcia6, E. Calvo7,

A. Ocana Fernandez3

1START Madrid-CIOCC, Centro Integral Oncológico Clara Campal, Madrid, Spain;2Experimental Therapeutics Unit, Medical Oncology Department, Hospital Clinico Universitario San Carlos, Madrid, Spain; 3Dept. Early Clinical Drug Development,START Madrid-FJD, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain;4Terapias Experimentales en Cáncer, IdISSC- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain; 5Medical Oncology, START Madrid-CIOCC,Centro Integral Oncológico Clara Campal, Hospital Madrid Norte Sanchinarro, Madrid,Spain; 6Clinical Research Phase I Trials Unit, START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid, Spain; 7Medical Oncology Division, START Madrid-CIOCC,Centro Integral Oncológico Clara Campal, Madrid, Spain

Background: Identiﬁcation of tumor associated antigens (TAAs) expressed on the cell membrane of tumoral cells is a main goal in cancer research. T cell engagers (TCE) are bi-speciﬁc antibodies that engage a TAA with an effector T cell receptor mainly CD3.

Kallikrein-2 (KLK2) is a surface protein for which TCE are currently in clinical development. In our study we explore genomic correlates and the transcriptomic and immunologic proﬁle of tumors with high expression of KLK2.

Methods: Primary prostate cancer data was downloaded from TCGA to study transcripts up or down regulated when high expression of KLK2 was present. Tumor Estimation Resource (TIMER) platform was employed to investigate the association between high expression of KLK2 and immune cell populations. Correlations between transcripts were performed using Spearman’s correlation test.

Results: KLK2 was speciﬁcally upregulated in prostate cancer compared with other solid tumors and normal tissue (tumor 5956.5 TPM versus normal 4175.26 TPM).

KLK2 expression did not associate with the presence of any immune cell population either innate or adaptive cells including CD8+ (Rho ¼ 0.339, p¼ 1.03E-12), CD4+ (Rho¼ -0.244, p ¼ 4.56E-07), B cells (Rho ¼ 0.047, p ¼ 0.332), neutrophils (Rho ¼ -0.139,p ¼0.004), dendritic cells (Rho ¼-0.152, p ¼ 0.001), or macrophages (Rho¼ 0.074, p¼0.128). No clear association was observed for any biomarker of T cell activationincluding CD8A, CD8B, GZMA, GZMb or PRF1, or an additional battery including more than 40 additional genes linked with T cell cytotoxic. A mild correlation was observed between high expression of KLK2 and TMPRSS2 (Rho ¼ 0.481, p ¼ 1,68E-11). Proteinprotein interaction analysis showed interactions with AR, KLK3, IGF1, IGFBP3 (PPI enrichment p-value: 4.51e-07), among others. Co- upregulated surface proteins include TMEFF2, OR51E2, CD320 and FAM17AB; and nonsurface proteins: RDH11,FX4D3, SSR4 and NDUFA13. None of them were speciﬁcally expressed in tumoral cells or associated with biochemical (PSA) relapse.

Conclusions: KLK2 is highly and exclusively expressed in prostate cancer mainly in inmune desert tumors. Future studies should be performed in other clinical scenarios like in androgen resistant prostate tumors.

Disclosure: V. Moreno Garcia: Financial Interests, Personal, Advisory Board: BMS, Janssen, Roche,Basilea, Bayer, AstraZeneca; Financial Interests, Personal, Full or part-time Employment: START;Financial Interests, Institutional, Local PI, AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro,Agenus, Amcure, Amgen, Astellas, AstraZeneca Bayer BeiGene BioInvent International AB, BMS,Boehringer Ingelheim, Boston, Celgene, Daichii Sankyo, Debiopharm, Eisai, e-Terapeutics, Exelisis,Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen,Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar,Novartis, Odonate Therapeutics, Pﬁzer, Pharma Mar, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanoﬁ, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, Upshersmith: Multiple. E. E. Calvo: Financial Interests, Personal, Advisory Board:Adcendo, Amunix, Anaveon, AstraZeneca, BMS, Janssen, MonTa, MSD, Nanobiotix, Nouscom,Novartis, Servier, TargImmune, T-knife, Chugai, Elevation Oncology, Ellipses Pharmacy, SyneosHealth,Genmab, Diaccurate; Financial Interests, Personal, Invited Speaker: OncoDNA, PharmaMar, Roche/Genentech; Financial Interests, Personal, Full or part-time Employment, Director, Clinical Research:HM Hospitales Group; Financial Interests, Personal, Full or part-time Employment, Medical Oncologist. Clinical Investigator. Director, Clinical Research: START Madrid - CIOCC (Centro Integral Oncológico Clara Campal); Financial Interests, Personal, Member of Board of Directors, External Independent member of Board of Directors: PharmaMar; Financial Interests, Personal, Ownership Interest: START, Oncoart Associated; Financial Interests, Personal, Steering Committee Member,Member of Data Monitoring Committee: BeiGene, Sanoﬁ, Merus; Financial Interests, Personal,Steering Committee Member: Novartis; Non-Financial Interests, Other, Non-for-proﬁt Foundation.

President and co-founder: INTHEOS (Investigational Therapeutics in Oncological Sciences) non-forproﬁt Foundation; Non-Financial Interests, , Advisory Role: PsiOxus; Non-Financial Interests, Other,Chair of the Independent Data Monitoring Committee: EORTC IDMC; Non-Financial Interests,Member of Board of Directors, Non-for-proﬁt Foundation, trustee member: Non-for-proﬁt Foundation PharmaMar; Non-Financial Interests, Advisory Role, Non-for-proﬁt foundation: CRIS Cancer Foundation, non-for-proﬁt ; Non-Financial Interests, Member: ASCO, ESMO, SEOM, EORTC. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1542

41P Evaluation of ARX517: A next-generation anti-PSMA

antibody drug conjugate for prostate cancer treatment, in preclinical enzalutamide-resistant and enzalutamidesensitive pharmacology models and in toxicology models

S. Zhang, D. Mills, J.Y. Kim, N. Knudsen, J. Nelson, Y. Buechler, L. Skidmore

Preclinical, Ambrx, Inc., La Jolla, CA, USA

B. Serambeque1, S. Ferreira1, M. Piñeiro2, S. Lopes2, B. Costa2, N.A. Pereira2,C.M. Marto3, M.F. Botelho3, M.J. Carvalho4, T. Pinho e Melo2, M. Laranjo1

1Coimbra Institute for Clinical and Biomedical Research (iCBR) area of Environment Genetics and Oncobiology (CIMAGO), Institute of Biophysics, Faculty of Medicine;CIBB; CACC, Univ Coimbra, Coimbra, Portugal; 2Coimbra Chemistry Centre-Institute of Molecular Sciences and Department of Chemistry, Univ Coimbra, Coimbra, Portugal;3Coimbra Institute for Clinical and Biomedical Research (iCBR), Area of Environment,Genetics and Oncobiology Research (CIMAGO), Institute of Biophysics, Faculty of Medicine; Institute of Experimental Pathology; CIBB; CACC, Univ Coimbra, Coimbra,Portugal; 4Gynecology Service, CHUC - Centro Hospitalar e Universitário de Coimbra,EPE, Coimbra, Portugal

Background: Cancer stem cells (CSC) motivate the investigation of novel anticancertargeted therapies. In endometrial cancer (EC), overexpression of aldehyde dehydrogenase (ALDH) was associated with endometrial CSC, highlighting its therapeutic target potential. Photodynamic therapy (PDT), a minimally invasive anticancer approach, emerges as a promising targeted therapy for endometrial CSC, through a structural modulation of optimized photosensitisers with aldehyde moieties. Thus, the aim is to investigate PDT based on the 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinefused chlorins (PX), modulated to target endometrial CSC by incorporation of aldehyde substituents.

Methods: A solution of a mono-esther/mono-alcohol derivative chlorin was added to Dess-Martin periodinane in dichloromethane solution and stirred to synthesise a mono-aldehyde derivative of 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused chlorin(A-PX). The presence of the aldehyde group was conﬁrmed by proton nuclear magnetic resonance (1H-NMR). The ALDH1A1-promoted oxidation of A-PX was followed through reverse-phase high-performance liquid chromatography (HPLC). This was done by reacting 50nM ALDH1A1 with 1mM A-PX in a 2% DMSO, Tris pH 7.5, KCl, DTT and b-NAD solution at 37 C. The reaction was stopped every 30’ with acetonitrile. and β-NAD solution at 37°C.The reaction was stopped every 30' with acetonitrile.ToTo evaluate A-PX-based PDT (7.5mW/cm2, 10J) the resazurin assay was performed on endometrial CSC.

S199

Results: The A-PX1H-NMR revealed a peak at 10.28ppm corresponding to the aldehyde. The kinetics of the enzymatic reaction, followed by HPLC, showed the decreasing relative area of the aldehyde peak (retention ¼ 2’13’’) in parallel with theincrease of the carboxylic acid (retention ¼ 3’04’’) formed by ALDH1A1-promotedoxidation, reaching complete conversion at 120’. Preliminary results of the A-PX-PDT cytotoxicity on the endometrial CSC pointed to decreased proliferation, while A-PX per se did not show toxicity.

Conclusions: It was possible to develop chlorins able to interact with ALDH1A1,allowing the in situ modiﬁcation of the hydrophilicity of the photosensitizer. A-PX seem to be effective PDT agents against endometrial CSC. The promising results encourage further studies to conﬁrm this rationale for endometrial CSC-targeted PDT.

Legal entity responsible for the study: Univ Coimbra.

Background: Prostate cancer is the second leading cause of cancer death among men in the United States. Metastatic castration-resistant prostate cancer (mCRPC) is an advanced disease stage in which patients ultimately fail androgen-deprivation therapies and exhibit a poor survival rate. Recently, prostate-speciﬁc membrane antigen(PSMA) has been validated as a mCRPC tumor antigen with its over-expression in tumors and low expression in healthy tissues. Using an expanded genetic code to create Engineered Precision Biologics, Ambrx has developed ARX517, a PSMA-targeted antibody drug conjugate (ADC), which is composed of a humanized anti-PSMA antibody site-speciﬁcally conjugated to a tubulin inhibitor drug-linker at a drug-toantibody ratio of 2. After binding to PSMA, ARX517 is internalized and catabolized,leading to cytotoxic payload delivery and cellular apoptosis. To minimize premature payload release and maximize delivery to tumor microenvironments, ARX517 employs a non-cleavable PEG linker and stable oxime conjugation chemistry, enhancing systemic stability.

Methods: ARX517 was evaluated in multiple pre-clinical pharmacology and toxicology models using standard methodology.

Results: In vitro studies demonstrate that ARX517 selectively induces cytotoxicity of PSMA-expressing tumor lines. ARX517 exhibited a long terminal half-life and high serum exposure in mice, and dose-dependent anti-tumor activity in both enzalutamide-sensitive and -resistant CDX and PDX prostate cancer models. Repeat dose toxicokinetic studies in non-human primates demonstrated ARX517 was tolerated at exposures well above therapeutic exposures in mouse pharmacology studies, indicating a wide therapeutic index.

Conclusions: In summary, ARX517 inhibited tumor growth in diverse mCRPC models,demonstrated a tolerable safety proﬁle in monkeys, and had a wide therapeutic index based on preclinical exposure data. Based on strong preclinical data and recent clinical validation of PSMA targeting, ARX517 is being evaluated in a phase 1/2 clinical trial (NCT04662580).

Editorial acknowledgement: Mark English, PhD, of Cancer Communications and Consultancy Ltd, Cheshire, UK, provided editorial assistance (funded by Ambrx).

Legal entity responsible for the study: Ambrx.

Funding: Ambrx.

Disclosure: S. Zhang, D. Mills, J.Y. Kim, N. Knudsen, J. Nelson, Y. Buechler, L. Skidmore: Financial Interests, Personal, Full or part-time Employment: Ambrx.

https://doi.org/10.1016/j.annonc.2023.09.1543

42P Developing a photodynamic therapy strategy targeted to endometrial cancer stem cells

Funding: Centre for Innovative Biomedicine and Biotechnology (CIBB) (UIDB/04539/2020, UIDP/04539/2020) and Coimbra Chemistry Centre (UIDB/00313/2020, UIDP/00313/2020) are supported by The Fundação para a Ciência e a Tecnologia (FCT), cofunded by COMPETE. Project Prova de Conceito (CENTRO-45-2021-30; 01/SAICT/2021, no 180078) funded by Portugal2020. Beatriz Serambeque (2020.07672. BD )and Bruna Costa (2022.12013. BD ) were awarded with a PhD Scholarship from FCT and European Social Fund.

https://doi.org/10.1016/j.annonc.2023.09.1544

43P

S200

Looking for therapeutic targets on the proteome proﬁle of endometrial cancer stem cells

M. Laranjo1, C. Mestre1, B. Serambeque1, A.S. Carvalho2, H.C. Beck3, M.F. Botelho4,M.J. Carvalho5, R. Matthiesen2

1Coimbra Institute for Clinical and Biomedical Research (iCBR), Area of Environment,Genetics and Oncobiology Research (CIMAGO), Institute of Biophysics, Faculty of Medicine; CIBB; CACC, Univ Coimbra, Coimbra, Portugal; 2INOVA4Health, NOVA Medical School (NMS), Faculdade de Ciências Médicas (FCM), Universidade Nova de Lisboa, Lisboa, Portugal; 3Clinical Biochemistry, Odense Universitetshospital, Odense,Denmark; ‘4Coimbra Institute for Clinical and Biomedical Research (iCBR), area of Environment, Genetics and Oncobiology Research (CIMAGO), Institute of Biophysics,Faculty of Medicine; Institute of Experimental Pathology; CIBB; CACC, Univ Coimbra,Coimbra, Portugal; 5Gynecology Service, CHUC - Centro Hospitalar e Universitário de Coimbra, EPE, Coimbra, Portugal

Background: Endometrial cancer (EC) is one of the most frequent gynaecological malignant diseases whose incidence presents an increasing trend. Cancer stem cells(CSC), a subpopulation of undifferentiated tumour cells identiﬁed in EC, are the main actors in the resistance mechanisms to conventional therapies. Thus, the main aim of this study is to identify novel molecular targets in endometrial CSC for the future development of innovative targeted therapies for EC.

Methods: Two EC cell lines, ECC-1 and RL95-2, were cultured, and endometrial CSC were obtained through an optimized 5-day sphere formation assay. A proteomic proﬁle of cell lines and endometrial CSC was determined through mass spectrometrybased proteomics. The analysis was performed through the comparison of CSC vs. cell line proteins signiﬁcantly up-regulated by a 40-fold change and their cellular localization. R package was used for statistical analysis.

Results: The proteomic analysis of ECC-1 samples allowed the identiﬁcation of 477 up-regulated ECC-1-CSC-speciﬁc proteins, 108 ECC-1-speciﬁc proteins, and 2306 common proteins. Regarding RL95-2 samples, the analysis identiﬁed 76 up-regulated RL95-2-CSC-speciﬁc, 994 cell line-speciﬁc, and 1420 common proteins. The cellular localization of up-regulated proteins identiﬁed from CSC populations was mainly the cytoplasm (25-31%), nucleus (19-23%), and membrane (21-22%). Regarding the functional analysis, the more regulated subcategories were the intracellular ferritin complex, poly(A) RNA binding, (acetyl-CoA carboxylase) kinase activity, (hydroxymethylglutaryl-CoA reductase (NADPH)) kinase activity, and ubiquitinyl hydrolase activity for ECC-1-CSC vs. ECC-1; the proteasome, cytosol, extracellular vesicular exosome, poly(A) RNA binding, glutamate dehydrogenase (NAD+) activity, and glutamate dehydrogenase (NADP+) activity for RL95-2-CSC vs. RL95-2; and poly(A)RNA binding, (acetyl-CoA carboxylase) kinase activity, NADPH kinase activity, and ubiquitinyl hydrolase activity for both.

Conclusions: CSC population-speciﬁc proteins were identiﬁed, as well as their cellular localization and functional enrichment. This information allows for the future development of endometrial CSC targeted therapies.

Funding: Centre for Innovative Biomedicine and Biotechnology (CIBB) (UIDB/04539/2020, UIDP/04539/2020) is supported by The Fundação para a Ciência e a Tecnologia(FCT), co-funded by COMPETE. Beatriz Serambeque was awarded a PhD Scholarship from FCT and European Social Fund (2020.07672. BD ).

https://doi.org/10.1016/j.annonc.2023.09.1545

44P PAUF as a target for treatment of high PAUF-expressing ovarian cancer

J. Cho1, Y.J. Kim1, F. Jiang1, J. Park2, H.H. Jeong3, J.E. Baek3, S-M. Hong4, S-Y. Jeong5,S.S. Koh3

1R&D, Prestige Biopharma IDC, Busan, Republic of Korea; 2Asan Institute for Life Sciences, Asan Medical Center - University of Ulsan, Seoul, Republic of Korea;3Biomedical Sciences, Dong-A University, Busan, Republic of Korea; 4Department of Pathology, Asan Medical Center - University of Ulsan, Seoul, Republic of Korea;5Convergence Medicine, Asan Medical Center - Asan Institute for Life Science, Seoul,Republic of Korea

Background: Pancreatic adenocarcinoma up-regulated factor (PAUF) plays an important role in tumor growth, metastasis, and immune evasion in the pancreatic tumor microenvironment, and recent studies suggest an association between PAUF expression and poor prognosis in ovarian cancer patients. However, the role of PAUF in ovarian cancer development has not been clearly understood at the molecular level, and whether PAUF can be used as a therapeutic target of ovarian cancer awaits more scientiﬁc evidence.

Methods: The current study characterized the functions of PAUF in ovarian cancer using cell-based assays and mouse xenograft experiments, and further evaluated whether an anti-PAUF antibody can become a potential ovarian cancer treatment in human ovarian cancer models.

Results: :Recombinant PAUF signiﬁcantly increased tumor metastatic capacity(migration, invasion, and adhesion) in all the ovarian cancer cell lines tested, except for the OVCAR-5 cell line which expresses PAUF at a much higher level than the other cells. PAUF-knockout in the OVCAR-5 cell line led to apparently delayed tumor growth in vitro and in vivo. Furthermore, the administration of an anti-PAUF antibody exhibited notable sensitizing and synchronizing effects on docetaxel in mice bearing the OVCAR-5 xenograft tumors, the docetaxel + anti-PAUF antibody combination group showed the most potent anti-tumor efﬁcacy demonstrated as a nearly 5-fold improved survival in this group (HR: 0.22, 95% CI: 0.09 to 0.54), compared to the control group (Table).

|Table: 44P Survival data in OVCAR-5 xenograft human ovarian cancer mous model. Treatments (started from day 0): Human IgG (control), Anti-PAU antibody (10 mg/kg, twice/week, 34 weeks), Docetaxel (10 mg/kg, once, o day 0), or Anti-PAUF antibody + Docetaxel (via the same regimens of the tw |Table: 44P Survival data in OVCAR-5 xenograft human ovarian cancer mous model. Treatments (started from day 0): Human IgG (control), Anti-PAU antibody (10 mg/kg, twice/week, 34 weeks), Docetaxel (10 mg/kg, once, o day 0), or Anti-PAUF antibody + Docetaxel (via the same regimens of the tw |Table: 44P Survival data in OVCAR-5 xenograft human ovarian cancer mous model. Treatments (started from day 0): Human IgG (control), Anti-PAU antibody (10 mg/kg, twice/week, 34 weeks), Docetaxel (10 mg/kg, once, o day 0), or Anti-PAUF antibody + Docetaxel (via the same regimens of the tw |Table: 44P Survival data in OVCAR-5 xenograft human ovarian cancer mous model. Treatments (started from day 0): Human IgG (control), Anti-PAU antibody (10 mg/kg, twice/week, 34 weeks), Docetaxel (10 mg/kg, once, o day 0), or Anti-PAUF antibody + Docetaxel (via the same regimens of the tw | |---|---|---|---|

|0 |15 |15 15 |15 |

|20 |15 |15 15 |15 |

|23 |13 |15 15 |15 |

|26 |10 |15 15 |15 |

|31 |3 |11 13 |15 |

|34 |2 |5 10 |14 |

|37 |0 |4 7 |9 |

|40 |0 |2 2 |6 |

|HR (95% CI) |1 |0.42 (0.19-0.93) 0.32 (0.14-0.74) 0.22 (0.09-0.54)|0.42 (0.19-0.93) 0.32 (0.14-0.74) 0.22 (0.09-0.54)|

e F n o drugs)

Volume 34 - Iss

0.42 (0.19-0.93) 0.32 (0.14-0.74) 0.22 (0.09-0.54)

Conclusions: Taken together, this study shows that the expression level of PAUF is an independent factor determining malignant behaviors of ovarian cancer and, for theﬁrst time, it suggests that PAUF may be a promising therapeutic target for high PAUFexpressing ovarian cancer. The anti-PAUF antibody used in this study, PBP1510, has gained orphan drug designation from the EMA, FDA, and MFDS (Korea), and entered phase I clinical trials.

Funding: This study was supported by the Korean Health Technology R&D Project(HA15C0002) through the Korea Health Industry Development Institute (KHIDI), a government-afﬁliated institution operating under the Ministry for Health and Welfare, ,Republic of Korea.

https://doi.org/10.1016/j.annonc.2023.09.1546

ue S2 - 2023

45P

Therapeutic potential of ISM8207: A novel QPCTL inhibitor,in triple-negative breast cancer and B-cell non-Hodgkin lymphoma

S. Rao1, Y. Fu2, M. Zhang2, L. Qin2, S. Bavadekar1, H. Cui2, C. Xu2, S. Chen2, C. Yang3,X. Xiang4, L. Liu4, L. Diao5, S. Yan3, X. Wang3, F. Ren2

1Clinical Development, Insilico Medicine, New York, NY, USA; 2Research & Development, Insilico Medicine, Shanghai, China; 3Research & Development, Shanghai Fosun Pharmaceutical Development Co.,Ltd, Shanghai, China; 4Biometrics and Data Science,Beijing Fosun Pharmaceutical Technology Development Co., Ltd., Beijing, China;5Research & Development, Beijing Fosun Pharmaceutical Technology Development Co., Ltd., Beijing, China

Background: Glutaminyl-peptide cyclotransferase-like protein (QPCTL), mediates the trafﬁcking of monocytes as well as the CD47/SIRPa interaction which blocks macrophage phagocytosis. Genetic deletion of QPCTL in tumor or host immune cells promotes anti-tumor activity. We evaluated ISM8207, a novel QPCTL inhibitor, in preclinical triple-negative breast cancer (TNBC) and B-cell Non-Hodgkin Lymphoma(B-NHL) models.

Methods: Gene expression datasets, METABRIC (TNBC), and GSE4475 and GSE10846(diffuse large B cell lymphoma [DLBCL]), were analyzed for association between QPCTL expression and overall survival (OS). In vitro SIRPa binding to the human cell lines (MDA-MB-231, TNBC; and Raji, B-NHL) was evaluated after pre-treatment with ISM8207. In vivo antitumor efﬁcacy was assessed in the murine 4T1 TNBC model and in human B-NHL OCI-Ly10 or Raji xenografts in CB17 SCID mice treated with ISM8207.

Results: Patient tumor dataset analyses revealed QPCTL was overexpressed in TNBC and DLBCL, and that a higher expression correlated with a shorter OS. ISM8207 treatment (IC50 < 0.5 nM in enzymatic assay) phenocopied the genetic deletion of QPCTL and reduced the binding of SIRPa to CD47 in TNBC cells, without affecting cell viability. In the murine 4T1 TNBC model, ISM8207 (30 mg/kg BID) demonstrated modest but signiﬁcant anti-tumor activity. Circulating monocytes and the binding afﬁnity of SIRPa to peripheral white blood cells were reduced. ISM8207 combined with an anti-PD-1 antibody potently and synergistically inhibited tumor growth, with Tumor Growth Inhibition (TGI) of w50%. The bulk RNA-seq proﬁling for combined ISM8207 and anti-PD-1-treated tumors showed a higher inﬁltrating potential of CD8+T-cells in the tumor microenvironment vs anti-PD-1 alone. ISM8207 (10 mg/kg BID)combined with rituximab resulted in synergistic effects in the B-NHL xenografts. In the Raji model, TGI with the combination was 86% vs 41% with rituximab alone. In the OCI-Ly10 model, 7/8 mice achieved complete remission with the combination vs 1/8 with rituximab alone. ISM8207 was well-tolerated with favorable ADME and PK properties.

Conclusions: These data strongly support the clinical evaluation of ISM8207 as a novel cancer immunotherapy in TNBC and B-NHL.

Funding: Shanghai Fosun Pharmaceutical Development Co. LTD and Insilico Medicine.

Disclosure: S. Rao, Y. Fu, M. Zhang, L. Qin, S. Bavadekar, H. Cui, C. Xu, S. Chen, F. Ren: Financial Interests, Personal, Full or part-time Employment: Insilico Medicine. C. Yang, S. Yan, X. Wang:Financial Interests, Personal, Full or part-time Employment: Shanghai Fosun. X. Xiang, L. Liu, L. Diao:Financial Interests, Personal, Full or part-time Employment: Beijing Fosun.

https://doi.org/10.1016/j.annonc.2023.09.1547

46P Effect of coadministration of antioxidant chlorophyllin with docetaxel on invasion and metastasis in triple-negative breast cancer in vivo/in vitro

A. Burus1, M. Ozcan2, H. Canpinar3, O. Bozdemir4, N.D. Zeybek5, Y. Bayazit6

1Medical Biochemistry Department, Hacettepe University Faculty of Medicine, Ankara,Turkey; 2Medical Biochemistry, Zonguldak Bulent Ecevit University, Zonguldak, Turkey;3Basic Oncology, Hacettepe University, Ankara, Turkey; 4Stem Cell Sciences, Hacettepe University, Ankara, Turkey; 5Histology and Embryology, Hacettepe University - Faculty of Medicine, Ankara, Turkey; 6Medical Biochemistry, Hacettepe University - Faculty of Medicine, Ankara, Turkey

Background: The drug resistance against chemotherapy and high metastasis rate in triple-negative breast cancer reduce the success of breast cancer treatment. Glutathione S-transferase P1 enzyme (GSTP1) expression increases in cancer cell lines and leads to the development of drug resistance against chemotherapy. The antioxidant chlorophyllin is shown to have an inhibitory effect on GSTP1. The purpose of this study is to investigate the effects of GSTP1 inhibitor chlorophyllin and/or its coadministration with anticancer drug docetaxel on metastatic processes in vitro/in vivo in the 4T1 triple-negative breast cancer cell line and animal model.

Methods: Cell viability, cell cycle, and cell migration were investigated by MTT test,ﬂow cytometry, and wound closure assay, respectively. Matrix metalloproteinase 9(MMP-9) expression, causing invasion, was determined by Western Blot in the 4T1 cell line and tissue samples. Further, total gelatinase enzyme activity was also detected by gelatin degradation assay. Total GST enzyme activity and glutathione levels of tissue were investigated by colorimetric methods. Micrometastatic foci in liver tissue sections were evaluated by histochemistry.

Results: As a result, coadministration of chlorophyllin and docetaxel signiﬁcantly inhibited cell migration in vitro. Chlorophyllin signiﬁcantly reduced the expression of MMP-9 in the tissue samples, and this effect was higher when it is coadministered with docetaxel. In coadministration, a signiﬁcant decrease was observed in the total gelatinase activity in vivo. It was also determined that chlorophyllin increased in vivo total glutathione levels and decreased GST enzyme activity. Finally, the micrometastases in the liver were reduced by coadministration.

Conclusions: Our results suggest that the coadministration of chlorophyllin and docetaxel may have a potential role in the control of metastatic processes by suppressing cell migration and invasion which is mainly characterized by gelatinase enzyme expression & activity.

Funding: Hacettepe University Scientiﬁc Research Projects Coordination Unit.

https://doi.org/10.1016/j.annonc.2023.09.1548

47P An ozone delivery system by cisplatin prodrug selfassembling micelles combining microwave to sensitizing immune checkpoint inhibitor in triple-negative breast cancer

D. Zheng1, T. Luo2, H. Shi3

1Breast Disease Center, West China Medical Center of Sichuan University, Chengdu,China; 2Head and Neck Oncology Department, West China School of Medicine/West China Hospital of Sichuan University, Chengdu, China; 3Laboratory of Integrative Medicine, Clinical Research Center for Breast, West China School of Medicine/West China Hospital of Sichuan University, Chengdu, China

Background: Immunotherapy based on T cells has gained great success and is now in its infancy. Despite a high mutation load, triple-negative breast cancer (TNBC) remains a poor response to the immune checkpoint blockades (ICBs) due to an infertile tumor microenvironment (TME). Chemotherapy shows an outstanding synergizing effect with ICB in TNBC due to its cell lysis effect. However, limited bioavailability, signiﬁcant systematic toxicity, and immunosuppressive metastatic niche induced by chemotherapy restrict its systematic application.

Methods: We constructed self-assembled micelles consisting of ﬂuorocarbon chainmodiﬁed cisplatin prodrugs, which loaded ozone-saturated perﬂuorodecalin (PFD)emulsion as a cargo. Cisplatin is controllably released from the prodrug by ROS triggered by the microwave excitation of ozone. The appearance of the ozone carried prodrug was visualized by Transmission electron microscope and the hydrodynamic sizes and stability were measured with nanoparticle tracking analysis. Cell function experiments were performed to assess the biological effect of the ozone-delivery prodrug in vitro. The biodistribution and biological effect of the ozone-loaded prodrug were also veriﬁed in 4T1 tumor-bearing mice model.

Results: The hydrodynamic sizes were about 130.5 nm of PtF and 174.7 nm of PFD@PtF, and both of the two showed good stability in weak acidic (pH ¼ 6.0),neutral (pH ¼ 7.0), and weak alkaline (pH ¼ 8.0) environment at 4C, room tem-perature, and 37C. Ozone was well stabilized by the PFD@PtF as the ROS donor which in turn boosts the intracellular GSH concentration, and decomposed rapidly upon the excitation of microwave. Once endocytosed by TNBC cells, Pt(IV) can be reduced and released from the prodrug upon the triggering of reducing substance(e.g. GSH). The released cisplatin crosses cell membranes to form cross-links with DNA, resulting in cell cycle arrest, apoptosis, and immunogenic cell death. A signiﬁcant inhibiting effect of tumor proliferation and TME reediting effect were observed in mice model.

Conclusions: We successfully constructed an ozone-delivery cisplatin prodrug with enhanced anti-tumor activity and attenuated toxicity.

https://doi.org/10.1016/j.annonc.2023.09.1549

S201

48P

Non-steroid anti-inﬂammatory treatment enhances the

efﬁcacy of modulated electro hyperthermia on triplenegative breast cancer and melanoma cancer models in vivo

N. Giunashvili

Institute of Basic and Translational Medicine, Semmelweis University, Budapest,Hungary

Background: Modulated electro-hyperthermia (mEHT) is an advanced option in the hyperthermia ﬁeld, applying a 13.56 MHz radiofrequency electromagnetic current to induce tumor-speciﬁc damage. This study investigates the mEHT-induced molecular effect and the potential of combination non-steroid anti-inﬂammatory drugs (NSAIDs)to enhance its anti-tumor effects in 4T1 triple-negative breast cancer (TNBC) and B16F10 melanoma mouse models.

Methods: 4T1 TNBC and B16F10 melanoma cell lines were injected into Balb/C and C57BL/6 mice, respectively. They have been treated according to the protocol with only mEHT or mEHT combined with non-selective COX-inhibitors (Aspirin) or selective COX2 inhibitors (SC236). Tumor volume was monitored by ultrasound and a digital caliper. At the end of the experiments, mice were euthanized and tumors excised for molecular studies.

Results: Here we report that mEHT monotherapy stimulates local IL1-beta and IL6,and consequently cyclooxygenase 2 (COX 2) production. These effects could be considered as part of a self-defensive, wound-healing reaction of the tumor to protect itself from the mEHT-induced stress. In the present study, we combined mEHT with non-steroid anti-inﬂmmatory drugs (NSAIDs), the non-selective (Aspirin), or the selective COX2 inhibitor (SC236) in vivo. Here we demonstrate that NSAID treatment synergistically increased the effect of mEHT in 4T1 TNBC. Tumor weight and tumor volume (measured by ultrasound and a digital caliper) were lowest, and the tumor destruction ratio (TDR) was the highest in the combination treated (NSAID + mEHT)groups. Tumor damage was accompanied by a signiﬁcant increase in cleaved caspase3 (cC3), suggesting an important role for apoptosis. Similarly, in the B16F10 melanoma model, lung nodules were signiﬁcantly less in mice treated with mEHT + Aspirin.

Conclusions: NSAIDs effectively enhance the mEHT anti-tumor effect in TNBC and melanoma cancer models; they increase tumor destruction, where apoptosis may play a role. Disecting the exact molecular mechanisms further is under our current investigation.

Background: Triple-negative breast cancer (TNBC) is characterized by aggressive clinicopathological features and is associated with a poor prognosis. Identifying patients who respond to chemotherapy and yet relapse early remains the subject of many studies and a critical goal for effective personalized therapies. In the present study, we investigated the role of miRNAs in TNBC that responded to neoadjuvant chemotherapy (NAC). Circulating miRNAs were isolated from TNBC patients who underwent NAC and who had a pathologic complete response (pCR).

Methods: The miRNA expression analysis was conducted by nCounter Human v3 miRNA assay (NanoString Technologies, Seattle, USA) on plasma samples. Sample collected from patients participating in a phase II prospective clinical trial. About 800 human miRNAs were screened, and the resulting data were normalized using the normalization method based on the low coefﬁcient of variation (low CV). Further analysis was carried out using parameters such as fold change and area under the curve (AUC).

Results: A total of 33 differentially expressed miRNAs were identiﬁed between relapsed and non-relapsed patients who achieved pCR. Of the 33 miRNAs, only one was downregulated. Of these, we identiﬁed 7 miRNAs (hsa-miR-654-5p, hsa-miR-433-5p, hsa-miR-520c-3p, hsa-miR-376a-2-5p, has-miR-4741, has-miR- 513c-3p, hsa-miR506-5p) which showed better accuracy to discriminate patients with pCR with a higher probability of relapse, with the area under the curve value ranging from 0.80 to 0.93. In network analysis, "TGF-beta signaling pathway", "cancer transcriptional dysregulation" and "JAK-STAT signaling pathway" were identiﬁed as the crucial pathways in breast cancer patients who also developed recurrence.

Conclusions: In conclusion, our study hypothesizes that circulating miRNAs may be useful non-invasive biomarkers to identify patients who are more likely to develop recurrence even after achieving pCR in TNBC patients.

Clinical trial identiﬁcation: NACATRINE trial (NCT02978495).

Funding: Department of Science and TechnologyeDECIT, Ministry of Health (grant no.879848/2018).

https://doi.org/10.1016/j.annonc.2023.09.1551

50P Application and mechanism of tarloxotinib in HER2-positive breast cancer

X. Shao1, D. Yang2, H. Zhou3, Q. Yu3, Y. Ding4, J. Tang3

1The First Clinical College, Nanjing University of Traditional Chinese Medicine, Nanjing,China; 2Department of Pharmacy, The Second Hospital of Nanjing, Nanjing, China;3General Surgery, The First Afﬁliated Hospital of Nanjing Medical University, Nanjing,China; 4Department of General Surgery, Jurong Branch Hospital of Jiangsu Province Hospital, Zhenjiang, China

Background: HER2 (Human epidermal growth factor receptor-2)-positive breast cancer occupies about 15%e20% of all breast cancer, the current treatment of which is still based on surgery and adjuvant targeted therapy with monoclonal antibody.

Problems of drug resistance and cardiotoxicity hinder the use of monoclonal antibodies. And, TKIs (Tyrosine Kinase Inhibitors) have the advantages of multi-target,reduced drug resistance and lower cardiotoxicity. Tarloxotinib is a prodrug that harnesses tumor hypoxia to generate high levels of a potent, covalent pan-HER TKI,Tarloxotinib-effector (Tarloxotinib-E), within tumor microenvironment. This tumorselective delivery mechanism was designed to minimize the dose-limiting toxicities.

Funding: Semmelweis University.

https://doi.org/10.1016/j.annonc.2023.09.1550

49P Circulating miRNA signatures to predict recurrence in patients with pathological complete response of triplenegative breast cancer

A.J.A. de Freitas1, C.R. Nunes2, R.L. Causin2, S. Calfa1, M.A. de Oliveira3,C. de Pádua Souza4, M.M.C. Marques1

1Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil;2Centro de Oncologia Molecular, Barretos Cancer Hospital, Barretos, Brazil; 3Nucleus of Epidemiology and Biostatistics, Barretos Cancer Hospital, São Paulo, Brazil;4Oncology Department, Hospital de Amor (Hospital De Cancer De Barretos) - Fundacao Pio XII, Barretos, São Paulo, Brazil

Methods: We used single-cell transcriptome analysis to characterize the transcriptional proﬁle of stimulated CAR-T. T cells engineered with second-generation CAR constructs (with 4-1BB or CD28 co-stimulation domains) were stimulated with antiCD3/CD28-coated beads and Nalm6 and subjected to microwell-based single-cell transcriptome analysis.

Methods: In this work, we developed a biological sonosensitive platelet (PLT) pharmacytes for favoring US/GSH-responsive combinational therapeutic of glutamine deprivation and augmented SDT. The amino acid transporter SLC6A14 blockade agent a-methyl-DL-tryptophan (a-MT)-loaded and MnO2-coated por- phyrinic metal-organic framework (MOF) nanoparticles were encapsulated in the PLTs through the physical adsorption of electrostatic attraction and the intrinsic endocytosis of PLTs.

Results:When the sonosensitive PLT phar- macytes reached tumor sites through their natural tendencies to TME, US stimulated the PLTs-loaded porphyrinic MOF to generate ROS, resulting in morphological changes of the PLTs and the release of nanoparticles. Subse- quently, intracellular high concentration of GSH and extracellular spatio-temporal controlled US irradiation programmatically triggered the release of a-MT, which enabled the synergistically ampliﬁed SDT by inducing amino acid starvation, inhibiting mTOR, and mediating ferroptosis. In addition, US stimulation achieved the targeted activation of PLTs at tumor vascular site, which evolved from circulating PLTs to dendritic PLTs, effectively blocking the blood supply of tumors through thrombus formation, and revealing the encouraging potential to facilitate tumor therapeutics.

Conclusions: It offers a bioinspired design strategy to improve SDT efﬁciency, and rends an innovative paradigm for cooperatively ablating refractory tumor.

Legal entity responsible for the study: University of Macau.

Funding: University of Macau.

https://doi.org/10.1016/j.annonc.2023.09.1553

53P Treatment of cancer cells based on circulating tumor cell’s expression proﬁle using off-label drugs

P. Apostolou1, G. Beis1, A. Iliopoulos1, I. Papasotiriou2

1R&D, Research Genetic Cancer Centre S.A., Florina, Greece; 2Oncology Department,Research Genetic Cancer Centre International GmbH, Zug, Switzerland

Background: Circulating tumor cells (CTCs) constitute a cell subpopulation with great prognostic value in oncology. They detach from the primary tumor, and through the blood stream can initiate metastatic spread to other organs. Their gene and protein expression proﬁle, provides useful information about their resistance to speciﬁc therapeutic agents, including chemotherapeutic drugs, targeted therapies (monoclonal antibodies (MoAbs) or small molecular weight molecules (SMW)), or their sensitivity to other treatment options, such as hyperthermia or radiation. The present study aimed to identify whether the expression proﬁle could contribute to success treatment using off-label drugs.

Methods: Blood samples were collected from more than 500 patients, suffering from different types of cancer. CTCs detected and isolated with Fluorescence Activated Cell Sorting (FACS), evaluated with speciﬁc biomarkers for each cancer type, and then used for gene and protein expression assays, with qPCR and Flow Cytometry respectively. In parallel, literature research was performed for these proteins, and the approved drugs against them. Based on the expression proﬁle, off-label drugs for the speciﬁc targets used and viability/chemosensitivity assays followed on patients’ isolated CTCs.

Results: Expression proﬁle of CTCs revealed overexpression in a wide variety of biomarkers, for whom there are already approved drugs, but only in speciﬁc types of cancer. The highest percentages observed for ALOX5, DHFR, DPYD, KIT, PDGFA, RET and others. The use of approved drugs against these targets, such us Zileuton,Pemetrexed, Capecitabine, Dasatinib, Imatinib and Cabozantinib respectively, led to decrease in CTCs’ viability independent the type of cancer up in approximately 25% of the cases. Among them, there were included also refractory cases (5%).

Conclusions: In this study, we demonstrated that CTCs’ expression proﬁle, could be an indicator of treatment response, using off-label drugs. It is noteworthy that efﬁcient data observed also in refractory cases, representing different types of cancer. Drug repositioning might be beneﬁcial for cancer patients, and it should be taken into consideration, mainly in cases where no other options are available.

Legal entity responsible for the study: I. Papasotiriou.

https://doi.org/10.1016/j.annonc.2023.09.1554

54P Enhanced oxidative phosphorylation of metastasis-initiating cells facilitates esophageal tumor cell seeding in lymph nodes

S. Li1, B. Zhang1, C. Huang2, X. Guan1

1Clinical Oncology Center, The University of Hong Kong - Shenzhen Hospital, Shenzhen,China; 2Clinical Oncology Center, Li Ka Shing Faculty of Medicine, The University of Hong Kong (HKUMed), Hong Kong, China

Background: Lymph nodes (LN) are the most frequent metastasis sites in oesophageal squamous cell carcinoma (ESCC), but the associated mechanisms are poorly understood. Tumor cells seed and survive at LN during the early adaptation step, which is the bottleneck for successful metastasis. However, the phenotypic and molecular characteristics of heterogeneous metastatic cells that contribute to such a challenging process remain elusive.

Methods: We established a human xenograft spontaneous LN metastasis model to capture tumor cell dissemination behaviors. We conducted single-cell RNA sequencing on tumor cells collected from primary tumors and metastatic LN to proﬁle the dynamic cellular and molecular changes in tumor cells associated with LN metastasis. We further identiﬁed and characterized the early metastasis tumor cells in LN through in vitro and in vivo functional assays.

Results: We revealed that LN metastasis is initiated by rare ESCC subpopulations with stemness and mesenchymal regulatory gene expression signatures. These tumor cell subpopulations are critical to driving metastasis in distant organs through the blood circulation in mice, supporting the metastasis-initiating cells (MICs) properties.

Importantly, these key driver cells were observed to convert the metabolic strategy to mitochondrial oxidative phosphorylation (OXPHOS) during cell seeding in the LN.

Enhanced OXPHOS in LN metastatic cells is induced by fatty acids and regulated by NRF2 signaling. Pharmacological inhibition of OXPHOS with IACS-010759 markedly attenuated metastasis in mice.

Conclusions: Our results demonstrate the important role of mitochondrial OXPHOS in promoting ESCC metastasis and suggest the clinical therapeutic potential of OXPHOS inhibitors for preventing metastatic spread in ESCC patients.

Funding: National Natural Science Foundation of China (82103643, 82072738,82072731).

https://doi.org/10.1016/j.annonc.2023.09.1555

55P Transcriptional proﬁles of engineered T cells stimulated with different receptor structures and co-stimulatory domains

U. Shin1, S-H. Kim2, C. Han1

1Immuno-Oncology Branch, NCC - National Cancer Center, Goyang, Republic of Korea;2Biomedical Laboratory Science, Catholic Kwandong University, Gangneung, Republic of Korea

Background: T cells engineered with chimeric antigen receptor (CAR-T) have shown success in treating hematological malignancies. However, the limited efﬁcacy and potential side effects hinder the use of CAR-T in solid tumors. Research on this heterogeneous cell therapeutics at single-cell level can advance the current understanding and strategy of CAR-T therapy.

Results: A broad spectrum of transcripts was differentially expressed in T cells under various conditions. The sequence derived from the 3’-untranslated region of the CAR transcript distinguished CAR-T from non-transduced T cells within the analyzed cell population. CAR-T stimulation, mediated by either CD3/CD28 or CAR, signiﬁcantly changed the gene-expression landscape compared to unstimulated CAR-Ts. Notably,CAR stimulation triggered higher expression of immune-related genes compared to CD3/CD28 stimulation. Additionally, comparing 4-1BB and CD28 co-stimulatory domains showed distinct transcriptional proﬁles contingent upon each co-stimulation signal.

Conclusions: This study revealed characteristic features of CAR-T signals affected by receptor structure (CD3/CD28 vs. CAR) and co-stimulation domain (4-1BB vs. CD28).

S203

These ﬁndings provide insights into a deeper understanding of CAR-T therapy, ultimately leading to the development of more effective CAR-T therapy.

Funding: National Research Foundation of Korea.

https://doi.org/10.1016/j.annonc.2023.09.1556

56P

SLC34A2-ROS1 L2026M+G2032R confers resistance to ROS1 tyrosine kinase inhibitors in Ba/F3 cells through a reduced ATP binding pocket volume

C. Dijkhuizen1, P. Korthuis1, J. Vilacha2, M. Smelt1, A.J. Van Der Wekken3,A. van den Berg4, L. Drayer1

1Institute for Life Science and Technology, Hanze University of Applied Sciences,Groningen, Netherlands; 2Faculty of Science and Engineering, Molecular Dynamics d Groningen Biomolecular Sciences and Biotechnology, University of Groningen, Groningen, Netherlands; 3Pulmonary Oncology, University of Groningen - UMCG - University Medical Center Groningen, Groningen, Netherlands; 4Faculty of Medical Sciences, University of Groningen - UMCG - University Medical Center Groningen,Groningen, Netherlands

Background: The ROS1 G2032R mutation is the most common on-target resistance mutation in crizotinib treated ROS1-positive lung cancer patients. The aim of our study was to investigate resistance mechanisms in SCL34A2-ROS1G2032Rpositive Ba/F3 cells against second line treatment with lorlatinib.

Methods: Ba/F3 SLC34A2-ROS1G2032Rcells were subjected to N-ethyl-N-nitrosourea(ENU) mutagenesis and clones were selected upon treatment with 1000 nM lorlatinib for 4 weeks. Resistant clones were analyzed for presence of on-target resistant mutations using Sanger sequencing. In addition, we generated subclones expressing SLC34A2-ROS1L2026M+G2032Rand SLC34A2-ROS1L2026Min Ba/F3 cells. Sensitivity to ROS1 TKIs was determined by measuring cell viability and ROS1 phosphorylation.

Molecular Dynamic simulations of the ATP binding pocket were performed for all ROS1 variants.

Results: The ENU-screen of 41 lorlatinib resistant clones revealed one with a mutation in the kinase domain: L2026M. Cell viability assays of the ENU-induced resistant cell line and the Ba/F3 cells transfected with the mutant SCL34A2-ROS1 fusion gene constructs revealed a decreased sensitivity of SLC34A2-ROS1L2026M+G2032Rcells for lorlatinib, crizotinib, entrectinib and repotrectinib compared to the single mutants.

Consistent with these ﬁndings, we observed phosphorylation of ROS1 fusion protein in the double mutant cells which was not inhibited upon treatment with ROS1 TKIs.

The single mutant cells showed as expected a clear reduction in phosphorylated ROS1 fusion protein . Molecular modeling to unravel the effect of the mutations demonstrated that the volume of the ATP-binding pocket was reduced in single and double mutants compared to wild type. The double L2026M+G2032R mutant displayed the smallest pocket.

Conclusions: :We identiﬁed a novel on-target mutation after inducing lorlatinib resistance in SLC34A2-ROS1G2032RBa/F3 cells. This SLC34A2-ROS1L2026M+G2032Rcell line was also resistant to crizotinib, entrectinib and repotrectinib. The resistance can be explained by a smaller ATP binding pocket in the mutated ROS1 fusion protein preventing effective binding of the investigated TKIs.

Funding: The Netherlands Organization for Scientiﬁc Research (NWO) Doctoral Grant for Teachers to C. Dijkhuizen Applied Research SIA (regieorgaan SIA) HBO-Postdoc Grant to M. Smelt.

Disclosure: A.J. Van Der Wekken: Financial Interests, Institutional, Funding: AstraZeneca, Boehringer Ingelheim, Pﬁzer, Roche, Takeda; Non-Financial Interests, Institutional, Advisory Board:AstraZeneca, Lilly, Roche, Takeda; Non-Financial Interests, Institutional, Speaker, Consultant, Advisor:AstraZeneca, BMS, Lilly, Pﬁzer, Roche; Financial Interests, Institutional, Other, involved in Clinical Studies: AstraZeneca, Amgen, Blueprint Medicin, Nuvalent, Novartis, Merck, Pﬁzer, Roche, Takeda.

https://doi.org/10.1016/j.annonc.2023.09.1557

57P Metastasis organotropism: Unveiling associated proteins using network biology

M. Carrolo1, J.A.I. Miranda2, A.F.R. Coelho2, A. Quintela1, F.R. Pinto2

1Medical Oncology Department, Hospital CUF Descobertas, Lisbon, Portugal; 2RNA Systems Biology, BioISI - Biosystems and Integrative Sciences Institute, Lisbon,Portugal

Background: The formation of distant metastases is the deadliest phase of cancer progression. Nevertheless, it is a very inefﬁcient process. Chances of a tumor cell surviving the metastatic process depend on its ability to communicate with the surrounding environment. We hypothesize that metastasis organotropism can be

partially explained by the intercellular communication established between cancer cells and other cells in the organ microenvironment.

Methods: Network biology tools are well suited for studying complex diseases such as cancer. Using this computational approach we looked at the complex interplay between proteins and pathways affected in metastasis and identiﬁed new metastasisassociated proteins. We built networks of tissue-speciﬁc intercellular protein-protein interactions between pairs of primary tumor location and metastasis tissues. Using these networks we identiﬁed interactions signiﬁcantly more frequent in organotropism tissue pairs (primary tumor and metastasis organ) that potentially inﬂuence the success of metastasis in speciﬁc organs.

Results: Overall, we identiﬁed 607 proteins involved in 1095 metastasis-associated interactions. Of these, 881 interactions were positively associated with metastasis,meaning that these interactions occur more frequently in organotropism tissue-pairs than in other tissue pairs. Of the 607 proteins found, 222 are already targeted by known drugs and 53 are targeted by drugs that are not used in cancer treatment.

Conclusions: Cell-cell communication is of paramount importance for the development of metastasis. Experimental studies of the non-oncological drugs targeting the 53 identiﬁed proteins are needed to select the most promising candidates to test in drug repurposing clinical trials.

https://doi.org/10.1016/j.annonc.2023.09.1558

59P Correlation of tumor microenvironment signature in advanced stage non-small cell lung cancer with EGFR mutation who received EGFR-TKIs

C. Ngamchokwathana1, S. Santisukwongchote2, N. Zungsontiporn1,P. Sitthideatphaiboon1, P. Chantranuwat2, C. Vinayanuwattikun1

1Division of Medical Oncology, Department of Medicine, King Chulalongkorn Memorial Hospital - Thai Red Cross Society, Bangkok, Thailand; 2Pathology, King Chulalongkorn Memorial Hospital - Thai Red Cross Society, Bangkok, Thailand

Background: The impact of tumor microenvironment in advanced non-small cell lung cancer (NSCLC) who had epidermal growth factor receptor (EGFR) mutation remained debated. We investigated the correlation of tumor microenvironment (PD-L1, CD8 and FOXP3) and the association of EGFR TKI treatment outcome.

Methods: A prospective study was conducted to recruit 100 participants who were diagnosed advanced NSCLC with EGFR mutation. All patients were received treatment with EGFR-tyrosine kinase inhibitors (TKIs). Tumor microenvironment composed of programmed cell death ligand-1 (PD-L1) expression, CD8+ tumor inﬁltrating lymphocyte (TILs) and forkhead box P3 (FOXP3+) TILs density were evaluated by immunohistochemistry. The primary endpoint was the correlation between PD-L1,CD8+, and FOXP3+ TILs density. The Correlations among TILs and clinicopathological characteristics/outcome of treatment were analyzed.

Results: Eighty-ﬁve patients with adequate tumor material were evaluated. Twelve(14%) patients expressed high PD-L1 (15%) or intratumoral CD8+ TILs (>10%). (14%) patients expressed high PD-L1 (≥15%) or intratumoral CD8+ TILs (>10%).TheThecorrelation of PD-L1 and intratumoral CD8+ TILs was signiﬁcantly (r ¼ 0.3034,p¼0.005). Multivariate analysis revealed that Inﬂamed tumor was correlated withshorten PFS with the HR of 2.110, 95%CI: 0.968-4.599, p-value 0.06.

Conclusions: Among advanced stage NSCLC with EGFR mutation, tumor microenvironment PD-L1 and intratumoral CD8+ TILs expression was correlated with outcome of treatment.

Funding: Health Systems Research Institute of Thailand.

https://doi.org/10.1016/j.annonc.2023.09.1559

60P Establishment and characterization of a novel lung adenocarcinoma cell line HX-JCJ harboring MET ex14 skipping mutation

X. Ou1, M. Feng2, Y. Wang3

1Cancer Center, SCU - Sichuan University - Huaxi Campus, Chengdu, China; 2Cancer Center, West China Hospital of Sichuan University, Chengdu, China; 3Cancer Center,West China School of Medicine/West China Hospital of Sichuan University, Chengdu,China

Background: MET exon14 skipping mutations are considered an important driver of oncogenesis and are observed in approximately 3-4% of patients diagnosed with nonsmall cell lung cancer (NSCLC). Various MET tyrosine kinase inhibitors (TKIs) are currently being developed for clinical use in the treatment of NSCLC patients with

MET exon14 skipping mutation. However, preclinical research in this area has been restricted due to the rarity of MET exon14 mutant cases. Almost all the studies conducted have been on patients or patent-derived xenografts (PDX). To address this issue, there is a need for a NSCLC cell line with MET exon14 skipping mutation. In this study, we have established a novel lung adenocarcinoma cell line that harbors MET exon14 skipping mutation. This new cell line represents a valuable tool for the research of MET targeted therapy.

Methods: The cell line was established using the primary tumor tissue from a 67-yearold male patient with NSCLC, and named as HX-JCJ. The cell line has been growing well for more than 10 months and has been passaged over 50 times. Phenotypes of the cell line, such as proliferation, invasion, protein expression, and xenografting were characterized in vitro and in vivo. MET ex14 skipping mutation of this cell line was validated by RT-PCR and Sanger sequencing.

Results: Drug screen showed that this cell line was extremely sensitive to KC1036(IC50¼4.8nm), which is a home-made small molecule inhibitor with strong anti-METand anti-angiogensis activity.

Conclusions: In conclusion, we successfully established a novel NSCLC cell line (HXJCJ) harboring MET ex14 skipping mutation from the primary tumor tissue, which may provide a promising cell model for further MET relevant research.

https://doi.org/10.1016/j.annonc.2023.09.1560

61P

Next generation sequencing and its clinical utility in advanced cancer: Single institute experience from lowmiddle income country

A. Badola1, P. Bansal1, P. Mehta2, M. Malhotra1, S.C. Cheemala1, S. Sood1, S. Anand1,V. Sekar1, P. Singh1, J. Verma1, A. Zaidi1

1Medical Oncology Department, Asian Institute of Medical Sciences, Faridabad, India;2Medical Oncology Department, Amrita Institute of Medical Sciences, Faridabad, India

Background: Advances in DNA sequencing over the past decade have made it possible to systematically study the genetic changes responsible for cancer development, and we now have a better understanding of the commonly involved processes and signaling pathways. As more genetic alterations become targetable by speciﬁc drugs,DNA sequencing is becoming part of routine clinical care but its clinical utility is not well known in low and middle income country.

Methods: This was a single center, retrospective cohort study, which include adult advanced metastatic solid tumor patient who underwent next generation sequencing(NGS) either on tissue block or liquid biopsy (Illumina NGS 560 genes 1000X coverage). Primary end point was to assess the clinical utility of NGS in advanced stage. Secondary end point was to assess the progression free survival (PFS) in patients who received treatment based on NGS.

Results: Over the period of 18 months (from 1stJanuary 2021 to 30th2022), a total of 93 patients were enrolled in the study, and their baseline characteristics are presented in the table. Patients received a median of 2 lines (range:0-4 ) of prior systemic therapy and genomic alteration were identiﬁed in 45% (n¼42) of them. Of the pa-tients with genomic alterations, 33% (n¼31) had a targeted therapy option availableeither in the form of an approved drug or a clinical trial. However, only 19% (n¼18) ofthe patients received treatment based on the results of NGS testing. Among these patients, 9%(n¼8) had a progression-free survival of 6 months or more followingNGS-guided treatment

|Table: 61P Baseline characteristics of study population(n[93) |Table: 61P Baseline characteristics of study population(n[93) | |---|---|

|Percentage (numbe of patients) |Percentage (numbe of patients) |

|Gender ||

|Male |60%(n[56) |

|Female |40%(n[37) |

|Type of Biopsy ||

|Tissue |71%(n[66) |

|Liquid |29%(n[27) |

|Genetic alteration present |45%(n[42) |

|Targetable approved treatment or |33% (n[31) |

|clinical trial available ||

|Patient received treatment as per Molecular alteration |19%(n[18) |

|PFS > 6 months in molecular alteration guided |9% (n[8) |

Conclusions: Advances in DNA sequencing over the past decade have made it possible to discover new genetic changes, and more genetic alterations are now targetable by speciﬁc drugs . However, in routine practice, the results are not very promising,especially in low- and middle-income countries where cost is a major constraint.

https://doi.org/10.1016/j.annonc.2023.09.1561

62P Prebiotics modulate gut microbiota-mediated T cell

immunity to enhance sintilimab inhibition of lung cancer

Q. Yan

Oncology, Chengdu Fifth People’s Hospital - West District, Chengdu, China

Background: Sintilimab (Sin) helps the body to restore the anti-tumor response of T lymphocytes. However, in clinical use, the treatment process is more complicated due to adverse effects and different dosing regimens. It is not clear whether prebiotics(PREB) have a potentiating effect on Sin for lung adenocarcinoma, and this study intends to investigate the inhibitory effect, safety and possible mechanism of Sin combined with PREB on lung adenocarcinoma from animal experiments.

Methods: HER2-positive breast cancer BT-474, SK-BR-3, HCC-1954 and JIMT-1 cells were treated with different concentrations of Tarloxotinib-E, Lapatinib and Tucatinib.

The IC50 values were determined by CCK-8 assay. Then, we used Western Blot to detect the changes in the phosphorylation of EGFR, HER2, HER3, HER4, AKT and ERK and the protein expression of Cleaved Caspase-3, Caspase-7 and Parp1. Flow cytometry was used to determine the apoptosis rates and mitochondrial membrane potentials, and the mitochondrial superoxide was detected by the Immunoﬂuorescence. Importantly, we used HPLC-TQ-MS to determine the ratio of Tarloxotinib-E released by Tarloxotinib. Finally, the subcutaneous xenograft mice were used to evaluate the antitumor effect and toxicity of Tarloxotinib in vivo.

Results: Tarloxotinib could be transformed into Tarloxotinib-E by breast cancer cells under hypoxia. Meanwhile, Tarloxotinib-E could effectively inhibit the level of HER family phosphorylation and downstream signaling in HER2-positive breast cancer cells, and superior to Lapatinib and Tucatinib. Mechanistically, Tarloxotinib-E induced apoptosis in HER2-positive breast cancer cells through a ROS-dependent manner, with signiﬁcant decrease in the potential of mitochondrial membrane and increase in mitochondrial superoxide. During the in vivo experiment, Tarloxotinib signiﬁcantly inhibited tumor growth in nude mice compared with Lapatinib.

Conclusions: Tarloxotinib released Tarloxotinib-E under hypoxic microenvironment of breast tumors, and inhibited the phosphorylation of HER2 dimers and downstream pathways to induce apoptosis in HER2-positive cells through a ROS-dependent manner. This lays a foundation for the further development of Tarloxotinib in HER2-positive breast cancer.

Funding: Nanjing Municipal Science and Technology Bureau Grant the Medical Engineering Cooperation Project No. 202110032.The Second Hospital of Nanjing Grant the Talent Support Program No. RCMS23004 and the High-level Talents Program No.

202302. Key Research Program of Gusu School No. GSKY20220105.The Postgraduate Research and Practice Innovation Program of Jiangsu Province No. KYCX22_1927.

https://doi.org/10.1016/j.annonc.2023.09.1552

51P

Nanoengineered sonosensitive platelets for synergistically augmented sonodynamic breast tumour therapy by

glutamine deprivation and cascading thrombosis

L. Zhou

Faculty of Health Sciences, University of Macau, Macau, China

Background: Ultrasound (US)-activated sonodynamic therapy (SDT) stands for a distinct antitumor modality because of its attractive characteristics including intriguing noninvasiveness, desirable safety, and high tissue penetration depth, which,unfortunately, suffers from compromised therapeutic efﬁcacy due to cancer cellinherent adaptive mechanisms, such as glutathione (GSH) neutralization response to reactive oxygen species (ROS), and glutamine addictive properties of tumors.

Methods: Lewis lung adenocarcinoma cells were inoculated into the right axilla of mice subcutaneously to prepare the Lewis lung cancer mouse model and treated in groups. The volume of transplanted tumors was measured, the histopathology of the liver and kidney of mice was observed by H&E staining, the levels of ALT, AST, UREA,CREA, WBC, RBC, and HGB in blood were analyzed biochemically; the ratio of T-cell subpopulations in blood, spleen, and bone marrow was detected by ﬂow cytometry,the expression of PD-L1 in tumor tissue was detected by immunoﬂuorescence staining, and 16S rRNA to analyze the diversity of fecal ﬂora.

Results: Sin inhibited tumor growth and regulated immune cell homeostasis in lung adenocarcinoma mice, but liver and kidney histopathology showed different degrees of damage after Sin treatment, while the addition of PREB reduced liver and kidney damage in lung adenocarcinoma mice and promoted Sin’s regulation of immune cells.

In addition, the beneﬁcial effects of Sin were associated with changes in intestinalﬂora diversity.

Conclusions: The mechanism by which Sintilimab combined with prebiotics inhibits tumor volume and regulates immune cell subpopulation balance in lung adenocarcinoma mice may be related to gut microbes.

Legal entity responsible for the study: Chengdu Fifth People’s Hospital.

https://doi.org/10.1016/j.annonc.2023.09.1562

63P Addition of human chorionic gonadotropin to the current standard mobilization approach with granulocyte-colony stimulating factor increases overall survival in a murine model of peripheral blood stem cell transplantation: Are we far enough for therapy?

A.C. Cismaru1, C. Tomuleasa2, S. Chira1, E. Isacescu1, G. Cismaru3, L-M. Gherman4,D.T. Gulei2, R. Muntean2, I. Berindan-Neagoe1

1Research Center for Functional Genomics, Biomedicine and Translational Medicine,UMF - University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania;2Medfuture - The Research Center for Advanced Medicine, UMF - University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania; 35th Department of Internal Medicine, Cardiology-Rehabilitation, UMF - University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania; 4Laboratory Animal Facility - Centre for Experimental Medicine, UMF - University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania

Background: One important limitation of the current standard approach of mobilizing hematopoietic stem cells (HSCs) in the peripheral blood (PB) using granulocyte-colony stimulating factor (G-CSF) for the prophylaxis of chemotherapy induced febrile neutropenia or in donors for PB stem cell transplantation (PBSCT) is insufﬁcient mobilization. Based on our preliminary results on the effect of human chorionic gonadotropin (HCG) on stimulating the peripheral mobilization of HSCs in vivo, the aim of the current study was to assess the effect of the addition of HCG to mobilization with G-CSF on the overall survival (OS) as the primary endpoint in a mouse model of PBSCT.

Methods: Male donor mice (n¼20) were pretreated with a single dose of either peg-G-CSF alone (group A, n¼10) or HCG + peg-G-CSF (group B, n¼10), 5 days prior toPBMC harvest. PBMCs were immediately transplanted to the equivalent number of Busulfan mieloablated female mice by intravenous tail injection and OS was assessed in both recipient groups.

Results: The median OS in the group of recipients transplanted with peg-G-CSF mobilized PBMCs (group A`) was 81 days. In the recipients transplanted with HCG+peg-G-CSF mobilized PBMCs (group B`} the median OS is not reached at 154 days with 90% of the recipients still being alive.

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Conclusions: Addition of HCG to the current standard mobilization approach with GCSF in donors has almost doubled the survival rate in the recipients of a murine model of PBSCT with the median OS not yet reached after 154 days. This prompts for the translation of the preclinical study`s approach in a human proof-of-principle/feasibility clinical trial.

Funding: The Executive Agency for Higher Education, Research and Innovation Funding (UEFISCDI), Ministry of National Education (MEN), Romania.

https://doi.org/10.1016/j.annonc.2023.09.1563

64P

Developing novel therapeutics for bladder cancer leveraging drosophila models

T. Moriguchi1, M. Sonoshita2, N. Shinohara3

1Department of Renal and Genitourinary Surgery, Hokkaido University Hospital, Sapporo, Japan; 2Institute for Genetic Medicine, Hokkaido University, Division of Biomedical Oncology, Sapporo, Japan; 3Department of Renal and Genitourinary Surgery, Hokkaido University Hospital, Sapporo, Hokkaido, Japan

Background: The prevalence of bladder cancer (BC) has been increasing worldwide.

Particularly, patients carrying the Basal/Squamous BC (BSBC) have poor prognosis.

Mammalian models such as cultured human BSBC cells and their xenografts have provided critical insights into its mechanisms, but effective therapeutics for BSBC is still lacking. Recently, the fruit ﬂy Drosophila has made signiﬁcant contributions to cancer research. Here, we employed Drosophila to generate the ﬁrst ﬂy model reproducing the BSBC genotypes and to discover novel therapeutic candidates for BSBC treatment.

Methods: BSBC often harbors mutations in genes ‘A’, ‘B’ and/or ‘C’. To model various alteration patterns in Drosophila, we employed the binary GAL4/UAS system, which targets expression of exogenous transgenes to a desired ﬂy tissue. We prepared GAL4 driver strains expressing a transcription factor GAL4 speciﬁcally in the eye cells and wing cells (GMR-GAL4 and nub-GAL4, respectively, for validating transgene functions),or the Malpighian tubule which corresponds to human bladder (for modeling BSBC genotypes). We also generated UAS transgenic strains which carry mutated cDNA and/or shRNA sequences as transgenes downstream of the GAL4 target UAS sequence.

Results: Previous studies have reported that induction of wild-type A in ﬂy eyes causes ‘rough eye’ phenotype by promoting apoptosis, which we conﬁrmed using the eye-speciﬁc GMR-GAL4 driver. We found that additional expression of missensemutated A or knockdown of A by shRNA rescued the phenotype as expected.

Furthermore, we conﬁrmed that overexpression of B using the same driver increased the ﬂy eye size as previously reported. Using the wing-speciﬁc nub-GAL4 driver, we validated that knockdown of C by shRNA reduced the ﬂy wing area, verifying its reported function to control tissue growth.

Conclusions: The eye and wing phenotypes induced by transgenes were consistent with their reported functions and our expectation, proving our strategy effective in validating functions of the transgenes and in modeling the BSBC genotypes in ﬂies.

We will next perform whole-body assays such as comprehensive genetic and drug screenings using these ﬂies to demonstrate the mechanisms of BSBC pathogenesis and to develop novel BSBC treatments.

https://doi.org/10.1016/j.annonc.2023.09.1564

65P Ionizing radiation induces vascular smooth muscle cell senescence through activating NF-kB-CTCF-p16 pathway

X. Zheng, Z. Liu, Y. Bin, J. Wang, X. Rao, G. Wu, X. Dong, F. Tong

Thoracic Oncology Department, Cancer Center, Union Hospital, Tongji Medical College,Huazhong University of Science and Technology, Wuhan, China

Background: Radiation injury of blood vessels (RIBV) is a serious long-term complication of radiotherapy, and the main pathophysiological change of which is atherosclerosis. Senescence of vascular smooth muscle cells (VSMCs) is implicated in the pathogenesis of radiation-induced atherosclerosis. The mechanisms underlying VSMCs senescence, however, remain poorly understood.

Methods: Using cultured human aortic smooth cells (HASMC) and SD male explored whether IR could induce transformation of senescent phenotype of VSMCs. ChIP assay explored whether SICC bind to p16 gene in irradiated cells. SA-b-gal staining indicate radiation-induced senescence.

Results: Using cultured human aortic smooth cells (HASMC) and SD male rats showed that IR could induce transformation of senescent phenotype of VSMCs with

signiﬁcant positive dose and time dependence in vitro and in vivo. IR activated DDR/NF-kB pathway and induced the nuclear loss of HMGB2 and thus spatial aggregation of CTCF, known as senescence-induced CTCF clusters (SICC), but had no signiﬁcant effect on the expression level of CTCF. And ChIP assay showed that SICC exhibited stronger binding ability to p16 gene in irradiated cells. Overexpressing HMGB2 and silencing CTCF abrogated radiation-stimulated p16 upregulation with less SICC formation. Suppression of the activation of NF-kB by PDTC (a common inhibitor of NFkB) attenuated radiation-induced senescence, indicated by less SA-b-gal staining,downregulation of p16. We also found that PDTC reduced radiation-induced nuclear loss of HMGB2 and formation of SICC.

Conclusions: In summary, we demonstrated here, for the ﬁrst time, that IR induced transformation of senescent phenotype of VSMCs in vivo and in vitro, and activated NF-kB pathway to initiate HMGB2 nuclear loss and thus promote the formation of SICC, which further strengthen the binding ability of CTCF and p16 gene, and resulted in the occurrence of radiation-induced senescence in VSMCs. These ﬁndings may have a signiﬁcant impact on the research of radiation-induced atherosclerosis and open a new prospective in the prevention and therapeutic intervention in RIBV.

Funding: National Natural Science Foundation of China.

https://doi.org/10.1016/j.annonc.2023.09.1565

66P Exploring the radiobiology and dosimetry of targeted alpha therapy as a tool to optimize its clinical application: A

preclinical study

M.F. Botelho1, I.A. Marques1, D. Cancelinha1, A. Belchior2, G. Costa3, A.S. Pires1,A.M. Abrantes1

Background: The use of molecular radionuclide therapy (MRT), such as targeted alpha therapy, is an emerging option for cancer treatment. The ﬁrst alpha-emitter approved for therapeutic use was radium-223 (Ra-223), indicated for metastatic castrationresistant prostate cancer (mCRPC), with exclusive bone metastasis. However, treatment outcomes are below expectations. There are some limitations, such as precise dosimetry, that could be addressed to improve clinical outcomes. In fact, there is no inclusion of radiobiology and molecular dosimetry data obtained in preclinical studies into MRT planning as occur for radiotherapy. Moreover, there is a lack of these data for MRT. Thus, the aim of this study was to develop preclinical studies to access radiobiology and dosimetry for MRT, namely for Ra-223.

Methods: Preclinical studies were conducted using metastatic PCa cells or spheroids,to better mimic tumor architecture, as cellular models of mCRPC. Radiobiological endpoints, such as viability, survival and death, were measured 7days post-irradiation of cellular models with increasing activities of Ra-223 (0-7040 Bq/mL) for 24h. The size, geometry and cell distribution of each cellular model were analyzed by confocal microscopy and values were used in combination with radiobiological and kinetics endpoints to perform cell dosimetry using MIRDcell V3.

Results: The exposure to increasing activities of Ra-223 induces a decrease in viability,survival with increasing of cell death for both cellular models, with biological effects depending on the cell model characteristics. These effects are less evident when evaluated in spheroids, when exposed to the same activities of Ra-223. These biological data were validated with dosimetric calculations that conﬁrm differences in absorbed doses depending not only on initial activity but also on cellular model characteristics.

Conclusions: The radiobiological and dosimetric studies showed that radiation effects for Ra-223 are dependent on molecular and structural characteristics of the cellular model, being the spheroids more representative of tumor architecture and better to conduct translational preclinical studies for MRT, as well as to obtain precise dosimetry.

Funding: This research was funded by the Foundation for Science And Technology(FCT), Portugal, through the Strategic Projects UIDB/04539/2020, UIDP/04539/2020,and by COMPETE-FEDER, reference number POCI-01-0145-FEDER-007440. Scholarship grants from FCT and European Social Funding to I.A.M. (SFRH/BD/136973/2018).

https://doi.org/10.1016/j.annonc.2023.09.1566

67P

The effect of non-viral gene-immune therapy via OX40L or 4-1BBL on murine subcutaneous CT26 colon cancer model

O. Rakitina, A. Kuzmich, D. Didych, S. Kondrateva, O. Bezborodova, I. Alekseenko

Group of Gene Immuno Oncotherapy, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russian Federation

Background: One way to signiﬁcantly reduce the incidence of systemic side effects of antitumoral immunotherapeutics is intratumoral gene-immune therapy. The use of non-viral systems is attractive for gene therapy due to low immunogenicity of the carrier, low production costs, and relatively high capacity. Thus, non-viral intratumoral gene-immune therapy is a promising area for development of antitumor drugs. OX40 and 4-1BB T cell co-stimulators are popular targets in immunotherapeutic drug development, but currently there are no approved drugs targeting these receptors.

We suppose that the natural ligands of these receptors, OX40L and 4-1BBL, would be effective in non-viral gene-immune therapeutics.

Methods: The antitumor effect of stable OX40L or 4-1BBL expression by inoculated cancer cells on CT26 tumor growth was studied. CT26 cell lines stably expressing OX40L or 4-1BBL were obtained, tumor graftability and growth in BALB/c mice were evaluated. Next, antitumor effect of non-viral gene-immune therapy with OX40L or 4-1BBL was studied, complexes of polymeric carrier with plasmid DNA encoding OX40L or 4-1BBL were prepared and injected three times into CT26wt subcutaneous tumors in BALB/c mice, starting when tumors reached 5015 mm3 when tumors reached 50±15 mm3..

Results: Stable expression of OX40L and 4-1BBL signiﬁcantly suppressed CT26 tumor growth, delayed tumor resorption was observed in the experimental groups. The use of OX40L and 4-1BBL in the context of gene-immune therapy had a signiﬁcant effect on CT26 tumor growth e median animal survival compared to the control group was increased by 26.5% (OX40L) and 41.2% (4-1BBL), life expectancy was increased by 24% (OX40L) and 24.5% (4-1BBL), tumor growth inhibition 10 days after treatment was 70% (OX40L) and 71.3% (4-1BBL). No visible immune-related adverse events(irAEs) were observed.

Conclusions: OX40L and 4-1BBL have a comparable potent antitumoral effect on CT26 tumor growth in the context of non-viral gene-immune therapy, and such therapeutic approach does not yield visible systemic irAEs.

Legal entity responsible for the study: Group of Gene Immuno Oncotherapy, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry.

Funding: This study was supported by RSF grant 22-25-00806, https://rscf.ru/project/22-25-00806/.

https://doi.org/10.1016/j.annonc.2023.09.1567

68P Dendritic polylysine with paclitaxel and triptolide codelivery for enhanced NSCLC ferroptosis through the accumulation of ROS

H. Xu1, Y. Wen2, M. Ni1, H. Jiang1, T. Wu1, X. Li3

1School of Pharmacy, Nanjing Medical University, Nanjing, China; 2Pharmacy, Jiangsu Cancer Hospital, Nanjing, China; 3Department of Geriatric Gastroenterology, Jiangsu Province Hospital/The First Afﬁliated Hospital of Nanjing Medical University, Nanjing,China

Background: The clinical application of Paclitaxel (PTX), a ﬁrst-line chemotherapeutic for NSCLC, is severely limited because of its developed resistance and insolubility. It is reported by our previous studies that the resistance to PTX is closely related to intracellular redox balance in cancer cells. Moreover, our preliminary data demonstrated that Triptolide (TPL) could improve the cytotoxicity of PTX through inducing ROS production. Most importantly, the synergistic anticancer effect between PTX and TPL is mainly through the induction of ferroptosis in NSCLC cell lines. To improve the delivery efﬁciency of both drugs, we constructed a novel nano-drug delivery system NDDS chemosynthesis by PEGylated generation 3 (G3) dendritic polylysine co-loaded with PTX and TPL (PTX-TPL-PEG-PLL, PTPP), which was endowed with the ability of tumor targeting and favorable solubility. this is the ﬁrst report on the dendritic polylysine loaded with PTX and TPL for NSCLC treatment. In addition, the enhanced ferroptosis-inducing effect of PTPP was mediated through ROS level, which illustrated the possible mechanism underlying the synergistic effect of PTX and TPL.

Methods: First, the PTPP was characterized by 1H NMR analysis, mass spectra, and HPLC. the in vitro synergetic effect and mechanism of PTX and TPL were explored by MTT assay and western blot. In vivo evaluation was performed in a xenograft mice model of NSCLC cell lines.

Results: The PTPP was synthesized successfully through covalent bonding and the MTT assay indicated the synergetic effect of PTX and TPL. Besides, regarding the mechanism, the TPL could promote the generation of ROS by inhibiting the NF-kB signaling pathway, which synergistically increased ROS level with PTX, inducing NSCLC cells ferroptosis. In the end, in vivo experiments suggested the outstanding tumorinhibiting ability of PTPP.

Conclusions: Overall, the current study suggested that PTPP exerted an excellent antitumor effect than PTX, TPL, or PTX combined with TPL through ferroptosis induction. PTPP may be a potential treatment system for NSCLC treatment.

https://doi.org/10.1016/j.annonc.2023.09.1568

69P Novel monoclonal antibodies can distinguish Cripto-1 from Cripto-3 proteins: Clinical implications and potential new biomarkers

J. Garcia-Sanmartin1, F. Cuttitta2, Y. Feng3, M.E. Sunday4, Y.S. Kim5, A. Martínez1

1Oncology, Center for Biomedical Research of La Rioja (CIBIR), Logroño, Spain; 2Tumor Angiogenesis Unit, National Cancer Institute - Technology Transfer Center, Frederick,MD, USA; 3Tumor Angiogenesis Unit, National Cancer Institute, Bethesda, MD, USA;4Clinical Science Department, Duke University Medical Center, Durham, NC, USA;5Cancer Prevention Science Branch, Division of Cancer Prevention, National Cancer Institute - Shady Grove Campus, Rockville, MD, USA

Background: Cripto-1 (CR1) is an oncofetal protein required for implantation and expressed in the adult during wound repair, inﬂammation, and tumorigenesis. A second gene codes for a very homologous protein, Cripto-3 (CR3). Both proteins contain 188 amino acids and differ only in 6 residues. Heretofore, all available antibodies cannot discriminate between these two proteins, preventing any investigation on their differential contributions to cancer biology. Here, we present the generation,characterization, and clinical implications of highly speciﬁc monoclonal antibodies(MoAbs) for these two proteins.

Methods: Different peptide fragments of either protein were used as antigens to generate mouse MoAbs (233 clones for CR1, 319 clones for CR3) that were selected by their target protein speciﬁcity through SPR and ELISA assays. Selected MoAbs were used for immunohistochemistry on tissue arrays including normal tissues as well as cancers of the lung, breast, colon, ovary, and prostate. MoAbs were also used for Western blotting and ELISA characterization of human serum (breast cancer vs healthy controls).

Results: MoAbs NCI 5G1-1 and NCI 5G11-2 were highly speciﬁc for CR1 and CR3,respectively. No crossreactivity was observed with the other protein. Immunohistochemical analysis of cancer specimens showed differential staining patterns, where some tumor cells expressed both proteins, others expressed only CR3, and still others show vascular endothelial cells stained for CR1 while tumor cells express CR3. In prostate, colon, and breast cancer, CR1 and/or CR3 protein expression correlates with clinical parameters, such as TMN_N, TMN_M, tumor stage, tumor grade, or PR expression. Lastly, both CR1 and CR3 interact with established binding proteins Nodal,GRP78 and Alk4 and competitively interfere with one another for targeted binding.

Conclusions: We describe for the ﬁrst time the development of MoAbs that discriminate human CR1 from CR3, conﬁrming that CR3 is translated into a protein in human cells, thus removing its pseudogene status. We also conﬁrm CR1, and propose CR3, as cancer prognosis and severity markers.

Legal entity responsible for the study: Center for Biomedical Research of La Rioja(CIBIR), Logroño, Spain.

Funding: Center for Biomedical Research of La Rioja (CIBIR), Logroño, Spain.

https://doi.org/10.1016/j.annonc.2023.09.1569

70P The human intratumor mycobiome is signiﬁcantly inﬂuenced by an individual’s race

D. Coster1, T. Margalit1, B. Boursi2, R. Shamir1

1Computer Science, Tel Aviv University (TAU), Tel-Aviv, Israel; 2Oncology, Chaim Sheba Medical Center, Ramat Gan, Israel

Background: Recently, the intratumor mycobiome has been characterized in 17,401 cancer patients, covering 35 cancer types from The Cancer Genome Atlas ( NarunskyHaziza et al., 2022 ), revealing a previously overlooked aspect of cancer research.

Moreover, Recent study showed that race is a key determinant of the human intratumor microbiome. We aimed to better understand the effects of patients’ demographic factors (age, sex, and race) on the intratumor mycobiome composition.

Methods: We analyzed the Narunsky-Haziza et al. de-contaminated and normalized intratumor fungal abundance data for 11 cancer types and 224 fungal species. We performed a systematic characterization of the tumor mycobiome across different cancer types using a propensity score algorithm, adjusting for the potential confounding factors of histological type and tumor stage.

Results: Fungus species abundances differed signiﬁcantly between races in all cancer types. For example, in breast cancer, we identiﬁed 42 signiﬁcantly differentially

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abundant fungal species in European vs. Asian, 45 species in European vs. African, and 56 in Asian vs. African. Notably, 19 fungal species Talaromyces marneffei, Scheffersomyces stipites, Debaryomyces fabryi, Lachancea lanzarotensis, Ogataea polymorpha, Tetrapisispora blattae, Fusarium proliferatum, Kazachstania Africana,Torulaspora delbrueckii, Naumovozyma castellii, Wickerhamomyces anomalus,Yamadazyma tenuis, Naumovozyma dairenensis, Sugiyamaella lignohabitans, Clavispora lusitaniae, Candida tropicalis, Vanderwaltozyma polyspora, Meyerozyma guilliermondii, Lachancea thermotolerans e had signiﬁcantly different abundances in all three race comparisons. Moreover, regarding age (>65) and sex, only 5 fungal species abundance in stomach adenocarcinoma varied signiﬁcantly for age and Malassezia sympodialis differed signiﬁcantly with respect to sex. In thyroid carcinoma, 3 species varied by age and Cordyceps militaris for sex.

Conclusions: Our research reveals that the composition of the fungal community within tumors varies signiﬁcantly across races, underscoring the importance of accounting for this demographic factor when conducting fungal-related analysis and clinical trials involving microbiota modulation.

Funding: Edmond J. Safra Bioinformatics Center in Tel-Aviv University.

https://doi.org/10.1016/j.annonc.2023.09.1570

71P

Preclinical characterization of ARX305: A next-generation anti-CD70 antibody drug conjugate for the treatment of CD70-expressing cancers

L. Skidmore, D. Mills, J.Y. Kim, K. Tatsukawa, N. Knudsen, J. Nelson, J.Wang, S. Zhang

Background: CD70 is an attractive tumor target due to its over-expression in numerous solid and hematological cancers and limited expression in healthy cells. In the last decade, multiple anti-CD70 antibody drug conjugates (ADCs) have been developed, but most have been discontinued due to unacceptable toxicity or a narrow therapeutic index. Using an expanded genetic code to create Engineered Precision Biologics, Ambrx has developed ARX305, a CD70-targeted next-generation ADC to potentially overcome the challenges associated with earlier ADCs. ARX305 is comprised of a proprietary, high-afﬁnity, humanized anti-CD70 antibody stably and site-speciﬁcally conjugated to AS269, a potent microtubule inhibitor. After binding to CD70 expressed on tumor cells, ARX305 is internalized and catabolized, releasing the cytotoxic payload pAF-AS269 which inhibits cellular proliferation. ARX305 utilizes stable oxime conjugation chemistry, a non-cleavable PEG linker, and a membraneimpermeable payload to minimize premature payload release in circulation and associated off-target toxicity.

Methods: ARX305 was evaluated in multiple pre-clinical pharmacology and toxicology models using standard methodology.

Results: In vitro studies demonstrate that ARX305 selectively induces cytotoxicity of CD70-expressing tumor lines. In multiple in vivo xenograft or disseminated models,ARX305 induced signiﬁcant tumor growth inhibition or regression whereas unconjugated antibody exhibited poor activity. The stable conjugation and cell-impermeable payload of ARX305 led to high serum stability, a long terminal half-life, and a similar exposure proﬁle as unconjugated antibody in rodent pharmacokinetic studies. Repeat dose studies in cynomolgus monkeys demonstrated ARX305 was tolerated at exposures well above therapeutic exposures in mouse pharmacology studies, indicating a wide therapeutic index.

Conclusions: In summary, the highly selective and potent anti-tumor activity in multiple tumor types and wide pre-clinical therapeutic index of ARX305 support clinical evaluation of this next generation anti-CD70 ADC. ARX305 is currently in a phase 1 dose-escalation study in China.

Funding: Ambrx and NovoCodex Biopharmaceuticals.

Disclosure: L. Skidmore: Financial Interests, Institutional, Full or part-time Employment: Ambrx. D.

Mills, J.Y. Kim, K. Tatsukawa, N. Knudsen, J. Nelson, J. Wang, S. Zhang: Financial Interests, Personal,Full or part-time Employment: Ambrx.

https://doi.org/10.1016/j.annonc.2023.09.1571

72P Impact of extended panel of genes for germline cancer testing

S. Dawood1, M. Wasfy2, R. Khoury2

1Oncology Department, Mediclinic City Hospital, Dubai, United Arab Emirates;2Medical Department, IPS Genomix, Beirut, Lebanon

Methods: A549 cell line was used. Expression of miR-23b, miR-133a, DR4, DR5, Apaf1, CUL3, CLTA/CLTC and KPNA-1 were estimated by RT-qPCR. Transfection effects of miR-23b inhibitor and Mimic-133a on TRAIL apoptosis pathway components expression. Western Blotting to TRAIL receptors compartmentalization after Mimic133a and TRAIL stimulus. MTT cell viability assay to evaluate TRAIL-induced cytotoxicity of miR-23b inhibition and Mimic-133a transfection.

Results: A549 was TRAIL resistant. miR-23b was superexpressed and miR-23b inhibition upregulated Apaf-1 and CUL3 expression. miR-133a was undetectable. Mimic133a transfection downregulated CLTA and DR5 expression. miR-23b inhibition and

Mimic-133a transfection promoted TRAIL sensitization.TRAIL receptors were predominantly located in nuclear compartment. Mimic-133a downregulated CLTA expression but did not alter receptors compartmentalization. Mimic-133a and TRAIL associated stimulus leaded to predominant nuclear TRAIL receptors localization in comparison to control cells.

Conclusions: Both miR-23b and -133a are involved in TRAIL cells resistance. Apaf-1 and CUL3 expression downregulation by miR-23b can contribute to resistance. miR133a role on TRAIL sensitization mechanisms must be further investigated. Mimic133a downregulated CLTA expression but did not alter TRAIL receptors compartmentalization, suggesting that receptors translocation is clathrin independent.CLTA expression control by miR-133a, however, can contribute to drug-resistance research.

Although more research is needed to fully clarify miRs roles on TRAIL-induced apoptosis, our ﬁndings deepen TRAIL resistance understanding.

Funding: FAPESP.

https://doi.org/10.1016/j.annonc.2023.09.1581

83P Impact of VHL-associated tumor treatment on mental health: An international patient survey

O. Iliopoulos1, C. Atkinson2, C. Cooper2, G. Taylor-Stokes2, J. Mann3, M. Sundaram4

1Centre for Cancer Research, Massachusetts General Hospital Cancer Center, Boston,MA, USA; 2Observational Research, Adelphi Real World - Adelphi Group, Bollington,UK; 3VHL Alliance, VHL Alliance, Boston, USA; 4Center for Observational and RealWorld Evidence, Merck, Rahway, NJ, USA

Background: Treatment (tx) options for patients (pts) with Von Hippel-Lindau syndrome (VHL) were previously limited to surgeries between regular scans, observation and txs that preserve organ function. Little data exists on the burden of VHL-associated tumor tx on the mental health of pts.

Methods: International, cross-sectional survey comprising pts in the United States,Canada, UK, France, and Germany. Pts recruited via the VHL Alliance. Pts must have renal cell carcinoma (RCC), pancreatic neuroendocrine tumors (pNET), and/or central nervous system hemangioblastoma (CNS Hb). Data collected included demographics,impact of most recent surgery on aspects of their condition (1-7 scale 1: greatly worsened and 7: greatly improved), feelings before/after their most recent surgery (1-5 scale, 1: completely disagree, 5: completely agree with presented statements), and treatment preference questions.

Results: Data collected from 220 pts (68% female, median age 40 years, median disease duration 16 years) in US (n¼108), CA (n¼37), UK (n¼21), FR (n¼3), and DE(n¼51). 146 pts reported RCC (66%), 122 pNET (56%), and 190 CNS-Hb (86%). 205(93%) pts had experienced surgery; 171 (78%) had experienced multiple surgeries(median ¼ 4). Top three concomitant self-reported conditions were anxiety (36%),depression (29%) and high blood pressure (28%). 24% of pts consulted a mental health specialist. 51% of pts indicated that their most recent surgery worsened their mental health (rated 1-3), 84% of pts agreed they felt anxious before their most recent surgery (rated 4-5). After their most recent surgery 50% of pts agreed they felt anxious. 33% of pts indicated improving quality of life was in their top 3 treatment goals; 17% indicated improving mental wellbeing was in their top 3 treatment goals.

73% of patients indicated they would prefer to take a pill which would possibly delay time until surgery, rather than watch and wait to see if the tumor would grow.

Conclusions: Pts with VHL-associated disease report anxiety and depression as the most common mental health conditions, and agree that upcoming surgery worsens their anxiety. Over half of pts reported that their most recent surgery worsened their mental health. Despite this, less than a quarter of pts consulted a mental health specialist.

Legal entity responsible for the study: Merck.

Funding: Merck.

Disclosure: O. Iliopoulos: Financial Interests, Personal, Speaker, Consultant, Advisor: Merck, C4 Therapeutics. C. Atkinson, C. Cooper, G. Taylor-Stokes: Financial Interests, Institutional, Sponsor/Funding, Received funding from Merck to conduct the study: Adelphi Real World. J. Mann: Financial Interests, Personal, Stocks/Shares: Merck. M. Sundaram: Financial Interests, Personal, Full or parttime Employment: Merck; Financial Interests, Personal, Stocks/Shares: Merck, BMS, AbbVie, J&J.

https://doi.org/10.1016/j.annonc.2023.09.1582

S211

84P

Microenvironment immune differences between sexes in multiple myeloma

M.D.L.A. Clavo1, K. Paez2, U. Infante3, L. Rodrigo3, Z.D. Morante Cruz4, J. Pinto5

1Facultad de Medicina Humana, San Luis Gonzaga University, Ica, Peru; 2Escuela Profesional de Medicina Humana-Filial Ica, Universidad Privada San Juan Bautista,Lima, Peru; 3Facultad de Ciencias Biológicas, San Luis Gonzaga University, Ica, Peru;4Medical Oncology Dept., INEN - Instituto Nacional de Enfermedades Neoplasicas,Lima, Peru; 5Unit of Basic and Translational Research, Auna Ideas, Lima, Peru

Background: Several studies showed that sex is a biological variable that inﬂuence immune response in several types of solid tumors; however, there is scarce information in hematological malignancies. In this work, we evaluate differences in immune cells compositions and immune response of multiple myeloma between sexes.

Methods: We conducted a computational biology study using transcriptomic data obtained from bone marrow aspiration collected from untreated multiple myeloma patients under the MMRF-COMMPASS protocol (study accession phs000748). Data was pre-processed and the expression levels were normalized to TPM (transcript per million). To evaluate differences in immune cells compositions, we quantiﬁed the immune cell in the tumor microenvironment with the analytic platform CIBERSORT.

Differences in activated immune pathways was evaluated with the gene set enrichment analysis (GSEA). Pre-processed counts were normalized to TMM (trimmed mean of M-values) and GSEA was performed using the GSEA java desktop application(v4.3.2). In both analysis, patterns of immune gene sets and the immune cell composition were compared between tumors from female vs. male patients. A p<0.05 and a FDR<25% were considered statistically signiﬁcant for GSEA analysis,while a p<0.05 and a FDR<0.05 6.1x10-5 was considered statistically signiﬁcant for CIBERSORT analysis.

Results: Overall, 451 males and 313 female patients were included. We detected in samples from female patients an enrichment of dendritic cells activated (p¼0.0023,FDR¼0,0257) and NK cells activated (p¼0.0059, FDR¼0,0326). In contrast, weobserved in male patients an enrichment of monocytes (p¼6.10x 10-5, FDR¼0,0013)and macrophages M1(p¼0,0050, FDR¼0,0326). The GSEA analysis revealed anoverregulation of natural killer cell degranulation (p¼0.007, FDR¼0.21624), positiveregulation of type I interferon mediated signaling pathway (p<0.0001,FDR¼0.23946), and regulation of natural killer cell proliferation (p¼0.01,FDR¼0.2495).

Conclusions: The computational analysis showed some differences in the immune microenvironment, between sexes in multiple myeloma. Studies about the inﬂuence of these differences in the clinical outcomes of patients should be evaluated.

https://doi.org/10.1016/j.annonc.2023.09.1583

85P In silico evaluation of the transcriptomic and immunologic proﬁle of lung adenocarcinomas with deletions or disruptive mutations of SMARCA4

E. Garcia Lorenzo1, C. Nieto-Jimenez2, C. Diaz-Tejeiro2, B. Doger de Spéville1,I. Moreno3, M. Pedregal1, L. Paniagua Herranz2, A. Sanvicente2, B. Gyorffy4,V. Moreno Garcia1, E. Calvo3, A. Ocana Fernandez2

1Dept. Early Clinical Drug Development, START Madrid-FJD, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain; 2Experimental Therapeutics Unit, Medical Oncology Department, Hospital Clinico Universitario San Carlos, Madrid, Spain; 3Dept.

Early Clinical Drug Development, START Madrid-CIOCC, Centro Integral Oncológico Clara Campal, Madrid, Spain; 4Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary

Background: Characterization of the immune microenvironment is key. In tumors with wide presence of genomic alterations like non-small cell lung cancer (NSCLC) the evaluation of the immune proﬁle can help to better select treatment options. In this study we explored the transcriptomic landscape of lung adenocarcinoma tumors(LUAD) with genomic alterations at SMARCA4.

Methods: Data from TCGA was downloaded to evaluate the expression of transcripts up or down regulated when deletions or disruptive mutations of SMARCA4 were present in LUAD. Median values were used and genes with fold change (FC) > than

2.5 were selected. Gene set enrichment analysis was performed with Enricher. TIMER platform was employed to investigate the association with immune cell populations.

Results: Of the 507 evaluated patients, disruptive mutations were present in 43 and gene deletions in 5. Molecular/biological functions enriched within the upregulated genes in tumors with SMACA4 deletions included: ncRNA 3’-end processing(GO:0043628) or ketosteroid monooxygenase activity (GO:0047086), among others;involving representative genes like CT45A10; SAGE1; CT45A3; CT45A5; CT45A1,AKR1C1; AKR1C2, CBR1 or CBR3. In tumors with no deletion the most represented molecular/biological functions included the antigen processing and presentation of lipid antigen via MHC class Ib (GO:0048003) with relevant genes as: CD1E; CD1C;CD1B; CD1A; CX3CR1; P2RY12, among others. Presence of CD1A, CD1B, CD1C, CD1E in

tumors with no SMARCA4 genomic alterations strongly associated with the presence of dendritic cells (DC) (Corr Rho 0.41, 0.48, 0.44 and 0.45, respectively) and dendritic resting cells (DRC) (Corr Rho 0.75, 0.70, 0.71 and 0.72, respectively). A direct comparison between SMARC4 deletions and DC and DRC, showed a clear negative correlation (Corr Rho -0.5, -4,3, respectively). Similar ﬁndings were observed with SMARC4 mutations (DC Corr -0.69, DRC Corr -0.91).

Conclusions: SMARCA4 deletions in LUAD tumors associated with loss of antigen presenting genes including CD1E; CD1C; CD1B; CD1A that are present in myeloid dendritic cells. We hypothesized that loss of antigen presentation functions can be present in LUAD with genomic alterations of SMARCA4.

https://doi.org/10.1016/j.annonc.2023.09.1584

86P Effect of chemotherapy-induced autophagic secretome on natural killer cell activity

A. Karlitepe1, E. Celik2, T. Sütlü2, T. Süzek3, M.K. Kilic Eren1

1Medical Biology, Aydin Adnan Menderes University Faculty of Medicine, Aydin,Turkey; 2Molecular Biology and Genetics, Bogazici University, Istanbul, Turkey;3Computer Engineering, Mugla Sitki Kocman University Faculty of Engineering, Mugla,Turkey

Background: Autophagy achieves a tumor-suppressing function in the initial stages of cancer by eliminating protein aggregates and damaged organelles that might promote genomic instability and lead to tumor formation. Autophagy induced by hypoxia or metabolic stress also plays an important role in the regulation of inﬂammatory pathways. In cancer cells, this may lead to secretion of pro- and/ or anti-inﬂammatory cytokines and chemokines which may help the immune escape of the tumor. However, the underlying mechanism of autophagy-mediated modulation of anti-tumor immune response is not yet fully understood. Our aim is to investigate whether chemotherapy-induced autophagy-associated secretome has the potential to modulate the NK cell-mediated anti-tumor immune responses.

Methods: Initially, western blot and immunostaining analyses were performed for autophagy markers (LC3I/II and p62) to demonstrate that Etoposide (Eto) induces autophagy in MCF-7 cells. LC/MS-MS analysis was performed to determine the content of chemotherapy-induced autophagic secretome in supernatants of autophagy-induced MCF-7 cell cultures. Finally, how the chemotherapy-induced autophagic secretome effects the capacity of DNAM1-NK-92 cells to target MCF-7 cells was determined by degranulation assays.

Results: We demonstrated Etoposide (Eto) induces autophagy in MCF-7 cells as conﬁrmed by detection of autophagy markers including LC3I/II and p62 by WB and by immunostaining analysis. LC/MS-MS results revealed that, metabolic enzymes, tumor antigens, chaperones and metastasis-related proteins were secreted during etoposide induced autophagy which could be reduced by use of Chloroquin. When wildtype or DNAM1 overexpressing NK-92 cells were treated with autophagic secretomes, it was observed that there were differences in the capacity of targeting MCF-7 cells.

Conclusions: This study provides new insights in the ﬁeld of chemo-immunotherapy by characterizing the chemotherapy-induced autophagic secretome and determining its possible effect on NK cells.

Legal entity responsible for the study: M.K. Kilic Eren.

Funding: Adnan Menderes University Scientiﬁc Research Foundation, The Scientiﬁc and Technological Research Council of Turkey.

https://doi.org/10.1016/j.annonc.2023.09.1585

87P WIP1 phosphatase promotes etoposide induced autophagy in medulloblastoma and neuroblastoma

H. Pilevneli1, A. Karlitepe1, N. Kaygusuz1, C. Ak1, M. Kilic Eren2

1Medical Biology, Aydin Adnan Menderes University Faculty of Medicine, Aydin,Turkey; 2Medical Faculty, Adnan Menderes University Training and Research Hospital,Aydin, Turkey

Background: Wip1/PPM1D is a serin/threonine phosphatase which is involved in timely termination of DNA damage response. Overexpression of Wip1 is commonly seen in human solid cancers including neuroblastoma and medulloblastoma that displays oncogenic features. Oncogenic Wip1 negatively regulates tumor suppressor responses such as apoptosis or senescence. Autophagy plays a tumor suppressor role by removing damaged organelles/proteins and limiting cell growth and genomic instability in cancer cells. The molecular mechanisms underlying autophagy’s tumorpromoting activities are largely unknown Here, we investigated the role of oncogenic

Wip1 phospahates in regulation of autophagy in neuroblastoma and medulloblastoma.

Methods: D283-med and IMR32 cells are grown according to ATTC protocol. Autophagy was stimulated with etoposide and inhibited with chloroquine. GSK2830371 is used to target Wip1. Autophagy markers are tested with WB analysis and with confocal microscopy analysis of LC3 I/II puncta formation. Vacuolazion was measured by quinacrine staining. Wip1-Ulk1 interaction was investigated via co-IP and colocalization analysis. BrDU/PI and Annexin V/7AAD assays were used to examine the cell cycle and apoptosis, respectively.

Results: In neuroblastoma and medulloblastoma cells, oncogenic Wip1 promotes etoposid induced autophagy and improves cancer cell survival. Wip1 phosphatase interacts with and dephosphorylates Ulk1 during etoposide induced autophagy which is associated with elevated p53 levels. Suppression of Wip1 and/or autophagy prevents degredation of pro-apoptotic proteins thus results in promotion of apoptosis.

Furthermore, inhibition of Wip1 and autophagy reduce cancer cells ability to colonize in vitro.

Conclusions: Oncogenic Wip1 play a key role in enhancing etoposide induced autophagy by dephosphorylating ULK1 and contributes to cancer cell survival. Wip1 mediated autophagy may be a promising therapeutic target for improvment of chemotherapy response.

Funding: TUBITAK.

https://doi.org/10.1016/j.annonc.2023.09.1586

88P

PPM1D/WIP1 phosphatase mediates basal and genotoxic stress-induced autophagy via ULK-1 de-phosphorylation

C. Ak1, A. Karlitepe2, H. Pilevneli2, N. Kaygusuz1, M.K. Kilic Eren3

1Department of Medical Biology, Adnan Menderes University, Faculty of Medicine,Aydin, Turkey; 2Department of Medical Biology, Adnan Menderes University, Medical School, Aydin, Turkey; 3Medical School, Department of Medical Biology, Adnan Menderes University, Faculty of Medicine, Aydin, Turkey

Background: PPM1D/WIP1 is a Ser/Thr phosphatase activated upon genotoxic stress in a p53 dependent manner and involved in regulation of DNA damage response(DDR) . Wip1 is ampliﬁed and over expressed in common human cancers and thus exerts oncogenic functions. Oncogenic Wip1 negatively regulates cellular responses to chemotherpy such as apoptosis and senescence. Here, we aimed to investigate the role of oncogenic Wip1 in induction of basal autophagy and chemotherpy mediated autophagy in breast cancer cells.

Methods: Etoposide was used to induce autophagy and Chloroquin (CQ) for inhibition. GSK2830371 was used to inhibit Wip1. LC3I/II conversion P62 degradation, total and phosphorylated (Ulk1 p-Ser757) levels were by analysed WB. Wip1-Ulk1 interaction was demonstrated by co-IP analysis. LC3 puncta formation was analysed by and immunoﬂuorescence staining. Apoptosis, cell cycle, and senescence were measured by AnnexinV/7AAD, BrdU/PI analysis and SAb-gal staining, respectively Colony formation assay was used to assess cells ability to colonize.

Results: Utilizing Wip1 over expressing MCF-7 cells, here we showed that oncogenic Wip1 increased basal autophagy and mediated etoposide-induced autophagy as conﬁrmed by accumulation of LC3-II, degradation of p62, and formation of LC3II puncta. Inhibition of Wip1 increased phosphorylation of Ulk1 from Ser757 both in basal and etoposide induced autophagy. Further, endogenous Wip1 co-precipitated with Wip1 during basal and etoposide induced autophagy. Inhibition of autophagy or Wip1 enhanced apoptosis in response to etoposide but not senescence.

Conclusions: In conclusion our data suggest that oncogenic Wip1 may increase basal autophagy to support the survival of cancer cells. In addition Wip1 dependent autophagy in response to chemotherpy agents may cause resistance to chemotherapy. Thus targeting of Wip1-Ulk1 may lead enhancement of the chemotherapy response as a promising therapetic strategy.

Funding: This work is supported by TUBITAK Gr.N . 119S135.

https://doi.org/10.1016/j.annonc.2023.09.1587

89P Cold atmospheric plasma-activated ﬂuids as a potential new intravesical agent for the treatment of bladder cancer

M.F. Botelho1, E. Tavares-da-Silva2, E. Pereira1, J. Craveiro3, L. Fernandes3,F. Caramelo1, A.M. Abrantes1, A.S. Pires1, A. Figueiredo4

1Coimbra Institute for Clinical and Biomedical Research (iCBR), Area of Environment,Genetics and Oncobiology Research (CIMAGO), Institute of Biophysics, Faculty of Medicine; CIBB; CACC, Univ Coimbra, Coimbra, Portugal; 2Dept. of Urology and Renal Transplantation, CHUC - Centro Hospitalar e Universitario de Coimbra - Hospital Geral,Coimbra, Portugal; 3Coimbra Institute for Clinical and Biomedical Research (iCBR),Area of Environment, Genetics and Oncobiology Research (CIMAGO), Institute of Biophysics, Faculty of Medicine, Univ Coimbra, Coimbra, Portugal; 4CHUC - Centro Hospitalar e Universitario de Coimbra - Hospital Geral, Coimbra, Portugal

Background: Cold atmospheric plasma (CAP) has been studied for cancer treatment.

One of its forms, CAP activated liquids (CAPAL), may be an alternative to intravesical agents to treat bladder cancer (BC). The surgical bipolar resectoscope, when in use, is a source of thermal plasma (TP), which exerts effects on the surrounding sodium chloride solution for irrigation (NaCl 0.9%), transforming it into a TP activated liquid(TPAL), which is produced in very close contact with the bladder wall. To accelerate a possible introduction of plasma-activated liquid in the treatment of BC, we decided to compare the properties and biological effects of CAPAL and TPAL.

Methods: An electronic device was designed by our group to create CAP. TP was produced by a resectoscope. NaCl 0.9% was exposed to CAP or TP during short periods of time (30, 60, 120, 180 seconds) creating CAPAL or TPAL. The reactive oxygen and nitrogen species (RONS) activity was evaluated using the OxiSelect RONS Assay Kit in each activated liquid. BC cell lines, TCCSUP (grade IV) and HT-1376 (grade III),were incubated with CAPAL or TPAL. Metabolic activity was evaluated by MTT assay and protein content by SRB assay, 24h post-incubation.

Results: In comparison to non irradiated NaCl 0.9%, both CAPAL and TPAL, in all exposure times resulted in a signiﬁcant rise in the activity of RONS. Regarding the biological activity of the activated liquids in the BC cell lines, both CAPAL and TPAL induced a decrease in cell metabolic activity and protein content in an exposure-time dependent manner. CAPAL induced a higher antitumor effect on the high-grade cell line (TCCSUP), while TPAL had a similar effect on both cell lines. Comparing the two activated liquids, CAPAL required longer exposure times to achieve the same effects observed with TPAL at lower exposure times.

Conclusions: This study shows that PAL can be a therapeutic agent for BC. Both TPAL and CAPAL showed similar biologics in BC cells. Currently, in clinical practice, TPAL is already in close contact with the bladder wall during surgery, however only brieﬂy and diluted by irrigation. This work intends to get one step closer to demonstrate that CAPAL can be a safe and effective BC treatment.

Funding: Foundation For Science And Technology (FCT), Portugal, through the Strategic Projects, UIDB/04539/2020, UIDP/04539/2020, and by COMPETE-FEDER, reference number POCI-01-0145-FEDER-007440. Scholarship grants from FCT and European Social Funding to E.P. (2021.05543. BD).

https://doi.org/10.1016/j.annonc.2023.09.1588

90P Discovery of CMPD1 as a tumor-speciﬁc cytotoxic microtubule inhibitor

M. Takada1, Y-C. Chen2, J. Wang1, H. Yamada1, M. Yu1, J. Sakakibara1, H. Fujimoto1,T. Nagashima1, M. Ohtsuka1, M. Takaku3, A. Suzuki2

1General Surgery Department, Chiba University, School of Medicine, Chiba, Japan;2Oncology, University of Wisconsin Carbone Cancer Center, Madison, WI, USA; 3Biological Sciences, University of North Dakota - School of Medicine and Health Sciences,Grand Forks, ND, USA

Background:Microtubule-targeting agents (MTAs) have been widely used as ﬁrst- and second-line agents in various cancers for several decades. Furthermore, the value of MTAs is currently increasing due to their usefulness as combination drugs with immune checkpoint inhibitors. However, many development resources have been devoted to molecular-targeted agents, and the development of new MTAs has not progressed, leaving many patients struggling with the toxicity of existing MTAs. In other words, there is an urgent need to develop new microtubule inhibitors with high cancer-speciﬁcity.

Methods: Time-lapse images were taken every 2-3 minutes for 24-72 hours. Microtubules nucleated from GMPCPP-stabilized seeds were prepared and imaged using total internal reﬂection ﬂuorescence (TIRF) microscopy (Ecklund KH et al. Nature Comm 2017 ). Tubulin polymerization activity, Trans-well migration assay were measured using the HTS-Tubulin Polymerization Assay Biochem Kit (Denver, CO, USA),CytoSelect 24-well cell invasion assay kits (Cell Biolabs). Orthotopic breast cancer model (MDA MB 231) and treatment - CMPD1 (i.p., 15mg/mouse/inj, 10 times for 3 wks), Taxol (i.p., 5mg/kg/inj, 10 times for 3 wks) were performed. Vascular invasion was identiﬁed by tumor cells within vessels in HE staining. RNAs Sequencing libraries

S213

were prepared with the TruSeq stranded mRNA kit and sequenced on NovaSeq6000 at Macrogen Japan.

Results: CMPD1, a known inhibitor of MAP kinase-activated protein kinase 2(MK2),rapidly induces microtubule depolymerization in several cancer cell-lines, resulting in robust prometaphase arrest. CMPD1 levels alter the fate of cancer cells, either inducing mitotic slippage or resulting in mitotic defects. CMPD1 inhibits microtubule polymerization and speciﬁcally induces microtubule depolymerization at the plus end in in vitro assays; resulting in signiﬁcant inhibition of tumor growth, cancer cell migration, and invasion in both in vitro and in vivo. Furthermore, clinically relevant low doses of CMPD1 induced severe and prolonged mitotic failure speciﬁcally in cancer cells, but not in non-transformed cells, with only modest effects on microtubules in vitro.

Conclusions: CMPD1 has the potential to serve as a cancer cell-selective MTA chemotherapeutic agent.

Funding: JSPS KAKENHI 21K08638.

https://doi.org/10.1016/j.annonc.2023.09.1589

91P

Erythroid precursor-differentiated myeloid cells promote pulmonary metastasis in hepatocellular carcinoma

W-H. Zhu

Third Afﬁliated Hospital, Sun Yat-Sen University, Guangzhou, China

Background: Pulmonary metastasis is the most frequently occurring distant metastases of hepatocellular carcinoma (HCC). However, the indicated mechanism of pulmonary metastasis in HCC remains unclariﬁed. Erythroid progenitor-differentiated myeloid cells (EDMCs) were reported to mediate immunosuppression and curtail antiPD-1/PD-L1 treatment efﬁcacy. The role of EDMCs in the metastasis of HCC and the development of pulmonary metastasis was investigated here.

Methods: The existence of EDMCs in the circulation and spleen of HCC mouse model were validated through Flow Cytometry. EDMCs were sorted using ﬂuorescenceactivated cell sorting. CFSE stained EDMCs transfer experiment were conducted to evaluated the Pulmonary metastasis promoting role in HCC mouse model. The transwell migration and invasion experiment of hepa1-6 cells (HCC cell line) cocultured with EDMCs were performed.

Background: Traditional genetic screening was based previously on the analysis of classical high penetrance genes such as BRCA1 and BRCA2. In the context of our clinical practice in Dubai, individuals fulﬁlling the criteria are tested for germline mutations to subsequently establish the clinical management. Our current standard diagnostic approach focuses on sequencing 110 genes through NGS leading to increase the chance of ﬁnding the causal mutation and to the widespread clinical use of genes for germline cancer testing.

Methods: A total of 111 cases were tested in UAE with a traditional panel (BRCA1,BRCA2 and CHEK2) from October 2013 till September 2016. Then we have integrated extended panels (36 then 110 genes) from October 2016 till March 2023 and tested 509 cases. Median age was 47 years. Cases were referred for genetic testing mainly due to personal history of breast and ovarian cancer.

Results: Mutations in traditionally screened cases represent 8.1% for BRCA1, BRCA2 and 1% for CHEK2 for all types of panels. However extended panel analysis had a higher detection rate of pathogenic mutations compared to traditional analysis with an average increase of 7% in several genes mainly MUTYH, TP53, MLH1, RAD51D,PALB2 (respectively 2.6%, 0.8%, 0.8%, 0.6%, 0.6%). The heterogeneity of the newly detected mutations identiﬁed reinforces the value of using an extended hereditary panel. Further analysis will correlate the characteristics of germline mutations and their correlation with the tumor type and with the age group.

Conclusions: To our knowledge this is the ﬁrst abstract from the MEA focusing on the impact of the analysis of extended panel of genes to patients with suspicion of hereditary cancer. Our ﬁndings reinforce the utility of extended panels involved in hereditary cancer predisposition in the diagnostic routine which may impact their clinical management. The use of this approach facilitates the detection of pathogenic mutations in non-BRCA1/2 genes and aided management. This will allow opportunities for enhanced surveillance and intervention in a range of tumors.

Legal entity responsible for the study: IPS Genomix.

Disclosure: S. Dawood: Financial Interests, Personal, Speaker, Consultant, Advisor: Newbridge,Caris Life Sciences, Janssen, BMS, Lilly, MSD, AstraZeneca, Pﬁzer, Novartis, Ipsen; Financial Interests,Personal, Other, Clinical studies: AZ; Financial Interests, Personal, Research Grant: MSD, Amgen. M.

Wasfy, R. Khoury: Financial Interests, Personal, Full or part-time Employment: IPS Genomix.

https://doi.org/10.1016/j.annonc.2023.09.1572

73P Preclinical and clinical presentation of the nerve-driven tumor spread

D.S. D.S. Sigorskia, M. Michalak1, S.Galli2,S. Hyeok Honga,E. Izycka-Swieszewskaa,Sigorski1, M. Michalak1, S. Galli2, S. Hyeok Hong3, E. I_zycka-Swieszewska4,J. Kitlinska3Kitlinska3

1Department of Oncology, University of Warmia and Mazury in Olsztyn, Olsztyn,Poland; 2Department of Pathology, Georgetown University Medical Center, Washington, DC, USA; 3Department of Biochemistry and Molecular & Cellular Biology,Georgetown University Medical Center, Washington, DC, USA; 4Department of Pathology and Neuropathology, Medical University of Gdansk, Gdansk, Poland

Background: Tumor inﬁltration by nerves and axial bone metastases often occur in prostate cancer (PCa) patients, however the mechanisms and the link between these processes are not well understood. Here, we report a PCa mouse model, which recapitulates this cancer route of spreading and correlates with radiological images from PCa patients.

Methods: The human androgen-independent PC3-ML cell line with reported bone metastasis potential was orthotopically injected into the prostate of SCID/Bg mice to observe the natural history of cancer spread instead of commonly used intratibial or intracardiac injections. The process of primary and secondary tumor development was monitored by magnetic resonance imaging (MRI). The tissues were collected and immunostained for neuronal markers, neuroﬁlament (NF), and tyrosine hydroxylase(TH), as well as prostate cancer cell marker, pan-cytokeratin, and a vascular marker,CD31. Additionally, clinical cases of patients with representative MRI images of bone metastases and PNI were selected.

Results: The mice MRI revealed the presence of primary prostate tumor with secondary tumors located mostly along the lumbar spinal cord and pelvis, which led to secondary bone inﬁltration. The histopathological analysis conﬁrmed the presence of PCa cells along the spine with its inﬁltration. The PCa cells created clusters, which spread along the small, NF-positive nerve ﬁbers that were directed into the bone area. We ruled out the retrograde vessel inﬁltration by CD31 immunostaining. The clinical relevance of our model was conﬁrmed by the radiological presentation of human PCa cases: 1) a patient with castration-sensitive PCa, with oligometastatic disease (one sacrum metastasis) and inﬁltration of neurovascular bundle; 2) a patient with castration-resistant PCa with PNI and a relapse in the ilium, who subsequently developed perispinal metastases along the lumbar plexus and spine.

Conclusions: Altogether, the results of our study suggest that PNI may be responsible for the initial PCa dissemination to bone. MRI imaging has adequate sensitivity to detect the nerve inﬁltration, however it is not commonly used in disseminated PCa patients. Consequently, the number of cases with spine inﬁltration and bone metastases may be underreported.

Legal entity responsible for the study: Georgetown University Medical Center.

https://doi.org/10.1016/j.annonc.2023.09.1573

74P

Characterization of ERBB2 variation and their association with immune response in solid tumours

D. Wang1, S. Yuan2, W. Zhizheng2, H. Chen2, F. Pang2

1Respiratory Medicine, Jinling Hospital Afﬁliated to Nanjing University School of Medicine, Nanjing, China; 2Medical Department, Shanghai OrigiMed Co., Ltd.,Shanghai, China

Background: ERBB2, a receptor tyrosine kinase, is commonly affected by mutations,ampliﬁcations, and overexpression in various types of cancers. Drugs targeting ERBB2 are gradually being promoted to various types of cancer. However, the variation of ERBB2 in Chinese population and the relationship between ERBB2 high expression abnormalities and the tumor immune microenvironment remains unclear.

Methods: We utilized genomic data from over 10,000 pan-cancer Chinese populations in CbioPortal to detect somatic mutations and copy number variations. We also performed RNA sequencing date in TCGA (pan-cancer Atlas studies) to determine ERBB2 expression in diverse cancer types and evaluate the immune gene characteristics and content of tumor-inﬁltrating immune cell populations.

Results: A total of 309 ERBB2 ampliﬁcations, 169 ERBB2 substitution or insertion deletions, and 28 ERBB2 fusions or rearrangements were detected in 10,194 patients.

The ERBB2 ampliﬁcation rate of breast cancer (23.84%), gallbladder cancer (13.75%)and urothelium cancer (8.33%) ranked the top three among all cancer types. Among the co-mutated genes with ERBB2 mutations, TP53 (68.8%), CDK12 (34.7%), and RARA(18.7%) have the highest proportion of mutations. Furthermore, among 10,967 RNA datasets in TCGA, breast cancer, esophageal squamous cell carcinoma, and gastric adenocarcinoma displayed the highest average expression levels of ERBB2. Patients with high ERBB2 expression exhibited similar TMB values to those with low ERBB2 expression. However, in breast cancer, colon cancer, lung adenocarcinoma and lung squamous carcinoma, ERBB2 high expression was signiﬁcantly associated with a higher proportion of activated mast cells, monocytes, and regulatory T cells, while the percentage of resting mast cells and M1 macrophages was notably lower.

Conclusions: Our study identiﬁed ERBB2 variation patterns among a cohort of Chinese solid tumor patients and demonstrated that ERBB2 abnormality high expression is associated with an activated immune system and a stronger inﬂammatory response. Our ﬁndings offer insights into the potential beneﬁts of using immune checkpoint inhibitors for this type of patient.

https://doi.org/10.1016/j.annonc.2023.09.1574

75P Double-stranded RNA transfection induced anti-tumour effect mediated by dual RIG-I and TLR-3 immune pathways

J.A. Tai1, C.Y. Chang2, T. Nishikawa1, K. Yamashita1, Y.D. Kuan1

1Device Application for Molecular Therapeutics, Graduate School of Medicine/Faculty of Medicine, Osaka University, Suita, Japan; 2Gene & Stem Cell Regenerative Therapy,Graduate School of Medicine/Faculty of Medicine, Osaka University, Suita, Japan

Background: Cancer immunotherapy is dependent on immunostimulation to reorganise the tumour microenvironment (TME) and to increase anti-tumour effects of immune cells. There are currently many immunostimulants applicable to cancer therapy, such as antibodies, molecular drugs and PAMP activators. Choice of immunostimulant may be key, but method of delivery of treatment is equally as important as different routes may stimulate different immune pathways. Despite of the rapid development of nucleic acid drugs in recent years, the effect of nucleic acid on tumor immunity needs to be further investigated. Polyinosinic:polycytidylic acid (poly I:C) is a synthetic double-stranded RNA analog that shows promise as an adjuvant in cancer vaccines or immunotherapies. Poly I:C is known to interact with Toll-like receptor 3(TLR3) when taken up by endocytosis, but when directly transfected into cells, poly I:C stimulates retinoic acid-inducible gene I (RIG-I) instead.

Methods: Poly I:C was used to mimic anti-tumour response after nucleic acid administration. Murine 4T1 mammary tumour-bearing BALB/c mice were treated with poly I:C by electroporation (EP) or syringe injection (SI) and monitored for

tumour growth. To determine whether poly I:C-activated immune pathways differed between delivery modes, RIG-I and TLR3 pathway inhibitors were used to inhibit poly I:C-induced anti-tumour effect in 4T1 tumour model.

Results: Our results showed that poly I:C EP treatment induced stronger tumour suppression effect and tumour-speciﬁc adaptive immune response than via SI. And that this EP-treated anti-tumour effect could be suppressed by both RIG-I and TLR3 pathway inhibitors, but not in SI, suggesting that treatment of poly I:C via different delivery modes do activate different immune pathways.

Conclusions: We have demonstrated that poly I:C could induce different anti-tumour effects dependent on treatment delivery method. Our results suggest that the effects of nucleic acid drugs may vary depending on how they are administered.

Legal entity responsible for the study: Osaka University.

Funding: Osaka University.

https://doi.org/10.1016/j.annonc.2023.09.1575

76P Improvement of whole-cell cancer vaccine anti-tumor effect by different injection methods

C.Y. Chang1, J.A. Tai2, Y.D. Kuan3, T. Nishikawa4, K. Yamashita2, M. Shimamura1

1Gene & Stem Cell Regenerative Therapy, Graduate School of Medicine/Faculty of Medicine, Osaka University, Suita, Japan; 2Device Application for Molecular Therapeutics, Graduate School of Medicine/Faculty of Medicine, Osaka University, Suita,Japan; 3Graduate School of Medicine, Osaka University, Suita, Japan

Background: It is common for cancer to recur even after successful treatment of the primary tumor. Recurrent or metastatic cancers are less responsive to existing therapies and often have high mortality rate. Whole-cell cancer vaccine, which utilizes patient-derived primary tumor tissue may be a promising approach in preventing recurrence. A major advantage is the provision of a plethora of patient-speciﬁc tumor antigens, but overall whole-cell vaccine efﬁcacy is still limited and insufﬁcient. To improve on the efﬁcacy of whole-cell cancer vaccine, we explored the use of different injection methods. It has been previously shown that injection method and location of injection may vary vaccine efﬁcacy and effects. Therefore, we investigated different injection methods to improve the effectiveness of the whole-cell cancer vaccine.

Methods: We compared the efﬁcacy of needle-syringe injection and needle-free(pyro-drive jet injector) injection to evaluate the differences in effectiveness of wholecell cancer vaccines using murine MC38 colon adenocarcinoma or 4T1 mammary tumor cell lines, by analyzing tumor challenge and the inhibition of cancer metastasis using the C57BL/6 and BALB/c mouse models. We also analyzed the in vitro activation of APCs and innate immune cells using the expelled whole-cell vaccine following each injection method by ﬂow cytometry, cytokine array and quantitative real-time PCR.

Results: Our results showed that whole-cell vaccine administered via needle-free injection induced higher tumor suppression effect and stronger tumor-speciﬁc immunity than traditional needle-syringe injection in both MC38 and 4T1 tumor models.

In vitro, the whole-cell cancer vaccine preparation discharged through the needle-free injection device induced a stronger immune stimulation on immune cells than from the syringe method.

Conclusions: In contrast to needle injection, needle-free injection of whole-cell cancer vaccine resulted in more pulverized cancer cell fragments, which potentiates APC phagocytosis and adaptive immune activation, thereby improving anti-tumor effect of the vaccine. Therefore, needle-free injection or pre-pulverized formulations should be considered to improve anti-tumor effects of whole-cell cancer vaccines.

Funding: Japanese Government KAKEN Grants.

https://doi.org/10.1016/j.annonc.2023.09.1576

S209

77P

Normative data on the sexual health questionnaires - QLQSHQ22, and the sexual domains of the QLQ-BR23/BR45 - for Norwegian general population with and without cancer

R.E. Åsberg1, G. Giskeødegård2, M.J. Hjermstad3, K.V. Reinertsen4, J. Karlsen5,M. Nilsen6, R.J. Reidunsdatter7

1Department of Circulation and Medical Imaging, NTNU - Norwegian University of Science and Technology - Faculty of Medicine and Health Sciences, Trondheim, Norway; 2Department of Public Health and Nursing,K.G. Jebsen Center for Genetic Epidemiology, NTNU - Norwegian University of Science and Technology, Trondheim,Norway; 3Department of Oncology, Regional Advisory Unit for Palliative Care, Oslo University Hospital - Ulleval Hospital, Oslo, Norway; 4National Advisory Unit for Late Effects After Cancer Treatment, Departement of Oncology, Oslo University Hospital -The Norwegian Radium Hospital, Oslo, Norway; 5Department of Oncology, St. Olavs Hospital, Trondheim, Norway; 6Department of Social Work, NTNU - Norwegian University of Science and Technology, Trondheim, Norway; 7Department Of Circulation And Medical Imaging, NTNU - Norwegian University of Science and Technology,Trondheim, Norway

Background: Sexual dysfunction is of the most common late effects after cancer.

Normative general population data on sexual health is essential for supporting the interpretation of patient-reported outcomes (PROMs) in cancer studies and clinical practice and can contribute to improve survivorship care. This study aims to provides age-, sex- and morbidity speciﬁc Norwegian normative values for the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires; the Sexual Health Questionnaire QLQ-SHQ22, and the sexual domains of the breast modules QLQ-BR23/QLQ-BR45 inindividuals with and without history of cancer.

Methods: A nationwide general population sample stratiﬁed by sex and age (18e29,30e39, 40e49, 50e59, 60e69, 70-79 years) was drawn from the Norwegian Population Register. Participants were notiﬁed through National online health services and postal mail. The survey included sociodemographic background, morbidity assessed bythe Self-Administered Comorbidity Questionnaire and sexual health assessed by the sexual health EORTC questionnaires.

Results: Of the 15,627 eligible individuals, 5,135 (33%) responded. Among these, 453 persons reported being diagnosed one or several times with cancer, and 4669 persons had no former history of cancer (breast, prostate, gynecological and others). Individuals with cancer scored signiﬁcantly lower (p<0.01) on several functional scales:libido (scores 54 vs. 70), sexual functioning (45 vs 58), sexual enjoyment (67 vs 76),and for women femininity (65 vs. 84). The most prominent differences in symptoms were fatigue (32 vs 20) and worry of incontinence (27 vs. 9). Women and individuals with comorbidities had in general poorer sexual health, and differences were most pronounced in the youngest age groups.

Conclusions: The present study is the ﬁrst to use normative EORTC data to compare sexual health in individuals with- and without cancer. Sexual health was in general signiﬁcantly poorer in individuals with history of cancer compared to individuals without cancer.

Legal entity responsible for the study: Randi Johansen Reidunsdatter.

Funding: Norwegian Cancer Society and Norwegian Breast Cancer Society.

https://doi.org/10.1016/j.annonc.2023.09.1577

78P Peroxiredoxin-1 knockout negatively affects the viability of ph+ B-cell acute lymphoblastic leukemia cells and sensitizes them to tyrosine kinase inhibitors

J. Hunia1, Ł Komorowski1,2, K. Szczygieł3, M. Firczuk1,4

1Department of Immunology, Medical University of Warsaw, Warsaw, Poland; 2Hospital pital for Sick Kids, Toronto, ON, Canada; 3Polpharma Biologics SA, Gdansk, Poland;for Sick Kids, Toronto, ON, Canada; 3Polpharma Biologics SA, Gdansk, Poland;4Laboratory of Immunology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland

Background: Breakpoint cluster region-Abelson (BCR:ABL1) gene fusion is an essential oncogene in both chronic myeloid leukemia (CML) and Philadelphia-positive (Ph+) Bcell acute lymphoblastic leukemia (B-ALL). While tyrosine kinase inhibitors (TKIs) are effective in up to 95% of CML patients, 50% of Ph+B-ALL cases do not respond to treatment or relapse. This calls for new therapeutic approaches for Ph+B-ALL. Dysregulation of redox homeostasis and reliance on the thioredoxin (TXN) antioxidant system has been previously shown in B-ALL. Herein, we investigated the role of peroxiredoxin-1 (PRDX1), an enzyme responsible for the scavenging of hydrogen peroxide, in Ph+myeloid and lymphoid leukemia.

Methods: PRDX1 knockout and apoptotic proteins were assessed by immunoblotting.

The numbers of viable BV173 (lymphoid) and K562 (myeloid) cells were evaluated by light microscope counting after discriminating dead cells with Trypan Blue staining.

Cell cycle and proliferation were assessed with MUSE and Click-iT EdU tests,respectively. The viability of K562 and BV173 knockouts treated with TKIs was assessed with propidium iodide staining and ﬂow cytometry.

Results: PRDX1 knockout reduced the numbers of viable BV173 cells grown in vitro,but did not affect the numbers of K562 cells. The addition of hydrogen peroxide

scavenges to the culture medium restored the viability of BV173 cells. We observed no signiﬁcant differences in cell proliferation or in cell cycle fractions in BV173sgPRDX1 cells. Notably, in contrast to the myeloid K562 cell line, lymphoid BALL cells lacking PRDX1 were much more sensitive to three tested TKIs: imatinib,dasatinib, and ponatinib.

Conclusions: The results reveal that the important role of PRDX1 for Ph+leukemic cell viability and sensitivity to TKIs is restricted to lymphoid leukemias. The observed reduced numbers of PRDX1 knockout cells were not the effect of an altered cell cycle or proliferation but most likely due to increased apoptosis. These ﬁndings are part of a larger ongoing in vitro and in vivo study examining the sensitization of Ph+lymphoid leukemia to TKIs through inhibition of the thioredoxin system and PRDX1.

Legal entity responsible for the study: Medical University of Warsaw.

Funding: SONATA BIS 2015/18/E/NZ5/00723 grant funded by the National Science Centre, entitled “Novel pro-oxidative strategies in the treatment of B cell acute lymphoblastic leukemia”.

https://doi.org/10.1016/j.annonc.2023.09.1578

79P Co-delivered crizotinib and geﬁtinib based on nanoparticle for synergically overcoming resistance lung

adenocarcinoma treatment

H. Zhou1, J. Deng1, B. Xu1, F. Zeng2

1Department of Thoracic Surgery, Guangdong Province People’s Hospital, Guangzhou,China; 2Institute of Geriatrics, Guangdong Province People’s Hospital, Guangzhou,China

Background: Geﬁtinib has been employed as a ﬁrst-line treatment for patients with NSCLC with EGFR mutation, but rapid drug resistance in tumors induces disease progression. Overactivation of PI3K/AKT is associated with geﬁtinib resistance (GR) in lung adenocarcinoma. Clinically, crizotinib inhibits AKT and extracellular regulated protein kinases (ERK) signal activation in various tumor cells.

Methods: Geﬁtinib and crizotinib were loaded into a hydrophobic core, which was formed by the amphiphilic block poly (ethylene glycol)epoly (hexyl ethylene phosphate) (GC@NP) through nano self-assembly method. And the anti-tumor effect and mechanism of GC@NP were veriﬁed in vivo and in vitro.

Results: According to particle characterization results, GC@NP had a homogeneous and and stable nanoscale, which was 40.1±1.1 nm. Especially, GC@NP had a good drugstable nanoscale, which was 40.11.1 nm. Especially, GC@NP had a good drugloading efﬁciency, the values are 6.52 0.21% and 7.09 0.39% for geﬁtinib loading efficiency, the values are 6.52 ± 0.21% and 7.09 ± 0.39% for gefitinib andandcrizotinib respectively. At the cellular level, GC@NP can be effectively ingested by PC9GR cells within 2 hours. When the concentration of geﬁtinib was set to 2 mM, the cell viability of the free geﬁtinib group was 90%, while GC@NP group was only about 50%. At the same time, GC@NP exhibited higher proliferative inhibition and apoptotic induction effects compared to free geﬁtinib group, the apoptosis rates were 25% and 5% respectively. At the animal level, GC@NP signiﬁcantly inhibited the growth and metastasis of PC9GR tumors, and also inhibited the brain metastasis associated with GR. Meanwhile, we validated GC@NP has good biosafety in the transgenic zebraﬁsh model. In the nude mouse tumor model, our results indicate that GC@NP can signiﬁcantly inhibit the growth of PC9GR tumors, while the combination of free geﬁtinib and crizotinib didn’t show signiﬁcant therapeutic effects. Mechanistically and importantly, GC@NP synergism promoted the dephosphorylation of the overactivated AKT signal and inhibited the feedback activation of ERK signal, which inducing apoptosis in PC9GR cells.

Conclusions: The co-delivery nanoparticle GC@NP we have constructed provides a potential therapeutic approach for advanced lung adenocarcinoma patients with targeting-drug resistance and brain metastasis.

Legal entity responsible for the study: Haiyu Zhou.

https://doi.org/10.1016/j.annonc.2023.09.1579

80P

Steroidal oximes: A new potential therapeutic approach for cancer treatment

M. Laranjo1, A.R. Gomes2, S. Costa3, A.M. Abrantes1, A.C. Gonçalves4, R. Alves4,M.F. Botelho1, E. Tavares-da-Silva5, S. Pires1, F. Roleira5

1Coimbra Institute for Clinical and Biomedical Research (iCBR) area of Environment Genetics and Oncobiology (CIMAGO), Biophysics Institute of Faculty of Medicine; CIBB;CACC, Univ Coimbra, Coimbra, Portugal; 2Coimbra Institute for Clinical and Biomedical Research (iCBR), CIMAGO, Biophysics Institute of Faculty of Medicine; CIEPQPF, Faculty of Pharmacy, Laboratory of Pharmaceutical Chemistry, Univ Coimbra, Coimbra,Portugal; 3Faculty of Pharmacy, Laboratory of Pharmaceutical Chemistry, Univ Coimbra, Coimbra, Portugal; 4Coimbra Institute for Clinical and Biomedical Research(iCBR) area of Environment Genetics and Oncobiology (CIMAGO), Laboratory of Oncobiology and Hematology and University Clinics of Hematology and Oncology,Faculty of Medicine; CIBB; CACC, Univ CoimbraA, Univ Coimbra, Coimbra, Portugal;5CIEPQPF, Faculty of Pharmacy, Laboratory of Pharmaceutical Chemistry, Univ Coimbra, Coimbra, Portugal

Background: Cancer still remains one of the life-threatening diseases worldwide despite the large number of therapeutic approaches currently available. Steroidal compounds possess numerous biological activities being antitumor one of them.

Oximes have also been associated with antitumor activity. Moreover, previous studies by our group demonstrated that steroidal oximes were also very potent against several types of cancer. Thus, we embarked in the design and synthesis of new steroidal oximes and evaluated their potential antitumor activity against lung, prostate,and triple-negative breast cancer cells, with the aim of ﬁnding alternative cytotoxic compounds for cancer treatment.

Methods: Compounds OX1, OX2, ExeOx and Formox and their parent compounds P1,OL2, Exe and Form were synthesized, and their cytotoxicity evaluated in H1299, PC3 and HCC1806 cell lines through SRB assay after the treatment of the cells with the compounds (1-75 mM). Cell viability, cell death proﬁle, alterations on cell cycle and mitochondrial membrane potential were assessed by ﬂow cytometry.

Results: All compounds decreased H1299, PC3 and HCC1806 cancer cell proliferation in a dose-dependent manner, with the exception of OX2. Overall, the parent compounds decreased cancer cell proliferation in a less pronounced way, proving that the introduction of an oxime group was beneﬁcial for the cytotoxicity displayed. Moreover, the best compound was OX1 in all cell lines with IC50 values of 18.69, 22.90 and

29.95 mM in H1299, HCC1806 and PC3, respectively. Flow cytometry studies with OX1 showed that this compound was able to decrease cell viability in all cell lines by causing cell death mainly by apoptosis, which was accompanied by a blockage at phases G2/M and S, depending on the cell line. Considering the mitochondrial membrane potential, OX1 induced mitochondrial dysfunction, which might also be related to apoptosis.

Conclusions: Our results show that OX1 possesses a beneﬁcial antitumor effect from the introduction of the oxime group, which is mediated by apoptosis. This effect encourages further studies on its mechanism of action and selectivity in order to discover new molecules for cancer treatment.

Funding: Foundation for Science and Technology (FCT), Portugal (Strategic Projects UID/NEU/04539/2019, UIDB/04539/2020, UIDP/04539/2020); COMPETE-FEDER(POCI-01-0145-FEDER-007440); PhD Fellowship from FCT and European Social Funding of Ana R. Gomes (UI/BD/150865/2021).

https://doi.org/10.1016/j.annonc.2023.09.1580

81P miR-23b and -133a role on TRAIL-induced apoptosis

pathway components expression and TRAIL sensitization in lung adenocarcinoma cells

D. Leite, E. Maquigussa, M.A. Boim

Medicine Department, UNIFESP, São Paulo, Brazil

Background: TRAIL-induced apoptosis pathway is a potential therapeutic target, but the majority of tumors are TRAIL-resistant. TRAIL receptors translocation is associated to TRAIL resistance. Besides TRAIL receptors, DR4 and DR5, other potentially TRAILinduced apoptosis pathway regulatory proteins are: Apaf-1, CUL3, CLTA (clathrin chain A , involved in TRAIL receptors nuclear translocation) and KPNA-1 ( involved in TRAIL receptors internalization). Overcome TRAIL resistance is essential to therapeutic strategies development.

6.90 months (95%CI, 4.90-9.20). 10 pts who developed FGFR2 kinase domain mutations (N549D/H/K/T, V564F/I/L, E565A/G/K) detected by liquid biopsy at baseline had ORR of 50%, DCR of 90% and mPFS of 7.03 months (95%CI, 0.95-11.86).

Conclusions: These pooled results suggest that tinengotinib has a manageable toxicity proﬁle in CCA pts. Notable clinical beneﬁt was noted with tinengotinib in FGFRaltered CCA pts with acquired resistance to prior FGFRi. A global phase III clinical trial is planned to further evaluate the efﬁcacy and safety of tinengotinib for CCA with FGFRi resistance.

Clinical trial identiﬁcation: NCT03654547, NCT04742959, NCT04919642.

Legal entity responsible for the study: TransThera Sciences (Nanjing), Inc.

Funding: TransThera Sciences (Nanjing), Inc.

Disclosure: M. Javle: Financial Interests, Personal, Advisory Role: QED Therapeutics, Oncosil,Incyte, Mundipharma, AstraZeneca, Merck, EMD Serono, Basilea Pharmaceutical; Financial Interests,Personal, Other: Rafael Pharmaceuticals, Incyte, Pieris Pharmaceuticals, Merck, Merck Serono,Novartis, Seagen, BeiGene, QED Therapeutics, Bayer, TransThera Biosciences. C. Liao: Financial Interests, Personal, Advisory Board: Incyte, AstraZeneca, Lantheus, Eli Lilly, Transthera, Ipsen; Financial Interests, Personal, Trial Chair: BMS. C. Fountzilas: Financial Interests, Institutional, Research Grant:Pﬁzer Inc, Taiho Oncology, Merck Sharp & Dohme Corp., National Comprehensive Cancer Network;Financial Interests, Institutional, Local PI: Seattle Genetics, Inc., TransThera Biosciences, AstraZeneca,Aravive, Inc., Merck Sharp & Dohme Corp., Puma Biotechnology, Kadmon, Astellas Pharma, Pﬁzer Inc, Dragonﬂy Therapeutics, MedImmune, LLC., Hoosier Cancer Research Network, Incyte Corporation, Rafael Pharmaceuticals, Kinex Phamaceuticals, Syndax Pharmaceuticals, SWOG, National Cancer Institute, Erythech Pharma, Lilly, Corcept Therapeutics, Ipsen, CG Pharmaceuticals, Biomea Fusion, Bellicum, Amgen Inc.; Non-Financial Interests, Institutional, Other, Principal Investigator on upcoming clinical trial evaluating biomarker for treatment selection in pancreatic cancer: Valar Labs.

D. Li: Financial Interests, Personal, Other, Consulting Fees: AstraZeneca, Eisai, Exelixis, Genentech,Ipsen Biopharmaceuticals, Merck, QED, Servier, DelCath, TerSera Therapeutics; Financial Interests,Institutional, Research Grant: Brooklyn Immunotherapeutics, AstraZeneca. M.S. Pelster: Financial Interests, Institutional, Other, Consulting: AstraZeneca, Bayer, CytomX, Daiichi Sankyo, Ipsen,Novartis, Pﬁzer, Seagen; Financial Interests, Institutional, Local PI: Agenus, Arcus Biosciences,Astellas, BeiGene, BioNTech, Bristol Myers Squibb, Codiak Biosciences, Eisai, Gilead, Gritstone Oncology, HiberCell, Immune-Onc Therapeutics, Leap Therapeutics, Novartis, OncXerna Therapeutics, Panbela Therapeutics, Revolution Medicines, Surface Oncology, SQZ Biotechnologies,

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Translational Genomics, TransThera Sciences, ZielBio, 1200 Pharma. S.A. Piha-Paul: Financial Interests, Personal, Advisory Role: CRC Oncology; Financial Interests, Institutional, Research Funding:AbbVie, Aminex, Biomarin, Boehringer Ingelheim, Bristol Myers Squibb, Cerulean Pharma, Chugai Pharma, Curis, Five Prime Therapeutics, Genmab, GSK, Helix BioPharma, Incyte, Jacobio, MedImmune, Medivation, Merck Sharp & Dohme, Novartis, Pieris Pharmaceuticals, Pﬁzer, Principa Biopharma, Puma Biotechnology, RAPT Therapeutics, Seagen, Taiho Oncology, Tesaro, TransThera Biosciences, Amphivena Therapeutics, Alkermes, Daiichi Sankyo, Lilly, ABM, Acepodia, ENB Therapeutics, Gene Quantum, Silverback Therapeutics, NIH/NCI, Cyclacel, F-Star, HiberCell, Immunomedics, Lytix Biopharma, Gilead Sciences, Phanes Therapeutics, Purinomia, ZielBio, Hengrui Pharmaceutical, Replimune, Synlogic, Epigenetix, Immorna, Jiangsu Simcere Pharmaceutical Co. Ltd.,Nectin Therapeutics. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1388

96P

Comparing the outcome of doublet therapy (gemcitabine and cisplatin) with triplet therapy (gemcitabine and

cisplatin, nab paclitaxel) in locally advanced or metastatic gall bladder cancer patients an open label randomised control trial

C. Khatri1, R. Rattan2, A. Narwariya2, P.K. Das2, J. Patowary2

1Medical Oncology Department, Charak Hospital and Research Centre Lucknow, Uttar Pradesh, India; 2Medical Oncology Department, Indraprastha Apollo Hospital, New Delhi, India

Background: To compare the doublet gemcitabine and cisplatin which is a standard of care in locally advanced or metastatic gall bladder cancer to a triplet gemcitabine,cisplatin and nab paclitaxel regime which has shown promising results in a single arm phase II study.

Methods: A total of 60 patients with locally advanced or metastatic gall bladder cancer were randomized 30 in each arm after imaging [contrast enhanced CT scan of chest, abdomen, and pelvis / MRI abdomen and pelvis with CECT chest /whole-body PET CT scan] and biopsy. Arm A received two drugs gemcitabine 1000mg/m2 i.v and cisplatin 25mg/m2 i.v on Day1 and Day8 of 21-day cycle and arm B received three drugs gemcitabine, 1000 mg/m2 , cisplatin, 25 mg/m2 , and nab-paclitaxel, 125 mg/m2 , on days 1 and 8 of 21-day cycle. Evaluation was done post 3 and 6 cycles of chemotherapy. Then patients were followed up every 6 months for 2 years period for assessment of primary and secondary endpoints of the study.

Results: The combination of gemcitabine and cisplatin (arm A) showed an overall radiological response rate (complete response and partial response) of 13.3% while it was 61.9 % in patients who received gemcitabine, cisplatin, and nab-paclitaxel. This difference was statistically signiﬁcant with a p-value of 0.004. The median progression-free survival for the patients who received gemcitabine and cisplatin was 4.5 months (95% CI, 4.0-4.9) vs 7.6 months (95% CI, 3.9-11.2) for the patients who were treated with gemcitabine, cisplatin, and nab-paclitaxel. This difference was statistically signiﬁcant with a p-value of 0.05. The median overall survival for the doublet significant with a p-value of ≤0.05. The median overall survival for the doublet waswas9.2 months (95% CI 2.6-15.7) vs not reached for the patients who were treated with gemcitabine, cisplatin, and nab-paclitaxel. There was no increase in grade 3 adverse events with the addition of nab-paclitaxel.

Conclusions: To conclude, our study showed that the triplet chemotherapy with gemcitabine and cisplatin and nab-paclitaxel was signiﬁcantly better in terms of overall response rate, and median progression-free survival with a longer follow up needed to comment on median overall survival.

Clinical trial identiﬁcation: CTRI/2021/09/036362.

Legal entity responsible for the study: C. Khatri.

https://doi.org/10.1016/j.annonc.2023.09.1389

97P Neoadjuvant durvalumab plus gemcitabine and cisplatin(D+GemCis) versus gemcis alone for localized biliary tract cancer (BTC): Results of a randomized, multicenter, openlabel, phase II trial (DEBATE)

C. Yoo1, J.O. Park2, K-P. Kim1, J. Hyung1, B-Y. Ryoo1, J.Y. Hong3, S.H. Shin4, T.J. Song5,D. Oh5, W. lee6, B.J. Kwak6, J.H. Lee6, D.W. Hwang6

1Oncology, Asan Medical Center - University of Ulsan College of Medicine, Seoul,Republic of Korea; 2Hematology/Oncology, Samsung Medical Center (SMC) - Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 3Hematology/Oncology, Samsung Medical Center (SMC), Seoul, Republic of Korea; 4Surgery, Samsung Medical Center (SMC), Seoul, Republic of Korea; 5Gastroenterology, Asan Medical Center - University of Ulsan, Seoul, Republic of Korea; 6Surgery, Asan Medical Center - University of Ulsan, Seoul, Republic of Korea

Background: D+GemCis demonstrated signiﬁcantly improved efﬁcacy in patients (pts)with advanced/metastatic BTC compared to GemCis alone. However, the efﬁcacy of D+GemCis in the neoadjuvant setting has not been studied.

Methods: This was a multicenter, open-label, non-comparative, randomized phase 2 trial including treatment-naïve pts with histologically or cytologically conﬁrmed localized BTC. Pts were randomly assigned (2:1) to receive either 4 cycles of neoadjuvant D+GemCis or GemCis alone. Postoperative 6 cycles of D were given if pts underwent surgery regardless of assigned neoadjuvant therapy. The primary endpoint was R0 resection rate. ctDNA analysis was performed using GuardantOmni platform.

Results: A total of 45 pts were enrolled (n¼31 in the D+GemCis arm and 14 in theGemCis arm). Intrahepatic cholangiocarcinoma (n¼18, 40%) was the most commonprimary tumor site and 69% (n¼31) had clinical stage III. Response rates were 36%(n¼11) in the D+GemCis arm and 7% (n¼1) in the GemCis alone arm. In theD+GemCis and GemCis arms, surgical exploration was performed in 68% (n¼21) vs36% (n¼5), curative-intent resection (R0+R1) in 61% (n¼19) vs 36% (n¼5), and R0resection in 48% (n¼15) vs 36% (n¼5), respectively. Median PFS were 15.1 mo (95%CI, 4.5-25.8) in the D+GemCis arm and 3.6 mo (0-13.0) in the GemCis alone arm. Pts able to receive curative-intent surgery after study treatment had signiﬁcantly better overall survival (p<0.001). No new safety signal for D+GemCis were identiﬁed. ctDNA analysis revealed that 5 pts (11%) had actionable genetic alterations including 4 with IDH1 R132C and 1 with ERBB2 ampliﬁcation, and 2 pts (4%) were MSI-H.

Conclusions: Neoadjuvant D+GemCis resulted in a higher surgical resection rate in pts with localized BTC, and surgical resection was associated with better survival. ctDNA analysis was shown to be a feasible method for assessing actionable target gene alterations in early BTC.

Clinical trial identiﬁcation: NCT04308174.

Funding: AstraZeneca and CKD Pharmaceuticals.

Disclosure: C. Yoo: Financial Interests, Personal, Invited Speaker: Bayer, Celgene, Eisai, Ipsen,Servier, ,Roche, Novartis; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Research Grant: AstraZeneca, Bayer, Servier; Financial Interests, Institutional,Research Grant: Genentech. J.O. Park: Financial Interests, Personal, Advisory Board: MedPacto, BMS(Celgene), Servier, MediRama, Adicet Bio, AstraZeneca, Merck Sereno; Financial Interests, Personal,Other, Travel support for a poster presentation at ASCO GI 2023: Minneamrita Therapeutics LLC;Financial Interests, Personal, Research Grant, Clinical research grant: MedPacto, Servier, BMS (Celgene); Financial Interests, Personal, Research Grant: Eutilex, ABL Bio. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1390

98P Efﬁcacy and safety of durvalumab plus gemcitabine and cisplatin in Chinese participants with advanced biliary tract cancer: Extension cohort of the phase III, randomised,

double-blind, placebo-controlled, global TOPAZ-1 study

S. Qin1, J-Q. Cai2, E. Li3, B. Xing4, L. Zhao5, C. Dai6, J. Li7, Y. Shen8, Z. Chen9, L. Liu10,Z. Lu11, A. Zang12, Y. Bai13, H. Liang14, J. Liang15, X. Liu16, J. Wang17, M-H. Chen18,R. Miao19, X. Qu19

1Department of Medical Oncology, Jinling Hospital, Nanjing, Jiangsu, China;2Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; 3Department of Medical Oncology,The First Afﬁliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China; 4Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education),Hepatopancreatobiliary Surgery Department I, Peking University Cancer Hospital and Institute, Beijing, China; 5Department of Hepatobiliary Surgery, Shandong Cancer Hospital; Institute Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China; 6Department of Hepatobiliary and Splenic Surgery, Shengjing Hospital Afﬁliated to China Medical University, Shenyang, China;7Department of Oncology, The First Afﬁliated Hospital, Nanchang University, Nanchang, China; 8Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Afﬁliated Hospital, School of Medicine, Zhejiang University, Hangzhou,China; 9Department of Medical Oncology, The Second Afﬁliated Hospital of Anhui Medical University, Hefei, China; 10Department of Hepatobiliary Surgery, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Afﬁliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; 11Department of Hepatobiliary Surgery, The First Afﬁliated Hospital of Bengbu Medical College, Bengbu, China; 12Department of Medical Oncology, Afﬁliated Hospital of Hebei University, Baoding, China; 13Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China;14Department of Oncology, Southwest Hospital, Third Military Medical University,Chongqing, China; 15Department of Oncology, The First Afﬁliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China; 16Department of Medical Oncology of PLA Cancer Center, Jinling Hospital, Nanjing, China; 17Department of Internal Medicine, The Afﬁliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital,Zhengzhou, China; 18Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan; 19R&D, AstraZeneca, Shanghai, China

Background: At the TOPAZ-1 (NCT03875235) primary analysis, ﬁrst-line treatment with durvalumab (D) + gemcitabine and cisplatin (GC) signiﬁcantly improved overall survival (OS) and progression-free survival (PFS) v placebo (P) + GC; the regimen has been approved by multiple health authorities globally for advanced biliary tract

cancer (BTC).1Here, we present prespeciﬁed exploratory analyses in an extended cohort of TOPAZ-1 enrolled in China.

Methods: Participants (pts) with BTC were randomised 1:1 to D (1500 mg) or P every 3 3 weeks (Q3W) + GC (G 1000 mg/m2 and C 25 mg/m2 on Days 1 and 8 Q3W) for ≤8weeks (Q3W) + GC (G 1000 mg/m2and C 25 mg/m2on Days 1 and 8 Q3W) for 8cycles, followed by D (1500 mg) or P Q4W until disease progression, unacceptable toxicity or other discontinuation criteria. The primary endpoint was OS. Secondary endpoints included PFS, objective response rate (ORR) and safety. Results from the China cohort (data cut-off [DCO] 14 Oct 2022, 72.3% OS maturity) are compared with the global cohort (primary analysis; DCO 11 Aug 2021, 61.9% OS maturity)1and a pooled global + China cohort (China and pooled cohort analyses are exploratory).

Results: Mouse with Pulmonary metastasis of HCC showed higher level of EDMCs in the circulation and spleen than those without Pulmonary metastasis. CFSE EDMCs stained with 5，6- carboxyﬂuorescein diacetate, succinimidyl ester (CFSE) were detected in the lung of HCC mouse after infusion though caudal vein and those infused mice developed more frequency of pulmonary metastasis than those without EDMCs infusion. IN the coculture experiment EDMCs promoted the migration and invasion of hepa1-6 cells.

Conclusions: EDMCs existed in the circulation of HCC mouse model. EDMCs could migrated from the circulation to the lung of HCC mice. EDMCs could facilitate migration and invasion of hepa1-6 cells migrate and invade. Thus, EDMCs can promote Pulmonary metastasis in Hepatocellular Carcinoma.

Legal entity responsible for the study: Wei-hang Zhu.

Funding: National Natural Science Foundation of China (81972677, 82103331),Guangdong Basic and Applied Basic Research Foundation (No. 2021A1515011022,2022A1515010547).

https://doi.org/10.1016/j.annonc.2023.09.1590

92P Discovery of novel AXL and MER inhibitors as potential anticancer and immune modulator drugs

H-P. Hsieh1, M-C. Li1, W-C. Yen1, J.T-A. Hsu1, T-K. Yeh1, W-S. Li2, H-C. Wu3

1Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, ,Miaoli, Taiwan; 2Institute of Chemistry/Biomedical Translation Research Center, Academia Sinica, Taipei, Taiwan; 3Institute of Cellular and Organismic Biology/Biomedical Translation Research Center, Academia Sinica, Taipei, Taiwan

Background: In cancer progression, abnormal expression of AXL could lead to tumor growth and metastasis and resistance to chemotherapy, while MER could identify apoptotic cancer cells and induce immune suppression in the tumor microenvironment. Combination of AXL and MER inhibitors could generate a synergistic effect,

enhancing antitumor responses, and further suppressing resistance formed by monotherapy with AXL selective or MER selective inhibitors. According to the explicit function of AXL and MER, the development of dual AXL and MER inhibitors may provide tremendous advantages to cancer patients.

Methods: Based on our experience in the discovery of an anti-EGFR and anti-HER2 clinical candidate, we introduced several AXL-active and MER-active pharmacophores into DBPR112. We also modiﬁed the scaffold and the solubilizing groups to improve the drug-like properties. We have constructed a comprehensive SAR study to discover promising AXL and MER inhibitors.

Results: Upon synthesizing about 200 compounds, we identiﬁed several potent dual AXL and MER inhibitors. These compounds were evaluated for their anti-AXL and antiMER activities, as well as their anti-tumor abilities. Our candidate 5K230 exhibited satisﬁed oral bioavailability (F% ¼ 55%) and promising in vivo antitumor effects inseveral mouse xenograft models, including MDA-MB-231, 4T1, MC-38 tumors. Our compound also overcome erlotinib-acquired resistance via the combination with erlotinib in the PC9 xenograft model.

Conclusions: We have described the discovery of potential AXL and MER inhibitors, in which we identiﬁed potential candidate 5K230 which showed potent anti-AXL and anti-MER activities. Moreover, 5K230 displayed anti-tumor efﬁcacy in several mouse xenograft models. Further preclinical evaluation of 5K230 is underway to develop it as a promising anticancer and immune modulator drug.

Legal entity responsible for the study: National Health Research Institutes.

Funding: National Health Research Institutes.

https://doi.org/10.1016/j.annonc.2023.09.1591

93P Transcriptome changes of immune cells across chemotherapy of triple-negative breast cancer

T.S. Gerashchenko1, A. Frolova2, A.A. Fedorov1, M. Patysheva1, M. Vashisth3,P. Iamshchikov1, O. Bragina4, N. Cherdyntseva2

1Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russian Federation; 2Laboratory of Molecular Oncology and Immunology, Cancer Research Institute,Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk,Russian Federation; 3Psychology, National Research Tomsk State University, Tomsk,Russian Federation; 4Department of Radionuclide Therapy and Diagnostics, Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russian Federation

Background: Immune system plays an important role in the development, treatment response, and progression of triple-negative breast cancer. Here, we aimed to assess the dynamics of cell populations and their transcriptome changes during neoadjuvant chemotherapy (NACT) in triple-negative breast cancer patients.

Methods: Mononuclear cells were puriﬁed from peripheral venous blood before NACT, after 3rd and 21st days of NACT using a ﬁcoll density gradient. Total cell concentration and viability (Calcein/DRAQ7) were assessed by ﬂow cytometry (Cytoﬂex,Beckman Coulter). Single cells were sequenced on a NextSeq 2000 (Illumina) using targeted panel Immune Response from Rhapsody Express (Becton Dickinson). Data were analyzed using Seurat and SingleR.

Results: According to single cell sequencing data we revealed 10 main populations of mononuclear leukocytes: C cells (CD79+), NK cells (KIR2DL+), classical (CD14+) and non-classical (CD16+) monocytes, T-cytotoxic cells (CD8+), T-helpers (CD4+), T-regs(FOXP3+), CD4 memory cells (CD4+, IL32+, KLRB+, RGS1+), CD8 naïve (CD8+, LEF1+,CCR7+, PIK3IP1+), CD4 naïve (CD4+, LEF1+, CCR7+, PIK3IP1+). 3 days after NACT overexpression of BAX, FOSb, JUN, CXCR4, CD69 genes were observed, that mediating apoptosis of CD4 memory/naïve and CD8 naïve lymphocytes, T regs and monocytes;chemotaxis and proliferation of NK and T-cytotoxic lymphocytes. The population of blood monocytes was selectively depleted (up to 3%). 21 days after NACT overexpression of CCR2, S100A9, ITGAM, CXCL8, CCL4, CCL5 genes were observed,mediating migration of monocytes to tissue, chemotaxis of immune cells and inﬂammation. The population of monocytes increased by up to 20%.

Conclusions: Chemotherapy affects the quantitative and qualitative composition of mononuclear leukocytes and changes their transcriptomic proﬁle towards proin-ﬂammatory activation. This study was funded by the Russian Science Foundation(grant #22-75-10128).

Funding: Russian Science Foundation, no.22-75-10128.

https://doi.org/10.1016/j.annonc.2023.09.1592

BILIARY TRACT CANCER, INCL. CHOLANGIOCARCINOMA

94MO

Volume

Advanced extrahepatic cholangiocarcinoma: Post-hoc analysis of the ABC-01, -02 and -03 clinical trials

A. Lamarca1, P.J. Ross2, H.S. Wasan3, R. Hubner4, M.G. McNamara4, A. Lopes5,D. Palmer6, J.W. Valle5, J.A. Bridgewater7

1Medical Oncology Department, Hospital Universitario Fundacion Jimenez Diaz,Madrid, Spain; 2Medical Oncology Department, Guy’s Hospital, London, UK;3Oncology Department, Hammersmith Hospital - Imperial College Healthcare NHS Trust, London, UK; 4Medical Oncology Department, The Christie NHS Foundation Trust,Manchester, UK; 5Medical Oncology, CRUK & UCL Cancer Trials Centre, London, UK;6Liverpool Clinical Trials Centre, University of Liverpool - Imaging Centre at Liverpool,ICaL (formerly NiCaL), Liverpool, UK; 7Medical Oncology, UCL Cancer Institute - Paul O’Gorman Building, London, UK

Background: Prior data suggest that patients with iCCA have a better prognosis

compared to other biliary tract tumours (BTC) (Lamarca et al, JNCI 2019). However,

the outcome for eCCA is not well described and some of the current studies focused

on this patient population may be challenging to contextualise.

Methods: The aim of this post-hoc analysis is to provide reference survival data for

patients with advanced eCCA treated with ﬁrst-line cisplatin-gemcitabine (CisGem)

chemotherapy within the prospective, randomised Advanced Biliary tract Cancer

(ABC)-01, -02 and -03 studies. Individual level data from patients with eCCA recruited

to these studies were retrieved.Survival analysis was performed using univariate and

multivariable Cox Regression. All statistical tests were two-sided.

Results: Of 534 patients recruited into the ABC-01, -02 and -03 studies,179 (33.5%)

had eCCA (107 distal (dCCA), 72 hilar (hCCA)). Of these, 117 were treated with CisGem and eligible for analysis. Most patients (n¼82; 70.1%) had metastatic disease atthe time of recruitment. Objective radiological response was achieved in 28 (23.9%)

of eCCA: 19 dCCA (27.9%) and 9 (18.4%) hCCA. The median progression-free survival

(PFS) for eCCA, dCCA and hCCA were 8.4 (95% CI 7.36-9.33), 8.3 (95% CI 6.3-9.4) and

8.4 months (6.5-10.6), respectively; median overall survival (OS): 12.8 months (95%CI

10.4-16.1), 14.3 (95% CI 8.8-17.4) and 12.2 (95% CI 8.3-16.1), respectively. eCCA with

locally advanced disease had longer median PFS (13.1 (95% CI 8.8-16.6) and OS (17.4

(95% CI 14.3-21.1) . Multivariable survival analysis for OS conﬁrmed worse OS for

eCCA with performance status of 2 (vs 0; HR 45.877 (95% CI 9.55-219.45)) and highMedian age was 60 years (24-81), 60% were female, 100% pts had ≥ 1 prior therapy baseline CA125 (HR 1.0007 (95% CI 1.0001-1.001; p-value 0.017) when adjusted for

other prognostic factors identiﬁed in the univariate analysis (stage, Ca 19.9). These

remained signiﬁcant when adjusted for site of eCCA (data not shown).

Conclusions: Patient outcomes were similar regardless of location of eCCA but worse

than those reported historically for iCCA (speciﬁcally OS). Performance status and

baseline tumour markers (CA125) were strongly associated with survival in eCCA.

Outcomes with ﬁrst-line CisGem + immunotherapy should also be explored.

Clinical trial identiﬁcation: NCT00262769; NCT00939848.

Legal entity responsible for the study: University College London (UCL).

Funding: This post-hoc analysis did not receive any external funding.The ABC-1, -02

and -03 clinical trials received funding from Cancer Research United Kingdom (CRUK)

and unrestricted educational grants from Lilly Oncology and AstraZeneca

Pharmaceuticals.

Disclosure: A. Lamarca: Financial Interests, Personal, Invited Speaker: AAA, AstraZeneca, Eisai,

GenFit, Incyte, Ipsen, Merck, Pﬁzer, QED, Servier, Advanz Pharma, Roche; Financial Interests, Personal, Advisory Board: Albireo Pharma, AstraZeneca, Boston Scientiﬁc, EISAI, GenFit, Ipsen, Nutricia,

QED, Roche, Servier, Taiho; Financial Interests, Personal, Writing Engagement: Incyte, QED, Servier;

Financial Interests, Institutional, Other, Access to FM molecular proﬁling: Roche; Non-Financial Interests, Principal Investigator, PI of trial: QED, Merck, AstraZeneca, Boehringer Ingelheim; Other,

Travel and educational support: Ipsen, Pﬁzer, Bayer, AAA, SIrTex, Novartis, Mylan, Delcath, Advanz

Pharma, Roche. H.S. Wasan: Financial Interests, Personal, Advisory Board, Advisory Boards and

Invited Speaker: Incyte, Pierre Fabre, Servier, Bayer, Roche/Genentech/ FM AG, Sirtex medical Erytech, Celgene, Array BioPharma, Merck KGaA: BMS; Financial Interests, Personal, Steering Committee Member, Trial steering committee and advisory: Zymeworks; Financial Interests, Personal and

Institutional, Coordinating PI, Trial PI steering committee and advisory: Sirtex Medical; Financial

Interests, Personal, Other, Consultancy for Submission for UK approval (BSI): ONCOSL; Non-Financial

Interests, Advisory Role, Trial steering committee: Pﬁzer; Non-Financial Interests, Advisory Role, UK

NICE submission: Bayer, Pierre Fabre. J.A. Bridgewater: Financial Interests, Personal, Advisory Board:

Taiho, BMS, Incyte, Basilea, Servier; Financial Interests, Institutional, Funding: Incyte. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1387

34 - Issue S2 - 2023

95MO Tinengotinib in patients with advanced, ﬁbroblast growth factor receptor (FGFR) inhibitor refractory/relapsed

cholangiocarcinoma

M. Javle1, L.A. Kankeu Fonkoua2, A. Mahipal3, C-Y. Liao4, C. Fountzilas5, D. Li6,M.S. Pelster7, S. Goel8, P. Peng9, C. Sun10, H. Wang10, K. Hennessy11, X. Fu10,L. Neo10, Y. Shan10, P. Huang10, D. Wu12, F. Wu9, J. Fan11, S.A. Piha-Paul13

1Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA;2Hematology and Oncology Department, Mayo Clinic, Rochester, NY, USA; 3Department of Oncology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA;4Gastrointestinal Oncology, University of Chicago e Department of Medicine, Chicago,IL, USA; 5Medicine Department, Roswell Park Comprehensive Cancer Center, Buffalo,NY, USA; 6Medical Oncology Department, City of Hope Comprehensive Cancer Center,Duarte, CA, USA; 7Gastrointestinal Research, Sarah Cannon Research Institute, Tennessee Oncology, Nashville, TN, USA; 8Medical Oncology Department, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA; 9TransThera Sciences (Nanjing), Inc.,Nanjing, China; 10Clinical Department, TransThera Sciences (Nanjing), Inc., Nanjing,China; 11Clinical Department, TransThera Sciences (US), Inc., Gaithersburg, MD, USA;12BD, TransThera Sciences (Nanjing), Inc., Nanjing, China; 13Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center -Main Building, Houston, TX, USA

Background: FGFR inhibitors (FGFRi) have a proven role for the management of FGFRaltered cholangiocarcinoma (CCA) after chemotherapy. However, disease progression occurs in 6-8 months. Secondary polyclonal mutations in the FGFR2 kinase domain represent a prominent acquired resistance mechanism. Tinengotinib was identiﬁed as a novel FGFRi with high potency to a variety of FGFR2 kinase domain mutations and has shown promising clinical results in CCA pts who have progressed on prior FGFRi.

Here, we present pooled data from three trials.

Methods: Pts received tinengotinib orally once daily for 28 days per cycle. Pooled analyses of treatment-related adverse events (TRAEs), overall response rate (ORR),disease control rate (DCR), and median progression-free survival (mPFS) in the stratiﬁed CCA population were performed.

Results: A total of 73 advanced CCA pts were enrolled between Dec 2019 - Mar 2023.

Median age was 60 years (24-81), 60% were female, 100% pts had 1 prior therapyincluding 47% pts with prior FGFRi, 97% had stage IV disease at screening. TRAEs were reported in 63 (86.3%) pts. 28 (38.4%) were Grade (G) 1-2, 32 (43.8%) were G3, 3(4.1%) were G4, no G5 was observed. The most common TRAEs (20%) were (4.1%) were G4, no G5 was observed. The most common TRAEs (≥20%) were hy-hy-pertension (43.8%, G3 19.2%), stomatitis (32.9%, G3 4.1%), diarrhea (30.1%, G3 4.1%)and palmar-plantar erythrodysesthesia (24.7%, G3 2.7%). Among 58 evaluable pts, the ORR and DCR were 20.7% and 75.9%, respectively. In 29 pts with FGFR2 alteration who received prior FGFRi, the ORR and DCR were 34% and 89.7%, respectively. 21 pts who acquired resistance to prior FGFRi had ORR of 38.1%, DCR of 95.2% and mPFS of

Results: In the China cohort, 130 pts were randomised (65 to D + GC, 65 to P + GC; 5/130 were recruited to the global cohort and 125/130 to the extension). OS and PFS beneﬁt with D + GC v P + GC in the China cohort (hazard ratio [HR], 0.78 and 0.79)were consistent with the global1and pooled cohorts (Table). OS rates at 12 and 18 months and ORR in the China cohort were numerically higher for D + GC v P + GC. D +GC was tolerable across cohorts.

|Table: 98P |Table: 98P |||||||| |---|---|---|---|---|---|---|---|---|

|China |China ||||Global1 Pooled, China |Global1 Pooled, China |global + |global + |

|D + |D + |GC n[65 P n[65 |+ |GC |D + GC n[341 P + GC n[344 |D + GC n[405 |P n[405 |+ GC |

|Median OS; 95% CI, |9.1; |6.3 |9.2; |7.1 |12.8;11.5; |12.6; ||10.9; 9.7 |

|months |e13.7 ||e10.2 ||11.1 e14.0 10.1 e12.5 |11.0 e13.6 ||e11.9 |

|OS HR; 95% CI |0.78; |0.51e1.18 |||0.80; 0.66e0.97 |0.79; ||0.67e0.94 |

|Median PFS; 95% CI, |4.7; |3.1 |4.4; |3.1 |7.2; 6.75.7; 5.6 |7.2; 6.4 |5.7; |5.4 |

|months |e6.4 |e5.4 |-5.4||e7.4e6.7 |e7.4 ||e5.9 |

|PFS HR; 95% CI |0.79; |0.52e1.19 |||0.75; 0.63e0.89 |0.76; ||0.65e0.89 |

|12-month OS, % |40.3 ||27.4 ||54.1 48.0 |52.0 ||44.6 |

|18-month OS, % |30.5 ||12.5 ||35.1 25.6 |34.3 |23.9|23.9 |

|ORR, % |12.3 |9.2 |9.2||26.7 18.7y |24.4 ||17.1z |

|Grade 3/4 TRAEs, %* |67.7 |63.1 |63.1||62.7 64.9 |63.4 ||64.3 |

|TRAEs leading to discontinuation, %* |16.9 |7.7 |||8.9 11.4 |10.2 ||10.7 |

*In safety analysis set. yTotal n¼343. zTotal n¼404. AE, adverse event; TRAE,treatment-related AE

Conclusions: Consistent with the global cohort, D + GC demonstrated a clinically meaningful OS and PFS beneﬁt compared with PBO + GC in pts enrolled in China. D +GC was tolerable and represents a potential new ﬁrst-line standard of care regimen in China. References 1. Oh et al. NEJM Evid 2022.

Clinical trial identiﬁcation: NCT03875235.

Editorial acknowledgement: Medical writing support, under the direction of the authors, was provided by Elaine Groat, PhD, of CMC Connect, a division of IPG Health Medical Communications, funded by AstraZeneca, in accordance with Good Publication Practice (GPP 2022) guidelines.

Legal entity responsible for the study: AstraZeneca.

Funding: AstraZeneca.

Disclosure: E. Li: Non-Financial Interests, Personal and Institutional, Principal Investigator:Department of Oncology, The First Afﬁliated Hospital of Xi’an Jiaotong University. B. Xing: NonFinancial Interests, Personal and Institutional, Principal Investigator: Beijing Cancer Hospital. C. Dai:Non-Financial Interests, Personal and Institutional, Principal Investigator: Shenjing Hospital of China Medical University. Z. Chen: Non-Financial Interests, Personal and Institutional, Principal Investigator: Department of Medical Oncology, The Second Afﬁliated Hospital of Anhui Medical University,Hefei, China. L. Liu: Non-Financial Interests, Personal and Institutional, Principal Investigator:Department of Hepatobiliary Surgery, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Afﬁliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Z. Lu: Non-Financial Interests, Personal and Institutional, Principal Investigator: Department of Hepatobiliary Surgery, The First Afﬁliated Hospital of Bengbu Medical College, Bengbu, China. H. Liang: Non-Financial Interests, Personal and Institutional,Principal Investigator: Department of oncology, the ﬁrst afﬁliated hospital of AMU. X. Liu: NonFinancial Interests, Personal and Institutional, Principal Investigator: Jinling Hospital, Afﬁliated Hospital of Medical School, Nanjing University, Nanjing, China Non-Financial Personal and Institutional Principal Investigator. J. Wang: Non-Financial Interests, Personal and Institutional, Principal Investigator: Department of Internal Medicine, The Afﬁliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, 127 Dongming Road, Jinshui District, Zhengzhou City, Henan Province, China. R. R. Miao: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. X.

Qu: Other, Personal, Full or part-time Employment: China R&D, AstraZeneca, Shanghai, China. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1391

99P Bevacizumab plus erlotinib maintenance versus observation in advanced biliary tract cancers: Results from the phase II component of a prospective integrated phase II-phase III parallel design superiority clinical trial (BEER-BTC study)

A. Ramaswamy1, V.S. Ostwal2, P.G. Bhargava1, S. Srinivas1, A. Kapoor3, M. Goel4,S. Patkar4, A. Gupta5, B. Sansar5, V. Kapu2, B. Mishra3, A. Sharma3, R.K. Rai6,P. Gupta6, S. Mandavkar1, M. Parulekar1, D. Chaugule1, N. Aier2, R. Patil1,

C. Nashikkar7

1GI Medical Oncology, Tata Memorial Hospital - Tata Memorial Centre, Mumbai,India; 2Medical Oncology, Tata Memorial Hospital - Tata Memorial Centre, Mumbai,India; 3Medical Oncology, Tata Memorial Hospital - Tata Memorial Centre, Varanasi,India; 4Surgical Oncology, Tata Memorial Hospital - Tata Memorial Centre, Mumbai,India; 5Medical Oncology, Homi Bhabha Cancer Hospital, Varanasi, India; 6Medical Oncology, Mahamana Pandit Madan Mohan Malviya Cancer Centre, Varanasi, India;7GI Medical Oncology, Tata Memorial Hospital - Parel, Mumbai, India

Background: Patients with chemotherapy-responsive advanced biliary tract cancer(BTC) are usually observed post 6 months of gemcitabine-based therapy, though most progress within a short time-span and there is limited prospective evidence for maintenance strategies.

Methods: The study is an integrated phase II e III randomised clinical trial (Clinical Trial Registry of India number: CTRI/2017/10/010112) conducted at 2 centres in India.

Eligible patients with advanced BTC who had responsive or stable disease status post 6 months of gemcitabine e based chemotherapy were randomly assigned (1:1) to either observation arm (O) or intervention arm (BEER), which was a combination of Bevacizumab 5 mg/m2 IV every 21 days plus erlotinib 100 mg once daily, . Both arms were continued till disease progression, signiﬁcant toxicity or patients choice. The primary endpoint of the phase II component was progression free survival, measured from randomization into the trial.

Results: Between May 2021 and November 2022, 98 patients (O: 48; BEER: 50)comprising 78 patients with gallbladder cancer (GBC) and 20 patients with cholangiocarcinoma (CC) were randomised with all 98 patients included in the ﬁnal analysis. With a median follow up of 11.2 months, patients in the BEER cohort showed an improved PFS compared to the observation cohort [5.2 months (95% CI: 3.4-6.9)vs. 3 months (95% CI: 2.5 - 3.5); p¼0.004]. The CC cohort tended to derive greaterbeneﬁt from BEER (6.7 months vs. 2.2 months) than the GBC cohort (4.3 months vs. 3 months). There were no grade 3 or grade 4 adverse events noted, though temporary cessation of erlotinib was required due to grade 2 skin rash in 7 patients (14%), and grade 2 oral stomatitis in 1 patient (2%).

Conclusions: The combination of bevacizumab and erlotinib improves progression free survival in patients with chemotherapy responsive advanced BTC in this phase 2 clinical trial. The ongoing phase III component of the study will evaluate whether the signiﬁcant beneﬁt in PFS translates to improvement in overall survival.

Clinical trial identiﬁcation: CTRI/2017/10/010112.

Funding: Cadilla Pharma Pvt Ltd (supported bevacizumab) Dr. Reddy’s Lab pvt Ltd(supported bevacizumab) LUPIN Pharma pvt Ltd Intas pvt Ltd.

Disclosure: A. Ramaswamy: Financial Interests, Institutional, Research Grant: Cipla Health Limited,Dr Reddy Laboratories, Zydus Lifesciences. V.S. Ostwal: Financial Interests, Institutional, Funding, IIS:Cadilla Pharmaceuticals pvt Lts, Reddy’s pvt Ltd, Lupin, BDR; Financial Interests, Personal, Invited Speaker, GI ESMO 22: AstraZeneca; Financial Interests, Institutional, Advisory Board: Mankind,Natco. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1392

100P

Hepatitis B virus (HBV)-related outcomes in patients (pts)with baseline HBV infection in the KEYNOTE-966 study of pembrolizumab (pembro) plus gemcitabine and cisplatin(gem/cis) for advanced biliary tract cancer (BTC)

S.L.

Chan1, R.S. Finn2, J.W. Valle3, R.K. Kelley4, C.

Yoo5, J. Furuse6, Z. Ren7

, T. Yau8,H.J. Klumpen9, M. Ozaka10, C. Verslype11, M. Bouattour12, J.O. Park13, J. Edeline14

≥

Ueno15, A. Vogel16, L. Yu17, U. Malhotra18, A.B. Siegel18, S. Qin19

1Clinical Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Sha Tin, Hong Kong, China; 2Division of Hematology/Oncology, Geffen School of Medicine,University of California, Los Angeles, Los Angeles, CA, USA; 3Division of

)

(

Cancer Sciences and Department of Medical Oncology, University of Manchester and The Christie NHS Foundation Trust, Manchester, UK; 4Medicine/Hematology-Oncology,University of California San Francisco - Parnassus Campus, San Francisco,

CA, USA;5Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 6Medical Oncology, Kyorin University Hospital, Tokyo, Japan;7Department of Hepatic Oncology,

Zhongshan Hospital Fudan University, Shanghai,China; 8Medicine, The University of Hong Kong, Hong Kong, China; 9Medical Oncology,Amsterdam University Medical Center, Amsterdam, Netherlands; 10Hepato-BiliaryPancreatic Medicine, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan; 11Digestive Oncology, UZ Leuven - University Hospitals Leuven - Campus Gasthuisberg, Leuven, Belgium; 12Liver Cancer Unit, APHP,Hôpital Beaujon, Clichy, France; 13Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine,Seoul, Republic of Korea; 14Medical Oncology Department, Centre Eugène Marquis,Rennes, France; 15Gasteroenterology Department, Kanagawa Cancer Center, Yokohama, Japan; 16Gastro/Hepato and Endocrinology Department, Hannover Medical School, Hannover, Germany; 17Biostatistics and Research Decision Sciences, Merck a

;

&Co. Inc., Rahway, NJ, USA; 18Global Clinical Development, Merck & Co, Rahway, NJ,USA;

19GI Cancer Center, Cancer Center of People’s Liberation Army, Nanjing, China

Background: Pembro + gem/cis signiﬁcantly improved OS versus placebo (pbo) +gem/cis as 1L therapy for unresectable or metastatic BTC in KEYNOTE-966(NCT04003636). Pembro monotherapy had limited impact on underlying HBV infection in advanced HCC. The effect of chemoimmunotherapy on

underlying HBV in pts with cancer is unknown. We characterized HBV-related outcomes in pts with HBV enrolled in KEYNOTE-966.

Methods: Pts were randomized 1:1 to pembro 200 mg or pbo Q3W for 35 cyclesplus gem/cis. Pts with clinically resolved HBV infection (ie, HBsAg negative, anti-HBc positive, and HBV DNA <20 IU/mL) were eligible. Pts with chronic

HBV infection (ie,HBsAg positive or HBV DNA 20 IU/mL) were eligible if antiviral therapy was started4 wk before study therapy if HBV DNA was >100 IU/mL. HBV DNA and HBsAg wereassessed every 6 wk in pts with undetectable HBV DNA at baseline (BL) not taking HBV therapy and every 12 wk in pts taking HBV therapy. Pts with HBV DNA >100 IU/mL were to

start HBV treatment. Pts on HBV therapy at BL were to stay on same therapy throughout the study. HBV reactivation and HBV-associated hepatitis were deﬁned per AASLD criteria.

Results: 164 (30.8%) of 533 pts in the pembro arm and 165 (30.8%) of 536 in the pbo arm had BL HBV infection, including 150 (28.1%) and 149 (27.8%) with clinically resolved and 14 (2.6%) and 16 (3.0%) with chronic HBV. In the pembro and pbo arms,

6.0% and 5.4% with clinically resolved and 100% and 93.8% with chronic HBV received antiviral drugs during the study. Among evaluable pts with clinically resolved HBV, 4(3.1%) of 127 in the pembro arm and 1 (0.8%) of 128 in the pbo arm had HBV reactivation. Among evaluable pts with chronic HBV, 1 (11.1%) of 9 in the pembro arm and 2 (15.4%) of 13 in the

pbo arm had HBV reactivation. All reactivation was detected by HBV DNA increase. No pts developed HBV-associated hepatitis.

Conclusions: The low incidence of HBV reactivation and lack of HBV-associated hepatitis in pts with clinically resolved or controlled chronic HBV on antiviral therapy suggest that with careful monitoring, pembro plus gem/cis is unlikely to affect ,

underlying HBV in advanced BTC.

Clinical trial identiﬁcation: NCT04003636, ﬁrst posted July 1, 2019.

Editorial acknowledgement: Editorial assistance in the writing of this abstract was provided by Melanie A.

Leiby, PhD, an employee of Merck Sharp & Dohme LLC,

≤

subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Legal entity responsible for the study: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Funding: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ,USA.

Disclosure: S.L. Chan: Financial Interests, Personal, Advisory Board: Eisai, AstraZeneca, MSD, BMS,Roche; Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, Eisai,

Roche, IPSEN, BMS;Financial Interests, Personal, Research Grant: Eisai, MSD. R.S. Finn: Financial Interests, Institutional,Funding: Merck Sharp & Dohme Corp.; Financial Interests, Institutional, Research Grant: Adaptimmune, Bayer, Bristol Myers Squibb, Eisai, Eli Lilly, Pﬁzer, Roche, Genentech; Financial Interests,Personal, Speaker, Consultant,

Advisor: AstraZeneca, Bayer, Bristol Myers Squibb, Exelixis, Cstone,Hengrui, Eisai, Eli Lilly, MSD, Pﬁzer, Roche, Genentech; Financial Interests, Personal, Other, honoraria:Genentech; Financial Interests, Personal, Advisory Board: AstraZeneca, Hengrui. J.W. Valle: Financial Interests, Institutional, Funding: Merck Sharp & Dohme Corp.; Financial Interests, Personal, Advisory Role: Ipsen, Novartis, AstraZeneca, Merck & Co., Inc., Rahway, NJ USA, Pﬁzer, PCI Biotech, Incyte,Keocyt, QED Therapeutics, Pieris Pharmaceutical, Genoscience Pharma, Mundipharma, Wren Laboratories, Nucana, Debiopharm Group, Imaging Equipment Ltd, Hutchison MediPharma, Zymeworks,Aptitude Health, Sirtex Medica, Baxter, Medivir, Cantargia AB, Autem Medical, Taiho Oncology,Servier, Boehringer Ingelheim; Financial Interests, Personal, Speaker’s Bureau: Novartis, Ipsen,Nucana, Imaging Equipment Limited, Mylan, Incyte, Servier, Delcath systems; Financial Interests,

Personal, Other, travel: Nucana, Lilly, Roche, AstraZeneca/MedImmune. R.K. Kelley: Financial Interests, Personal, Advisory Board, Compensation for service on advisory board in 2019: Genentech/Roche; Financial Interests, Personal, Other, IDMC membership 2018-2020: Genentech/Roche;Financial Interests, Personal, Advisory Board, 2020: Gilead, Exact Sciences; Financial Interests, Personal, Advisory Board, Advisory board member in 2021: Kinnate; Financial Interests, Institutional,Steering Committee Member: Agios, AstraZeneca, Merck; Financial Interests, Institutional, Local PI:Agios, AstraZeneca, BMS, Eli Lilly, EMD Serono, Genentech/Roche, Merck, QED, Taiho, Novartis,Relay Therapeutics, Surface Oncology, LOXO Oncology; Financial Interests, Institutional, Coordinating PI: Bayer, Exelixis, AstraZeneca, Merck; Financial Interests, Institutional, Research Grant: Partner Therapeutics; Non-Financial Interests, Advisory Role, IDMC chair and member: Genentech/Roche;Non-Financial Interests, Principal Investigator: Exelixis, AstraZeneca; Non-Financial Interests, Advisory Role, IDMC member: Merck. C. C. Yoo: Financial Interests, Personal, Invited Speaker: Bayer, Celgene, Eisai, Ipsen, Servier, Roche, Novartis; Financial Interests, Personal, Advisory Board:AstraZeneca; Financial Interests, Personal, Research Grant: AstraZeneca, Bayer, Servier; Financial Interests, Institutional, Research Grant: Genentech. J. Furuse: Financial Interests, Institutional,Funding: Merck Sharp & Dohme Corp.; Financial Interests, Institutional, Research Grant: Astellas,AstraZeneca, Incyte Biosciences Japan, Eisai, MSD, Ono Pharmaceutical, Sanoﬁ, JPharma, Daiichi Sankyo, Sumitomo Dainippon, Taiho Pharmaceutical, Takeda, DeltaFly Pharma, Chugai Pharma;Financial Interests, Personal, Other, honoraria: Ono Pharmaceutical, Incyte Biosciences Japan, Eisai,Eli Lilly Japan, Yakult Honsha, Servier Japan, Novartis Pharma, Takeda, Bayer, EA Pharma, Teijin Pharma, Daiichi Sankyo, Terumo; Financial Interests,

Personal, Advisory Board, honoraria: Chugai Pharmaceutical, AstraZeneca, MSD, Taiho Pharmaceutical; Financial Interests, Personal, Advisory Board: Onco Therapy Science, Astellas, Takara Bio, Merck Bio. Z. Ren: Financial Interests, Institutional, Funding: Merck Sharp & Dohme Corp.; Financial Interests, Personal, Advisory Role: MSD,AstraZeneca, Roche; Financial Interests, Personal, Invited Speaker: Bayer, MSD, Roche. T. Yau:Financial Interests, Institutional, Funding: Merck Sharp & Dohme Corp.; Financial Interests, Personal,Advisory Role: Bristol Myers Squibb, MSD, AstraZeneca, Eisai, Ipsen; Financial Interests, Personal,Other, travel: Roche, Bayer; Financial Interests, Personal, Stocks/Shares: Moderna; Financial Interests, Personal, Writing Engagement: Taiho, Ipsen; Financial Interests, Institutional, Research Funding: Bristol Myers Squibb, MSD, Exelixis, Eli Lilly, AstrZeneca, Roche, Taiho . H.J. Klumpen:Financial Interests, Institutional, Invited Speaker, current treatments of cholangiocarcinoma: Medtalk; Financial Interests, Institutional, Invited Speaker, Podcast on treatment of HCC: CCO; Financial Interests, Institutional, Advisory Board: Janssen, AstraZeneca; Financial Interests, Institutional, Local PI, IMBRAVE 050: Roche; Financial Interests, Institutional, Local PI, FIGHT 302: INCYTE; Financial Interests, Institutional, Local PI, LEAP 012: MSD; Financial Interests, Institutional, Local PI, TAS120:Taiho; Financial Interests, Institutional, Local PI, Compete, Compose: ITM Solucin GmbH; Financial Interests, Institutional, Local PI, Keynote 966: MSD; Financial Interests, Institutional, Local PI, COSMIC 312: Exelixis; Other, Subdomain leader G5.1: EURACAN; Other, In the Netherlands: Member National Guideline committee for biliary tract cancer; Other, in the Netherlands: Member of the National guideline committee for HCC. M. Ozaka: Financial Interests, Institutional, Funding: Merck Sharp & Dohme Corp.; Financial Interests, Personal, Other, honoraria: Taiho Pharmaceutical, Yakult Honsha, MSD, Ono Pharmaceuticals, Nihon, Servier, Bayer, Pﬁzer. C.

Verslype: Financial Interests,Personal, Advisory Board: Roche, Bayer; Financial Interests, Personal, Invited Speaker: Ipsen, Bayer;Financial Interests, Institutional, Research Grant, unrestricted: Bayer; Non-Financial Interests,Member, Lobby group: Pancreatic Cancer Europe. M. Bouattour: Financial Interests, Personal,Advisory Board: MSD, BMS, Sirtex Medical, Ipsen, AbbVie, AstraZeneca, Servier, Taiho; Financial Interests, Personal, Invited Speaker: Roche; Non-Financial Interests, Principal Investigator: MSD,BMS, Sirtex Medical, AstraZeneca. J.O. Park: Financial Interests, Personal, Advisory Board: MedPacto,BMS (Celgene), Servier, MediRama, Adicet Bio, AstraZeneca, Merck Sereno; Financial Interests,Personal, Other, Travel support for a poster presentation at ASCO GI 2023: Minneamrita Therapeutics LLC; Financial Interests, Personal, Research Grant, Clinical research grant: MedPacto, Servier,BMS (Celgene); Financial Interests, Personal, Research Grant: Eutilex, ABL Bio. J. Edeline: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, MSD, Bayer, Boston Scientiﬁc, Eisai, Ipsen,Servier; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, MSD, Bayer, Merck Serono, Eisai, Ipsen, BMS, Basilea, Servier, Incyte, BeiGene, Taiho; Financial Interests, Personal,Steering Committee Member: MSD; Financial Interests, Institutional, Coordinating PI: BMS, BeiGene;Financial Interests, Institutional, Local PI: BMS, MSD, Roche, BeiGene, Bayer, Novartis, Taiho, Servier,Agios; Non-Financial Interests, Principal Investigator: Unicancer. M. Ueno:

■

Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai Pharmaceutical, Incyte, MSD, Nihon Servier, Ono Pharmaceutical, Taiho Pharmaceutical; Financial Interests, Personal, Advisory Board: Nippon Boehringer Ingelheim; Financial Interests, Institutional, Local PI: Astellas Pharma, AstraZeneca, Chugai Pharmaceutical, DFP, Daiichi Sankyo, Eisai, Incyte, MSD, Merck Biopharma, Ono Pharmaceutical,Taiho Pharmaceutical, Novartis. A. Vogel: Financial Interests, Personal, Advisory Board: Amgen,AstraZeneca, Böhringer Mannheim, Eisai, Incyte, Ipsen, Janssen, MSD, PierreFabre, Roche, Servier,Sirtex, Tyra, Tahio; Financial Interests, Personal, Invited Speaker: BMS, Eisai, Incyte, Ipsen, Lilly, MSD,Roche; Financial Interests, Personal, Steering Committee Member: Roche, MSD, BeiGene, Jiangsu Hengrui Medicines. L. Yu: Financial Interests, Personal, Full or part-time Employment: Merck Sharp

Results: A total of 278 pts were included in this analysis (178 pts from the NIFTY trial and 99 pts from the FIReFOX trial). The nal-IRI plus 5-FU/LV group (n¼88) showed

signiﬁcantly better overall survival compared to the mFOLFOX group (n¼49, p ¼0.02), mFOLFIRI group (n¼50, p ¼ 0.03), and 5-FU/LV group (n¼90, p ¼ 0.008).Multivariable analysis showed consistent trends with adjusted HR of 1.44 (95% CI

0.93-2.07, p ¼ 0.11), 1.36 (95% CI 0.92-2.03, p ¼ 0.13), and 1.52 (95% CI 1.37-1.09-2.10, p ¼ 0.01), respectively. Also, nal-IRI plus 5-FU/LV group showed trends towardbetter progression-free survival compared to the other 3 groups with adjusted HR of

1.44 (95% CI 0.98-2.11, p ¼ 0.06), 1.29 (95% CI 0.87-1.89, p ¼ 0.20), and 1.88 (1.38-2.55, p < 0.001), respectively.

Conclusions: Nal-IRI plus 5-FU/LV showed better survival outcomes when compared to mFOLFOX, mFOLFIRI, or 5-FU/LV alone. Nal-IRI plus 5-FU/LV may be a preferable second-line regimen for advanced BTC pts without targetable genetic alterations.

Funding: Servier.

https://doi.org/10.1016/j.annonc.2023.09.1396

104P

Final analysis of the prospective, randomized phase II STAMP trial: Adjuvant gemcitabine plus cisplatin (GemCis)versus capecitabine (CAP) in node-positive extrahepatic cholangiocarcinoma (CCA)

H. Jeong1, K-P. Kim1, J.H. Jeong1, D.W. Hwang2, J.H. Lee2, K-H. Kim2, D-B. Moon2,M.A. Lee3, S.J. Park3, H. Chon4, J-H. Park5, J.S. Lee6, B-Y. Ryoo1, C. Yoo1

1Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 2Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 3Internal Medicine Department, The Catholic University of Korea - Seoul St. Mary’s Hospital - Catholic Medical Center, Seoul, Republic of Korea; 4Medical Oncology, Bundang Cha Medical Center, Seongnam, Republic of Korea; 5Department of Radiation Oncology, Asan Medical Center - University of Ulsan, Seoul, Republic of Korea; 6Department of Clinical Research Center, Asan Medical Center - University of Ulsan, Seoul, Republic of Korea

Background: The primary analysis of the STAMP trial demonstrated that adjuvant GemCis did not improve disease-free survival (DFS) compared to CAP in patients (pts)with resected, lymph node (LN)-positive extrahepatic CCA. As overall survival (OS)data were not matured at primary analysis, we report the updated analysis with an additional 19 months (mo) of follow-up.

Methods: Pts with adenocarcinoma of perihilar/distal bile duct with regional LN metastasis who underwent curative-intent surgery was randomized to receive GemCis(Gem 1000 mg/m2, Cis 25 mg/m2 on days 1, 8) or CAP (1250 mg/m2 twice daily on days 1e14) every 3 weeks for 8 cycles. Primary endpoint was DFS. Secondary endpoints were OS and safety. All P values were one-sided and considered signiﬁcant if <

0.1.

Results: A total of 101 pts (50 in the GemCis and 51 in the CAP group) were included in the intention-to-treat population. The median follow-up duration was 52.8 mo(one-sided 90% CI, 50.1-58.2). In the GemCis and CAP groups, the median DFS was

14.6 mo (10.7-16.5) and 11.1 mo (8.4-12.7), respectively, and the 4-year DFS rates were 15.9% (9.4-24.0) and 19.4% (12.4-27.5) respectively (HR ¼ 1.02 [0.76-1.37], P ¼0.47). Median OS was 35.0 mo (29.5-42.7) and 32.3 mo (28.3-45.6), respectively, and the 4-year OS rates were 35.7% (26.5-45.1) and 38.4% (29.2-47.5), respectively (HR ¼1.04 [0.75-1.44], P ¼ 0.43). Subgroup analyses showed consistent results withoutsigniﬁcant interactions in the DFS and OS between groups, except that pts with R1 resection favored CAP in DFS and OS, and females favored GemCis in OS.

Conclusions: In this ﬁnal analysis of the STAMP trial, adjuvant GemCis did not improve OS compared with CAP in LN-positive extrahepatic CCA. Biomarker analyses,including ctDNA-guided minimal residual disease (MRD), are currently underway.

Clinical trial identiﬁcation: NCT03079427.

Funding: Chong Kun Dang Pharm, Ildong pharmaceuticals.

Disclosure: J.H. Jeong: Financial Interests, Personal, Other, honoraria: Boryung Pharmaceutical,Daewoong Phar- maceutical, Eisai, inno.N, Lilly, Novartis, Pﬁzer, Roche. H. Chon: Financial Interests,Personal, Advisory Role: Roche, BMS, Boryoung. C. Yoo: Financial Interests, Personal, Invited Speaker:Bayer, Celgene, Eisai, Ipsen, Servier, Roche, Novartis; Financial Interests, Personal, Advisory Board:AstraZeneca; Financial Interests, Personal, Research Grant: AstraZeneca, Bayer, Servier; Financial

Interests, Institutional, Research Grant: Genentech. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1397

105P A phase II study of SHR-1316 plus IBI310 in patients with advanced intrahepatic cholangiocarcinoma after failure ofﬁrst-line therapy

J. Fan1, J. Zhou1, G. SHI1, X. Huang1, X. Guo1, J. Lu1, F. Liang2, Y. Chen3, D. Wu4, Y. Ji5,Y. Hou6, X. Meng1, Z. Tang1, X. Huang1, Q. Ye1, S. Qiu1, Q. Gao1, Y. Shi1, H. Sun1, H. Li7

1Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China; 2Clinical Research Unit, Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, China; 3Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; 4Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China; 5Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China; 6Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, Changning, China; 7Clinical Research & Development, Jiangsu Hengrui Pharmaceuticals Co., Ltd., Shanghai, China

Background: Advanced intrahepatic cholangiocarcinoma (iCCA) is highly invasive and holds high mortality due to limited therapeutic strategies after failure of ﬁrst-line therapy. This study aimed to evaluate the efﬁcacy and safety of anti-PD-L1 antibody SHR-1316 in combination with anti-CTLA-4 antibody IBI310 for patients (pts) with previously treated advanced iCCA.

Methods: The study was an ongoing open-label, single-arm, phase 2 trial. Unresectable, locally advanced or metastatic iCCA pts who had failed ﬁrst or subsequentline therapy were enrolled. A combination of SHR-1316 (IV 20mg/kg q3w) and IBI310(IV 3mg/kg q3w) were administered for 4 cycles, followed by SHR-1316 monotherapy until disease progression, unacceptable toxicity, or a maximum of 2 years after enrollment. The primary endpoint was objective response rate (ORR). Secondary objectives included safety, overall survival (OS), progression-free survival (PFS), and disease control rate (DCR). Response was evaluated according to RECIST1.1. Adverse effects (AEs) were assessed according to CTCAE V5.0.

Results: Up to May 1, 2023, 39 pathologically conﬁrmed advanced iCCA pts were enrolled. Median age was 59 years (range 28 to 74). Previous treatments included systemic chemotherapy (39 pts), anti-PD-1 antibody (21 pts), and tyrosine kinase inhibitors (26 pts). At date cut-off, the median follow-up was 6.1 months (95%CI, 0.2-18.7), 28 pts were alive, 18 pts remained on treatment. Of 25 evaluable pts, 2 pts achieved complete response and 3 had partial response. The conﬁrmed ORR and DCR were 20.0% and 60.0%, respectively. Notably, the ORR for pts previously treated with anti-PD-1 antibody was 16.7% (2/13). Median PFS and OS was not reached yet. Grade 3 or higher AEs occurred in 16 pts (41.0%), most commonly jaundice (15.4%), rash(10.3%), ALT elevation (7.7%), anaphylaxis (7.7%), AST elevation (5.1%), diarrhea(5.1%) and dyspnea (5.1%).

Conclusions: The treatment of SHR-1316 combined with IBI310 was tolerable and showed promising antitumor activity in iCCA refractory to standard therapy. Further studies are required to identify predictive/prognostic biomarkers to improve selection of pts most likely to beneﬁt from this treatment strategy.

Clinical trial identiﬁcation: NCT04634058.

Legal entity responsible for the study: The Clinical Medicine Research Pilot Project of Shanghai Medical School of Fudan University.

Funding: The Clinical Medicine Research Pilot Project of Shanghai Medical School of Fudan University.

|Table: 104P |Table: 104P |Table: 104P | |---|---|---|

||GemCis CAP |HR (CI) and P-value |

|DFS events/pts |40/50 41/51 ||

|Median DFS (months) |(CI) 14.6 (10.7-16.5) 11.1 (8.4-12.7) |1.02 (0.76-1.37) P ¼ 0.47 |

|4Y DFS rates (%) (CI) |15.9 (9.4-24.0) 19.4 (12.4-27.5) ||

|Deaths/pts |33/50 33/51 ||

|Median OS (months) |(CI) 35.0 (29.5-42.7) 32.3 (28.3-45.6) |1.04 (0.75-1.44) P ¼ 0.43 |

|4Y OS rates (%) (CI) |35.7 (26.5-45.1) 38.4 (29.2-47.5) ||

https://doi.org/10.1016/j.annonc.2023.09.1398

S221

106P

S222

The impact of alterations in cancer driver genes and other potentially targetable mutations on progression and overall survival in patients with biliary tract cancer treated on the randomised phase III multicentre BILCAP clinical trial

V.E. Crolley1, R. Guest2, A.D. Beggs3, E. Jaynes4, S. Thorn5, J. Herrero1, I. Tomlinson6,J.W. Valle7, J.N. Primrose8, J.A. Bridgewater9

1Cancer Institute, University College London, London, UK; 2Clinical Surgery, University of Edinburgh, Edinburgh, UK; 3Institute of Cancer & Genomic Science, The University of Birmingham - Medical School, Birmingham, UK; 4Pathology, University Hospital Southampton NHS Foundation Trust, Southampton, UK; 5Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, UK; 6Nufﬁeld Department of Medicine,University of Oxford, Oxford, UK; 7Medical Oncology Department, The Christie NHS Foundation Trust, Manchester, UK; 8Hepaticopancreatobiliary Surgery, Southampton General Hospital, Southampton, UK; 9UCL Cancer Institute, UCL Cancer Institute - Paul O’Gorman Building, London, UK

Background: The BILCAP clinical trial established adjuvant capecitabine as the current standard of care treatment after biliary tract cancer resection.

Methods: Translational work from this clinical trial involved collecting archived ﬁxed formalin tissue from consented BILCAP patients and carrying out low-pass whole genome (lp-WGS), targeted gene (TGS) and RNA sequencing (RNAseq) for copy number (CN), mutation and gene-fusion analysis. In total, 98 patients underwent RNAseq, 95 of 98 underwent lp-WGS and 39 of 98 underwent TGS.

Results: 47 patients had intrahepatic cholangiocarcinoma, 47 patients had gallbladder cancer, 2 patients had perihilar cholangiocarcinoma, and 2 patients had distal cholangiocarcinoma. 62 (63.3%) patients were female, and 48 (49.0%) received adjuvant capecitabine. FGFR2 gene fusions were present in 24 patients (24.5%), as were fusions in NTRK1 (n¼4, 4.1%), FGFR1 (n¼4, 4.1%), FGFR3 (n¼2, 2.0%) and FGFR4 (n¼2,2.0%). Known pathogenic mutations were seen in IDH1(n¼4, 10.3%, total number ofmutations¼8, 20.5%), IDH2 (n¼1, 2.6%, total n¼6, 15.4%), and FGFR2 (n¼1, 2.6%,total total n=7, 17.9%). Commonly amplified (CN ≥4) genes included NTRK1 (n=28,n¼7, 17.9%). Commonly ampliﬁed (CN 4) genes included NTRK1 (n¼28,29.5%), ERBB2 (n¼27, 28.4%) and MDM2 (n¼20, 21.1%) with MYC (n¼19, 20.0%),EGFR (n¼16, 16.8%) and MET (n¼15, 15.8%) also ampliﬁed. Nearly all the alterationsinvestigated did not signiﬁcantly affect recurrence risk (PFS) or overall survival (OS),including FGFR2 fusions (OS hazard ratio (HR) 1.11 p¼0.762, PFS HR 1.10 p¼0.763).However, the presence of amplified EGFR (CN ≥4) significantly decreased both OSthe presence of ampliﬁed EGFR (CN 4) signiﬁcantly decreased both OS(HR 5.40 p¼0.01) and PFS (HR 3.44 p¼0.04).

Conclusions: The BILCAP cohort shows a wide variety of driver and potentially targetable mutations in unselected biliary tract cancer patients, comparable to similar datasets. Of note, patients with EGFR ampliﬁcation had signiﬁcantly reduced OS and PFS. This indicates that EGFR ampliﬁcation may be an important indicator in determining prognosis and could provide an attractive target for future targeted anticancer therapy in biliary tract cancer.

Clinical trial identiﬁcation: EudraCT 2005-003318-13.

Funding: Incyte.

Disclosure: A.D. Beggs: Financial Interests, Personal, Speaker, Consultant, Advisor: 2CureX, Birmingham Biotech, Check4Cancer, Oxford Nanopore Technologies; Financial Interests, Personal,Research Funding: AstraZeneca, Incyte, Oxford Nanopore Technologies; Financial Interests, Personal,Other, Honoraria: Illumina; Financial Interests, Personal, Other, Travel, Accommodations, Expenses:Oxford Nanopore Technologies. J.W. Valle: Non-Financial Interests, Personal, Advisory Role: Aptitude Health, AstraZeneca, Baxter, Boehringer Ingelheim, Cantargia AB, Debiopharm Group, Hutchison MediPharma, Imaging Equipment Limited, Incyte, Ipsen, Keocyt, Medivir, Merck, Mundipharma,Novartis, Nucana, PCI Biotech, Pﬁzer, Pieris Pharmaceuticals, QED Therapeutics, Servier, Sirtex Medical, Taiho Oncology, Wren Laboratories, Zymeworks; Financial Interests, Personal, Advisory Role: Autem Medical; Non-Financial Interests, Personal, Advisory Board: Genoscience Pharma; NonFinancial Interests, Personal, Speaker’s Bureau: Delcath Systems, Imaging Equipment Limited, Incyte,Mylan, Novartis, Nucana, Servier; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: AstraZeneca/MedImmune, Lilly, Nucana, Roche. J.N. Primrose: Financial Interests, Personal,Other, Honoraria: AstraZeneca. J.A. Bridgewater: Financial Interests, Personal, Advisory Board: Taiho,BMS, Incyte, Basilea, Servier; Financial Interests, Institutional, Funding: Incyte. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1399

107P Comprehensive genomic proﬁling of “The German-registry of incidental gallbladder carcinoma” cases

N.B. Agaoglu, L. Kochen, D.W. Müller, D. Vortmeyer, T. Habibzada, S-E. Al-Batran,T.O. Goetze

Oncology Department, IKF - Institut für Klinische Krebsforschung GmbH, Frankfurt am Main, Germany

Background: Gallbladder cancer (GBC) is a biliary tract cancer with an aggressive progression and poor prognosis. Although high throughput sequencing revealed some driver variations in genes like EGFR, TP53, SMAD4, ARID1A, PIK3CA, and CDKN2A/B,there is no speciﬁc biomarker for GBC. Due to the low incidence rate, the studies are limited and generally covered under all biliary tract cancer (BTC) types. Here we present the clinical, histopathological, and molecular spectrum of a large series of patients from the German Registry of Incidental GBC.

Methods: A total of 1040 (793 female and 247 male) completely documented cases with a median age of diagnosis 70.79 (min:30-max:98) were enrolled in the study. The majority of tumors were diagnosed at pathological stage pT2 (60.6%), and distant metastasis was detected in 15.2% of cases. The patients presented a tumor grade of G2 or G3 with a ratio of 53% and 36%, respectively. Among the cohort, 116 cases were already analyzed by a targeted panel (FMI Heme Panel) which combines more than 400 DNA and 250 RNA-sequenced genes.

Results: In 91 of the cases, at least one pathogenic gene variation was detected.

The median TMB was 4.67 (0e52.95) mutations/Mb, and in 6.5% of the cases, the total TMB was 10 mutations/Mb (“TMB-intermediate/high”). The tumor total TMB was ≥10 mutations/Mb ("TMB-intermediate/high"). The tumor withwiththe highest TMB (52.95 mutations/Mb) presented 12 pathogenic variants. TP53 was the most commonly altered gene (59.34%), followed by CDKN2A (20.6%)ampliﬁcations. In 11.2% of the cases, likely functional fusions/rearrangements were also detected.

Conclusions: This study presents one of the largest isolated GBC cohorts, analyzed by a comprehensive targeted NGS panel with a precision oncology approach. Theseﬁndings will provide insights into a rare but severe type of upper GI cancer. The analysis is currently ongoing, and a further 84 patients will be molecularly characterized till the meeting to be able to present complete molecular data of 200 patients.

Clinical trial identiﬁcation: NCT05222854.

Legal entity responsible for the study: Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest.

https://doi.org/10.1016/j.annonc.2023.09.1400

108P FGFR2 fusions and their impact on efﬁcacy of standard chemotherapy in patients with biliary tract cancer

B. Zheng-Lin1, D. Walden1, J. Larson2, S. McDonnell2, J. Frank2, P. Raman3,

C. Eslinger3, B. Ueberroth3, F-S. Ou2, N. Larson2, M.B. Sonbol1, C. Wu3, N. Tran4,H. Babiker5, M. Borad1, L. Roberts6, D. Ahn1, T. Bekaii-Saab1

1Department of Hematology and Oncology, Mayo Clinic, Phoenix, AZ, USA; 2Department of Quantitative Health Sciences, Mayo Clinic, Rochester, NY, USA; 3Department of Internal Medicine, Mayo Clinic, Phoenix, AZ, USA; 4Department of Hematology and Oncology, Mayo Clinic, Rochester, NY, USA; 5Department of Hematology and Oncology,Mayo Clinic, Jacksonville, FL, USA; 6Department of Gastroenterology and Hepatology,Mayo Clinic - Rochester, NY, USA

Background: The incidence of biliary tract cancer (BTC) is increasing globally, while its survival remains dismal. FGFR2 fusions offer a potential therapeutic option with oral inhibitors, although the optimal treatment sequence for these patients remains unclear.

Methods:We included patients from all three Mayo Clinic sites diagnosed with FGFR2 fusion-positive (F2P) BTC and used patients with FGFR2 fusion-negative (F2FN) BTC as historical controls. We estimated overall survival (OS) and progression-free survival(PFS) using Kaplan-Meier techniques.

Results: We identiﬁed 43 F2P and 155 F2FN patients with BTC. The most common gene fusion partner was BICC1 (28%). FGFR2 fusion was associated with age gene fusion partner was BICC1 (28%). FGFR2 fusion was associated with age ≤6565years (74% vs 44%), female gender (72% vs 45%), intrahepatic BTC (95% vs 71%), and advanced stage at diagnosis (60% vs 11%). In advanced disease, 25 patients in the F2P group received ﬁrst-line (1L) chemo of which 14 (56%) received gemcitabine/cisplatin(GC). In the F2FN group, 37 had 1L chemo, 16 (43%) with GC. The F2P group had signiﬁcantly lower PFS compared to F2FN patients, respective median PFS were 5.4(95% CI 3.8-9) vs 7.6 months (95% CI 4.6-13.3) (p¼0.038). In the F2P group whoreceived second-line (2L) therapy, PFS was longer with an FGFR inhibitor (8.2 months,95% CI 7.2-NE) vs. chemo (5.5 months, 95% CI 4.8-19.3) (Table). The median OS was signiﬁcantly higher in the F2P patient who never received an FGFR inhibitor (14.8 months, 95% CI 13.2-NE) vs F2FN group (9.6 months, 95% CI 5.52-22.9) (p¼0.04).

|Table: 108P Median PFS in F2FN and F2P groups based on 1L and 2L therapie |Table: 108P Median PFS in F2FN and F2P groups based on 1L and 2L therapie |Table: 108P Median PFS in F2FN and F2P groups based on 1L and 2L therapie |Table: 108P Median PFS in F2FN and F2P groups based on 1L and 2L therapie |Table: 108P Median PFS in F2FN and F2P groups based on 1L and 2L therapie | |---|---|---|---|---|

||FGFR2 Fusion Negative |FGFR2 Fusion Negative |FGFR2 Fusion Positive |FGFR2 Fusion Positive |

||N |PFS, months (95% CI) |N |PFS, months (95% CI |

|1L chemo |37 |7.6 (4.6-13.3) |21 |5.4 (3.8-9) |

|1L FGFR inhibitor |0 |na |4 |7.7 (2.1-NE) |

|1L Overall |37 |7.6 (4.6-13.3) |25 |5.9 (3.8-8.5) |

|2L chemo |20 |10 (4.6-13.8) |9 |5.5 (4.8-19.3) |

|2L FGFR inhibitor |0 |na |16 |8.2 (7.2-NE) |

|2L Overall |20 |10 (4.6-13.8) |25 |8.4 (7.2-13.8) |

Volume34 -

Conclusions: Our study highlights the distinct features of FGFR2 fusion-positive BTC,which is associated with a signiﬁcantly longer OS despite a shorter PFS on standard 1L chemo. These ﬁndings underscore the need for trials to evaluate the efﬁcacy of 1L FGFR inhibitors in these patients.

Issue S2 - 2023

Funding: Incyte Pharmaceuticals National Cancer Institute.

Disclosure: N. Tran: Financial Interests, Institutional, Funding, Grant K23MD017217-01A1: NIH. M.

Borad: Financial Interests, Institutional, Advisory Board: Senhwa, Adaptimmune, Agios, Halozyme,

Celgene, EMD Merck Serono, Toray, Dicerna, Taiho, Sun Biopharma, Isis Pharmaceuticals, Redhill,

Boston Biomed, Basilea, Incyte, Mirna, Medimmune, Bioline, Sillajen, ARIAD, Puma Pharmaceuticals,

Novartis Pharmaceuticals, QED Pharmaceuticals, Pieris Pharmaceuticals; Financial Interests, Personal, Advisory Board: ADC Therapeutics, Exelixis Pharmaceuticals, Inspyr Therapeutics, G1 Therapeutics, Immunovative Therapies, OncBioMune Pharmaceuticals, Western Oncolytics, Lynx Group;

Financial Interests, Personal, Other: AstraZeneca. L. Roberts: Financial Interests, Institutional,

Advisory Board: Bayer, BTG International, Exact Sciences, Gilead Sciences, GlycoTest, Redhill, TARGET

PharmaSolution, Fujiﬁlm Medical Systems; Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Exact Sciences, Gilead Sciences, GRAIL, QED Therapeutics, TAVEC. D. Ahn: Financial

Interests, Personal, Advisory Board: Advanced Accelerator Applications, Daiichi Sankyo Company ,

Eisai Inc, Exelixis , Genentech USA, Inc., Ipsen Biopharmaceuticals, Inc , Novartis . T. Bekaii-Saab:

Financial Interests, Institutional, Advisory Board: Bayer, Pﬁzer, Incyte, Ipsen, Seattle Genetics, Genentech, Merck KGA, Merus, Eisai, Servier; Financial Interests, Institutional, Other, DSMB: Merck;

Financial Interests, Personal, Advisory Board: AbbVie, Boehringer Ingelheim, Janssen, AstraZeneca,

Daiichi Sankyo, Natera, Celularity, Exact Science, Sobi, BeiGene, Xilis, Foundation Medicine, Stemline,

Blueprint, Celularity, Caladrius, Glaxo SmithKline, Deciphera, Zai Labs, Illumina, Sanoﬁ; Financial

Interests, Personal, Other, DSMB: AstraZeneca, Exelixis, The Valley Hospital, Fibrogen; Financial Interests, Personal, Other, DSMC: PanCAN; Financial Interests, Personal, Royalties, WO/2018/183488:

HUMAN PD1 peptide vaccines and uses thereof e Licensed to Imugene: Imugene; Financial Interests, Personal, Royalties, WO/2019/055687: Methods And Compositions For The Treatment Of

Cancer Cachexia e Licensed to Recursion: Recursion; Financial Interests, Institutional, Research

Grant: Agios, Arys, Bayer, Amgen, Ipsen, Clovis, Pﬁzer, Celgene, Novartis, Arcus, Atreca, Mirati,

Merus, Abgenomics, BMS; Financial Interests, Institutional, Coordinating PI: Boston Biomedical,AmoyDx© HER-2(29D8) assay and the well-established Ventana PATHWAY anti-HER-Incyte; Financial Interests, Institutional, Steering Committee Member: Seattle Genetics; NonFinancial Interests, Advisory Role: Imugene, Sun Biopharma. All other authors have declared no

conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1401

109P

DNA damage repair pathways in biliary tract cancer: A new target for precision medicine?

I. Mavroeidi1, T. Reissig1, S. Kalbourtzis2, S-T. Liffers3, T. Herold4, S. Kasper-Virchow1,H-U. Schildhaus5, M.H.H. Schuler6, J. Siveke3

1Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany; 2Institute of Pathology, West German Cancer Center, University Hospital Essen, Essen, Germany; 3Bridge Institute of Experimental Tumor Therapy, Universitätsklinikum Essen, Essen, Germany; 4Institute of Pathology, Universitätsklinikum Essen, Essen, Germany; 5Institute of Pathology,University Hospital of Essen, Essen, Germany; 6Department of Medical Oncology,West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen,Germany

Background: Biliary tract cancers (BTC) show a high mortality quote and heterogeneity in terms of clinical and molecular proﬁle. Aim of this work is the molecular characterisation of a BTC cohort focusing on genomic alterations of DNA damage repair (DDR) genes.

Methods: A retrospective analysis of the clinical course and mutation status of patients with locally advanced or metastatic BTC treated at the West German Tumour Centre of the University.113 (96%) patients received the MAPK-TRON DNA-based NGS panel (47 included genes), 81 (72%) patients the AmoyDx HRD Focus panel (32 genes), which focuses on DDR genes. DNA mismatch repair (MMR) status was determined in 59 patients by immunohistochemistry and DNA sequencing. 33 patients received an RNA fusion assay (FusionPlex CTL panel [Archer]) too. The primary endpoints of the study were the time in ﬁrst palliative regime till disease progression(Time on Treatment¼TTE) and the overall survival (OS). To form a clear deﬁned DDRcohort, the annotation of DDR gene alterations was not only performed by the local Institute of Pathology but also by quering the databases ClinVar and COSMIC.

Results: The cohort of the present study was divided in 7 molecular subgroups: TP53(34/118, 29%), KRAS (25/118, 21%), IDH1/2 (18/118, 15.2%), PIK3CA (8/118, 7%) and BRAF (6/118, 5%) and FGFR2 (5/33, 15%, with different fusion partners). BRAF- und PIK3CA-mutated BTC showed a slight beneﬁt in primary endpoints, whereas KRASand TP53- mutated showed worse prognosis. 13 DDR-mutated BTC were identiﬁed(13.5%). The patients with DDR mutations showed a weak but coherent beneﬁt in all primary endpoints (OS, TTE, TTE under platinum-based therapy). Comparison of our data with BTC data of The Cancer Genome Atlas (TCGA) in cbioportal showed a similar trend in OS (19,1 months in TCGA data vs 22,7 months in the studied cohort).

Conclusions: Pathogenic alterations in DDR pathway genes were seen in 13.5% of the cases studied. DDR-deﬁcient BTC patients showed a trend for better OS and TTE representing a potential subgroup that could beneﬁt from targeted treatment strategies, like PARP-inhibitors. Moreover the slight beneﬁt of DDR-mutated BTC under platinum-based therapy supports the hypothesis of better response of DDR-mutated tumours to platinum.

Disclosure: S. Kasper-Virchow: Other, Personal, Sponsor/Funding, Honoraria from Merck Serono,MSD, Novartis, BMS, Amgen, Roche, Sanoﬁ-Aventis, Servier, Incyte and Lilly; Research Funding from

Merck Serono, Lilly, BMS, Roche: Merck Serono, MSD, Novartis, BMS, Amgen, Roche, Sanoﬁ-Aventis,Servier, Incyte and Lilly. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1402

110P Detection of HER2 overexpression in biliary tract cancers:Comparison of AmoyDx HER-2 (29D8) assay with

Comparison of AmoyDx® HER-2 (29D8) assay with ventanaventana PATHWAY anti-HER-2/neu (4B5) assay

H. Dong1, W. Su2, H. Lu3, Z. Liu3, Z. Tang3, Z. Huang2, L. Ruan3, C. Zhu2

1Department of Pathology, Shanghai Eastern Hepatobiliary Surgery Hospital,Shanghai, China; 2Department of Translational Medicine, Amoy Diagnostics Co., Ltd.,Xiamen, China; 3Department of Research and Development, Amoy Diagnostics Co.,Ltd., Xiamen, China

Background: The human epidermal growth factor receptor 2 (HER2/neu), a member of epidermal growth factor receptor protein family, play a role as predictive and prognostic biomarkers in various tumor types, particularly biliary tract cancers (BTCs),a heterogeneous group of poor-prognosis solid tumors with limited treatment options. Accurate evaluating of HER2 overexpression is essential for selection and determination of eligible patients for HER2-directed therapy. Herein, we report the results of an immunohistochemistry (IHC) concordance study comparing the AmoyDx HER-2(29D8) assay and the well-established Ventana PATHWAY anti-HER2/neu (4B5) assay using a BTC cohort of 432 samples.

Methods: Performance of the AmoyDx© HER-2 (29D8) assay was compared againstPerformance of the AmoyDx HER-2 (29D8) assay was compared against the Ventana PATHWAY anti-HER-2/neu (4B5) assay using 432 pre-selected BTC samples. Further ISH testing was successfully performed in 134 of the samples to identify HER2-positive and HER2-negative samples according to standard criteria.

Results: There was a high concordance between results from the AmoyDx 29D8 and PATHWAY 4B5 assays for HER2-negative (IHC 0, 1 +) and HER2-positive (IHC 2 + , 3 +)BTCs (98.38%, 425/432). When combined with the ISH results, the aggrement was even increased to 99.29% (422/425) (Table). In addition, the low concordance(34.63%, 9/26) between the two assays for IHC 1+ samples, indicating that the detecton criteria for HER2 IHC 0 and 1+ still need further clariﬁcation, which reminds researchers to carefully select appropriate assays if they focus on BTC with HER2-low expression types.

|Table: 110P Comparison of HER2 scorings derived from the indicated assays Ventana PATHWAY anti-HER-2/neu (4B5) |Table: 110P Comparison of HER2 scorings derived from the indicated assays Ventana PATHWAY anti-HER-2/neu (4B5) |Table: 110P Comparison of HER2 scorings derived from the indicated assays Ventana PATHWAY anti-HER-2/neu (4B5) |Table: 110P Comparison of HER2 scorings derived from the indicated assays Ventana PATHWAY anti-HER-2/neu (4B5) | |---|---|---|---|

|||+ - |Total |

|Am oyDx HER-2 (29D8 )|+ |19 2 |21 |

||- |1 403 |404 |

||Total |20 405 |425 |

|Positive percent agreement ||95.00% (95%CI: 75.13%, 99.87%) ||

|Negative percent agreement ||99.51% (95%CI: 98.23%, 99.94%) ||

|Overall percent agreement |Overall percent agreement |99.29% (95%CI: 97.95%, ||

99.85%)

Conclusions: Our data demonstrate that AmoyDx 29D8 exhibited high concordance with PATHWAY 4B5, and could provide critical information for the selection of HER2-targeted therapy for BTC patients.

Disclosure: W. Su, H. Lu, Z. Liu, Z. Tang, Z. Huang: Financial Interests, Personal, Full or part-time Employment: Amoy Diagnostics. L. Ruan, C. Zhu: Financial Interests, Personal, Advisory Board: Amoy Diagnostics. All other authors have declared no conﬂicts of interest.

Methods: Potentially prognostic factors were evaluated using Cox proportional hazards models with treatment and each factor. An exploratory adjusted HR for D + GC vs PBO + GC was estimated with a model adjusting for prognostic factors identiﬁed by stepwise selection. Unstratiﬁed Cox proportional hazards models and interaction tests were performed to assess potential predictive factors. Data cut-off was 25 February

2022.

Results: Potentially prognostic clinical factors are shown (Table). The HR for D + GC vs PBO + GC, adjusted for disease status, primary tumour location, sex, PD-L1, neutrophil to lymphocyte ratio (NLR), cancer antigen 19-9 (CA19-9), carcinoembryonic antigen(CEA), liver metastasis, liver involvement (locally advanced or metastatic site in liver/gallbladder), body weight, LDH, albumin and total bilirubin, was 0.70 (95% CI 0.59e

0.84). OS HRs for D + GC vs PBO + GC were <1 across assessed clinical (Table) and laboratory factors; no predictive factors for D + GC were found.

ly unresectable; LA, locally advanced; M, metastatic; R, recurrent

Conclusions: Beneﬁt with D + GC was consistent across assessed factors and stable after adjusting for potentially prognostic factors, supporting D + GC as ﬁrst-line treatment for aBTC.

Disclosure: A.R. He: Financial Interests, Personal, Research Grant: AstraZeneca, Genentech, Merck;Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Eisai, BMS. M. Bouattour: Financial Interests, Personal, Advisory Board: MSD, BMS, Sirtex Medical, Ipsen, AbbVie, AstraZeneca, Servier,Taiho; Financial Interests, Personal, Invited Speaker: Roche; Non-Financial Interests, Principal Investigator: MSD, BMS, Sirtex Medical, AstraZeneca. V.G. Gupta: Financial Interests, Personal,Stocks/Shares: Zydus Life, RPG Life. L. Evesque: Financial Interests, Personal, Advisory Board: Servier,Amgen, MSD, Merck. D.B. Zhen: Financial Interests, Personal, Advisory Board: QED Therapeutics,Ipsen; Financial Interests, Other, Local PI and Coordinating PI: Merck; Financial Interests, Invited Speaker: TME Pharma, AstraZeneca, Bristol Meyers Squibb, Legend Biotech, Genentech, Cornerstone Pharmaceuticals, Eli Lilly, Seagen, NeoTx Therapeutics, Daiichi Sankyo; Non-Financial Interests,Leadership Role, Binaytara Foundation: Gastrointestinal Oncology Education Chair; Non-Financial Interests, Other, Panel Member of NCCN Neuroendocrine and Adrenal Tumor Guidelines: National Comprehensive Cancer Network. J.O. Park: Financial Interests, Personal, Advisory Board: MedPacto,BMS (Celgene), Servier, MediRama, Adicet Bio, AstraZeneca, Merck Sereno; Financial Interests,Personal, Other, Travel support for a poster presentation at ASCO GI 2023: Minneamrita Therapeutics LLC; Financial Interests, Personal, Research Grant, Clinical research grant: MedPacto, Servier,BMS (Celgene); Financial Interests, Personal, Research Grant: Eutilex, ABL Bio. A. Sookprasert:Financial Interests, Personal, Invited Speaker: AstraZeneca, Bristol, Easai, Merck, Roche, Jansen,Pﬁzer, Novartis. A. Salvatierra: Non-Financial Interests, Personal and Institutional, Principal Investigator: Fundacion Ars Medica. G.M. Vaccaro: Financial Interests, Personal, Speaker’s Bureau: Incyte;Financial Interests, Personal, Advisory Board: AstraZeneca, GlaxoSmith Kline; Financial Interests,Personal, Advisory Role: Servier. S.A. Ostoich: Non-Financial Interests, Personal, Principal Investigator: Hospital Provincial del Centenario. T. Satoh: Financial Interests, Personal, Invited Speaker,invited speaker and advisory: Ono Pharmaceutical, Daiichi-Sankyo; Financial Interests, Personal,Invited Speaker, Invited speaer and adovisory: Bristol-Myers; Financial Interests, Personal, Invited Speaker, Invited speaker and advisory: Elli-Lilly, Yakult-HOnsha; Financial Interests, Personal, Invited Speaker: Chugai Pharmazeutical, Merck-Biopharm, Takeda, Taiho; Financial Interests, Personal,Advisory Board: Takara-Bio; Financial Interests, Institutional, Invited Speaker: Merck-Biopharm;Financial Interests, Institutional, Invited Speaker, Research Grant and Endosed Department: Ono Pharmaceutical, Chugai Pharmaceutical, Yakult Honsha; Financial Interests, Institutional, Invited Speaker, Research Grant: Bristol-Myers, Elli-Lilly, Daiichi Sankyo, Parexell, Giliad, Taiho, Hutch-Med.

M. _Zotkiewicz: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. N. Rokutanda: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests,Personal, Stocks/Shares: AstraZeneca. H. Kim: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. D. Oh: Financial Interests, Personal, Advisory Board: AstraZeneca,Novartis, Genentech/Roche, Merck Serono , Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA, MSD; Financial Interests,Institutional, Research Grant: AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, Handok.

https://doi.org/10.1016/j.annonc.2023.09.1395

103P Individual patient data (IPD) meta-analysis of randomised trials to compare efﬁcacy of second-line ﬂuoropyrimidinebased chemotherapy in advanced biliary tract cancer (BTC)

|Table:102P |Table:102P |||| |---|---|---|---|---|

|Predictive |Predictive ||Prognostic |Prognostic |

|Disease |IU .79 (.65e.95) |.93 |2.14 (1.69e2.76) |<.01 |

|status |R .76 (.49e1.20) ||||

|ECOGPS |0 .87 (.68e1.12) |.14 |1.29 (1.09e1.53) |<.01 |

||1 .70 (.55e.89) ||||

|Disease |LA .54 (.32e.88) |.13 |1.35 (1.05e1.76) |.02 |

|classiﬁcation |M .80 (.67e.97) ||||

|NLR |<3 .75 (.56e1.01) |.83 |2.14 (1.79e2.58) |<.01 |

||≥3 .76 (.61-.94)||||

|CA19-9 |<500 U/.72 (.57e.92) |.53 |2.08 (1.73e2.50) |<.01 |

||mL ||||

||≥500U/ .82 (.62-1.08)||||

|CEA |<5 ng/.75 (.58e.97) |.75 |1.78 (1.49e2.14) |<.01 |

||≥5ng/ .81 (.63-1.05)||||

|Liver |Y .83 (.66e1.06) |.32 |1.37 (1.56e1.63) |<.01 |

|metastasis |N .69 (.54e.88) ||||

|Liver |Y .76 (.63e.91) |.76 |1.67 (1.32e2.14) |<.01 |

|involvement |N .77 (.49e1.20) ||||

J. Hyung1, M. Kang2, I. Kim3, K-P. Kim1, B-Y. Ryoo1, J. Cheon4, H. Ryu5, J.S. Lee6,G.K. Abou-Alfa7, J-W. Kim2, I. Choi8, J.H. Park8, J.W. Kim2, C. Yoo1

1Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 2Internal Medicine, Seoul National University Bundang Hospital,Seongnam, Republic of Korea; 3Internal Medicine, Inje University Haeundae Paik Hospital, Busan, Republic of Korea; 4Internal Medicine, Ulsan University Hospital,University of Ulsan College of Medicine, Ulsan, Republic of Korea; 5Internal Medicine,Chungnam National University Hospital, Daejeon, Republic of Korea; 6Clinical Epidemiology and Biostatistics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 7Medicine, Memorial Sloan Kettering Cancer Center,New York, NY, USA; 8Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Republic of Korea

Background: For patients (pts) with advanced BTC with progression on gemcitabine plus cisplatin (GemCis), ﬂuoropyrimidine-based chemotherapy, including liposomal irinotecan (nal-IRI) plus ﬂuorouracil and leucovorin (5-FU/LV) and 5-FU/LV plus oxaliplatin (FOLFOX) showed clinical beneﬁt in prior randomized trials (NIFTY and ABC06). However, there is no trial for head-to-head comparison among these agents.

Methods: We performed IPD meta-analysis of two multicenter, randomized trials performed in South Korea, which compared efﬁcacy of second-line chemotherapy for advanced BTC after progression on GemCis, including the phase 2b NIFTY trial (nal-IRI plus 5-FU/LV vs. 5-FU/LV, NCT03524508) and the phase 2 FIReFOX trial (modiﬁed FOLFOX [mFOLFOX] vs. modiﬁed 5-FU/LV plus irinotecan [mFOLFIRI], NCT03464968).

ITT population of the two trials were included and survival outcomes were compared between the 4 treatment groups by pairwise log-rank test. Hazards ratio (HR)adjusted by potential prognostic variables was estimated by Cox proportional hazards modeling with shared frailty to account for the trials effect.

&Dohme Corp.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc., Rahway, NJ, USA. U.

Malhotra: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme Corp.;Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc., Rahway, NJ, USA. A.B. Siegel: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme Corp.; Financial Interests,Personal, Stocks/Shares: Merck & Co., Inc., Rahway, NJ, USA. S. Qin: Financial Interests, Institutional,Research Funding: MSD; Financial Interests, Personal and Institutional, Principal Investigator: Cina.

https://doi.org/10.1016/j.annonc.2023.09.1393

101P

aOut aOut of pts with a BL and ≥1 post-BL scoreof p

Quality of life (QoL) outcomes in patients (pts) with

zanidatamab (zani)-treated HER2-positive (HER2+) biliary tract cancer (BTC) in the phase IIb HERIZON-BTC-01 study

H.S. Wasan1, J.J. Harding2, J. Fan3, D-Y. Oh4, H.J. Choi5, J.W. Kim6, H-M. Chang7,L. Bao8, H. Sun3, T. Macarulla9, F. Xie10, J-P. Metges11, J. Ying12, J.A. Bridgewater13,M. Tejani14, E.Y. Chen15, M.P. Ducreux16, J. Ma17, P. Garﬁn18, S. Pant19

1Department of Oncology, Imperial College Healthcare NHS Trust, London, UK;2Department of Internal Medicine, Memorial Sloan Kettering Cancer Center, New York,NY, USA; 3Department of Liver Surgery, Zhongshan Hospital of Fudan University,Shanghai, China; 4Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; 5Department of Internal Medicine, Severance Hospital Yonsei University Health System, Seoul, Republic of Korea; 6Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea;7Department of Oncology, Asan Medical Center University of Ulsan College of Medicine, Seoul, Republic of Korea; 8Department of Internal Medicine, Hubei Cancer Hospital, Hubei, China; 9Department of Oncology, Vall d’Hebrón University Hospital,Vall d’Hebrón Institute of Oncology, Barcelona, Spain; 10Department of Internal Medicine, The Third Afﬁliated Hospital of the Chinese PLA Naval Military Medical University, Shanghai, China; 11Department of Oncology, ICH CHRU de Brest e Hopital Morvan, ARPEGO Network, Brest, France; 12Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, China; 13Department of Medical Oncology, UCL Cancer Institute, London, UK; 14Department of Medical Oncology, AdventHealth Cancer Institute, Orlando, FL, USA; 15Department of Hematology & Medical Oncology,Oregon Health & Science University, Knight Cancer Institute, Portland, OR, USA;16Department of Medical Oncology, Paris-Saclay University, Gustave Roussy, Villejuif,France; 17Department of Clinical Development, BeiGene, Ltd., Beijing, China;18Department of Clinical Research, Zymeworks BC Inc., Vancouver, BC, Canada;19Department of Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA

Background: In the pivotal HERIZON-BTC-01 study, the HER2 bispeciﬁc antibody zani demonstrated rapid, durable responses (conﬁrmed objective response rate, 41% by independent central review; median duration of response, 12.9 mo; data cut-off: Oct 2022) and manageable safety in pts with HER2+ BTC. Here we report QoL outcomes for those pts with HER2+ BTC.

Methods: HERIZON-BTC-01 (NCT04466891), an ongoing open-label, global phase 2b study, evaluated zani (20 mg/kg IV every 2 wks) in pts with HER2+ (gene ampliﬁcation with immunohistochemistry of 2+ or 3+), locally advanced, unresectable or metastatic BTC (gallbladder cancer, intra-/extra-hepatic cholangiocarcinoma) who received prior gemcitabine-containing treatment (tx). QoL, an exploratory endpoint, was assessed using the EQ-5D-5L descriptive system and visual analogue scale (VAS) at baseline (BL)and every 8 wks; best on-treatment score (BONT) was the lowest descriptive or highest VAS value observed post-BL.

Results: A total of 80 pts with HER2+ BTC were evaluated for primary efﬁcacy analyses (median age, 64 years; 56% female). Of these, 1 (1%) had complete response(CR), 32 (40%) had partial response (PR), 22 (28%) had stable disease (SD) and 24(30%) had progressive disease (PD); 1 pt was not evaluable. Pts with CR or PR reported the greatest improvement in QoL followed by those with SD, while pts with PD generally reported worsening QoL (Table). Median VAS scores improved by generally reported worsening QoL (Table). Median VAS scores improved by ≥1010points from BL to time of BONT for pts with CR and PR, by 5 points for pts with SD and worsened by 10 points for pts with PD. In each dimension, the proportion of pts reporting ‘no problem’ increased more from BL to BONT for pts with PR than for pts with SD or PD.

|Table:101P EQ-5D-5L QoL outcomes in pts with HER2+ BTC by tumour response Conﬁrmed Best Overall Tumour Response |Table:101P EQ-5D-5L QoL outcomes in pts with HER2+ BTC by tumour response Conﬁrmed Best Overall Tumour Response |Table:101P EQ-5D-5L QoL outcomes in pts with HER2+ BTC by tumour response Conﬁrmed Best Overall Tumour Response |Table:101P EQ-5D-5L QoL outcomes in pts with HER2+ BTC by tumour response Conﬁrmed Best Overall Tumour Response |Table:101P EQ-5D-5L QoL outcomes in pts with HER2+ BTC by tumour response Conﬁrmed Best Overall Tumour Response |Table:101P EQ-5D-5L QoL outcomes in pts with HER2+ BTC by tumour response Conﬁrmed Best Overall Tumour Response |Table:101P EQ-5D-5L QoL outcomes in pts with HER2+ BTC by tumour response Conﬁrmed Best Overall Tumour Response |Table:101P EQ-5D-5L QoL outcomes in pts with HER2+ BTC by tumour response Conﬁrmed Best Overall Tumour Response |Table:101P EQ-5D-5L QoL outcomes in pts with HER2+ BTC by tumour response Conﬁrmed Best Overall Tumour Response | |---|---|---|---|---|---|---|---|---|

||CR BL n[1 |BONT n[1 |PR BL n[31 |BONT n[32 |SD BL n[21 |BONT n[22 |PD BL n[24 |BONT n[19 |

|Media score n VAS |40 80 ||80 |95 |80 |88 |80 |70 |

|Media change n VAS from BLa |40 |||10 ||5 ||-10 |

|Least s respon level (no pr n (%) Mobili evere se oblem), ty |0 |0 23 |0 23 |0 23 |(74) 30 (94) 16 |(74) 30 (94) 16 |(76) 19 |(86) 15 (63) 12 (63) |

|Self-care |0 |0 28 |0 28 |0 28 |(90) 31 (97) 18 |(90) 31 (97) 18 |(86) 19 |(86) 23 (96) |

|Usualactivities |0 |0 23 |0 23 |0 23 |(74) 29 (91) 11 |(74) 29 (91) 11 |(52) 15 |(68) 16 (67) |

|Pain/discomfort |0 |1 (100) 15 |1 (100) 15 |1 (100) 15 |(48) 28 (88) 10 |(48) 28 (88) 10 |(48) 13 |(59) 10 (42) 7 |

|Anxitey/ |0 |0 18 |0 18 |0 18 |(58) 28 (88) 12 |(58) 28 (88) 12 |(57) 14 |(64) 13 (54) |

|depression |||||||||

ts with a BL and 1 post-BL score

Conclusions: In HERIZON-BTC-01, pts with HER2+ BTC who responded to zani reported improved QoL compared with BL, while those with PD reported worsening QoL compared with BL. These results support the continuing development of zani as a HER2+ BTC tx option.

Clinical trial identiﬁcation: NCT04466891, ﬁrst posted July 10, 2020.

Editorial acknowledgement: Medical writing support, under the direction of the authors, ,was provided by Tara Suntoke, of CMC AFFINITY, a division of IPG Health Medical Communications, with funding from Jazz Pharmaceuticals, in accordance with Good Publication Practice (GPP 2022) guidelines.

Legal entity responsible for the study: Jazz Pharmaceuticals, Zymeworks BC Inc., and BeiGene Ltd.

Funding: Pharmaceutical/biotech: Jazz Pharmaceuticals, Zymeworks BC Inc., and BeiGene Ltd.

Disclosure: H.S. Wasan: Financial Interests, Personal, Advisory Board, Advisory Boards and Invited Speaker: Incyte, Pierre Fabre, Servier, Bayer, Roche/Genentech/ FM AG, Sirtex Medical Erytech,Celgene, Array BioPharma, Merck KGaA: BMS; Financial Interests, Personal, Steering Committee Member, Trial steering committee and advisory: Zymeworks; Financial Interests, Personal and Institutional, Coordinating PI, Trial PI steering committee and advisory: Sirtex Medical; Financial Interests, Personal, Other, Consultancy for Submission for UK approval (BSI): ONCOSL; Non-Financial Interests, Advisory Role, Trial steering committee: Pﬁzer; Non-Financial Interests, Advisory Role, UK NICE submission: Bayer, Pierre Fabre. J.J. Harding: Financial Interests, Personal, Advisory Board:Adaptimmune, Bristol Myer Squib, CytoMx, Eisai, Exelexis, Elevar, Hepion, Eli Lilly, AstraZeneca,Medivir, QED, Sevier, Merck. D. Oh: Financial Interests, Personal, Advisory Board: AstraZeneca,Novartis, Genentech/Roche, Merck Serono , Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA, MSD; Financial Interests,Institutional, Research Grant: AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, Handok.

H. Chang: Financial Interests, Institutional, Local PI: BeiGene, Ltd., Senhwa biosciences, Taiho Oncology, Astellas Pharma Global Development, AbbVie. H. Sun: Financial Interests, Personal, Invited Speaker: AstraZeneca, Eisai, Roche, MSD, Hengrui, TopAlliance, Innovent, Bayer; Non-Financial Interests, Institutional, Local PI: AstraZeneca, Eisai, Roche, MSD, Hengrui, Innovent. T. Macarulla:Financial Interests, Personal, Advisory Board: Ability Pharmaceutical, SL, AstraZeneca, Basilea Pharma, Batxer, BioLineRX Ltd, Celgene SLU, Eisai, IPSEN Pharma, Incyte; Financial Interests, Personal, Other, Direct research fund: Servier, Merck, Sharp and Dhome, Novocure, QED Therapeutics Inc, Roche, Sanoﬁ-Aventis, Zymeworks; Financial Interests, Personal, Invited Speaker: Lilly, Janssen;Financial Interests, Institutional, Research Grant: Amc Medical Research, Armo Biosciences, Basilea,Biokeralty Research Institute, Merck Sharp & Dohme, Oncomed Pharmaceuticals, QED Therapeutics,VCN Biosciences, AbbVie Farmaceútica, Ability Pharmaceuticals, Agios, Amgen, Aslan, AstraZecena,Bayer, BeiGene, Biolinerx, Blueprint Medicines, Boston Biomedical, Bristol Myers Squibb (BMS),Cantargia, Celgene, Eisai, Erytech Pharma, F. Hoffmann-la Roche, Fibrogen, Genentech, Hallozyme,Immunomedics, Incyte, Ipsen, Lab. Menarini, Lilly, Loxo Oncology, Medimmune, Merimarck, Millenim, Nelum, Novartis, Novocure, Pﬁzer, Pharmacyclics, Roche, Zymeworks; Non-Financial Interests,Member: American Society of Clinical Oncology - ASCO, “Sociedad Española de Oncología Médica” e SEOM, Sociedad Europea de Oncología Médica - ESMO. J. Metges: Financial Interests, Personal,Expert Testimony: Astellas, MSD; Financial Interests, Personal, Invited Speaker: BMS, MSD, Daiichi.

J.A. Bridgewater: Financial Interests, Personal, Advisory Board: Taiho, BMS, Incyte, Basilea, Servier;Financial Interests, Institutional, Funding: Incyte. E.Y. Chen: Non-Financial Interests, Institutional,Research Funding: Taiho Oncology, Inc.; Non-Financial Interests, Personal and Institutional, Invited Speaker: Horizon CME. M.P. Ducreux: Financial Interests, Personal, Invited Speaker: Roche, Amgen,Pierre Fabre, Merck Kga, Pﬁzer, Bayer, Lilly, Servier; Financial Interests, Personal, Advisory Board:Roche, Basilea, Sotio, Pierre Fabre, Bohringer, Rafael, Servier, Zymeworks, Ipsen, Bayer, HalioDX, Lilly,Glaxo Smith Kline, Daiichi Sankyo; Financial Interests, Institutional, Advisory Board: AstraZeneca;Financial Interests, Institutional, Funding, Partial funding of a trial evaluating the role of bevacizumab in NET: Roche; Financial Interests, Institutional, Funding, Partial funding of a trial evaluating the role of steptozotocin in NET: Keocyt; Financial Interests, Institutional, Local PI: Rafael,Amgen; Financial Interests, Institutional, Funding: Bayer; Other, My wife is head of the oncology business unit in the French Afﬁliate of Sandoz: Sandoz France. J. Ma: Financial Interests, Personal,Full or part-time Employment: BeiGene.Ltd. P. Garﬁn: Financial Interests, Personal, Full or part-time Employment, Also own equity: Zymeworks; Financial Interests, Personal, Stocks or ownership: Seage.

S. Pant: Financial Interests, Personal, Advisory Role: Zymeworks, Ipsen, Novartis, Janssen, Boehringer Ingelheim, AskGene Pharma; Financial Interests, Institutional, Research Funding: Mirati Therapeutics, Lilly, Xencor, Novartis, Rgenix, Bristol Myers Squibb, Astellas Pharma, Framewave, 4D Pharma,Boehringer Ingelheim, NGM Biopharmaceuticals, Janssen, Arcus Biosciences, Elicio Therapeutics,bionte, Ipsen, Zymeworks, Pﬁzer, ImmunoMET, Immuneering, Amal Therapeutics. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1394

S219

102P

IU, initial

Potentially prognostic factors of overall survival in advanced biliary tract cancer in the randomised phase III TOPAZ-1 study

A.R. He1, M. Bouattour2, V.G. Gupta3, L. Evesque4, D.B. Zhen5, J.O. Park6,

A. Sookprasert7, A. Salvatierra8, G.M. Vaccaro9, S.C. Oh10, S.A. Ostoich11, T. Satoh12,M. _Zotkiewicz13, N. Rokutanda14, H. Kim15, D-Y. Oh16

1Division of Hematology and Oncology, Lombardi Comprehensive Cancer Center,Georgetown University, Washington, DC, USA; 2Medical Oncology, AP-HP Hôpital Beaujon, Paris, France; 3Department of Medical Oncology, Artemis Hospitals, Gurugram, Delhi, India; 4Medical Oncology Department, La Centre Antoine Lacassagne,Nice, France; 5Division of Medical Oncology, Department of Internal Medicine, University of Washington, Fred Hutchinson Cancer Center, Seattle, WA, USA; 6Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 7Medical Oncology Unit, Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen,Thailand; 8Fundacion Ars Medica, San Salvador de Jujuy, Jujuy, Argentina; 9Clinical Oncology, Providence Cancer Institute, Portland, OR, USA; 10Division of Hematology and Oncology, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea; 11Department of Oncology, Hospital Provincial del Centenario, Rosario, Argentina; 12Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka, Japan; 13Late Oncology Statistics, Oncology Biometrics, AstraZeneca, Warsaw, Poland; 14Oncology R&D, Late-Stage Development, AstraZeneca, Gaithersburg, MD, USA; 15Statistics,AstraZeneca, Osaka, Japan; 16Division of Medical Oncology, Department of Internal Medicine, Seoul National University Hospital and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea

Background: In TOPAZ-1 (NCT03875235), durvalumab (D) + gemcitabine and cisplatin(GC) improved overall survival (OS) vs placebo (PBO) + GC in participants with advanced biliary tract cancer (aBTC; primary analysis: hazard ratio [HR] 0.80, 95%conﬁdence interval [CI] 0.66e0.97, p¼0.021 [signiﬁcance threshold p¼0.03]) andafter a further 6.5 months of follow-up (HR 0.76, 95% CI 0.64e0.91). This exploratory analysis assessed baseline clinical factors for potential prognostic (associated with OS)or predictive (of OS beneﬁt with D + GC) value in TOPAZ-1.

https://doi.org/10.1016/j.annonc.2023.09.1403

111P The concordance between circulating tumor DNA and tissue genomic proﬁling in patients with advanced biliary tract cancer

S. Woo1, S. Hwang2, G. Kim2, H. Kang2, D.S. Kyung3, W. Lee3, H-P. Kim3, B. Kang4,C. Kim4, H.J. Chon4

1Department of Biomedical Science, CHA University, Seongnam, Republic of Korea;2Department of Pathology, Cha Bundang Medical Center, Seongnam, Republic of Korea; 3Clinical Support Team, IMB Dx, Inc., Seoul, Republic of Korea; 4Department of Medical Oncology, CHA Bundang Medical Center, Seongnam, Republic of Korea

Background: Recent advances in molecular proﬁling have revealed potential therapeutic targets for biliary tract cancer (BTC). However, difﬁculties in obtaining an adequate sample could hamper molecular evaluations in patients with BTC. Circulating tumor DNA (ctDNA) can thus help address any challenges associated with the

S223

|Table:112P |Table:112P |Table:112P |Table:112P |Table:112P |Table:112P | |---|---|---|---|---|---|

|Genomic characteristics ||Age <[50 n[92 |Age <[50 n[92 |age>50 n[454 [BA1] |age>50 n[454 [BA1] |

|||n |% |n |% |

|Molecular proﬁle available |No |29 |32% |204 |45% |

|available|Yes |63 |68% |250 |55% |

|Actionable alteration |No |41 |65% |141 |56% |

|alteration|Yes |22 |35% |109 |44% |

|Main actionable |No alteration |11 |17% |43 |17% |

|alterations |Mutation IDH1/2 |8 |13% |40 |16% |

||Fusion FGFR 1-4 |8 |13% |21 |8% |

||Ampliﬁcation HER2 |3 |5% |15 |6% |

||Mutation BRAF V600E |0 |0% |10 |4% |

||EGFR |2 |3% |7 |3% |

||Fusion NTRK |6 |10% |11 |4% |

||Mutation KRAS G12C |1 |2% |3 |1% |

|Other relevant alterations |KRAS |16 |25% |40 |16% |

|alterations|TP53 |25 |40% |91 |36% |

||CDKN2A/B |8 |13% |63 |25% |

|MMR status |dMMR/MSI |0 |0% |11 |7% |

|(n¼199) |pMMR/MSS |47 |100% |141 |93% |

|Targeted therapies administration |No |41 |65% |141 |56% |

|administration|Yes |22 |35% |109 |44% |

limited use of tissue-based analysis in BTC. In this study, we aimed to evaluate the concordance between ctDNA and tissue genomic proﬁling in patients with advanced BTC and evaluate the feasibility of liquid biopsy in the treatment of patients with BTC.

Methods: Patients who underwent tissue-based next-generation sequencing (NGS)before systemic chemotherapy for advanced BTC at CHA Bundang Medical Center from January 2019 to December 2022 and for whom sufﬁcient plasma samples were available for ctDNA analysis (AlphaLiquid100 from IMB Dx) were included. available for ctDNA analysis (AlphaLiquid@100 from IMB Dx) were included.ClinicallyClinically important (tier 1 or 2) variants detected in tissues with a variant allele frequency(VAF) of >0.05 were considered as true positive for concordance.

Results: Of one hundred two patients, 49.0%, 26.5%, and 24.5% had intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gall bladder cancer,respectively. The concordance between intra-patient ctDNA and tumor tissue for mutations indicated 84.8% sensitivity and 79.4% positive predictive value. In ctDNA,targetable alterations were detected in 34.3% of patients, such as IDH1 mutation(7.8%), FGFR2 fusion (2.0%), microsatellite instability (MSI)-high (2.0%), ERBB2 ampliﬁcation (4.9%), PIK3CA hotspot mutations (6.9%), BRCA1/2 mutations (9.8%),and MET ampliﬁcation (2.9%). Among the two FGFR2 fusions, one FGFR2-TNS1 fusion was novel, because it was not targeted in tissue NGS panel. Lastly, patients with high ctDNA VAF showed poor prognosis in gemcitabine-cisplatin based chemotherapy in both overall survival and progression-free survival (p ¼ 6.9 x 10-6and p ¼ 9.8 x 10-10),respectively.

Conclusions: ctDNA-based genotyping demonstrated acceptable concordance with tissue genomic proﬁling in patients with advanced BTC. Thus, liquid biopsy using ctDNA could complement the limitation of tissue-based genomic analysis in BTC.

Legal entity responsible for the study: Hong Jae Chon.

Funding: National Research Foundation of Korea [NRF] grants funded by the Korean government [MSIT] [NRF-2023R1A2C2004339 to HJC] and Basic Science Research Program through the National Research Foundation Korea [NRF] funded by the Ministry of Education [NRF-2019R1A6A1A03032888].

Disclosure: D.S. Kyung, W. Lee, H. Kim: Financial Interests, Full or Part-time Employment: IMB Dx.

https://doi.org/10.1016/j.annonc.2023.09.1404

112P

S224

Clinical, genomic and transcriptomic characteristics of young-onset biliary tract cancers

T. Pudlarz1, L. Antoun2, A. Rousseau3, R. Nicolle4, M. Gelli5, E. Fernandez de Sevilla6,S. Cosconea1, L. Tselikas7, R. Barbe8, A. Turpin9, M. Deloger1, A. Italiano10,

M. Valery11, A.A. Tarabay12, V. Boige13, D. Malka14, C. Smolenschi13,

A. Hollebecque15, M.P. Ducreux16, A. Boileve13

1Département de Médecine Oncologique, Gustave Roussy - Cancer Campus, Villejuif,France; 2Gustave Roussy Cancer Campus, Villejuif, France; 3Institut Gustave Roussy,Villejuif, France; 4Programme Carte d’Identité des Tumeurs, Ligue Contre le Cancer,Paris, France; 5Surgery, Gustave Roussy - Cancer Campus, Villejuif, France; 6Département D’anesthésie, Chirurgie et Interventionnel, Gustave Roussy, Villejuif, France;7Interventional Radiology Department, Institut Gustave Roussy, Villejuif, France;8Diagnostic Imaging, Institut Gustave Roussy, Villejuif, France; 9Oncologie Médicale,Hopital Claude Huriez, Lille, France; 10DITEP, Gustave Roussy - Cancer Campus, Villejuif,France; 11Medical Oncology Department, Gustave Roussy, Villejuif, France; 12Medical Oncology Department - GI, Gustave Roussy - Cancer Campus, France; 13Département de Médecine Oncologique, Institut Gustave Roussy, Villejuif, France; 14Institut Mutaliste Montsouris, Paris, France; 15DITEP, Institut Gustave Roussy, Villejuif, France;16Medical Oncology Department, Gustave Roussy - Cancer Campus, Villejuif, France

Background: Biliary tract cancers (BTC), including cholangiocarcinomas (CCA) are rare but aggressive cancers primarily affecting patients (pts) >70 years (median age at diagnosis : 72-78 years). However, there has been a rise in the incidence of CCA among younger individuals (<50 years). This study aimed to investigate clinical,genomic and transcriptomic characteristics and outcomes of young-onset BTC/CCA(YOC) pts.

Methods: We identiﬁed all consecutive patients with histologically conﬁrmed CCA treated at Gustave Roussy (France) between 2015 and 2021 as part of the ACABIPRONOBIL multicenter cohort study. Clinical data were extracted from medical records. Genomic data were obtained through in-house or Foundation Medicine®Genomic data were obtained through in-house or Foundation Medicine panels. Transcriptomic analyses were performed for 58 pts (13 YOC) at metastatic diagnosis.

Results: Of the 546 pts with CCA, 92 (16.8%) had YOC (median age, 42 years; range,27-50). Median overall survival (mOS) from 1stline therapy was 22.7 months (mo)(95%CI: 18.3-27.6) for YOC patients vs 19.2 mo (95%CI: 18.0-22.0) for non-YOC patients (p¼0.14). Molecular proﬁling was more often performed for YOC pts (68% vs55%, p<0.05). Rates of actionable molecular alterations (IDH1/2, BRAF, FGFR2, NTRK,HER2, MSI) and targeted therapies administration did not differ between YOC and non-YOC pts. CDKN2A alterations were less frequent in YOC than in non-YOC pts(12.6% vs 25.2%, p<0.05). Differentially expressed genes between YOC and non-YOC pts with Gene Set Enrichment Analysis were mostly genes involved in immunity and WNT signaling pathways.

Volume 34 - Issue S2 -

Conclusions: Although tending to have a more advanced disease at diagnosis, YOC patients had OS similar to that of non-YOC pts, and no more actionable molecular alterations. Our ﬁndings suggest that the biological mechanisms driving CCA in YOC patients may be different from those in older patients and warrant further investigation.

Funding: Gercor.

https://doi.org/10.1016/j.annonc.2023.09.1405

113P Molecular proﬁling of biliary tract cancers in patients of African and European ancestries

Z.I. Hu1, A. Danner De Armas1, D.C. Pavlick2, J.S. Ross3, S. Lee4, M. Eluri1, M. Javle1

1Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA;2Cancer Genomics Research, Foundation Medicine, Inc, Cambridge, MA, USA; 3Pathology Department, Foundation Medicine, Inc, Cambridge, NY, USA; 4Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX,USA

Background: Molecular differences between genetic ancestries in patients (pts) with bilary tract cancers (BTCs) and how they affect prognosis and treatment response are largely unknown. Compounding this problem is clinical trial enrollment for racial minorities with BTCs have been historically low, making it difﬁcult to assess differences in treatment response between genetic ancestries. Our prior data indicated signiﬁcant variation in somatic cancer genes between Caucasian and Asian pts.

However, variations in African ancestry (AA) pts have not been described.

Methods: 12,932 cases of BTCs of AA and European ancestries (EA) were reviewed from 3 databases (Foundation Medicine (n¼10,849), MD Anderson Cancer Center(n¼167) and AACR Genie (n¼1,916). BTCs were divided into intrahepatic (ICC) andextrahepatic (ECC) cholangiocarcinomas and gallbladder cancers (GBC). Prevalence of alterations in 30 genes between genetic ancestries were compared using Fischer’s exact test on the Foundation Medicine database. P-values were corrected for false discovery rate using the Benjamini/Hochberg adjustment.

Results: We identiﬁed key clinical and genomic differences between AA and EA BTC cases in all 3 databases. The mean age of AA pts at diagnosis was earlier (62.3 years)compared to EA pts (65.1 years) (p<0.05). There was a higher percent of female AA BTC cases (63.2%) compared to female EA BTC cases (52.4%) (p<0.05). AA BTC cases had a statistically signiﬁcant higher prevalence of TP53 (55.1% vs 39.7%) and TERT(10.0% vs 5.4%) alterations (p<0.001) compared to EA BTC cases. AA BTC cases also had a statistically signiﬁcant higher prevalence of STK11, CCNE, ERBB2, and ARID2 alterations (p<0.05), and lower prevalence of IDH1, ARID1A, BAP1, BRAF, and PBRM1 alterations (p<0.05) compared to EA BTC cases. AA ICC cases had a statistically signiﬁcant higher prevalence of FGFR2 (16.8% vs 11.7%) alterations (p<0.001) compared to EA ICC cases.

2023

Conclusions: Our results highlight signiﬁcant differences in genomic proﬁles among BTC cases of different genetic ancestries and support further research in how these differences contribute to prognosis and treatment response to targeted therapies.

Disclosure: D.C. Pavlick: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine. J.S. Ross: Financial Interests, Personal, Full or part-time Employment, Medical Director:Foundation Medicine; Financial Interests, Personal, Stocks/Shares: Roche Holdings, Tango Therapeutics, Celsius Therapeutics. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1406

114P

Prospective longitudinal tumor-informed ctDNA in resectable biliary tract cancers

G. King1, S.A. Cohen1, E.G. Chiorean1, W.P. Harris1, R. Yeung2, J. Park2, D.B. Zhen3,A.L. Coveler1, A. Diehl1, R. Safyan1, A. Jurdi4, C. Brdiges4

1Medical Oncology, University of Washington, Fred Hutchinson Cancer Center, Seattle,WA, USA; 2Surgery, University of Washington Medical Center, Seattle, WA, USA; 3Division of Medical Oncology, Department of Internal Medicine, University of Washington, Seattle; Fred Hutchinson Cancer Center, Seattle, WA, USA; 4Oncology, Natera,Inc., San Carlos, CA, USA

Background: Circulating tumor DNA (ctDNA) is an emerging strategy to deﬁne minimal residual disease (MRD) in resected cancers. Data in biliary tract cancers (BTC) is limited.We describe a prospective evaluation of ctDNA as part of a feasibility study of multi-platform proﬁling of resected BTC (NCT04561453).

Methods: We conducted a prospective multi-platform proﬁling study for resectable BTC from 2020 to 2023, which included tumor-informed ctDNA testing (SignateraTM,Natera USA) obtained pre-operatively, within 6 weeks post-operatively prior to adjuvant therapy (MRD detection) and longitudinally every 3 months thereafter until death or last follow-up.

Results: 12 patients were included, median age 70 years (range 61-83), 6 female. BTC subtypes: intrahepatic (9) and perihilar (1) cholangiocarcinoma, and gallbladder carcinoma (2). Median follow up was 20.5 months (range 6-33 months). Median tumor size was 5.2cm (range 2.1-8.3 cm), stage II-III disease 67%, R1 resection 33%. All patients received post-operative therapy: adjuvant capecitabine (9), chemoradiation(2), gemcitabine and cisplatin (1). Two patients received neoadjuvant gemcitabine and cisplatin. Pre-operatively, all 12 patients (100%) had detectable ctDNA, while only 4 pts (33%) had elevated CA 19-9. For post-operative MRD detection, 2/12 patients had a detectable ctDNA level, while none had an abnormal CA 19-9. Among 10 patients with undetectable ctDNA MRD postoperatively, 5 patients have remained ctDNA negative without evidence of recurrence, 4 of which are ctDNA negative for negative without evidence of recurrence, 4 of which are ctDNA negative for ≥1818months (range 20-33 months). During adjuvant therapy, 2 patients converted from ctDNA positive to negative, neither have recurred. During longitudinal follow up, 4/12 patients have conﬁrmed recurrence: 1 patient was ctDNA MRD positive while the others converted from negative to positive during adjuvant therapy or surveillance.

Rise in ctDNA preceded radiographic recurrence in all patients with recurrence.

Conclusions: Baseline ctDNA had higher detection rate compared to CA 19-9 prior to resection. Longitudinally negative ctDNA was associated with improved recurrence free survival. Assessing ctDNA levels may have potential utility in evaluating response in the absence of radiographically visible disease.

Clinical trial identiﬁcation: NCT04561453.

Disclosure: A. Jurdi: Financial Interests, Institutional, Full or part-time Employment: Natera;Financial Interests, Personal, Stocks/Shares: Natera. C. Brdiges: Financial Interests, Institutional, Full or part-time Employment: Natera. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1407

115P Inhibition of KLF5 reduces tumor growth and sensitizes to chemotherapy-induced cell death in experimental models of cholangiocarcinoma

A. Landa Magdalena1, P.M. Rodrigues1, O. Erice1, N.A. Paiva1,

M.G. Fernandez-Barrena2, P. Olaizola1, A. Lapitz1, C.J. O’Rourke3, J.B. Andersen3,D.F. Calvisi4, M. Azkargorta5, F. Elortza5, I. Goicoechea6, C.H. Lawrie6, L. Bujanda1,M.J. Perugorria1, J.M. Bañales1

1Liver Diseases Group, Biodonostia Health Research Institute, San Sebastian, Spain;2Division of Hepatology, CIMA-University of Navarra, Pamplona, Spain; 3BRIC,Department of Health & Medical Sciences, University of Copenhagen, Copenhagen,Denmark; 4Institute of Pathology, University of Regensburg, Regensburg, Germany;5Proteomics Platform, CIC bioGUNE - Centro de Inv. Cooperativa en Biociencias, Derio,Spain; 6Molecular Oncology Group, Biodonostia Health Research Institute, San Sebastian, Spain

Background: Cholangiocarcinoma (CCA) comprises a heterogeneous group of cancers with bad prognosis. Krüppel-like factors (KLF) are a family of transcription factors involved in organogenesis, differentiation and cellular homeostasis. Here, we studied the role of KLF5 in CCA development and evaluated the therapeutic potential of its inhibition.

Methods: KLF5 expression was measured in human CCA tissues [Copenhagen(n¼210), TCGA (n¼36), Job (n¼78), TIGER-LC (n¼90) and San Sebastian cohorts(n¼12)] and cell lines. KLF5-/- CCA cells were created by CRISPR/Cas9. The functionaleffects of KLF5 genetic silencing with CRISPR technology, or chemical inhibition with ML264, were evaluated in vitro and in vivo.

Results: KLF5 expression was upregulated in human CCA tissues from 5 different patient cohorts compared to surrounding normal liver tissue. High KLF5 levels correlated with lymph node invasion and worse overall survival. In vitro, KLF5 protein and mRNA levels were overexpressed in human CCA cells compared to normal human cholangiocytes. Functionally, KLF5-/- CCA cells displayed decreased cell proliferation,migration, invasion and colony formation while promoting cell cycle arrest at G1/S and apoptosis in vitro, when compared to control cells. In agreement, KLF5-/- CCA cells did not develop any tumor after subcutaneous or orthotopic injection in a xenograft animal model of CCA. Likewise, chemical inhibition of KLF5 with ML264 hampered CCA cells proliferation and migration in vitro and blocked tumor growth in vivo. Lastly,both genetic and chemical inhibition of KLF5 sensitized CCA cells to chemotherapyinduced apoptosis in vitro, and the combination of gemcitabine + cisplatin and ML264 completely halted CCA tumor growth in mice. Accordingly, KLF5-/- CCA display altered levels of several proteins related to chemoresistance when compared to control cells,that were shown to signiﬁcantly correlate with KLF5 expression in human CCA tissues.

Conclusions: Increased KLF5 is a general event in CCA, contributing to cancer progression and chemoresistance. KLF5 inhibition with ML264 may represent a potential therapeutic strategy for CCA.

Legal entity responsible for the study: Biodonostia Health Research Institute.

Funding: Carlos III Health Insistute - FIS Project.

https://doi.org/10.1016/j.annonc.2023.09.1408

116P Circulating tumour DNA- based minimal residual disease detection for biliary tract cancer

Z. Li1, P. Yan1, Q. Hao2, L. Guo2, F. Pang2, X. Jiang1, Y. Yu1

1Department of Biliary Surgery, Third Afﬁliated Hospital of Naval Military Medical University, Shanghai, China; 2Medical Department, Shanghai OrigiMed Co., Ltd,Shanghai, China

Background: Although circulating tumor DNA-based minimal residual disease (MRD)is useful for prediction of prognosis, but clinical value of MRD for BTCs are remain clear.

Methods: The OriMIRACLE STMMRD assay (OrigiMed, Shanghai, China) uses whole exome sequencing (WES) for detecting patient-speciﬁc somatic alterations from tumor tissues and for blood a personalized panel designed to target up to 45 variants.

Results: A total of 26 biliary tract cancer (BTC) patients including 13 gallbladder carcinoma and 13 extrahepatic cholangiocarcinoma patients were enrolled. Among the patients, 53.85% (14/26) were male and 46.15% (12/26) were female, and the median age was 61 years, ranging from 49 to 73 years old. Fifteen patients underwent radical surgery, 4 patients underwent local tumor resection and 7 patients could not undergo radical surgery. Based on WES, we found that 58.33% (4005/6866) of the mutated genes were unique to each patient and100% (26/26) of patients successfully constructed MRD panels, suggesting that tumor-informed MRD is superior to panelbased MRD in BTC. For each patient, we selected up to 45 clonal somatic mutations for a personalized ctDNA assay design. MRD detection was performed on 26 cases and revealed a positive rate of 42.31% (11/26). Among the 11 patients with positive MRD at postoperative or, 71% (5/7) of patients who could not undergo radical surgery, 100% (4/4) of the patients underwent local tumor resection and 13.3% (2/15) of patients underwent radical surgery. MRD detection was performed 4 times on one female GBC patient with stage IV throughout the treatment course. we found that

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MRD at baseline was positively detected by tumor-informed assay with a higher variant allele fraction (VAF), and decreased after neoadjuvant therapy. CT image also showed local control of the tumor, but CA199 and CEA levels were elevated in patients with obstruction, suggesting the limits of tumor markers in BTC patients with obstruction.

Conclusions: Up to 58% of mutated genes of BTC are unique individually, and 100% of patients successfully constructed MRD panels, which may be more suitable for monitoring with tumor-informed MRD panel. The VAF of ctDNA could be used to predict the efﬁcacy of neoadjuvant therapy and tumor progression in BTC patients.

https://doi.org/10.1016/j.annonc.2023.09.1409

117P

Genomic landscape of biliary tract cancers from India show distinct geographic variation

N. Rohatgi1, A. Agarwal2, V. Maniar3, S. Patil4, A. Bahl5, S. Advani6, P.K. Julka7,S. Limaye8, A. Kakroo9, A. Kumar10, M. Javle11

1Medical Oncology, Fortis Memorial Research Institute, Gurugram, India; 2Medical Oncology, Fortis Hospital, Shalimar Bagh, New Delhi, India; 3Medical Oncology,Mumbai Oncocare Centre (MOC Ghatkopar), Mumbai, India; 4Radiation Oncology,HCG HealthCare Global Enterprises Ltd, Bangalore, Karnataka, India; 5Medical Oncology, Fortis Memorial Research Institute, Gurugram, Delhi, India; 6Medical Oncology, Sushrut Hospital and Research Centre, Mumbai, India; 7Department Of Medical Oncology, Max Oncology Day Care Centers, New Delhi, India; 8Medical Oncology, Sir H N Reliance Foundation Hospital, Mumbai, India; 9Medical Oncology Department, Hemato-Oncology Clinic Vedanta - Navrangpura, Ahmedabad, India;10Medical Affairs, Roche Product India Pvt Ltd, Mumbai, India; 11Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA

Background: Biliary tract cancers (BTC) are a group of heterogeneous tumors that include intrahepatic, perihilar, and distal cholangiocarcinoma and gall bladder cancers(1). India has a high burden of biliary tract tumors, particularly gallbladder cancers. It contributes to 10% of global burden of gall bladder cancers. Within India, the IndoGangetic doab has a higher incidence of BTCs of 21/100,000 individuals affected (2).

Cholangiocarcinoma and gall bladder cancers have distinct genomic diversity (3).

Genomic proﬁling of BTCs from India are scarce. Understanding of genomic diversity of BTCs in India shall help in strategizing therapy and prevention. Aim The main objectives of the study are: 1. Retrospective analysis of genomic proﬁle of biliary tract cancers from India 2. Pathway analysis of BTCs based on genomic proﬁling.

Methods: 46 BTC cases from India were recruited for the study spanning 10 centers across India. All the cases were tested using comprehensive genomic proﬁling under Foundation One CDx or Foundation One Liquid CDx assay. Only the genomic results were used for retrospective analysis.

Results: 33 cases of cholangiocarcinoma and 13 cases of gallbladder cancers were analyzed. The most commonly altered genes in cholangiocarcinoma were TP53 (45%),CDKN2A/B (33%), ARID1A (21%), KRAS (21%). The most commonly altered genes in gallbladder were TP53 (77%), CDKN2A/B (31%), RB1 (23%) and SMAD4 (23%).

Pathway analysis showed a distinct difference between cholangiocarcinoma and gallbladder tumors. Transcriptional factors and Immune-modiﬁer pathways were enriched in gallbladder tumors compared to cholangiocarcinoma, while the cell cycle pathway was more commonly altered in cholangiocarcinoma. When the cholangiocarcinoma cases were stratiﬁed by demographic origin within India, we found cell cycle pathway genes to be signiﬁcantly less among North Indian samples, while RAS-RAF pathway was signiﬁcantly more among North Indian samples.

Conclusions: The genomic landscape of BTCs in India showed distinct variation compared to the rest of the world. A trend of variation in the genomic landscape of BTCs between North & South India was observed. Further study with higher sample size is warranted.

Disclosure: A. Kumar: Financial Interests, Personal, Other, Author is an employee of Roche Products India Pvt Ltd.: Roche Products India Pvt Ltd. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1410

118P Artiﬁcial intelligence (AI)-powered spatial analysis of tumorinﬁltrating lymphocytes (TILs) as a predictive biomarker for anti-PD-1 in advanced biliary tract cancer (BTC)

Y. Bang1, C-K. Lee2, K. Bang3, H-D. Kim1, K-P. Kim1, J.H. Jeong1, B-Y. Ryoo4, C. Oum5,S. Kim5, Y. Lim5, G. Park5, C-Y. Ock5, J.H. Shin6, C. Yoo4

1Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 2Division Of Medical Oncology, Yonsei Cancer Center,Yonsei University, Seoul, Republic of Korea; 3Department of Oncology, Chung-Ang University, Gwangmyeong Hospital, Gyeonggi-do, Republic of Korea; 4Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 5Oncology Group, Medical Affairs, Lunit Inc., Seoul, Republic of Korea;6Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

Background: Recently, anti-PD-1/L1 plus gemcitabine and cisplatin (GemCis) has demonstrated signiﬁcant survival beneﬁts in randomized phase 3 trials for advanced BTC. However, no biomarker has been established for anti-PD-1 in BTC. Here, we assessed TILs using artiﬁcial intelligence (AI)-powered spatial analysis in advanced BTC treated with anti-PD-1.

Methods: An AI-powered whole-slide image (WSI) analyzer (Lunit SCOPE IO, Lunit,Seoul, Korea) was used to segment tumor epithelium and stroma, and identiﬁcation of intratumor TIL (iTIL) and stromal TIL (sTIL). H&E-stained WSI from pre-treatment samples was acquired from Asan Medical Center and Yonsei Cancer Center (n ¼ 354),and a total of 337 samples (95.2%) after quality control were used for the ﬁnal analysis. Immune phenotypes (IP) were deﬁned as follows: inamed as high iTIL and sTIL; immune-excluded as low iTIL and high sTIL; immune-desert as low TIL overall.

Among them, 29 patients (pts) were available for multi-color ﬂow cytometry analysis(FACS) using peripheral blood mononuclear cells (PBMC), collected at baseline and C1D8.

Results: All patients were treated with anti-PD-1 monotherapy, and 188 pts (55.8%)were treated as 2ndline. In overall pts, anti-PD-1 showed median overall survival (OS)of 5.7 months (mo), median progression-free survival (PFS) of 2.0 mo, and objective response rates (ORR) of 10.1%. IP were classiﬁed as inﬂamed in 40 pts (11.9%), immune-excluded in 167 (49.6%), and immune-desert in 130 (38.6%). The inﬂamed group showed better OS (12.5 vs. 5.1 mo, P<0.001), PFS (5.0 vs. 2.0 mo, P¼0.001),and ORR (27.5% vs. 7.7%, P<0.001) than non-inﬂamed groups. In the FACS, the inﬂamed group showed signiﬁcantly higher proportion of baseline CD8+Tem and lower baseline CD8+Tnaive than non-inﬂamed groups. At C1D8 of anti-PD-1,CD69+CD8+T, GZMB+CD8+T, and PRF1+CD8+T cells were increased, while PD1+CD8+T cells was decreased in PBMC of the inﬂamed group.

Conclusions: Immune phenotype classiﬁed by AI-powered spatial TIL analysis was effective to predict the efﬁcacy outcomes of advanced BTC pts treated with anti-PD-1 therapy. Further evaluation is required in the setting of anti-PD-1/L1 plus GemCis.

Disclosure: C. Ock: Financial Interests, Institutional, Advisory Board: Lunit corporate. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1411

119P Management of biliary tract cancers in older patients: A French multicenter cohort study

M. Valery1, J. Edeline2, J. Henriques3, L. Antoun1, H. Bourien2, A. Lebeaud4,

N. Fares5, C. Tournigand6, T. Lecomte7, D. Tougeron8, V. Hautefeuille9, A. Vienot10,N. Williet11, J-B. Bachet12, D. Malka13, C. Smolenschi1, A. Hollebecque1,

J-R. Paccard14, A. Turpin15, A. Boileve1

1Medical Oncology Department, Gustave Roussy, Villejuif, Cedex, France; 2Medical Oncology Department, Centre Eugene - Marquis, Rennes, France; 3Methodology and Quality of Life Unit in Oncology, EA 3181, CHU Besançon, Hôpital Jean Minjoz,Besançon, France; 4Medical Oncology Department, Hopital Claude Huriez, Lille,France; 5Digestive Oncology Department, Centre Hospitalier Universitaire de Toulouse

- Hopital Rangueil, Toulouse, France; 6Medical Oncology Department, Centre Hospitalier Universitaire Henri-Mondor AP-HP, Creteil, France; 7Hepato-Gastroenterology and Digestive Cancerology, CHU de Tours, Hôpital Trousseau, Tours, France; 8Gastroenterology and Digestive Oncology, CHU Poitiers - Jean Bernard Hôpital, Poitiers,France; 9Gastroenterology and Digestive Oncology Department, CHU Amiens-Picardie

- Site Nord, Amiens, France; 10Medical Oncology Department, CHRU Besancon -Hopital Jean Minjoz, Besancon, France; 11Gastroenterology and Digestive Oncology,Hopital Nord, St Etienne, France; 12Hepato-Gastroenterology and Digestive Oncology Department, Groupe Hospitalier Pitié Salpetriere, Paris, France; 13Department of Medical Oncology, Institut Mutualiste Montsouris, Paris, France; 14Medical Oncology and Hepatogastroenterology Department, Hospices Civiles de Lyon - HCL - Lyon University Hospital Center, Lyon, France; 15Medical Oncology Department, Hopital Claude Huriez, Lille, France

Background: Biliary tract cancers (BTC) including cholangiocarcinomas (CCA) and gallbladder cancer (GBC) are uncommon tumors with poor prognosis, often diagnosed after age of 70, where comorbidities and altered performance status (PS) are more

frequent. We aimed to compare clinical characteristics, molecular proﬁle, and outcomes of patients (pts) with BTC < and 70 years old.

Methods: A retrospective chart review was performed in treated BTC pts in 16 French centers from 2003 to 2021. Data on demographics, therapeutic management, molecular proﬁle, progression-free survival (PFS) and overall survival (OS) were collected.

Results: Overall, 1256 pts with BTC were included (male, 52%; median age, 64.5 years), including 384 pts (31%) over 70. Older pts had poorer PS (PS 2, 17% vs 8%;p<0.0001) and more comorbidities (1 comorbidity, 89% vs. 78%; p<0.0001). Theywere diagnosed more frequently with extrahepatic CCA and GBC (respectively, 18%vs.12% and 16% vs. 13%, p¼0.0073) and less advanced disease stage at diagnosis(bilobar liver involvement, 29% vs 37%; p¼0.008). They were offered less frequentlyﬁrst-line systemic therapy (87% vs 97%, p<0.0001)(gemcitabine 3% vs 0.3%; gemcis 31% vs 35%; gemox 54% in 2 groups; p¼0.007) and molecular proﬁling (43% vs 65%,p<0.0001) than pts <70. Proportions of actionable alterations were signiﬁcantly different, with more HER2 ampliﬁcations and less IDH1 mutations and FGFR2 fusions in older patients (p¼0.0419). MSI status were similar between groups. OS afterresection was similar in older and younger pts (median OS, 47.0 months (mo) [95%CI:

37.8-71.9] vs 48.8 mo [95%CI 41.4-57.3]), but shorter in older pts at advanced stage(14.6 [95%CI 12.7-16.5] vs. 17.4 mo [95%CI 16.1-18.9), p<0.0001). First-line PFS did not differ (median, 6.6 mo [95%CI 5.5-7.2] vs 5.8 mo [95%CI, 5.3-6.2), p¼0.61).

Conclusions: Older BTC pts presented more frequently eCCA and GBC and a less advanced disease at diagnosis. At advanced stages, older pts had poorer OS and received less often ﬁrst-line chemotherapy. If treated, PFS of older pts was similar to younger pts. Molecular proﬁling was less often performed in older pts.

https://doi.org/10.1016/j.annonc.2023.09.1412

120P

Management of biliary tract cancers in early onset patients:A French multicenter real-life study from the ACABIPRONOBIL cohort

A.Lebeaud1, L. Antoun2, J-R. Paccard3, J. Edeline4, N. Fares5, C. Tournigand6,

T. Lecomte7, D. Tougeron8, V. Hautefeuille9, A. Vienot10, J. Henriques11, N. Williet12,J-B. Bachet13, C. Smolenschi14, A. Hollebecque14, D. Malka15, C. Neuzillet16,

D. Vernerey11, A. Boileve17, A. Turpin1

1Department of Medical Oncology, CHU Lille, Lille, France; 2Gustave Roussy Cancer Campus, Villejuif, France; 3Medical Oncology and Hepatogastroenterology Department, Hospices Civiles de Lyon - HCL - Lyon University Hospital Center, Lyon, France;4Medical Oncology Department, Centre Eugène Marquis, Rennes, France; 5Digestive Oncology Department, Centre Hospitalier Universitaire de Toulouse - Hopital Rangueil,Toulouse, France; 6Oncology, Centre Hospitalier Universitaire Henri-Mondor AP-HP,Creteil, France; 7Gastroenterology, CHU de Tours, Hôpital Trousseau, Chambray-lèsTours, France; 8Gastroenterology and Digestive Oncology, CHU Poitiers - Jean Bernard Hôpital, Poitiers, France; 9Gastroenterology and Digestive Oncology Department, CHU Amiens-Picardie - Site Nord, Amiens, France; 10Medical Oncology Department, CHRU Besancon - Hopital Jean Minjoz, Besancon, France; 11Methodology and Quality of Life Unit in Oncology, EA 3181, CHU Besançon, Hôpital Jean Minjoz, Besançon, France;12Gastroenterology and Digestive Oncology, Hopital Nord, St Etienne, France; 13Hepato-Gastroenterology and Digestive Oncology Department, Groupe Hospitalier Pitié Salpetriere, Paris, France; 14Drug Development Department (DITEP), Gustave Roussy -Cancer Campus, Villejuif, France; 15Department of Medical Oncology, Institut Mutualiste Montsouris, Paris, France; 16Gastrointestinal Oncology, Medical Oncology Department, Curie Institute, Paris, France; 17Medical Oncology Department, Gustave Roussy, Villejuif, France

Background: Biliary tract cancers (BTC) including cholangiocarcinoma (CC) and gallbladder cancer (GBC) are rare cancers with poor prognosis. Few data are available on early-onset BTC (EOBTC) deﬁned as patients (pts) under age of 50.

Methods: A retrospective chart review was performed in pts treated for BTC in 14 French centers between 2003 and 2021. Data on demographic characteristics, therapeutic management, and molecular proﬁle were collected. Progression-free survival(PFS) and overall survival (OS) were estimated by the Kaplan Meier method. Prognostic factors were assessed by univariate and multivariate analyses by Cox regression.

Results: Overall, 1256 pts with BTC were included. Patients with EOBTC (n¼188, 15%)had less comorbidities according to Charlson score (63.5% vs 84.4%, p<0.0001),higher tumor stage (cT3-4: 49.9% vs 32.17%, p¼0.0126), bilobar liver involvement(47.7% vs 32.1%, p¼0.0002) and metastatic disease (67.5% vs 57.49%, p¼0.0097)compared to older pts, but did not differ regarding primary tumor location (intrahepatic vs extrahepatic CC vs GBC),WHO performance status (PS 0-1: 94.4% vs 85.5%,p¼0.15), and sex-ratio (50.8% vs 53.4% of males). First-line systemic therapy foradvanced BTC (n¼818, 65.2%) was mostly a doublet by GEMCIS (45.5% vs 32.1%,p¼0.0091) or GEMOX (43.3% vs 56.5%, p¼0.0091) in EOBTC vs non-EOBTC respec-tively. EOBTC pts received more frequently a 2ndline therapy (89.5% vs 80.9%,p¼0.02). For advanced BTC pts, median (m)OS was 17.0 mo vs 16.2 mo (p¼0.08) andmPFS was 5.8 mo vs 6.0 mo (p¼0.89), in EOBTC vs older pts respectively. Molecularproﬁling was performed in 72.6% of EOBTC pts vs 52.4% in older pts (p¼0.0019), and

less actionable alterations were found (e.g. IDH1 mutations, 7.8% vs 16.6%; p¼0.029;FGFR2-fusion, 11.7% vs 8.9%; p¼0.029). We did not ﬁnd any usual prognostic factorsin BTC (CEA, CA19-9, PS, neutrophile-lymphocyte ratio, number of extra-hepatic metastases) associated with EOBTC survival.

Conclusions: Pts with EOBTC have a more advanced disease at diagnosis, are treated more heavily at an advanced stage, and have similar PFS and OS in comparison to older BTC pts. Molecular proﬁling was more often performed in EOBTC pts but less actionable alterations were found.

Legal entity responsible for the study: GERCOR.

Funding: ACABI: Association pour l’étude des cancers et affections des voies biliaires.

Disclosure: J. Edeline: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, MSD,Bayer, Boston Scientiﬁc, Eisai, Ipsen, Servier; Financial Interests, Personal, Advisory Board: Roche,AstraZeneca, MSD, Bayer, Merck Serono, Eisai, Ipsen, BMS, Basilea, Servier, Incyte, BeiGene, Taiho;Financial Interests, Personal, Steering Committee Member: MSD; Financial Interests, Institutional,Coordinating PI: BMS, BeiGene; Financial Interests, Institutional, Local PI: BMS, MSD, Roche, BeiGene, Bayer, Novartis, Taiho, Servier, Agios; Non-Financial Interests, Principal Investigator: Unicancer.

C. Tournigand: Non-Financial Interests, Leadership Role: GERCOR; Non-Financial Interests, Advisory Role: Fondation APHP. T. Lecomte: Financial Interests, Personal, Invited Speaker: Ipsen, Pierre Fabre,AstraZeneca, BMS; Financial Interests, Personal, Advisory Board: Sanoﬁ, Merck Serono, Servier,Amgen, Deciphera, Advanced Accelerator Application Pierre Fabre; Financial Interests, Institutional,Local PI: AstraZeneca, Mirati, ALX Oncology; Financial Interests, Institutional, Funding: Leopharma,Pierre Fabre. D. Tougeron: Financial Interests, Personal, Advisory Board: AstraZeneca, Sanoﬁ,AMGEN, MSD, Roche, Servier, Pierre Fabre, BMS, Bayer; Non-Financial Interests, Member of Board of Directors: Federation francophone de cancerologie digestive. V. Hautefeuille: Financial Interests,Personal, Invited Speaker: Novartis, Merck, Amgen; Financial Interests, Personal, Advisory Board:AAA, Ipsen, Pierre Fabre; Financial Interests, Institutional, Invited Speaker: Deciphera, Esteve. N.

Williet: Financial Interests, Personal, Advisory Board: Accord healthcare, AstraZeneca, Mayoly, MSD,Pierre Fabre, Servier, Viatris, LeoPharma; Financial Interests, Personal, Non-ﬁnancial beneﬁts: Ipsen,Merck, MSD, Servier. J. Bachet: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca,Bayer, BMS, GSK, Merck-Serono, MSD, Pierre Fabre, Roche, Sanoﬁ, Servier; Non-Financial Interests,Personal, Other: Amgen, Merck Serono, Roche, Servier. A.ator, CO42216; WP42627; CO40939: Roche; Non-Financial Interests, Principal Investigator,MCLA-158: Merus; Non-Financial Interests, Principal Investigator, SGNB6A: Seattle Genetics; NonFinancial Interests, Principal Investigator, TAS-120-202: Tahio; Non-Financial Interests, Principal Investigator, Krystal-10: Mirati; Non-Financial Interests, Principal Investigator, ADP-0033: Adaptimmune; Non-Financial Interests, Principal Investigator, ACT16902: Sanoﬁ; Non-Financial Interests,Principal Investigator, C4201002: Pﬁzer; Non-Financial Interests, Principal Investigator, RLY-4008:Relay Therapeutics; Non-Financial Interests, Principal Investigator, CC-90011: Celgene/BMS; NonFinancial Interests, Principal Investigator, Loxo-IDH: Loxo/Lilly; Non-Financial Interests, Principal Investigator: AstraZeneca; Non-Financial Interests, Principal Investigator, SN-201 study: Sotio; NonFinancial Interests, Principal Investigator, Tropics-03: Gilead; Non-Financial Interests, Principal Investigator, BI1403: Boehringer Ingelheim. hollebecque: Financial Interests, Personal,Invited Speaker: Servier, Incyte, Eisai; Financial Interests, Personal, Advisory Board: Basilea, Tahio,Relay Theraeutics, QED Therapeutics, Debiopharm, MSD, Boehringer Ingelheim; Financial Interests,Institutional, Funding: Incyte; Financial Interests, Institutional, Research Grant: AstraZeneca; NonFinancial Interests, Principal Investigator, M19-345: AbbVie; Non-Financial Interests, Principal Investigator, CO42216; WP42627; CO40939: Roche; Non-Financial Interests, Principal Investigator,MCLA-158: Merus; Non-Financial Interests, Principal Investigator, SGNB6A: Seattle Genetics; NonFinancial Interests, Principal Investigator, TAS-120-202: Tahio; Non-Financial Interests, Principal Investigator, Krystal-10: Mirati; Non-Financial Interests, Principal Investigator, ADP-0033: Adaptimmune; Non-Financial Interests, Principal Investigator, ACT16902: Sanoﬁ; Non-Financial Interests,Principal Investigator, C4201002: Pﬁzer; Non-Financial Interests, Principal Investigator, RLY-4008:Relay Therapeutics; Non-Financial Interests, Principal Investigator, CC-90011: Celgene/BMS; NonFinancial Interests, Principal Investigator, Loxo-IDH: Loxo/Lilly; Non-Financial Interests, Principal Investigator: AstraZeneca; Non-Financial Interests, Principal Investigator, SN-201 study: Sotio; NonFinancial Interests, Principal Investigator, Tropics-03: Gilead; Non-Financial Interests, Principal Investigator, BI1403: Boehringer Ingelheim. D. Malka: Financial Interests, Personal, Advisory Board:AbbVie, Agios, Amgen, AstraZeneca, BMS, Bayer, HalioDx, Incyte, MSD, Merck Serono, Pierre Fabre Oncologie, Roche, Servier, Taiho; Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca,BMS, Bayer, Foundation Medicine, HalioDx, Incyte, Leo Pharma, MSD, Merck Serono, Pierre Fabre Oncologie, Roche, Sanoﬁ, Servier, Viatris, Veracyte; Financial Interests, Personal, Writing Engagement: Medscape; Other,bTravel expenses for medical congresses: Amgen, Bayer, BMS, Merck Serono, Pierre Fabre Oncologie, Roche, Sanoﬁ, Servier, Viatris. C. Neuzillet: Financial Interests,Personal, Advisory Board: Amgen, AstraZeneca, Baxter, BMS, Fresenius Kabi, Incyte Biosciences,Merck, MSD, MundiPharma, Viatris, Novartis, Nutricia, OSE Immunotherapeutitcs, Pierre Fabre,Roche, Sanoﬁ, Servier; Financial Interests, Institutional, Research Funding: AstraZeneca, BMS, Fresenius Kabi, Nutricia, OSE Immunotherapeutics, Roche, Servier, Viatris. A. Turpin: Financial Interests,Personal, Expert Testimony: Merck Serono, Viatris, Incyte Biosciences; Financial Interests, Personal,Advisory Board: Servier, AstraZeneca, MSD, BMS. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1413

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121P

PemiBil: Efﬁcacy and safety of pemigatinib in advanced cholangiocarcinoma with FGFR2 fusions/rearrangements in real-world, results of multicentric French cohort from ACABI consortium

B. Delaunay1, A. Hollebecque2, M. Bouattour3, J.F. Blanc4, E. Assenat5, A. Turpin6,M. Sarabi7, G. Roth8, D. Tougeron9, J. Edeline10, M. Ben Abdelghani11, A. Vienne12,S. Hiret13, P. Artru14, M. Stacoffe15, D. Malka16, C. Neuzillet17, A. Lievre18,

R. Guimbaud19, N. Fares1

1Digestive Oncology Department, Centre Hospitalier Universitaire de Toulouse -Hopital Rangueil, Toulouse, France; 2Medical Oncology, Institut Gustave Roussy, Villejuif, France; 3Liver Oncology and Therapeutic Innovation Functional Unit, Beaujon Hospital APHP, Clichy, France; 4Oncologie Digestive, CHU Bordeaux - Hopital St. André,Bordeaux, France; 5Medical Oncology, ICM - Institut du Cancer de Montpellier,Montpellier, France; 6Medical Oncology Department, Hopital Claude Huriez, Lille,France; 7Medical Oncology, Centre Léon Bérard, Lyon, France; 8Hepato-Gastroenterology Department, CHU Grenoble-Alpes - Le site nord à La Tronche - Hopital Michallon, La Tronche, France; 9Gastroenterology and Digestive Oncology, CHU Poitiers - Jean Bernard Hôpital, Poitiers, France; 10Medical Oncology Department, Centre Eugene - Marquis, Rennes, France; 11Oncology Department, ICANS - Institut de Cancérologie Strasbourg Europe, Strasbourg, France; 12Oncology, CHU Sud Réunion, Saint Pierre, France; 13Oncology Department, ICO Institut de Cancerologie de l’Ouest René Gauducheau, Saint-Herblain, France; 14Gastrointestinal Oncology Department, Hôpital Privé Jean Mermoz, Lyon, France; 15Medical Oncology, CHRU Hopitaux de Tours -Hopital Bretonneau, Tours, France; 16Department of Medical Oncology, Institut Mutualiste Montsouris, Paris, France; 17GI Oncology, Medical Oncology Department,Curie Institute, Paris, France; 18Department of Gastroenterology, CHU de Rennes -Hopital Pontchaillou, Rennes, France; 19Digestive Oncology Department, Centre Hospitalier Universitaire de Toulouse - Hopital Rangueil, Toulouse, France

Background: Fibroblast growth factor receptor 2 (FGFR2) fusions or rearrangements(f/r) occur in up to 14% of patients with intrahepatic cholangiocarcinoma (iCCA).

PEMIGATINIB, an oral FGFR 1-3 inhibitor, demonstrated signiﬁcant efﬁcacy in the phase II FIGHT-202 study with a response rate of 37% in heavily pretreated patients.

Neither phase III nor phase IV data are currently available but due to the reported efﬁcacy, PEMIGATINIB was FDA and EMA approved and is available in France since July 2020. Our study aimed to evaluate the efﬁcacy and safety of pemigatinib and the disease proﬁle of iCCA with FGFR2 fusions/rearrangements in an unselected population.

Methods: This national multicenter retrospective cohort collected data on demographics, therapeutic management, toxicity proﬁle, objective response rate, progression-free survival and overall survival from French patients with advanced cholangiocarcinoma with FGFR2 f/r who received PEMIGATINIB since July 2020.

Results: From July 2020 to September 2022, 50 patients were included. At diagnosis the mean age was 57 years with 74% female, mainly ECOG 0-1 (82%). 58% had received two or more previous systemic therapies. The objective response rate was

45.3% (3 complete responses and 21 partial responses, n ¼ 24). The median pro-gression-free survival was 9 months (IIQ 6-14) and the median overall survival was 18 months (IIQ 12-NA). Neither clinical nor molecular characteristics were predictive factors for treatment response. The most common toxicities were hyperphosphatemia(58%), nail toxicity (58%) and fatigue (58%). 35% of patients developed grade 3 toxicity at the 13.5 mg daily dose. 57.5% (n ¼ 19) of patients with progression wereable to receive at least one subsequent line of treatment, mostly a new FGFR inhibitor(58%). The median overall survival from the locally advanced or metastatic stage was 37 months.

Conclusions: Our study conﬁrms the efﬁcacy of pemigatinib in an unselected population with high response rates and survivals similar to the FIGHT-202 data. It also conﬁrms the good tolerability of pemigatinib and the better prognosis of iCCA with FGFR2 f/r.

Legal entity responsible for the study: Dr Nadim Fares, MD PhD, Digestive Oncology Department, Centre Hospitalier Universitaire de Toulouse - Hopital Rangueil, Toulouse, France.

https://doi.org/10.1016/j.annonc.2023.09.1414

122P Largest examination of cholangiocarcinoma (CCA) patients(pts) treated with novel targeted therapies after extended molecular proﬁling on liquid biopsies

U. Mahmood1, E. Muhamad Faizul2, S. Howlett1, D. Hochhauser1, K-K. Shiu1,J.A. Bridgewater1, K.H. Khan1

1Department of Gastrointestinal Oncology, UCLH - University College London Hospitals NHS Foundation Trust, London, UK; 2Department of Oncology, UCL - University College London, London, UK

Background: CCA is associated with poor outcomes with limited treatment options.

Targeted therapies have recently gained traction in CCA but data remains sparse in this domain. Here, we present the largest multi-institutional review to date evaluating outcomes following targeted agents in this pt population.

Methods: All consecutive CCA pts receiving systemic therapy between 2010 - 2022 at UCLH were included. Treatment response, survival outcomes and predictors of clinical beneﬁt were evaluated. Pt demographic factors, disease characteristics and survival outcomes were evaluated using the Kaplan-Meier method and Cox proportionalhazards models.

Results: Of the 147 screened pts, 119 (81%) underwent molecular proﬁling. We identiﬁed 48 (40%) eligible CCA pts where 47 received molecularly guided targeted treatment. Most pts received targeted agents in a 2ndtreatment line setting (N ¼ 26).Frequently observed genomic alterations occurred in FGFR (N ¼ 21), BRCA (N ¼ 8),KRAS (N ¼ 7), IDH (N ¼ 5) and PIK3 (N ¼ 3) genes. The median progression-freesurvival (PFS) following 1st, 2ndand 3rdline systemic therapy and overall survival (OS)were: 8.38 (5.45 - 13.50), 5.52 (3.22 - 7.85), 8.15 (2.79 - not reached) and 27.07 (24.21

- 36.63) months, respectively. Median duration of clinical beneﬁt (DoCB) (complete response, partial response and stable disease) in 2ndline treatment setting was 3.10(2.31 - 4.20) and 5.32 (2.89 - 8.41) months in the chemotherapy and targeted agent(with or without chemotherapy) cohorts, respectively. In a 3rdline setting, the median DoCB was 5.03 (2.63 - 5.42) and 8.34 (2.87 - 14.09) months in the chemotherapy and targeted agent (with or without immunotherapy) cohorts, respectively. This duration extended to 9.66 (3.06 - 14.06) months among futibatinib recipients. Duration of 2nd line targeted treatment was associated with PFS (P < 0.0001) and OS (P < 0.0001).

Duration of 3rdline targeted treatment was associated with PFS (P ¼ 0.001) but notOS (P ¼ 0.14).

Conclusions: Our study demonstrated the efﬁcacy of novel therapeutic agents in CCA.

Liquid biopsies can reliably provide information on extended molecular proﬁling to aid pt selection for personalised therapeutics.

Legal entity responsible for the study: Dr. Khurum Khan.

Disclosure: D. Hochhauser: Financial Interests, Personal, Stocks/Shares: Roche, Novartis; Financial Interests, Personal, Speaker’s Bureau: Pierre Fabre; Financial Interests, Personal, Funding: Merck Serono; Financial Interests, Personal, Other: Celgene. K.erono; Financial Interests, Personal, Advisory Board, On Mirati GI Global Advisory Board: Mirati Therapeutics; Financial Interests, Personal, Invited Speaker, To update company on indications/updates in landscape of immunotherapy and vaccines in GI cancers:Nouscom; Financial Interests, Personal, Advisory Board, Advisory on Cancer of Unknown Primary,new indications of molecular proﬁling usingFoundation Medicine 1: Roche; Financial Interests,Personal, Advisory Board, Advisory Board on Lonsurf for chemorefractory mCRC in readiness for NICE application: Servier; Financial Interests, Institutional, Local PI, For MATTERHORN Trial: AstraZeneca; Financial Interests, Institutional, Coordinating PI, UK Chief Investigator on KEYNOTE 177,KEYNOTE 859, KEYNOTE 811, LEAP 17, MK1308A-008 trials: MSD; Financial Interests, Institutional,Research Grant, Chief Investigator of investigator initiated, MSD funded NEOPRISM-CRC trial: MSD;Financial Interests, Institutional, Local PI, UCLH PI for LEAP 15 and MK4280A-007 trials: MSD;Financial Interests, Institutional, Coordinating PI, UK Chief Investigator for NOUS209-001 trial:Nouscom; Financial Interests, Institutional, Coordinating PI, UK Chief Investigator for CUPSICO trial:Roche; Financial Interests, Personal, Steering Committee Member, Steering Committee Member of CUPISCO trial: Roche; Non-Financial Interests, Member: ASCO, Association of Cancer Physicians UK.

Shiu: Financial Interests, Personal, Invited Speaker, Educational Webinars on CRC and UGI cancer management with immunotherapy: BMS;Financial Interests, Personal, Advisory Board, Advisory Board on Regorafenib for chemorefractory mCRC in readiness for NICE application: Bayer; Financial Interests, Personal, Invited Speaker,Educational webinars on Pembrolizumab for MSI-High CRC, as well as OG cancers: MSD; Financial Interests, Personal, Advisory Board, For Pembrolizumab in CRC of OG cancers pre or NICE application or post NICE approval: MSD; Financial Interests, Personal, Invited Speaker, Webinars on updates on management of mCRC: Merck Serono; Financial Interests, Personal, Advisory Board, On Mirati GI Global Advisory Board: Mirati Therapeutics; Financial Interests, Personal, Invited Speaker, To update company on indications/updates in landscape of immunotherapy and vaccines in GI cancers:Nouscom; Financial Interests, Personal, Advisory Board, Advisory on Cancer of Unknown Primary,new indications of molecular proﬁling usingFoundation Medicine 1: Roche; Financial Interests,Personal, Advisory Board, Advisory Board on Lonsurf for chemorefractory mCRC in readiness for NICE application: Servier; Financial Interests, Institutional, Local PI, For MATTERHORN Trial: AstraZeneca; Financial Interests, Institutional, Coordinating PI, UK Chief Investigator on KEYNOTE 177,KEYNOTE 859, KEYNOTE 811, LEAP 17, MK1308A-008 trials: MSD; Financial Interests, Institutional,Research Grant, Chief Investigator of investigator initiated, MSD funded NEOPRISM-CRC trial: MSD;Financial Interests, Institutional, Local PI, UCLH PI for LEAP 15 and MK4280A-007 trials: MSD;Financial Interests, Institutional, Coordinating PI, UK Chief Investigator for NOUS209-001 trial:Nouscom; Financial Interests, Institutional, Coordinating PI, UK Chief Investigator for CUPSICO trial:Roche; Financial Interests, Personal, Steering Committee Member, Steering Committee Member of CUPISCO trial: Roche; Non-Financial Interests, Member: ASCO, Association of Cancer Physicians UK.

J.A. Bridgewater: Financial Interests, Personal, Advisory Board: Taiho, BMS, Incyte, Basilea, Servier;Financial Interests, Institutional, Funding: Incyte. K.H. Khan: Other, Institutional, Advisory Role: Bayer Health; Other, Institutional, Other: Servier. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1415

123P

Artiﬁcial intelligence (AI)-powered analysis of human epidermal growth factor receptor-2 (HER2) and tumorinﬁltrating lymphocytes (TILs) in advanced biliary tract cancer (BTC)

G. Kim1, C. Kim2, B. Kang2, S. Shin3, T. Lee3, S. Song3, S. Kim3, M. Mostafavi3,H. Song3, S. Pereira3, H. Chon2

1Department of Pathology, CHA Bundang Medical Center, Seongnam, Republic of Korea; 2Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, Seongnam, Republic of Korea; 3Oncology, Lunit Inc., Seoul, Republic of Korea

Background: HER2 is overexpressed in a subset of BTC patients, and recent developments in HER2-targeted agents are expanding therapeutic options. However,accurately assessing HER2 expression is challenging in BTC, especially at a lowexpression level. We evaluated HER2 expression as well as TILs density through AI models in BTC.

Methods: Whole-slide images (WSI) of pre-treatment HER2 immunohistochemistry(IHC) slides, matched H&E-stained slides and clinicopathological data were obtained from advanced or metastatic BTC patients at CHA Bundang Medical Center in South Korea, between 2019 and 2022. An AI-powered HER2 analyzer classiﬁes tumor cells by HER2 staining intensity (H0, H1, H2, or H3) and quantiﬁes the cells in each staining category. Then, it calculates HER2 categories (0/1+/2+/3+) following the latest ASCO/CAP HER2 IHC guidelines. For evaluating immune landscape, a separate WSI analyzer identiﬁed and quantiﬁed. TILs within the cancer epithelium or stroma from H&Estained slides.

Results: In a total of 328 patients, the AI-scored HER2 categories were 0 in 92 (28.9%),1+ in 137 (43.1%), 2+ in 68 (21.4%), and 3+ in 21 (6.6%). The overall concordance of HER2 categories between the AI and pathologists’ readings was 75.3%. HER2 3+ rates by AI in intrahepatic, extrahepatic, gallbladder, and Ampulla of Vater are estimated to be 3.1%, 3.4%, 21.4%, and 5.9%, respectively. HER2-expressing tumors (1+, 2+, and 3+) 3+) have significantly higher densities of stromal TILs (983.2 ± 1347.5 / mm2) thanhave signiﬁcantly higher densities of stromal TILs (983.2 1347.5 / mm2) thanHER2-negative tumors (683.5 739.7 / mm2, p¼0.012) and there were no signiﬁcantTIL density differences between HER2-high expressing (3+) and low expressing tumors(1+, 2+), which were consistent with either by the AI or pathologists.

Conclusions: AI-powered HER2 scoring showed good agreement with pathologists’scoring, and HER2-expressing tumors harbored high stromal TIL in BTC. Objective expression analysis and the associated differences in immunogenicity will be important for future treatment strategies.

Funding: Lunit Inc.

https://doi.org/10.1016/j.annonc.2023.09.1416

124P Clinicopathological nomogram for predicting ﬁbroblast growth factor receptor 2 (FGFR2) gene fusion/

rearrangement (F/R) in intrahepatic cholangiocarcinoma(iCCA)

|Table: 125P Key results by country* |Table: 125P Key results by country* |Table: 125P Key results by country* |Table: 125P Key results by country* |Table: 125P Key results by country* |Table: 125P Key results by country* | |---|---|---|---|---|---|

||France (N[ 167)(N [ |Germany 150) |Italy (N[ 153) |Spain (N[ 167) UK (N[ |155) |

|Male, % |67.1 66.7 ||55.6 |65.9 57.4 ||

|Age ‡60, % |73.1 60.7 ||76.5 |76.0 85.2 ||

|Site of primary ||||76.0||

|BTC tumor, % ||||||

|Intrahepatic CCA |31.1 35.3 ||51.0 |28.7 29.0 ||

|Extrahepatic CCA |30.5 28.0 ||26.8 |29.3 34.8 ||

|Gallbladder |23.4 29.3 ||11.1 |28.7 24.5 ||

|Ampulla of Vater |13.8 6.0 ||9.8 |13.2 7.7 ||

|Unknown |1.2 1.3 ||1.3 |0 3.9 ||

|ECOG at diagnosis, % ||||||

|0 |20.4 14.7 ||27.5 |18.6 32.9 ||

|1 |52.1 48.0 ||64.1 |67.7 52.3 ||

|2+ |22.2 22.0 ||8.5 |11.4 11.6 ||

|Unknown |5.4 15.3 ||0 |2.4 3.2 ||

|GemCis 1L regimen, % |28.7 30.0 ||69.9 |44.3 67.7 ||

|Median rwOS (months) |17.8 18.3 ||14.7 |13.1 8.8 ||

*All decimals have been rounded to the nearest tenth, thus the overall % may result in getting a value slightly higher than 100%.

M. Bensi1, D. Giannarelli2, C. Bagalà1, M. Niger3, F. Bergamo4, D. Barone1,

M.D. Rizzato4, F. Nichetti3, A. Spring1, A. De Rosa4, V. Beccia1, G. Ricagno4,

C.C. Pircher3, F. Ardito5, B. Barbaro6, F. Giuliante5, E. Martinelli7, F.G.M. De Braud3,S. Lonardi4, G. Tortora1, L. Salvatore1

1Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; 2Biostatistical Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; 3Medical Oncology,Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy; 4Oncology 1, Veneto Institute of Oncology IOV e IRCCS, Padua, Italy; 5Hepatobiliary Surgery, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS,Rome, Italy; 6Radiologia Diagnostica e Interventistica Generale, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; 7Department of Precision Medicine,Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy

Background: FGFR2 gene F/R is present in 10-15% of iCCA and FGFR2 inhibitors have demonstrated signiﬁcant antitumor activity in this population. However, speciﬁc clinicopathological features of iCCA patients (pts) harboring FGFR 2 gene F/R have not yet been well clariﬁed. So far, limited literature data seem suggest a correlation between FGFR2 gene F/R and young age and female gender. The aim of this study is to construct a nomogram predicting FGFR2 gene status.

Methods: iCCA pts from four Italian Institutions were retrospectively collected. The following clinicopathological variables were selected: gender; age (< 55 vs following clinicopathological variables were selected: gender; age (< 55 vs ≥5555years); synchronous vs metachronous metastases (mts); number of metastatic sites (1 vs >1), lung/distant lymph-node/peritoneal/bone mts (present vs absent). A multivariate logistic regression model was used to screen out independent predictive factors with a cut-off of 0.10 and a nomogram was established.

Results: Among 464 iCCA pts retrospectively evaluated, 63 (14%) had FGFR2 gene F/R. Univariate and multivariate analysis suggested that age < 55 years [odds ratio(OR): 2.06, 95% conﬁdence interval (CI) 1.15-3.9], bone mts (OR: 2.58, 95% CI 1.28-5.20) and female gender (OR: 1.53, 95% CI 0.88e2.67) were independent predictive

factors of FGFR2 gene F/R. A predictive nomogram was established: pts with the highest score (age < 55 years, bone mts, female gender) had a 60% chance to bear FGFR2 gene F/R iCCA [AUC 0.64 (95% CI: 0.57 -0.72)] in comparison to pts with low score (age 55 years, no bone mts, male gender) which had a 7% chance to score (age ≥ 55 years, no bone mts, male gender) which had a 7% chance to havehaveFGFR2 positive iCCA.

Conclusions: In the era of molecular characterization, we have developed a simple nomogram for predicting FGFR2 gene status in iCCA. This nomogram might help clinicians to identify pts more likely to harbour FGFR2 gene F/R and increase their therapeutic opportunities. An external validation-set will be analyzed to improve predictive performance.

Legal entity responsible for the study: Fondazione Policlinico Gemelli.

https://doi.org/10.1016/j.annonc.2023.09.1417

125P Real-world treatment patterns in patients with biliary tract cancer (BTC): Retrospective chart review survey in Europe(GARNET-2)

J.A. Bridgewater1, M. Paskow2, A. Szende3, P. Messina4, J. Sah5, B. Baur2

1Research Department of Haematology, UCL Cancer Institute, University College London, London, UK; 2Global Medical Affairs, AstraZeneca, Gaithersburg, MD, USA;3Product Development and Market Access Consulting, Fortrea, Leeds, UK; 4RWE &Analytics, Fortrea, Milan, Italy; 5Oncology Outcomes Research, AstraZeneca, Gaithersburg, MD, USA

Background: BTC is a diverse group of hepatic and perihepatic malignancies with a 5-year survival rate of <20%. This study described real-world treatment patterns and HER2-negative tumors (683.5 ±739.7 / mm2, p=0.012) and there were no significantoutcomes among patients with advanced and/or unresectable (aBTC) in France,Germany, Italy, Spain, and the United Kingdom (UK).

Methods: In this retrospective, web-based chart review survey, physicians reported anonymized patient-level data for adult patients diagnosed with aBTC between May 2018 and October 2021 who received ﬁrst-line (1L) systemic therapy (index date).

Patients were followed from index date until death or last available date at abstraction. Patient characteristics, treatment patterns, and clinical outcomes were summarized descriptively.

Results: A total of 196 physicians extracted data for 792 aBTC patients who initiated 1L systemic therapy. More patients had intrahepatic cholangiocarcinoma (CCA;

34.8%), than extrahepatic CCA (29.9%), gallbladder (23.5%), and ampullary cancer(10.2%) whereas 1.5% patients had missing information. During follow-up(median¼12.4 months), less than half of patients were prescribed gemcitabine +cisplatin (GemCis; 47.9%) as 1L. Median 1L treatment duration was 5.3 months with disease progression (49.2%) being the most common reason for treatment discontinuation. Only 33.1% received 2L and 4.1% received 3L+ of treatment. Median realworld overall survival (rwOS) from index date was 13.4 months, with regional variation (Table).

Conclusions: This study demonstrated the unmet needs of patients with aBTC, with less than half of the patients receiving standard-of-care e GemCis (ESMO recommendation) and a median rwOS of just over one year suggesting the need for new

S229

|Table: 126P |Table: 126P ||| |---|---|---|---|

|No ADJ |No met |36.6 |22.8-57.3 |

||met |21.6 |17.8-29.0 |

|ADJ |No met |45.7 |33.7-not reached |

treatments that extend survival.With the recent approval of immunotherapy for aBTC patients, exploration of the beneﬁts in real-world is needed. Additional efforts in the earlier detection of BTC are essential to improve survival.

Disclosure: J.A. Bridgewater: Financial Interests, Personal, Advisory Board: Taiho, BMS, Incyte,Basilea, Servier; Financial Interests, Institutional, Funding: Incyte. M. Paskow: Financial Interests,Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares:AstraZeneca. A. Szende: Financial Interests, Personal, Full or part-time Employment: Labcorp Drug Development; Financial Interests, Personal, Stocks/Shares: Labcorp Drug Development. P. Messina:Financial Interests, Personal, Full or part-time Employment: Labcorp, IQVIA. J. Sah: Financial Interests, Personal, Stocks/Shares: AstraZeneca; Financial Interests, Personal, Full or part-time Employment: AstraZeneca. B. Baur: Financial Interests, Personal, Full or part-time Employment:AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca.

https://doi.org/10.1016/j.annonc.2023.09.1418

126P

S230

Biliary tract cancer (BTC) characterization on a cohort of patients (pt) from the Spanish RETUD Registry

A. Lacasta1, T. Macarulla2, A.O. Castillo Trujillo3, M.M. Herrera Juarez4,

A.J. Munoz Martin5, R. Vidal Tocino6, C. Fabregat2, R.M. Rodríguez7,

M. Lobo de Mena8, P. Peinado9, M. Granja Ortega10, A. Fernandez Montes11,B. Grana Suarez12, E. Martinez de Castro13, J. Gallego Plazas14, R. Vera15,I.C. Ales Diaz16, I. Ghanem17, I. Gallego Jimenez18, E. Aranda Aguilar7

1Department of Medical Oncology, UGC Oncología Guipúzcoa, San Sebastian(Donostia), Spain; 2Department of Medical Oncology, Hospital Universitario Vall dHebron, Instituto Oncológico Vall d’Hebrón (VHIO), Barcelona, Spain; 3Department dHebron, Instituto Oncologico Vall d'Hebron (VHIO), Barcelona, Spain; 3Department ofof Medical Oncology, Asturias Central University Hospital, ISPA, Oviedo, Spain;4Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid,Spain; 5Oncología Médica, Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain; 6Department of Medical Oncology, Hospital Universitario de Salamanca, IBSAL, Salamanca, Spain; 7Oncología Médica, IMIBIC,Universidad de Córdoba, CIBERONC, Instituto de Salud Carlos III. Hospital Universitario Reina Sofía, Cordoba, Spain; 8Oncología Médica, Consorcio Hospital General Universitario de Valencia, Valencia, Spain; 9Oncología Médica, Centro Integral Oncológico Clara Campal, HM Hospitales, Madrid, Spain; 10Department of Medical Oncology,Hospital Clínico San Carlos. Instituto de Investigación Hospital Clínico San Carlos(IdISSC), Universidad Complutense, Madrid, Spain; 11Department of Medical Oncology,Complejo Hospitalario Universitario de Ourense, Ourense, Spain; 12Department of Medical Oncology, Hospital Universitario de A Coruña. Instituto Investigación Biomédica INIBIC, A Coruña, Spain; 13Department of Medical Oncology, University Hospital Marqués de Valdecilla, IDIVAL, Santander, Spain; 14Department of Medical Oncology, Hospital General Universitario de Elche, Elche, Spain; 15Department of Medical Oncology, Complejo Hospitalario de Navarra, Pamplona, Spain; 16Department of Medical Oncology, H. Universitario Regional de Málaga, Malaga, Spain;17Department of Medical Oncology, Hospital Universitario La Paz, Madrid, Spain;18Department of Medical Oncology, H. Virgen del Rocío, Seville, Spain

Background: BTC constitutes a heterogeneous group of invasive tumors, including intrahepatic, perihilar, and extrahepatic cholangiocarcinoma, and gallbladder carcinoma (GC). We aimed to characterize the epidemiology, clinical management, and survival outcomes of BTC pt in our environment.

Methods: We evaluated a large real-world cohort of pt diagnosed with BTC from 1st January 2017 to 31st December 2022 from the Spanish RETUD registry. We described the demographic and clinical features, therapies received and outcomes. We assessed progression-free survival (PFS) and overall survival (OS) using the Kaplan-Meier method in different settings.

Results: A total of 1,285 evaluable pt were included in 28 Spanish sites. The median age was 69.2 years, and 56.2% were men. At primary diagnosis, tumors were mostly intrahepatic (54.8%), followed by extrahepatic (28.5%), and GC (14.6%). Overall,

48.7%, 22.6%, and 28.6% pt were diagnosed with metastatic, locally advanced, and resectable disease, respectively. Only 29.5% of pt underwent surgical resection and

9.6% locoregional procedures. Most pt (74.8%) received systemic treatment as a ﬁrstline strategy (86.2%), mainly gemcitabine-based combinations (90%), with 62.7% of pt receiving cisplatin plus gemcitabine (CISGEM). At the database cut-off, 945 pt had died because of disease progression. The median OS at the advanced setting was 9.2 months (m) (95% conﬁdence interval [95CI]: 8.3-10.3). The median PFS in pt with advanced BTC exposed to ﬁrst-line CISGEM was 5.5 m (95CI 5.0-6.0) with a median OS of 11.6 m (95IC 10.8-12.5). For pt with resectable BTC, OS was analyzed based on whether they received adjuvant treatment (ADJ) and developed metastases (met)during follow-up (see table)

Volume 34 - Is

met

25.4

21.4-32.6

Conclusions: This study provides insights into the clinical characteristics and management of BTC in the real-world framework in Spain. Our results are consistent with the literature, nevertheless, they must be considered in the context of a currently evolving scenario.

Editorial acknowledgement: Medical writing assistance was provided by Carla Martín Cortázar from Evidenze Health España S.L. during the preparation of this abstract.

Legal entity responsible for the study: This study has been promoted by the Spanish Group of Digestive Tumour Treatment (TTD).

Funding: Incyte and AstraZeneca.

Disclosure: A. Lacasta: Other, Institutional, Other, Travel, Accomodation, Expenses: Roche, Merck.

T. Macarulla: Financial Interests, Personal, Advisory Board: Ability Pharmaceutical, SL, AstraZeneca,Basilea Pharma, Batxer, BioLineRX Ltd, Celgene SLU, Eisai, IPSEN Pharma, Incyte; Financial Interests,Personal, Other, Direct research fund: Servier, Merck, Sharp and Dhome, Novocure, QED Therapeutics Inc, Roche, Sanoﬁ-Aventis, Zymeworks; Financial Interests, Personal, Invited Speaker: Lilly,Janssen; Financial Interests, Institutional, Research Grant: Amc Medical Research, Armo Biosciences,Basilea, Biokeralty Research Institute, Merck Sharp & Dohme, Oncomed Pharmaceuticals, QED Therapeutics, VCN Biosciences, AbbVie Farmaceútica, Ability Pharmaceuticals, Agios, Amgen, Aslan,AstraZeneca, Bayer, BeiGene, Biolinerx, Blueprint Medicines, Boston Biomedical, Bristol Myers Squibb (BMS), Cantargia, Celgene, Eisai, Erytech Pharma, F. Hoffmann-La Roche, Fibrogen, Genentech, Hallozyme, Immunomedics, Incyte, Ipsen, Lab. Menarini, Lilly, Loxo Oncology, Medimmune,Merimarck, Novocure, Millenim, Nelum, Novartis, Zymeworks, Pﬁzer, Pharmacyclics, Roche; NonFinancial Interests, Member: American Society of Clinical Oncology - ASCO, “Sociedad Española de Oncología Médica” e SEOM, Sociedad Europea de Oncología Médica - ESMO. A.J. Munoz Martin:Other, Institutional, Other, Consulting or Advisory role: Sanoﬁ, Pﬁzer, BMS; Other, Institutional,Ofﬁcer, Consulting or Advisory role: AstraZeneca, MSD; Other, Institutional, Speaker’s Bureau: Rovi,STADA, Amgen, Merck; Other, Institutional, Research Funding: Rovi, Celgene, Leo Pharma; Other,Patent, royalties or other intellectual property; Other, Institutional, Other, Travel, Accomodation,Expenses: AstraZeneca, Amgen, Merck, Roche. R. R. Vidal Tocino: Financial Interests, Personal, Invited Speaker: Amgen, Merck, Servier, Bristol Myers Squibb, Bayer, MSD; Financial Interests, Personal,Advisory Board: Servier, GSK; Non-Financial Interests, Member: ACLO- Asociación Castellano-Leonesa de Oncología, SEOM- Sociedad Española de Oncología Médica; Other, Travel and Accommodation:Servier, Roche, MSD. M. Lobo de Mena: Financial Interests, Personal, Invited Speaker: Leo Pharma,Servier. A. Fernandez Montes: Financial Interests, Personal, Other, Invited Speaker: Amgen, AstraZeneca, Eisai, Lilly, MSD, Pierre Fabre, Servier. J. Gallego Plazas: Financial Interests, Personal, Advisory Board: AAA, Amgen, Bayer, BMS, Eisai, Ipsen, Lilly, Merck, MSD, Pierre-Fabre, Roche, Servier;Financial Interests, Personal, Invited Speaker: AAA, Amgen, Bayer, BMS, Ipsen, Lilly, Merck, MSD,Novartis, Servier; Financial Interests, Personal, Other, Educational: Amgen, Ipsen, Merck, Novartis,Pierre-Fabre, Roche; Financial Interests, Institutional, Funding: Astellas, AstraZeneca, BMS, Daiichi Sankyo, Lilly, Servier; Non-Financial Interests, Member of Board of Directors: Spanish Society Medical Oncology, Spanish Group Of Neuroendocrine an Endocrine Tumours; Non-Financial Interests, Project Lead: AGAMENON-SEOM Registry of Esophagohastric Cancer. R. R. Vera: Financial Interests, Personal,Advisory Board: Roche, Amgen, Sanoﬁ; Financial Interests, Personal, Invited Speaker: Merck, Bayer,Eisai, Servier; Financial Interests, Personal, Other, Program Coordinator: Lilly. I. Ghanem: Other,honoraria: Servier, Merck; Other, Cosulting or Advisory Role: Servier, Pierre Fabre; Other, Consulting or Advisory Role: Merck; Other, Speaker’s Bureau: Servier, Merck, Pierre Fabre, Roche; Other, Travel,Accomodation, Expenses: Servier, Merck, Amgen, Bayer, Pierre Fabre. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1419

127P Prognostic signiﬁcance of intratumoral and peritumoral budding in distal extrahepatic bile duct carcinoma

S-Y. Jun1, S-M. Hong2, S. An1

1Pathology, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Incheon, Republic of Korea; 2Pathology, Asan Medical Center - University of Ulsan, Seoul, Republic of Korea

Background: Although tumor budding (TB) has been recognized as a representative adverse prognosticator in gastrointestinal malignancies, it is not well elucidated in distal-extrahepatic bile duct carcinoma (DBDC).

Methods: Herein, we investigated the prognostic signiﬁcance of peritumoral (PTB)and intratumoral (ITB) budding according to the modiﬁed DBDC staging of the 8th edition of the American Joint Committee on Cancer. PTB and ITB were independently evaluated in a cohort of DBDC patients (n¼410) based on the 2016 InternationalTumor Budding Consensus Conference (ITBCC).

Results: High levels of PTB (PTBHigh, grade 2) and ITB (ITBHigh, grade 3) Results: High levels of PTB (PTBHigh, ≥ grade 2)and ITB (ITBHigh, ≥grade 3) werewereidentiﬁed in 316 (77%) and 238 (58%) cases, respectively. In univariate analysis,PTBHighand ITBHigh(both P¼0.001); larger size and sclerosing tumor growth pattern(both P<0.001); higher histologic grade (P¼0.006); extrapancreatic location(P¼0.015); adenocarcinomas unrelated to intraductal papillary neoplasm of the bileduct (IPNB) (P¼0.008); pancreatic, duodenal, and lymphovascular invasion (allP<0.001); perineural invasion (P¼0.003); cancer involvement of the bile ductresection margin, nodal metastasis, and higher T and N categories and disease stages(all P<0.001) were associated with shorter patient overall survival (OS) times. In

sue S2 - 2023

multivariate analysis, PTBHighand ITBHighremained poor independent prognostic indicators of OS in DBDC patients. Speciﬁcally, ITBHighcould predict poor prognosis(P¼0.025) in patients with stage I (T1N0) DBDC.

Conclusions: Both PTBHighand ITBHighwere strong prognostic indicators in patients with DBDC. Thus, ITB could be used to predict worse prognoses in patients with DBDC, in which PTB is difﬁcult to assess, especially for patients with stage I (T1N0)DBDC.

https://doi.org/10.1016/j.annonc.2023.09.1420

128P

Biliary tract cancers: Epidemiological and prognosis trends of Latin American population

M.D.C. Diaz Romero1, G. Calderillo Ruiz1, E. García1, B. Carbajal2, D.A.G. Padilla3,G.E. Trejo-Duran4, P. Morales Esponda Mendoza6, D.L. Guerra Figueroa6

1Medical Oncology Department, INCAN - Instituto Nacional de Cancerologia, Mexico City, Mexico; 2Clinical Research, INCAN - Instituto Nacional de Cancerologia, Mexico City, Mexico; 3Dept. Cirugía Oncológica, INCAN - Instituto Nacional de Cancerologia,Mexico City, Mexico; 4Radiation Oncology, The National Cancer Institute, Mexico City,Mexico; 6Facutlad de Medicina, UNAM - Universidad Nacional Autonoma de Mexico,Mexico City, Mexico

Background: Biliary tract cancers are heterogeneous tumors deﬁned by the anatomical location, intrahepatic, cholangiocarcinoma (ICC), extrahepatic (ECC),gallbladder and ampulla of Vater cancer (AVC).The outcome of treatment by location remains unclear in Latin American population, resulting in inconsistently data to enhance treatment decisions and outcome. The aim of this study is to describe the epidemiological features and prognosis of overall survival of Latin American population with biliary tract cancers.

Methods: Retrospective, observational study. Included patients treated at the National Cancer Institute between 2008 and 2022. Statistical analysis required: X2 and t test, Kaplan Meier, Log Rank and Cox Regression. Statistical signiﬁcance differences were assessed when p was bilaterally <0.05.

Results: A total 786 of patients diagnosed with biliary tract cancer were included in the analysis. Patients had a median age of 61 years (24-96). Alcohol consumption and smoking were observed in 22% and 29% respectively. Regarding comorbidities, 22%had Type2DM, 27% HAS, and obesity & overweight was present in 13% and 32%respectively. Anatomical location included ICC (19%;n¼151), ECC (22%;n¼172), gall-bladder (33%;n¼259) and AVC (26%;n¼204). Female were more prevalent in gall-bladder and ICC (79% & 71%) (p<0.001). Median time to diagnosis was 3 months (0e 120); extent of disease was observed as localized (18%;n¼144), local-advanced(20%;n¼158), and metastatic (60%;n¼472). In metastatic patients, mean number ofmetastasis was 1 (1-7), being liver (66%), retroperitoneum (7%), and lung (6%) the most frequent sites. Comparing Chemotherapy and extent of disesase, 35%, 53%, and 55% patients received treatment for localized, unresectable, and metastatic (p[0.001). An OS analysis was conducted considering location, ICC patients showed a median-OS of 9months, ECC a median-OS of 12months, gallbladder a median-OS of 1months and AVC did not reach median-OS (p<0.001).

Conclusions: Prognosis and outcome for patients with biliary tract cancer differ depending on the anatomical subsite. This is one of the main studies describing epidemiological features, and outcome in Latin American patients with biliary tract.

https://doi.org/10.1016/j.annonc.2023.09.1421

129P Prognostic factors associated with survival in resected biliary tract cancers: A multicentre Italian experience

M. Ghidini1, M. Paccagnella2, M. Salati3, F. Bergamo4, M. Ratti5, B. Galassi1,O. Garrone1, M. Rovatti6, L. Caccamo7, E. Gringeri8, A. Zerbi9, G. Torzilli10,S. Bozzarelli11, L. Rimassa12

1Oncology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan,Italy; 2Fondazione ARCO - Cuneo, Azienda Ospedaliera St. Croce e Carle, Cuneo, Italy;3Medical Oncology Dept, Azienda Ospedaliero - Universitaria Policlinico di Modena,Modena, Italy; 4Oncology 1, Veneto Institute of Oncology IOV e IRCCS, Padua, Italy;5Oncology Department, ASST Cremona - Azienda Socio-Sanitaria Territoriale, Cremona, Italy; 6Surgery Unit, ASST Cremona - Azienda Socio-Sanitaria Territoriale, Cremona, Italy; 7Liver Transplant Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; 8Hepatobiliary Surgery and Liver Transplantation Unit, Azienda Universitaria Ospedaliera di Padova, Padua, Italy; 9Pancreatic Unit, IRCCS Humanitas Research Hospital, Department of Biomedical Sciences, Humanitas University, Milan,Italy; 10Department of Hepatobiliary and General Surgery, Department of Biomedical Sciences, Humanitas University, Milan, Italy; 11Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Milan, Italy;12Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Department of Biomedical Sciences, Humanitas University,Milan, Italy

Background: Biliary tract cancers (BTC) are classiﬁed as gallbladder tumours (GBC)and intrahepatic (iCCA) or perihilar and distal extrahepatic cholangiocarcinomas(eCCA). BTC’s 3-year recurrence rate is up to 80%. Capecitabine (CAP) is the standard for adjuvant (adj) chemotherapy (CT). We collected a retrospective multicentre Italian series of resected BTC and analysed the impact of adj CT on survival.

Methods: Main variables were ECOG performance status (PS), pre-surgical (SUR) Ca

19.9 value, type of SUR, site, histology, invasion (T), nodal status (N), vascular invasion(V) resection margins (R), grade (G). Median follow-up (FU) was estimated with reverse Kaplan-Meier (KM) approach; median RFS (RFS) and median overall survival(OS) were estimated by KM method.

Results:We included 142 all-stages BTC resected from 2005 to 2022, adj CT was given to 69 BTC. With median FU of 89 months (mo), overall RFS and OS were 17 and 30 mo. Lower ECOG PS was associated with longer RFS and OS (p<0.001). A pre-SUR Ca19.9 29 was associated with longer RFS in iCCA (p¼0.001) and OS both in Ca19.9 ≤ 29 was associated with longer RFS in iCCA (p=0.001) and OS both in iCCAiCCA(p¼0.010) and GBC (p¼0.019). Lower T was associated with longer RFS (p¼0.002)and OS (p<0.001) in iCCA and GBC but not in eCCA. N0 status correlated with longer RFS in iCCA (p<0.001) and OS both in iCCA and GBC (p<0.006). R0 status was associated with longer RFS in eCCA (p¼0.043) and GBC (p<0.001), showing longer OSonly in GBC only (p<0.001). V0 status was associated with longer RFS (p¼0.017) andOS (p¼0.009) in iCCA . Adj CT didn’t impact both on RFS (p¼0.539) and OS (p¼0.978)in the whole cohort. After stratiﬁcation by site, eCCA showed an advantage given by adj CT on mRFS (p¼0.047). Comparing all adj CT, CAP performed better in iCCA, with amRFS of 19 mo. Multivariate Cox regression analysis for RFS and OS was stratiﬁed for iCCA, eCCA and GBC: ECOG PS, R and N status retained signiﬁcant correlation with RFS(p<0.001, p<0.001 and p¼0.034, respectively) and OS (p<0.001, p<0.001, p¼0.013,respectively). Pre-SUR Ca19.9 value correlated with OS (p¼0.001).

Conclusions: In our series, adj CT didn’t impact on survival except for eCCA. Evaluation of multiple prognostic variables (including T, N, R and V status and pre-SUR Ca19.9) is necessary to identify a subgroup of BTC that can beneﬁt more from adj CT.

https://doi.org/10.1016/j.annonc.2023.09.1422

130P Phase I study evaluating KIN-3248, a next-generation,irreversible pan-FGFR inhibitor, in patients with advanced cholangiocarcinoma, urothelial carcinoma and other solid tumors harboring FGFR2 and/or FGFR3 gene alterations

B. Garmezy1, M. Borad2, C-C. Lin3, L-T. Chen4, C.A. Perez5, S. Kato6, B. Tam7,P. Severson8, C.S. Quah9, J.J. Harding10

1Research, Sarah Cannon Research Institute, Nashville, TN, USA; 2Oncology Department, Mayo Clinic Cancer Center, Scottsdale, AZ, USA; 3Department of Oncology,NTUH - National Taiwan University Hospital, Taipei, Taiwan; 4Hematology Department, Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung, Taiwan;5Medical Oncology, Florida Cancer Specialists, Fort Myers, FL, USA; 6Medical Oncology,University of California San Diego - UCSD, La Jolla, CA, USA; 7Clinical Sciences, Kinnate Biopharma, San Diego, CA, USA; 8Translational Medicine, Kinnate Biopharma Inc., San Diego, CA, USA; 9Clinical Development, Kinnate Biopharma, San Diego, CA, USA;10Medicine, Memorial Sloan Kettering Evelyn H. Lauder Breast Center, New York, NY,USA

Background: Preclinical and clinical evidence indicates that activating FGFR1-4 gene alterations drives oncogenesis and tumor growth. Pharmacological inhibition of FGFR1-4 leads to tumor shrinkage and disease control, supporting development of FGFR inhibitors. A critical limitation of currently approved, clinical-stage FGFRi is the

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emergence of secondary, on-target resistance mutations (mutn) that reduce duration of response. About 70% of cholangiocarcinoma (CCA) patients treated with FGFRi exhibit secondary FGFR2 kinase domain resistance mutn at the time of relapse. KIN3248 is a next-generation, selective, irreversible, small molecule pan-FGFRi, designed to inhibit primary FGFR oncogenic alterations as well as secondary kinase domain mutn associated with disease progression. Preclinically, KIN-3248 has favorable pharmaceutical properties, is well-tolerated with continuous, daily oral administration in GLP toxicology studies and is efﬁcacious against primary FGFR2 and FGFR3 oncogenic driver alterations as well as secondary FGFR2 resistance mutn (eg, gatekeeper and molecular brake) in human cancer cells and PDX models.

Trial design: KN-4802 (NCT05242822) is a ﬁrst in human, multicenter, Ph1 study of KIN-3248 in pts with advanced and metastatic solid tumors (AMST) harboring FGFR2 and/or FGFR3 gene alterations. KIN-3248 is given continuously in 28-day cycles until drug intolerance or disease progression. The study is conducted in 2 parts: Part A is a dose escalation of KIN-3248 to MTD/RP2D. Part B evaluates a selected dose of KIN3248 in previously treated intrahepatic cholangiocarcinoma (ICC) or urothelial carcinoma (UC), treatment naïve ICC or UC, or other AMST. Enrollment criteria include ECOG PS 0-1 and prior standard treatment with clinical beneﬁt, if appropriate. Primary endpoints are safety and preliminary antitumor activity. Secondary objectives include pharmacokinetic and pharmacodynamic assessments including measures of FGFR pathway modulation. Planned sample size is 140 pts and the study is enrolling patients in the US, EU and globally.

Clinical trial identiﬁcation: NCT05242822.

Legal entity responsible for the study: Kinnate Biopharma Inc.

Funding: Kinnate Biopharma Inc.

Disclosure: B. Garmezy: Financial Interests, Institutional, Research Grant: AbbVie, AstraZeneca,CRISPR Therapeutics, Exelixis, Genetech, Janssen, Loxo Oncology, Arcus Biosciences, Xencor, Aveo Oncology, Zenshire, Accutar Biotechnology, Kinnate Biopharma, Jubilant Therapeutics, Janux Therapeutics, Mink Therapeutics, Nuvation Bio, Profound Bio, Kineta; Financial Interests, Institutional,Other, Consulting: Amgen, Arvin’s, Aveo, Bayer, Exelixis, Janssen, Merck, Sanoﬁ-Aventis. M. Borad:Financial Interests, Institutional, Research Funding: Kinnate Biopharma. C. Lin: Financial Interests,Personal, Other, Travel support: BeiGene, Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Blueprint Medicines, Bristol Myers Squibb, Daiichi Sankyo, Novartis, AbbVie, PharmaEngine,Merck KGaA, Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Eli Lilly, Novartis,Roche; Financial Interests, Personal, Other, Travel Support: IMPACT Therapeutics. L. Chen: Financial Interests, Personal, Invited Speaker: PharmaEngine (TW), ONO, BMS, Eli Lilly, Ipsen, Novartis, TTY(TW), C-Stone (TW); Financial Interests, Personal, Other, Medical Monitoring for clinical trial.: Taivex(TW); Financial Interests, Personal, Other, DSMC member for clinical trials: OBI (TW); Financial

Interests, Personal, Advisory Board: MSD, AstraZeneca, SynCore (TW); Financial Interests, Personal,Advisory Board, Scientiﬁc Advisory Committee: ScinoPharm Taiwan, Onward; Financial Interests,Personal, Full or part-time Employment, Co-afﬁliated, Distinguished Investigator and Senior Physician Staff: National Institute of Cancer Research, National Health Research Institutes, Taiwan;Financial Interests, Personal, Full or part-time Employment, Professor of Internal Medicine: Kaohsiung Medical Univrsity Hopsital, Kaohsiung Medical University, Kaohsiung, Taiwan; Financial Interests, Personal, Member of Board of Directors, Independent Director: ScinoPharm Taiwan, Ltd.;Financial Interests, Personal, Advisory Board, Alpha-enolase speciﬁc antibodies: HuniLife Biotechnology, Inc., Taiwan; Financial Interests, Personal, Steering Committee Member, TOPAZ-1, phase III trial: AstraZeneca; Financial Interests, Personal, Steering Committee Member, ATTRACTIONs trials,ATT-2 (3L), ATT-4 (1L), ATT-5 (Adjuvant) and ATT-6 (1L).: ONO; Financial Interests, Personal, Trial Chair, SynCore CT4006, phase 3 trial: Syncore BioPharma, Taiwan; Financial Interests, Institutional,Trial Chair, Research funding and study medication for TCOG IIT.: Celgene; Financial Interests,Institutional, Trial Chair, Industry-sponsored, phase 2 bridging trial in TCOG.: TTY, Taiwan; Financial Interests, Institutional, Steering Committee Member, C3651003 (Cancer cachexia), Operations steering Committee, country lead: Pﬁzer; Non-Financial Interests, Principal Investigator, Investigatorinitiated trials: Taiwan Cooperative Oncology Group, National Institute of Cancer Research, Taiwan;Non-Financial Interests, Institutional, Product Samples, Medication support for TCOG trial. : Syncore BioPharma, Taiwan; Non-Financial Interests, Member of Board of Directors, Managing Director:Taiwan Oncology Society, Taiwan; Non-Financial Interests, Leadership Role, President (2021.09 w):Taiwan NeuroEndocrine Tumor Society (TNETS); Non-Financial Interests, Member of Board of Directors: Taiwan Pancreas Society, Taiwan; Non-Financial Interests, Institutional, Product Samples,Medication for TCOG trials: TTY; Non-Financial Interests, Institutional, Product Samples, Targeted Cancer Panel NGS testing.: ACTgenomics (TW); Non-Financial Interests, Other, International Staring Committee Member (ISCM), Academic Planning Committee, JSMO: Japanese Society of Medical Oncology (JSMO); Non-Financial Interests, Leadership Role, Council Member: Asian Oncology Society(AOS). C.A. Perez: Financial Interests, Institutional, Local PI: Accutar Biotech, Kinnate Biopharma,Relay Therapeutics, Seagen Inc, Kura Oncology, Hyamab Inc, Xilio Therapeutics, Elucida Oncology,Tallac Therapeutics, Ribbon Therapeutics, Mirati Therpeutics, Elpiscience Biopharmaceuticals, Dracen Pharmaceuticals, Zhuhai Yufan Biotechnologies Co., Genentech, Inc., Jazz Pharmaceuticals,Artios Pharma. S. Kato: Financial Interests, Personal, Other, Consultant: Medpace, Foundation Medicine, Neogenomics, CureMatch; Financial Interests, Personal, Invited Speaker: Chugai, Roche/Genentech, Bayer; Financial Interests, Personal, Advisory Board: Pﬁzer; Financial Interests, Personal,Research Funding: ACT Genomics, Sysmex, Konica Minolta, OmniSeq, Personalis, Function Oncology.

B. Tam: Financial Interests, Personal, Full or part-time Employment: Kinnate Biopharma; Financial Interests, Personal, Stocks/Shares: Kinnate Biopharma, Samumed. P. Severson: Financial Interests,Personal, Full or part-time Employment: Kinnate Biopharma; Financial Interests, Personal, Stocks/Shares: Kinnate Biopharma. C.S. Quah: Financial Interests, Personal, Full or part-time Employment:Kinnate Biopharma Inc; Financial Interests, Personal, Stocks/Shares: Kinnate Biopharma Inc. J.J.

Harding: Financial Interests, Personal, Advisory Board: Adaptiimune, Bristol Myer Squib, CytoMx,Eisai, Exelexis, Elevar, Hepion, Eli Lilly, AstraZeneca, Medivir, QED, Sevier, Merck.

https://doi.org/10.1016/j.annonc.2023.09.1423

BIOMARKERS (AGNOSTIC)

131O

A composite biomarker for evaluation of homologous recombination repair deﬁciency in a pan-cancer cohort

M. Rübsam1, M. Rheinnecker1, B. Hutter1, M. Fröhlich1, C.E. Heilig2,

N. Paramasivam1, M. Oles1, C. Ball3, H. Glimm3, M. Hlevnjak1, M. Zapatka4N. Paramasivam2,M.Oles2,C.Ball3,H.Glimm3, M. Hlevnjak1,M.Zapatka4,,P. Lichter4, S. Fröhling2, R.F. Schlenk5, D. Hübschmann1

1Computational Oncology Group, Molecular Precision Oncology Program, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany; 2Division of Translational Medical Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany; 3Department for Translational Medical Oncology, National Center for Tumor Diseases (NCT/UCC) Dresden, German Cancer Research Center(DKFZ) Heidelberg, Faculty of Medicine and University Hospital Carl Gustav Carus,Technische Universität Dresden, and Helmholtz-Zentrum Dresden-Rossendorf (HZDR),Dresden, Germany; 4Division of Molecular Genetics, German Cancer Research Center(DKFZ) and National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany; 5Clinical Trial Center, National Center for Tumor Diseases (NCT) Heidelberg,German Cancer Research Center (DKFZ), and Heidelberg University Hospital, Heidelberg, Germany

Background: Assessing the functional state of homologous recombination repair(HRR) is crucial to predict an effective response to PARP inhibitor (PARPi) treatment or platinum-based chemotherapy in cancer patients. Drug approvals are currently mostly based on mutations in BRCA1 and BRCA2 or genomic scarring alone. Composite biomarkers may extend the discriminative power and make targeted treatment approaches available to a wider range of patients and entities.

Methods: Whole-genome or -exome sequencing (WGS or WES) data from 739 patients including various rare cancers were evaluated for germline and somatic alterations in one of 183 genes related to HRR as well as for genomic patterns of HRR deﬁciency (HRD), i.e. exposure to single-base substitution signature 3, quantiﬁcation of HRD-derived loss of heterozygosity (LOH-HRD), and the number of large-scale state transitions (LST). The individual markers were integrated into a composite biomarker,the TOP-ART score, with a scoring system (0-7) and compared to the other published HRR biomarkers. Currently, this biomarker is used to determine eligibility for the TOPART trial (ClinicalTrials.gov identiﬁer: NCT03127215, olaparib/trabectedin vs. physician’s choice, estimated study completion: December 2023).

Results: The occurrence and severity of HRD predicted by the TOP-ART score varies between entities. Strong associations were found between genomic patterns of HRD and mutations affecting several genes, including but not limited to BRCA1 and BRCA2.

The phenotypic susceptibility to BRCA1 and BRCA2 impairment varies between entities and depends on zygosity. TOP-ART score positivity (score 3; 312 cases) tities and depends on zygosity.TOP-ART score positivity (score ≥3; 312 cases) over-over-laps with but is more inclusive than HRDetect (55 cases) and CHORD (26 cases). In particular, we identify patients who were biomarker-negative for HRDetect and CHORD, but positive in the TOP-ART score, and achieved long-lasting disease control upon treatment with olaparib/trabectedin.

Conclusions: The TOP-ART score is a novel composite HRR biomarker developed and validated in an observational precision oncology cohort. It has the potential to broaden access to targeted treatments and is prospectively used to determine eligibility for the TOP-ART trial.

Clinical trial identiﬁcation: NCT03127215 Study of Olaparib/Trabectedin vs. Doctor’s Choice in Solid Tumors (NCT-PMO-1603) Estimated Primary Completion Date:December 2023 Estimated Study Completion Date: December 2023.

Funding: German Cancer Consortium (DKTK).

Disclosure: C.E. Heilig: Financial Interests, Institutional, Research Funding: AstraZeneca, Pﬁzer,Roche, PharmaMar. M. Hlevnjak: Financial Interests, Personal, Stocks/Shares: Illumina, GSK, PharmaMar. S. Fröhling: Financial Interests, Personal, Advisory Board: Bayer, Illumina, Roche; Financial Interests, Personal, Invited Speaker: Amgen, Eli Lilly, Illuminna, PharmaMar, Roche. R.F. Schlenk:Financial Interests, Institutional, Research Funding: AstraZeneca, Boehringer Ingelheim, Pﬁzer,PharmaMar, Roche, Daiichi Sankyo; Financial Interests, Personal, Speaker’s Bureau: Daiichi Sankyo,Pﬁzer; Financial Interests, Personal, Advisory Board: AbbVie, Daiichi Sankyo, Jazz, Pﬁzer. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2856

132MO Molecular proﬁling of 991 prospectively recruited rare

cancers patients in EUROPE: First results of ARCAGEN e an EORTC-SPECTA and EURACAN study

M. Morfouace1, J. Oliveira2, N. Penel3, J. Peron4, M. Pracht5, B. Brasiuniene6,A. Capela Marques7, C. Gennigens8, L. Greillier9, M-S. Robert10, H.J. Klumpen11,R. Peeters12, L.F.L. Licitra13, N. Girard14, J.A. Gietema15, W. de Herder16,

E. Kapiteijn17, A. Idbaih18, I.L. Ray-Coquard19, J-Y. Blay20

1EORTC AISBL/IVZW - European Organisation for Research and Treatment of Cancer,Brussels, Belgium; 2Oncology Department, Instituto Portugues de Oncologia do Porto Francisco Gentil, EPE (IPO-Porto), Porto, Portugal; 3Medical Oncology Department,Centre Oscar Lambret, Lille, France; 4Medical Oncology Department, Ch Lyon Sud,Pierre Benite, France; 5Medical Oncology Department, Centre Eugene - Marquis,Rennes, France; 6Medical Oncology Department, National Cancer Institute, Vilnius,Lithuania; 7Medical Oncology Department, CHVNG/E - Centro Hospitalar de Vila Nova de Gaia/Espinho - Unidade 1 - EPE-SNS, Vila Nova De Gaia, Portugal; 8Department of Medical Oncology, Centre Hospitalier Universitaire Sart Tilman, Liège, Belgium;9Multidisciplinary Oncology and Therapeutic Innovations, Hopital St. Marguerite Assistance Publique Hopitaux de Marseille, Marseille, France; 10Project Direction,EORTC AISBL/IVZW - European Organisation for Research and Treatment of Cancer,Brussels, Belgium; 11Medical Oncology Department, Amsterdam UMC - Vrije University Medical Centre (VUmc), Amsterdam, Netherlands; 12Internal Medicine Dept.,Erasmus MC - University Medical Center, Rotterdam, Netherlands; 13Head and Neck Medical Oncology Unit, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy;14Thorax Institute, Institut Curie, Paris, France; 15Medical Oncology Department,UMCG - University Medical Center Groningen, Groningen, Netherlands; 16Medical Oncology Department, Erasmus MC - Erasmus University Rotterdam, Rotterdam,Netherlands; 17Medical Oncology Dept., Leiden University Medical Center (LUMC),Leiden, Netherlands; 18Neuro-Oncology, Hopital Pitié Salpetrière AP-HP, Paris, France;19Medical Oncology Department, Centre Léon Bérard, Lyon, France; 20Medicine Department, Centre Léon Bérard, Lyon, France

Background: Within the EORTC-SPECTA platform, the ARCAGEN collaborative study between EORTC and EURACAN was initiated in June 2019 and aimed to assess the prevalence of genomic alterations, high tumor mutational burden (TMB) and microsatellite instability (MSI), as well as actionability in patients diagnosed with advanced rare cancers (deﬁned with an incidence<6/105/y).

Methods: Patients with a rare adult solid tumor of one of the 10 domains or EURACAN in advanced phase were proposed for the ARACAGEN study as part of the SPECTA program.

Disclosure: Y. Huang: Financial Interests, Institutional, Funding: MSD. M. Xu, N. Li: Financial Interests, Personal, Full or part-time Employment: MSD China. Y. Mao: Financial Interests, Personal,Full or part-time Employment: MSD China; Financial Interests, Personal, Stocks/Shares: Merck & Co.,Inc., Rahway, NJ USA. A. Gozman: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme Corp.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2861

137P VEGFR-3 expression proﬁling by histology and mRNA signature to classify patient population for the selective VEGFR-3 inhibitor EVT801

C.A. Gomez-Roca1, P. Fons2, P-B. Ancey2, P. Cassier3, J-P. Delord4, L. Davenne2,M. Fitzgerald5, M. Mandron6, M.R. Paillasse7, J. Friend8, P. Rochaix9

1Medical Oncology and Clinical Research Department, Institut Universitaire du Cancer-Toulouse- Oncopole, Toulouse, France; 2Translational Biomarkers, Evotec, Toulouse,France; 3Medical Oncology Department, Centre Léon Bérard, Lyon, France; 4Medical Oncology Department, IUCT - Institut Universitaire du Cancer de Toulouse - Oncopole,Toulouse, France; 5Kazia Therapeutics Limited, Sydney, NSW, Australia; 6Clinical Development Solution, Evotec (France) Sas, Toulouse, France; 7Innovate Oncology,Evotec (France) Sas, Toulouse, France; 8Medicine, Kazia Therapeutics Limited, Sydney,NSW, Australia; 9Histopathology Department, Institut Universitaire du Cancer -Toulouse- Oncopole, Toulouse, France

Background: EVT801 is a highly selective small molecule inhibitor of VEGFR-3 and acts by inhibiting tumor lymphangiogenesis and angiogenesis. A phase I clinical study(NCT05114668) has started to characterize safety, tolerability, pharmacokinetics of EVT801. Clinical samples from these patients will be used to explore preliminary signals of clinical efﬁcacy and investigate the biological activity of the drug using several biomarkers. Among them, we have investigated VEGFR3 expression proﬁling by histology.

Methods: We validated a highly speciﬁc protocol for VEGFR-3 immunohistochemistry labelling and a VEGFR-3 mRNA signature, readily transferable to clinical centers.

Results: Initially, VEGFR-3 expression was assessed in 29 primary kidney cancer samples and 23 metastatic kidney cancer samples with CD34 to stain vessels and D2-40 to track lymphatics. We detected VEGFR-3 expression in the endothelial cells within the kidney tumor but not in the tumor cells. Remarkably, we observed a very distinct delineation between the kidney tumor vasculature, which showed high VEGFR-3 expression, and the normal adjacent tissue, which was devoid of VEGFR-3 expression. In addition, we found that VEGFR-3 expression in metastases from kidney tumors matched the expression pattern of the primary tumor. Then, We have demonstrated that it exists a strong correlation between VEGFR-3 expression by histology and VEGFR-3 mRNA signature. We applied both VEGFR-3 signatures in different indications of interest like soft tissue sarcomas and lung cancers.

Conclusions: We were able to quantify VEGFR-3 expression by histology and mRNA signature in the kidney and soft tissue sarcoma cohorts plus several others, such as

S235

hepatocarcinoma and non-small cell lung cancer. This enables us to select indications that might beneﬁt from EVT801 as a monotherapy (e.g., clear cell renal cell carcinoma and soft tissue sarcomas) or in combination with standard of care. Accordingly,VEGFR-3 expression is retrospectively quantiﬁed during the EVT801 phase 1 clinical trial and may be used to stratify patients in the future.

Clinical trial identiﬁcation: NCT05114668.

Legal entity responsible for the study: Kazia Therapeutics Limited.

Funding: Kazia Therapeutics Limited.

Disclosure: C.A. Gomez-Roca: Financial Interests, Personal, Invited Speaker: BMS, Roche / Genentech,Pierre Fabre; Financial Interests, Personal, Other, IDMC member: Pharmamar; Financial Interests, Personal, Advisory Board: Macomics; Financial Interests, Institutional, Research Grant: Roche / Genentech;Financial Interests, Institutional, Coordinating PI: BMS, Amunix, Hookipa, Kazia Therapeutics, IDEAYA;Financial Interests, Personal, Steering Committee Member: BMS, Genentech; Non-Financial Interests,Member of Board of Directors: FITC (Société française d’Immuno-Thérapies du Cancer); Non-Financial Interests, Ofﬁcer: ESMO Membership Committee, ESMO - MCBS Extended Working Group; NonFinancial Interests, Ofﬁcer, Young Investigators Committee at imCORE: inFLAME; Non-Financial Interests,Member of Board of Directors, Network of Early Phase Units: OncoDistinct; Non-Financial Interests,Leadership Role: FITC (Société française d’Immuno-Thérapies du Cancer). P. Fons, P. Ancey, L. Davenne,M. Mandron, M.R. Paillasse: Financial Interests, Personal, Full or part-time Employment: Evotec. P.

Cassier: Financial Interests, Personal, Advisory Board: Merck Serono/EMD, Roche, Amgen, Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Other,Advisor: OSE Immunotherapeutics; Financial Interests, Institutional, Local PI: AbbVie, Blueprint, Exelixis,GSK, Janssen, Novartis, Roche, Taiho, LOXO/Eli Lilly; Financial Interests, Institutional, Coordinating PI:Amgen; Non-Financial Interests, Institutional, Product Samples: Plexxikon, Novartis, MSD, AstraZeneca,GSK. J. Delord: Financial Interests, Institutional, Advisory Board: BMS, MSD, Pierre Fabre, Roche;Financial Interests, Institutional, Invited Speaker: Merck Serono; Non-Financial Interests, Institutional,Research Grant: Amgen, AstraZeneca, BMS, Genentech, MSD, Transgene. M. Fitzgerald, J. Friend:Financial Interests, Personal, Full or part-time Employment: kazia therapeutics. P. Rochaix: Financial Interests, Institutional, Training: Roche Diagnostic.

https://doi.org/10.1016/j.annonc.2023.09.2862

138P

CR/PR/SD toxicity o

Precision medicine phase II study evaluating the efﬁcacy of olaparib in patients with progressive solid cancers and

carriers of homologous recombination repair genes

alterations

M. Polito1, C. Le Tourneau2, A. DeMontfort1, S. Cousin3, M. Toulmonde3,C.A. Gomez-Roca4, K. Bourcier3, I. Korakis4, F. Bertucci5, E. Mitry5, C. Mazza3,P. Cassier1, C. Coutzac1, A. Italiano3, V.K. Attignon1, R. Mayet1, D. Perol1,

M.P. Sablin2, J-Y. Blay1, O. Tredan1

1Medical Oncology, Centre Léon Bérard, Lyon, France; 2Department of Drug Development and Innovation (D3i), Institut Curie, Paris, France; 3Medical Oncology Department, Institut Bergonie - Centre Régional de Lutte Contre le Cancer (CLCC),Bordeaux, France; 4Medical Oncology and Clinical Research Department, Institut Universitaire du Cancer -Toulouse- Oncopole, Toulouse, France; 5IPC - Institut PaoliCalmettes, Marseille, France

Background: The improved understanding of the biological mechanisms of the homologous recombination repair and the emergence of PARP inhibitors has opened new therapeutic options for patients with progressive cancers on standard treatments. The MOST study was designed to treat patients with metastatic solid tumors according to speciﬁc molecular alterations. We present here the results of the olaparib cohort.

Methods: The MOST trial is an ongoing multicenter, prospective, randomized study conducted in six French university hospitals. Patients known to have germline or somatic alterations in the homologous recombination genes received olaparib(300mg, BID) outside standard recommendations, until disease progression, unacceptable toxicity, patient’s or investigator’s decision. Disease response was evaluated at 12 weeks of treatment per RECIST criteria.

Results: Amongst the 213 included patients (63.4% female, median age: 58 years [26-85], median number of prior lines of treatment: 3 [1-16]) e.g. platinium 63%), the main initial tumor sites were breast (25.8%), pancreas (19.2%), colorectal (7.5%),sarcoma (6.1%) and brain (5.2%). Tumor response after 12 weeks (W12) according to main HRD genes altered (>5%) are presented in table. Patients with PALB2 mutations showed the best disease control rate. Grade 3 or higher adverse events were reported in 81 patients (38%).

/PD according to RECIST. Treatment discontinuation before W12 was due to r patient decision.

Conclusions: Overall, only a minority of patients beneﬁt from olaparib treatment after 12 weeks of treatment even though their tumor harbor HRD gene alterations, with a 3-month PFS rate of 23% (48/213). Translational research is ongoing to explore which genomic signature is associated with olaparib response.

Clinical trial identiﬁcation: NCT02029001.

Legal entity responsible for the study: Centre Léon Bérard, Lyon.

https://doi.org/10.1016/j.annonc.2023.09.2863

139P The characteristics in Chinese NSCLC patients with different BRAF mutation classes

Q. Wang1, D. Fu2, X. Li2, L. Zhang3, X. Dong4, F. Pang2

1Respiratory Medicine, The Second Afﬁliated Hospital of Nanjing Medical University,Nanjing, China; 2Medical Department, Shanghai OrigiMed Co., Ltd, Shanghai, China;3Operational Department, OrigiMed Shanghai Co., Ltd., Shanghai, China; 4Pathology and Production center, Shanghai OrigiMed Co., Ltd, Shanghai, China

Background: Compared with BRAF Class II and Class III mutations in non-small cell lung cancer (NSCLC), BRAF Class I mutations can be effectively targeted by inhibitors.

However, the characteristics of Chinese NSCLC with different BRAF mutation types are still unclear. Thus, the more comprehensive exploration of BRAF mutation proﬁle in Chinese NSCLC was investigated to guide the development of personalized treatment strategies.

Results: Within 3.5 years, 991 patients were enrolled within 14 countries in Europe,918 were evaluable, receiving a molecular proﬁle (92.60% success rate), with a median turn-around time of 13.25 days [range 11.5-17]. Molecular proﬁling was preferentially performed on FFPE material (FoundationOne, 73.5%), if not feasible, liquid biopsy was used as a rescue (FoundationOne Liquid, 26.5%). The 3 most common histotypes were cancer of unknown primary (CUP, 103, 11.2%), mesothelioma (80,

8.7%), cholangiocarcinoma (72, 7.8%). Clinically relevant molecular alterations were identiﬁed in 606 patients (66%), with top alterations seen in TP53 (28.5% of all enrolled patients), CDKN2A/B (16.8%), KRAS (9.2%). The TMB was above 10 for 53 patients (5.3%) and 9 MSI-high patients were identiﬁed. A differential proﬁle was seen between FFPE and blood analysis due to CHIP identiﬁcation (DNMT3A, MLL2,TET2 for example). Altogether, 456 patients (46%) received a therapy recommendation based on the molecular analysis: 63 (6.8%) patients for an already approved treatment (ESCAT 1A); 232 (25.3%) for an off-label use of an approved treatment in another indication with similar molecular alteration (ESCAT IC, II or III); and 161(17.5%) for a clinical trial. Response rate, duration of response and survival will be presented.

Conclusions: Close to 50% of patients with rare cancers received a therapeutic recommendation based on molecular characterization, a majority within clinical trials.

Molecular characterization should be recommended routinely for rare cancers in advanced phase.

Clinical trial identiﬁcation: SPECTA NCT02834884.

Legal entity responsible for the study: EORTC.

Funding: Hoffman-La Roche.

Disclosure: M. Morfouace: Financial Interests, Personal, Other, Employee: Merck Healthcare. J.

; Financial Interests, Personal, Invited Speaker, Lecture Presentation: Sevier pharma; Financial Interests, Personal, Invited Speaker, Invited Speaker, Writing Engagement: Baltmeda UAB; Financial Interests, Personal, Invited Speaker, Lecture, Speaker, Expert Testimony: Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker, Invited Speaker (chair of the season): Esmo; Financial Interests, Personal, Invited Speaker: Medison Pharma Lithuania;Financial Interests, Personal, Local PI, working in clinical trials: Novartis Pharma AG; Financial Interests, Personal and Institutional, Coordinating PI, Working with Clinical Trial: EORTC; Financial Interests, Personal, Local PI, working with clinical trial: Ergomed, AstraZeneca Lietuva UAB; Financial Interests, Personal, Steering Committee Member, SC member for ENGOT-EN10 clinical trial DUO-E:AstraZeneca; Financial Interests, Personal and Institutional, Local PI, Work with Clinical Trial: Labcorp Drug development; Financial Interests, Personal and Institutional, Local PI, Work with Clinical Trials:NSGO, PSI CRO AG; Non-Financial Interests, Member: Lithuanian Society of Oncologist; NonFinancial Interests Member, Member of Gynecological Cancer Group and Melanoma Group: EORTC;Non-Financial Interests, Member, member of NSGO and NSGO-CTU Scientiﬁc Committee Member:NSGO - Nordic Society of Gynecological oncology; Non-Financial Interests, Member: The society of Lithuanian medical oncologists; Non-Financial Interests, Member of ESMO and POWG of ESMO:ESMO; Other, Assoc. Prof position: Vilnius University of Lithuania Faculty of Medicine. L. L. Greillier:Financial Interests, Personal, Advisory Board: AbbVie, AstraZeneca, BMS, MSD, Novartis, Sanoﬁ,Takeda, Roche; Financial Interests, Personal, Invited Speaker: Lilly, Pﬁzer; Financial Interests, Institutional, Local PI: AstraZeneca, AbbVie, BMS, MSD, Novartis, Takeda, Pﬁzer, PharmaMar; Financial Interests, Institutional, Coordinating PI: Sanoﬁ; Financial Interests, Personal, Local PI: Roche. H.J.

Klumpen: Financial Interests, Institutional, Invited Speaker, Current Treatments of Cholangiocarcinoma: Medtalk; Financial Interests, Institutional, Invited Speaker, PODCAST on treatment of HCC: CCO; Financial Interests, Institutional, Advisory Board: Janssen, AstraZeneca; Financial Interests, Institutional, Local PI, IMBRAVE 050: ROCHE; Financial Interests, Institutional, Local PI, FIGHT 302: INCYTE; Financial Interests, Institutional, Local PI, LEAP 012: MSD; Financial Interests, Institutional, Local PI, TAS120: Taiho; Financial Interests, Institutional, Local PI, COMPETE, COMPOSE: ITM Solucin GmbH; Financial Interests, Institutional, Local PI, KEYNOTE 966: MSD; Financial Interests,Institutional, Local PI, COSMIC 312: Exelixis; Other, Subdomain leader G5.1: EURACAN; Other, In the Netherlands: Member National Guideline Committee For Biliary Tract Cancer; Other, in the Netherlands: Member of the National guideline committee for HCC. L.F.L. Licitra: Financial Interests,Personal, Advisory Board, for Expert Opinion in Advisory Boards: AstraZeneca, Bayer, BMS, Eisai,MSD, MerckeSerono, Boehringer Ingelheim, Hoffmann-La Roche Ltd, Novartis, Roche, Debiopharm International SA, Sobi, Incyte Biosciences Italy srl, Doxa Pharma srl, Amgen, Nanobiotics and GSK;Financial Interests, Institutional, Research Grant, Funds received by my institution for clinical studies and research activities in which I am involved: AstraZeneca, BMS, Boehringer Ingelheim, Celgene International, Eisai, Exelixis, Debiopharm International SA, Hoffmann-La Roche Ltd, IRX Therapeutics,Medpace, MerckeSerono, Merck Healthcare KGaA, MSD, Novartis, Pﬁzer, Roche, Buran. N. Girard:Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS, MSD, Roche, Pﬁzer, Mirati, Amgen,Novartis, Sanoﬁ, Gilead; Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, MSD,Roche, Pﬁzer, Janssen, Boehringer Ingelheim, Novartis, Sanoﬁ, AbbVie, Amgen, Lilly, Grunenthal,Takeda, Owkin, Leo Pharma, Daiichi Sankyo, Ipsen; Financial Interests, Institutional, Research Grant,Local: Roche, Sivan, Janssen; Financial Interests, Institutional, Funding: BMS, Leo Pharma; Financial Interests, Institutional, Research Grant: MSD; Non-Financial Interests, Ofﬁcer, International Thymic Malignancy Interest Group, President: ITMIG; Other, Family member is an employee: AstraZeneca.

J.A. Gietema: Financial Interests, Institutional, Research Grant, Research grant paid to the institution UMCG: Roche, Siemens, AbbVie. W. de Herder: Financial Interests, Personal, Advisory Board:Novartis, Ipsen; Financial Interests, Personal, Invited Speaker: Novartis, Ipsen; Non-Financial Interests, Leadership Role, Chairman EURACAN Domain 4 Rare Cancer of the Neuroendocrine System:EU. E. Kapiteijn: Financial Interests, Institutional, Advisory Board: BMS, Novartis, Pierre Fabre, Merck,Delcath, Bayer, Lilly; Financial Interests, Institutional, Coordinating PI: BMS, Pierre-Fabre, Delcath. A.

Methods: During the years 2021 and 2022, a total of 806 individuals who had a positive result from LDCT screening and underwent surgery or biopsy were included in the study. Plasma samples from these participants were analyzed for nucleosomes containing histone modiﬁcations including H3K27Me3, H3K36Me3, or the H3.1 histone tone isoform by quantitative immunoassay (Nu.Q, Belgian Volition SRL). Amongisoform by quantitative immunoassay (Nu.Q, Belgian Volition SRL). Among

these individuals, 648 were diagnosed with either lung cancer or a pre-cancerous Speaker: Nacionalinis mokymy centras VSJ; Financial Interests, Personal, Invited Speaker, Lecturelesion, while 158 were diagnosed with a benign lesion based on pathological reports.

Logistic regression was used to analyze the assay data, and a simple algorithm was developed to predict whether a nodule was benign or malignant. The algorithm was created using samples collected in 2021 (n¼561) as a training set and validated usingsamples collected in 2022 (n¼245).

Results: The plasma epigenetic nucleosome assay for detecting lung cancer showed a diagnostic sensitivity of 92% and a speciﬁcity of 82% using a simple regression algorithm, trained on data from the 2021 group. The AUC for differentiating between cancerous and benign nodules was 88%. When the assay was applied to data from 2022, it achieved an AUC of 77% for distinguishing between cancer and benign nodules, with a sensitivity of 60% and a speciﬁcity of 84%. The validation test revealed that the algorithm correctly identiﬁed patients with stage I cancer and carcinoma in situ in 58% and 61% of cases, respectively.

Conclusions: This large validation study indicates that the epigenetic nucleosome assay has predictive, diagnostic, and prognostic value and could reduce the falsepositive rate of LDCT.

Funding: Belgian Volition.

Disclosure: P. Chen: Financial Interests, Institutional, Funding: volition. D. Pamart, T. Bygott:Financial Interests, Personal, Full or part-time Employment: Volition. M. Herzog: Financial Interests,Personal, Full or part-time Employment: Belgian Volition; Financial Interests, Personal, Stocks/Shares: VolitionRx; Non-Financial Interests, Member: ASCO. J. Micallef: Financial Interests, Personal,Ofﬁcer, Chief Scientiﬁc Ofﬁcer: VolitionRx Ltd; Financial Interests, Personal, Stocks/Shares: VolitionRx Ltd. J. Chen: Financial Interests, Institutional, Local PI: Volition. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2858

134P TERT-associated DNA polymerases genes link CAF and CD8+T cells to improve immunotherapy response rate across multiple cancers

Z. Luo1, Y. Xie2, Y. Deng1, Y. Che3, X. Bi2, H. Zhao1, X. Bi1

1Department Of Hepatobiliary Surgery, Chinese Academy of Medical Sciences and Peking Union Medical College - National Cancer Center, Cancer Hospital, Beijing,China; 2Department of Urology, National Cancer Center - Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China; 3Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Background: Cancer cells exhibit heightened basal levels of responses to DNA breaks,accumulating DNA polymerases family (DNA-pol) as repair protein, thereby increasing DNA mutation and neoantigens. Based on this, we investigated the potential of DNApol as an immunotherapy biomarker and its underlying mechanism.

Methods:We conducted a pan-cancer analysis of DNA-pol gene dysregulation in 6366 samples. Normal ﬁbroblast, cancer-associated ﬁbroblast, and CD8+ T cells were cultured from cancer patients (3 esophagus, 5 lung, 5 renal, and 3 liver cancer), then treated them with PD-L1 inhibitor or overexpressing TERT for RNA-seq and proteomics. 996 multiple cancer cases with ICIs were collected to test biomarker efﬁciency.

A phase II clinical trial is evaluating our biomarker prospectively.

Results:We deﬁned a distinct signature score of DNA-pol genes upregulated in cancer(DNA-pol-up) and linked to worse prognosis (HR¼1.2). DNA-pol-up program dysre-gulation led to immune processes alteration and was related to upstream activation of TERT signaling (z-score¼3.6) in ingenuity pathway analysis and linked to immu-nologically active tumors by recruiting CD8+ T cell and downregulating CAF. DNA-polup score was elevated in PD-L1-treated CAF and TERT-overexpressed CD8+ T cell, in MSI-H cancer, also related to more neoepitope peptides, TMB (Rho¼0.54), cancerstemness (Rho¼0.78), and tumor purity (Rho¼0.29). Cancers that activate this pro-gram carried distinct genomic proﬁles with PIK3CA, KRAS, and TP53 mutations. This signature was an independent predictor for ICIs response (OR¼2.52), even out-performing cytolytic activity, MSI, TMB (OR¼0.9). In 12 clinical trial datasets, thissignature could stratify the responding patients (maxAUC¼0.762). In our phase IIclinical trial, 34 liver cancer were enrolled with 3-year follow-up, it also has a satisfactory performance in predicting the ORR (AUC¼0.699) and classiﬁes mortality rate(HR¼2.3).

Conclusions: Our ﬁndings identify a distinct transcriptional pattern of DNA-pol genes across cancers, which highlighted the role of DNA-pol family genes in predicting the immunotherapy response for the ﬁrst time, and TERT could be a novel vaccine candidate for improving immunotherapy response.

Legal entity responsible for the study: X. Bi, H. Zhao, Z. Luo.

Funding: Zhiwen Luo was awarded a funding for research in Israel (China Scholarship Council No. 202106210312). CAMS Innovation Fund for Medical Sciences (CIFMS)(2021-I2M-C&T-B-043, 2021-I2M-C&T-B-052); Beijing CSCO Clinical Oncology Research Foundation (Y-XD202001-0111, Y-2019AZMS-0082, Y-XD202002-0370).

https://doi.org/10.1016/j.annonc.2023.09.2859

135P

The lymphocyte stability index (LSI) forms a pan-cancer peripheral biomarker for overall survival post initiation of immune checkpoint blockade (ICB)

R.A. Watson1, O. Tong1, C. Taylor1, G. Vallance2, F. Matos Santo1, M. Little3, B. Sun4,B. Shine5, M.R. Middleton2, N.A. Coupe2, M. Payne2, B.P. Fairfax1

1Department of Oncology, The MRC Weatherall Institute of Molecular Medicine Oxford, Oxford, UK; 2Oncology and Haematology, Oxford University Hospitals NHS Foundation Trust - Churchill Hospital, Oxford, UK; 3Medical Oncology, Churchill Hospital - Oxford University Hospitals NHS Foundation Trust, Oxford, UK; 4Nufﬁeld Department of Clinical Neuroscience, John Radcliffe Hospital University of Oxford,Oxford, UK; 5Clinical Biochemistry, John Radcliffe Hospital University of Oxford, Oxford,UK

Background: Robust, pan-cancer peripheral blood biomarkers for response to immune checkpoint blockade (ICB) are lacking. We have previously shown that a single

nucleotide polymorphism at rs16906115 (intronic to IL7) associates with increasedported in 19 (79%) of the 24 pts enrolled. Grade ≥3 treatment-related AEs occurredrisk of ICB toxicity, but promotes increased lymphocyte count stability post-initiation of treatment. Individuals with a stable lymphocyte count had improved progressionfree (PFS) and overall survival (OS) in metastatic melanoma (MM). We hypothesise

that the Lymphocyte Stability Index (LSI) can predict outcome to ICB across a range of

cancers.

Methods: We retrospectively collected treatment, blood count and survival data on

all individuals treated with ICB since 2014 at Oxford University Hospitals NHS Foundation Trust (n¼706). We performed survival analysis based on lymphocyte stability.The LSI was calculated by dividing the post-treatment lymphocyte count by the pretreatment count.

Results: Using a replication cohort, we validated our previous ﬁnding that patients

with stable LSI (>0.8) had signiﬁcantly improved overall survival in MM. This was also

the case for those with stable LSI and a diagnosis of non-small cell lung cancer

(NSCLC) or metastatic renal cell carcinoma (mRCC) with previous pre-treatment. Using

a Cox proportional hazards model to control for a range of covariates including age

and number of prior treatments, a stable LSI was associated with a hazard ratio for

death of 0.38 (95% CI: 0.26-0.56, p<0.0001) for MM (combined cohorts), 0.49 (95%

CI: 0.33-0.77, p<0.001) for NSCLC and 0.33 (95% CI: 0.14-0.89, p¼0.013) for pre-treated mRCC. Patients with MM and stable LSI treated with single-agent PD-1

blockade had equivalent survival to those treated with combination ICB.

Conclusions: The LSI is an extremely simple dynamic peripheral biomarker for survival

following ICB treatment across multiple cancers with an underlying molecular and

genetic association. Application of LSI in MM permits effective patient stratiﬁcation,

delineating those who single-agent ICB provides equivalent beneﬁt to combination

anti-PD1 and anti-CTLA-4 treatment, potentially sparing them of the associated

toxicity burden.

Funding: The Wellcome Trust, Cancer Research UK, National Institute for Health

Research.

https://doi.org/10.1016/j.annonc.2023.09.2860

136P Pembrolizumab in patients of Chinese descent with microsatellite instability-high/mismatch repair deﬁcient advanced solid tumors: KEYNOTE-158

Y. Mao1, X. Wu2, N. Xu3, Y. Bai4, D. Wang5, X. Chen6, X. Yin7, Y. Deng8, J. Yang9,J. Zhang10, J. Tang11, Y. Huang12, J. Li13, M. Xu14, N. Li15, Y. Mao16, A. Gozman17,J. Xu18

1Gastroenterology, Renji Hospital Shanghai Jiaotong University School of Medicine,Shanghai, China; 2Gynecologic Oncology, Fudan University Shanghai Cancer Center,Shanghai, China; 3Medical Oncology Department, The First Afﬁliated Hospital of Medical School of Zhejiang University, Hangzhou, China; 4Nangang, Harbin Medical University Cancer Hospital, Harbin, China; 5Gynecologic Oncology, Chongqing University Cancer Hospital, Chongqing, China; 6Gynecologic Oncology, Obstetrics & Gynecology Hospital of Fudan University, Shanghai, China; 7Gastroenterology and Urology, Hunan Cancer Hospital, Changsha, China; 8Clinical Oncology, The Sixth Afﬁliated Hospital, Sun Yat-sen University, Guangzhou, China; 9Clinical Oncology,Fujian Provincial Cancer Hospital, Fuzhou, China; 10Gynecologic Oncology, Afﬁliated Cancer Hospital of Guangxi Medical University, Nanning, China; 11Gynecologic Oncology, Hunan Cancer Hospital, Changsha, China; 12Gynaecologic Oncology, Hubei Cancer Hospital, Wuhan, China; 13Medical Oncology, The First Afﬁliated Hospital of Xiamen University, Xiamen, China; 14Clinical Research, MSD (China) Co., Ltd., Beijing,China; 15Statistics, MSD (China) Co., Ltd., Beijing, China; 16Clinical Research, MSD(China) Co., Ltd., Shanghai, China; 17Clinical Research - Oncology, Merck & Co., Inc.,Rahway, NJ, USA; 18Gastrointestinal Oncology, The Fifth Medical Center of Chinese People’s Liberation Army General Hospital, Beijing, China

Background: The multicohort KEYNOTE-158 (NCT02628067) trial supported the US FDA and EMA approval of pembrolizumab across multiple microsatellite instabilityhigh (MSI-H)/mismatch repair deﬁcient (dMMR) advanced solid tumors. The incidence of MSI-H/dMMR advanced cancer in patients (pts) of Chinese descent is similar to that reported in Western populations (Liu et al 2019, Cancer Research 79:616). In

cohort L of KEYNOTE-158, we evaluated the efﬁcacy and safety of pembrolizumab in pts of Chinese descent with MSI-H/dMMR solid tumors.

Methods: In this nonrandomized, phase 2, open-label trial, pts aged 18 years Methods: In this nonrandomized, phase 2, open-label trial, pts aged ≥ 18 years ofofChinese descent were enrolled. These pts had to have conﬁrmed MSI-H/dMMR unresectable or metastatic cancers who had 1 prior lines of therapy. Eligible unresectable or metastatic cancers who had ≥1 prior lines of therapy. Eligible ptsptsreceived 200 mg pembrolizumab Q3W for up to 35 cycles, until progression, unacceptable toxicity, or pt/investigator withdrawal. MSI-H/dMMR status was assessed centrally by PCR or ICH. The primary endpoint was ORR per RECIST 1.1 by independent central review. Secondary endpoints were DOR, PFS, OS and safety. The database cut-off date was July 26, 2022.

Results: At data cut-off, a total of 24 pts were enrolled of which 20 pts were for efﬁcacy evaluation having at least 6 months (mo) of follow-up. The overall ORR was

70.0% (95% CI: 45.7%- 88.1%) for the 20 pts. The median DOR was not reached (NR)(range, 2.1+ - 19.3+) with a 12-mo DOR rate of 85.7%. Median PFS was NR (95% CI:

15.8-NR) with an 18-mo PFS rate of 68.0%. The median OS was NR (95% CI: 9.5, NR)with an 18-mo OS rate of 80.2%. Treatment-related adverse events (AE) were reported in 19 (79%) of the 24 pts enrolled. Grade 3 treatment-related AEs occurredin 4 (17%) pts with no grade 5 AEs. Immune-mediated AEs occurred in 8 pts (33%). Of these pts, 2 (8%) had grade 3 AEs (myositis or rash in 1 pt each). No grade 4 or 5 immune-mediated AEs occurred.

Conclusions: Pembrolizumab provided clinically meaningful antitumor activity and durable responses in pts of Chinese descent with MSI-H/dMMR tumors, with a manageable safety proﬁle. No new safety signals were identiﬁed. These results are consistent with those reported for patients in the global population.

Clinical trial identiﬁcation: NCT02628067; ﬁrst posted on December 11, 2015.

Editorial acknowledgement: Editorial assistance provided by Jose Casasnovas Nieves,PhD, an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.,Rahway, NJ, USA.

Oliveira: Financial Interests, Personal, Other, Advisory board, Invited Speaker: AstraZeneca, Roche,Novartis, Janssen; Financial Interests, Personal, Invited Speaker: GSK, BMS, MSD, Bayer; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Institutional, Funding, Investigator Initiated Clinical Trial funding: AstraZeneca. B. Brasiuniene: Financial Interests, Personal, Other,lecture, advisory board, publications, expert testimony; reimbursement of travel expenses: sia ;Financial Interests, Personal, Writing Engagement, editor work in the local journal: UAB; Financial Interests, Personal, Advisory Board, lecture - speaker, expert testimony; reimbursement of travel expenses: AstraZeneca Lietuva UAB; Financial Interests, Personal, Invited Speaker, lecture-speaker:Merck Serono UAB; Financial Interests, Personal, Advisory Board, lecture-speaker, writing engagement, expert testimony: ElI Lilly Lietuva UAB; Financial Interests, Personal, Advisory Board, Meeting,

S233

Conference, Scientiﬁc Programme Organization, Search for the Speakers, Chair of The Meeting,Speaker: Nacionalinis mokymu

centras VSIÎ

Idbaih: Financial Interests, Personal, Advisory Board, Advisory board: Novocure, Leo Pharma,Boehringer Ingelheim, Novartis; Financial Interests, Institutional, Local PI, Clinical research: Enterome, Bristol Myers Squibb; Financial Interests, Institutional, Coordinating PI, Clinical research:Carthera; Financial Interests, Institutional, Local PI, Basic/Translational research: Carthera; Financial Interests, Institutional, Local PI, Basic and Translational research: Sanoﬁ, Nutrithéragène, Servier,Transgene; Other, Travel Funding: Carthera, Leo Pharma, Novocure, Enterome. I.L. Ray-Coquard:Financial Interests, Personal, Advisory Board: Roche, GSK, AstraZeneca, Mersana, Deciphera, Amgen,Oxnea, Merck Sereno, Agenus, Novartis, Macrogenics, Clovis, EQRX, Adaptimmune, Eisai, SUTRO,BMS, Adaptimmune, Daiichi Sankyo; Financial Interests, Institutional, Other, COLIBRI translational research: BMS; Financial Interests, Institutional, Advisory Board, translational research NEOPREMBROV trial: MSD; Non-Financial Interests, Principal Investigator: PAOLA1; Non-Financial Interests, Other, President: GINECO. J. Blay: Financial Interests, Personal, Advisory Board: Bayer,Deciphera, GSK, Roche; Financial Interests, Personal, Invited Speaker: PharmaMar; Financial Interests, Institutional, Invited Speaker: MSD, MSD; Financial Interests, Personal, Other, Member of The Supervisory Board: Innate Pharma; Financial Interests, Institutional, Funding: MSD, BMS,Deciphera; Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, Bayer, GSK,Novartis, OSE pharma. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2857

133MO

Differentiation of malignant and benign lung nodules using epigenetically modiﬁed nucleosomes in plasma

P-H. Chen1, T-M. Tsai2, D. Pamart3, T. Bygott3, M. Herzog3, J. Micallef3, J-S. Chen2

1Surgery, National Taiwan University Hospital Hsin - Chu Branch, Hsinchu City, Taiwan;2Surgical Oncology, NTUCC - National Taiwan University Cancer Center, Taipei, Taiwan;3Research and Development, Belgian Volition SRL, Isnes, Belgium

Background: Recent lung cancer screening trials indicate that low-dose computed tomography (LDCT) has been successful in reducing mortality in high-risk patients.

Nonetheless, the high frequency of false-positives leads to expense and possible harm, emphasizing the necessity for complementary biomarkers. To address this, we aimed to enhance the accuracy of lung cancer screening by utilizing a lung cancerspeciﬁc immunoassay panel for epigenetically modiﬁed nucleosomes in plasma to help differentiate between benign and malignant nodules.

Methods: Data was collected on a total of 2,030 cases of NSCLC throughout China between October 2018 and October 2021. Next Generation Sequencing (NGS) is based on the sequencing of tissue samples on the YUANSUTMpanel (OrigiMed,Shanghai, China) with 706 cancer-related genes. Wilcoxon Rank Sum Test were applied to signiﬁcance statistics.

Results: Among the samples, BRAF mutations were detected in 82 cases (4.0%, 82/2030), including 19 Class I (0.9%, 19/2030, V600E), 13 Class II (0.6%, 13/2030, K601E,L597R/Q, G464V, G469A/V), and 11 cases Class III (0.5%, 11/2030, G466A/E, N581I,D594G/N). In addition, 39 cases (1.9%, 39/2030) remained unclassiﬁed: 22 (1.0%, 22/2030) with potential signiﬁcance. The BRAF mutations were more commonly observed in primary tumors (p¼0.066) and the Class I mutations were more prevalentin female patients (63.2%, 12/19, p¼0.005). In addition, the median TMB (7.21 mut/Mb) of Class I mutations tumor was signiﬁcantly lower than that of Class II mutations(median TMB ¼12.69 mut/Mb), III mutations (median TMB ¼22.32 mut/Mb) andunclassiﬁed BRAF mutations (median TMB ¼10.33 mut/Mb)(p ¼ 0.033), implying thatthe patients with Class I mutations may not be suitable for immunotherapy compared with patients with Class II and III mutations. Furthermore, TP53, LRP1B, STK11,SPTA1and MAGI2 were signiﬁcantly over-mutated in Class II and III (p<0.06) and SETD2 is over-mutated in Class I (p<0.001), might suggesting relatively poor prognosis in NSCLC patients.

Conclusions: The characteristics of Chinese NSCLC were further explored, including BRAF mutation types, the incidence of related co-mutations and TMB value, which is helpful to formulate targeted therapy strategies to adapt to different types of BRAF mutation functions according to their genomic and clinical characteristics.

Legal entity responsible for the study: OrigiMed Inc.

Funding: OrigiMed Inc.

https://doi.org/10.1016/j.annonc.2023.09.2864

140P Colorectal adenoma subtypes exhibit distinct molecular proﬁles- implications to early detection

F.M. Mancuso1, P. Canal Noguer1, K. Kruusmaa2

1R&D Department, Universal Diagnostics S.A., Seville, Spain; 2R&D Department, Universal Diagnostics d.o.o., Ljubljana, Slovenia

|Table:138P Tumor status at week 12 for the main molecular alterations (>5%) |Table:138P Tumor status at week 12 for the main molecular alterations (>5%) |Table:138P Tumor status at week 12 for the main molecular alterations (>5%) |Table:138P Tumor status at week 12 for the main molecular alterations (>5%) |Table:138P Tumor status at week 12 for the main molecular alterations (>5%) | |---|---|---|---|---|

|Tumorstatus CR |or PR SD ||PD discontinuation |Treatment |

|All patients (n¼213) |n¼14 (6%) n ¼34 |(16%) |n¼161 (76%) n¼4 |(2%) |

|Gene altered, N (% of |population) ||||

|BRCA1, N ¼ 26 (12.2%) 0 |(0.0%) 3 |(11.5%) |23 (88.5%) 0 |(0.0%) |

|BRCA2N¼ 49 (23%) 8 |(16.3%) 5 |(10.2%) |36 (73.5%) 0 |(0.0%) |

|PALB2N¼ 15 (7%) 4 |(26.6%) 2 |(13.3%) |8 (53.3%) 1 |(6.6%) |

|ATM N¼ 49 (23%) 1 |(2%) 11 |(22.4%) |37 (75.5%) 0 |(0.0%) |

|BAP1 N¼ 14 (6.6%) 1 |(7.1%) 3 |(21.4%) |10 (71.4%) 0 |(0.0%) |

Background: Colorectal adenomas (AA) are pre-cursors for 85% of the cancers.

Methylation and copy-number alterations are well described in colorectal cancer(CRC) context. We aimed to investigate these signals on AA sub-types.

Methods: Whole-genome Enzymatic Sequencing was performed on advanced adenoma (AA) and adjacent control (CNT) tissues of serrated (14), tubular (26), tubulovillous (24) and villous (10) patient samples, alongside colorectal cancer (CRC) stage I samples (23). Differential methylation analysis pipeline was applied, ﬁrst to identify regions that are signiﬁcantly altered between all AA subgroups and CNT tissue and then further investigated for sub-type and CRC I level differences. Additionally, mutation and copy-number alteration (CNA) detection were performed, alongside pathway enrichment.

Results: Initial differential methylation analysis revealed 7725 regions signiﬁcantly altered between AA and CNT tissue. 137 and 2093 and 91 of those were

hypermethylated between serrated vs tubular, serrated vs tubulovillous, tubular vs tubulovillous sub-types respectively. Main pathways, differentiating serrated adenomas from the rest, belong to cAMP signalling, regulation of pluripotency of stem cells, while regions separating tubular and tubulovillous were enriched for WNT signalling. These differential signals could not be seen in stage I CRC samples, which presented CNT-like methylation. The CNA signals were mostly present in tubular or tubulovillous samples. The most frequent signals could be seen in chr7, 12, 19 and 20.

Majority of CRC I exhibited CNA in chr 7, 8 and 20, indicating difference processes to be in place between AA and CRC I progression. Differences could also be observed on sub-type level, when looking at tumour mutational burden and speciﬁc mutations in APC and KRAS genes.

Conclusions: Colorectal adenoma histological subtypes show distinctly different methylation, CNA and mutational signals, between groups and compared CRC I. Theseﬁndings are especially important when developing early detection or cancer prevention tests trying to capture adenoma (sub-type level) signatures. These results have been followed by plasma-based biomarker detection studies for pre-cancer screening intent.

Legal entity responsible for the study: Universal Diagnostics S.A.

Funding: Universal Diagnostics S.A.

Disclosure: F.M. Mancuso, P. Canal Noguer, K. Kruusmaa: Financial Interests, Personal, Full or parttime Employment: Universal Diagnostics.

https://doi.org/10.1016/j.annonc.2023.09.2865

141P

Microsatellite instability and its relationship with systemic inﬂammation as prognostic factors in localised colorectal cancer

J.H. Yeo1, J.H. Park2, H.K. Ahn3, I. Park4, Y.S. Kim5, E.K. Cho2, D. Shin3, W-S. Lee6,J.H. Baek7, S.J. Sym8

1Hemato-Oncology, Hanyang University College of Medicine, Myongji Hospital,Goyang, Republic of Korea; 2Internal Medicine, Gachon University Gil Hospital,Incheon, Republic of Korea; 3Medical Oncology, Gachon University Gil Hospital,Incheon, Republic of Korea; 4Medical Oncology, Asan Medical Center - University of Ulsan, Seoul, Republic of Korea; 5Internal Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon, Republic of Korea; 6Colon and Rectal Surgery, Gil Medical Center, Gachon University College of Medicine, Incheon, Republic of Korea;7Colon and Rectal Surgery, Gachon University Gil Hospital, Incheon, Republic of Korea;8Medical Oncology & Internal Medicine Dept., Gachon University Gil Hospital,Incheon, Republic of Korea

Background: Microsatellite instability-high (MSI-H) is a well-known favorable prognostic marker in localized colorectal cancer (CRC) patients, mainly due to local antitumor immunity of cytotoxic T cells. The tumor-induced systemic inﬂammation is also proven to be responsible for pro-tumor immunity. Despite the importance of tumor microenvironment, the relationships between MSI status, systemic inﬂammation, and their prognostic effects in CRC patients have not been widely studied.

Methods: We retrospectively analyzed a total of 1130 patients who had diagnosed as stage I to III CRC and had surgical resection from Jan 2007 to Oct 2016 at Gil Medical Center in South Korea. MSI status was evaluated by polymerase-chain reaction (PCR)of mononucleotide repeats. Neutrophil-lymphocyte ratio (NLR), from the blood cell count drawn before any treatment, was used to represent systemic inﬂammation.

Univariable and multivariable analysis were performed with Cox’s proportional hazard model to identify prognostic factors in localized CRC patients.

Results: Among 1130 patients of stage I to III CRC, 84 (7.4%) patients had MSI-H CRC,and the majority of MSI-H CRCs were found in stage II patients (12.2%, n¼46/378).MSI-H was signiﬁcantly associated with high NLR (20.2% vs 7.4%, p<0.001) as well as right-sided (67.4% vs 20.9%, p<0.001), poorly differentiated (17.4% vs 2.8%,p<0.001), less perineural invasion (11.6% vs 22.4%, p¼0.020), and low BMI (5.8% vs14.3%, p¼0.028). Combining MSI and NLR, MSS/NLR5 group showed worst PFS 14.3%, p=0.028). Combining MSI and NLR, MSS/NLR≥5 group showed worst PFS andandOS OS consistently throughout stage I to III(p=0.017).Interestingly,MSI-H/NLR≥5 groupconsistently throughout stage I to III (p¼0.017). Interestingly, MSI-H/NLR5 groupshowed worse PFS and OS than MSS/NLR<5 group in stage II patients (p¼0.006). Inmultivariable analysis, MSS/NLR5 group was related signiﬁcantly with poor PFS multivariable analysis, MSS/NLR≥5 group was related significantly with poor PFS (HR(HR4.19, 95% CI 1.37-12.83, p¼0.012), and showed a trend toward poor OS (HR 4.42,95% CI 0.84-23.11, p¼0.079).

Conclusions: MSI-H was signiﬁcantly associated with high NLR, and its prognostic effect outweighed that of MSI-H, especially in stage II CRC. Therefore, we should consider more about factors of tumor microenvironment such as high NLR, as one of criteria to classify high-risk stage II CRC, which needs adjuvant chemotherapy.

https://doi.org/10.1016/j.annonc.2023.09.2866

142P Correlating total tumor volume on CT-Scan and liquid biopsy ctDNA in 1017 patients with metastatic cancer: A novel study

Y. Belkouchi1, L. Dawi2, L. Lawrance3, S. Ammari3, D. Vasseur4, F.Wirth2, O. Gautier2,P-H. Cournede3, J. Hadchiti2, C. David2, F. Bidault2, C. Balleyguier5, M. Kind6,

H. Talbot7, A. Italiano8, N. Lassau9

1OPIS Inria, CentraleSupélec - Paris-Saclay Campus, Gif Sur Yvette, France; 2Imaging,Gustave Roussy, Paris, France; 3Imaging, Gustave Roussy - Cancer Campus, Villejuif,France; 4Molecular Biology, Gustave Roussy - Cancer Campus, Villejuif, France; 5Imaging, Institut Gustave Roussy, Villejuif, France; 6Imaging, Institut Bergonie, Bordeaux,France; 7Imaging, CentraleSupélec - Paris-Saclay campus, Gif Sur Yvette, France; 8Early Phase Trials Unit, Institute Bergonié, Bordeaux, France; 9Gustave Roussy - Cancer Campus, Villejuif, France

Background: Liquid biopsy is an emerging technology capable of detecting cancer,while CT-imaging is the gold standard. We aim to correlate imaging features from CTscans to liquid biopsy ctDNA tumor fraction (TF) and blood Tumor Mutational Burden(bTMB).

Methods: This retrospective multicentric study included 1017 patients with metastatic cancer who underwent a variety of treatments. Liquid biopsy and contemporaneous CT-scans were collected. TF and bTMB values were computed using FoundationOne Liquid CDX solution by Roche, with high tumor fraction being over 10%. Two expert radiologists outlined all cancerous lesions in the largest axial diameter. Total tumor volume (TTV) was deﬁned as the sum of estimated lesion volumes. Training set consisted of data from several imaging centers, while the validation set was single-center. Continuous value distributions by category were tested using the Mann-Whitney U-test, and a threshold was set with ROC curve analysis using Youden’s Index. This cutoff deﬁned high and low groups, and a X2test of independence was used to examine the correlation. Sensitivity and speciﬁcity were reported with imaging features taken as the gold standard. Subanalyses were run on patients with liver lesions.

Results: Overall, 55294 lesions were annotated, most commonly located in the lung(n¼20074), liver (n¼11297) and lymph nodes (n¼10222). The train and validationsets included 599 and 418 patients. Preliminary analyses were performed on the train set. Patients with low TF had signiﬁcantly less TTV than those with high TF (p<0.001).

ROC analysis yielded an AUC of 0.63 with a threshold of 106 cm3. Correlation was signiﬁcant between TTV and TF categories (X2test: p<0.001). The sensitivity and speciﬁcity were 76% and 42%. For patients with liver lesions (n¼253) , TTV thresholdwas 108 cm3 with an AUC of 0.66. Correlation was signiﬁcant between TTV and TF categories (X2test: p<0.001). The sensitivity and speciﬁcity were 82% and 42%.

Conclusions: Analysis showed signiﬁcant correlation between TTV and ctDNA TF.

Sensitivity was higher for patients with liver lesions, suggesting that some organs shed tumoral DNA more than others. The study of tumor heterogeneity on imaging and its correlation to bTMB is in progress.

https://doi.org/10.1016/j.annonc.2023.09.2867

143P Is liquid biopsy a good tool for microsatellite instability(MSI) assessment in solid tumors?

J.E. Rodriguez1, K. Beshiri1, D. Vasseur2, A. Bayle1, P. Cascetta3, A. Patrikidou3,M.V. Sanchez Becerra3, M. Tagliamento3, M. Aldea3, L. Zullo3, J.T.M.L. Ribeiro4,M. Sakkal1, K. Ouali1, C. Parisi1, A. Hollebecque1, O. Cabaret5, E. Rouleau5,L. Lacroix5, A. Italiano1, C. Smolenschi1

1Drug Development Department (DITEP), Gustave Roussy - Cancer Campus, Villejuif,France; 2Molecular Biology, Gustave Roussy - Cancer Campus, Villejuif, France;3Medical Oncology Department, Institut Gustave Roussy, Villejuif, France; 4Breast Unit,Gustave Roussy - Cancer Campus, Villejuif, France; 5Medical Biology and Pathology Department, Gustave Roussy - Cancer Campus, Villejuif, France

Background:Within the last decade, immunotherapy revolutionized cancer treatment and patients (pts) prognosis. MSI is a validated biomarker of response to immune checkpoint blockers (ICB). In daily practice, Immunohistochemistry (IHC) and polymerase chain reaction (PCR) are the most recommended techniques for MSI detection. Lately, next generation sequencing (NGS) performed on liquid biopsy emerged as a new tool for MSI detection and can be used as an alternative to IHC/PCR analysis on tissue. We aim to describe the characteristics of a cohort of pts with MSI solid tumors detected by liquid biopsy and to evaluate the concordance with IHC and NGS testing.

Methods: Data was collected from medical records and molecular proﬁle reports(Foundation One Liquid CDx Assay e 324 genes) performed within the STING trial(NCT04932525) between June 2021 and April 2023.

Results: Among 4535 pts who underwent liquid biopsies, we found 1.5% (n¼70 ) ptswith a MSI positive status. The main characteristics were: 51% (n¼36) were male witha median age of 68 years [32-89]. 24% of pts (n¼17) had a known Lynch Syndrome.Most common tumor locations were colorectal (23%) and endometrial (16%). Median tumor fraction was 26% [10%-73%] and median tumor mutational burden (TMB) 113

S237

mut/Mb [4-1450]. 40% (n¼28) of pts had MSI positive tumor assessed by IHC and55% (n¼39) by NGS, with a concordance of 41%. A proportion of 58% (n¼41)received ICB for advanced disease; pembrolizumab was the most frequent ICB

administered and 66% (n¼27) had received a median of 3 [1-8] prior lines of cytotoxicdrugs. Median progression free survival (PFS) for concordant MSI status was 25

months (m) vs 9 m for non-concordant MSI (p¼0.03), respectively.

Conclusions: MSI concordance on liquid biopsy with MSI on tumor were considerably

lower than reported in the literature. However, PFS was better in pts with a

concordant status than those with either MSI/IHC or MSI/NGS alone or in tissue.

Disclosure: A. Hollebecque: Financial Interests, Personal, Invited Speaker: Servier, Incyte, Eisai;

Financial Interests, Personal, Advisory Board: Basilea, Tahio, Relay Theraeutics, QED Therapeutics,

Debiopharm, MSD, Boehringer Ingelheim; Financial Interests, Institutional, Funding: Incyte; Financial

Interests, Institutional, Research Grant: AstraZeneca; Non-Financial Interests, Principal Investigator,

M19-345: AbbVie; Non-Financial Interests, Principal Investigator, CO42216; WP42627; CO40939:

Roche; Non-Financial Interests, Principal Investigator, MCLA-158: Merus; Non-Financial Interests,

Principal Investigator, SGNB6A: Seatle Genetics; Non-Financial Interests, Principal Investigator, TAS120-202: Tahio; Non-Financial Interests, Principal Investigator, Krystal-10: Mirati; Non-Financial Interests, Principal Investigator, ADP-0033: Adaptimmune; Non-Financial Interests, Principal Investigator, ACT16902: Sanoﬁ; Non-Financial Interests, Principal Investigator, C4201002: Pﬁzer; NonFinancial Interests, Principal Investigator, RLY-4008: Relay Therapeutics; Non-Financial Interests,

Principal Investigator, CC-90011: Celgene/BMS; Non-Financial Interests, Principal Investigator, LoxoIDH: Loxo/Lilly; Non-Financial Interests, Principal Investigator: AstraZeneca; Non-Financial Interests,OncoKEM by confronting its results with the findings obtained through a standard Principal Investigator, SN-201 study: Sotio; Non-Financial Interests, Principal Investigator, Tropics-03:

Gilead; Non-Financial Interests, Principal Investigator, BI1403: Boehringer Ingelheim. A. Italiano:

Financial Interests, Personal, Advisory Board: Bayer, Roche, Philips, Chugai, GSK; Financial Interests,

Institutional, Coordinating PI: Bayer, AstraZeneca, Roche, MSD, Ipsen, Merck. All other authors have

declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2868

144P

Artiﬁcial intelligence supported treatment decisions for precision oncology

D.T. Rieke1, X. Wang2, M. Schmidt1, D. Soll1, G. Hilfenhaus1, M. Nassir1, C. Sigler1,M. Knoedler1, U. Keilholz1, U. Leser2, M. Benary3

1Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, Berlin,Germany; 2Wissensmanagement in der Bioinformatik, Humboldt-Universität zu Berlin,Berlin, Germany; 3Core Unit Bioinformatics/Comprehensive Cancer Center, Charité -Universitätsmedizin Berlin, Berlin, Germany

Background: Clinical interpretation of complex biomarkers for personalized treatment

decisions requires extensive manual investigations of literature and databases. Recent

progress in artiﬁcial intelligence (AI) and conversational large language models (LLM)

suggests that these might be useful for assisting with automated screening and

integration of large biomedical datasets. To better deﬁne their role in this application,

we investigated several recent LLM as a support tool for precision oncology.

Methods: We generated ten ﬁctional cases of patients with advanced cancers and

genetic alterations. Each of the cases was submitted to four LLM (ChatGPT, Galactica,

Perplexity, BioMedLM) and one physician as expert human annotator to identify

personalized treatment options (TO). TO were blinded and presented to a molecular

tumor board (MTB) if they were a) identiﬁed by a human, b) identiﬁed by more than

one LLM or c) identiﬁed by a LLM and associated with clinical evidence. MTB

members were asked to rate the likelihood of TO to come from an AI on a scale from

0 to 10 (0 extremely unlikely, 10 extremely likely) and to rate their usefulness.

Results: A median number of 4 and 3, 7.5, 11.5, and 13 TO per patient were identiﬁed

by the human expert and four LLM, respectively. When considering the expert as gold

standard, the four LLM reached median F1 scores of 0.04, 0.17, 0.14, and 0.19 over all

patients combined. Combined TO by LLM reached a precision of 0.29 and a recall of

0.29 for a F1 score of 0.29 over all patients. When rated for recognizability as AIgenerated, LLM-generated TO achieved a median of 8 (range 1 to 10) in contrast to 2

points (range 0 to 6) for manually annotated cases. At least one LLM-generated TO

per patient was generally considered useful by MTB members. Two unique useful TO

(including one unique treatment strategy) were identiﬁed only by a LLM.

Conclusions: Treatment recommendations of LLM in PO cases do not yet reach the

quality and credibility of human experts. However, they can already generate useful

ideas. Considering the speed of technological progress, LLM could increasingly assist

with the screening and selection of relevant biomedical literature to support evidence-based, personalized treatment decisions.

Disclosure: D.T. Rieke: Financial Interests, Personal, Advisory Board: Bayer, Alacris Theranostics;involving a smaller set of genes. In this study, we used KEM (Knowledge ExtractionFinancial Interests, Personal, Invited Speaker: Roche, BMS, Lilly; Non-Financial Interests, Principal Investigator: Bayer. M. Schmidt: Financial Interests, Personal, Advisory Role: Mika-Health. U. Keilholz:

Financial Interests, Personal, Other: Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Glycotope,

Innate, Lilly, MedImmune, Merck Serono, MSD, Novartis, Pﬁzer, Roche, Sirtex. All other authors have

https://doi.org/10.1016/j.annonc.2023.09.2869

145P Identiﬁcation of biomarkers of survival across multiple cancer types using eXplainable artiﬁcial intelligence

F. Angileri1, M. Kindermans2, V.K. Attignon3, M. Afshar2, J-Y. Blay4, J. Boulahfa2,S. Boyault5, S. Chabaud6, G. Clave2, G. Garin3, F. Parmentier2, D. Perol7, E. Sohier3,T. Turcat2, O. Tredan8, A. Viari9, P. Saintigny10

1Translational Medicine Department, Center Leon Berard, Lyon, France; 2Data Science,Ariana Pharma, Paris, France; 3Translational Research Department, Centre Léon Bérard, Lyon, France; 4Medicine Department, Centre Léon Bérard, Lyon, France;5Cancer Genomic, Centre Léon Bérard, Lyon, France; 6Clinical Research Unit, Centre de Recherche en Cancerologie de Lyon (CRCL), Lyon, France; 7Clinical Research Department, Centre Léon Bérard, Lyon, France; 8Medical Oncology, Centre Léon Bérard, Lyon,France; 9Plateforme Bioinformatique, INRIA Head Ofﬁce, Le Chesnay, France; 10CRCL Department, Centre Léon Bérard, Lyon, France

Background: In this study, we use KEM® (Knowledge Extraction and Management)In this study, we use KEM (Knowledge Extraction and Management)explainable Artiﬁcial Intelligence (xAI) platform to systematically explore association rules in a heterogeneous patient database accounting for above 30 cancer types and thus identify biomarkers characterizing patients with higher chances of survival. The list of candidates’ biomarkers included drug scores generated by OncoKEM, an list of candidates' biomarkers included drug scores generated by OncoKEM, an Al-AItranscriptional-based therapeutic recommendation-tool that computes scores for up to 205 drugs based on the drug’s transcriptional signatures and the tumor transcriptional proﬁle. The goal was to demonstrate the biological relevance of OncoKEM by confronting its results with the ﬁndings obtained through a standard pathway analysis.

Methods: Data was retrieved from the PROFILER study (NCT01774409), a molecular screening program, and aggregated into a consolidated database totaling 247 patients and 215,670 variables that included survival, baseline descriptors, gene expression,derived REACTOME pathway dysregulations, and OncoKEM scores. KEM derived REACTOME pathway dysregulations, and OncoKEM scores. KEM xAIxAI platform extracted 55,335 relations associating candidate biomarkers and survival.

These results were then ﬁltered based on Support (number of examples), Lift (relative probability) and statistical signiﬁcance. The remaining relations were ﬁnally split into 2 sets to study the associations between survival and respectively pathways dysregulations or OncoKEM lations or OncoKEM® scores.scores.

Results: Our analysis ﬁrst identiﬁed 4 pathway dysregulations that were associated with the overall survival (hazard ratio ranged from 2.36 to 2.80). 3 of these pathways were related to tubulin. Consistently, 4 OncoKEM scores were then identiﬁed were related to tubulin. Consistently, 4 OncoKEM® scores were then identified asas associated with survival (hazard ratio ranged from 2.20 to 2.52) and all 4 corresponded to microtubule inhibitor drugs: ixabepilone, cabazitaxel, vinﬂunine and brentuximab vedotin.

Conclusions: Our analysis enabled the identiﬁcation of biomarkers of survival across cancer types. The consistency of the ﬁndings both demonstrated the biological relevance of OncoKEM for microtubule inhibitor drugs and paved the way for relevance of OncoKEM for microtubule inhibitor drugs and paved the way for thethe use of this tool as a prognostic marker for refractory cancers.

Clinical trial identiﬁcation: NCT01774409.

Funding: Ariana Pharma.

https://doi.org/10.1016/j.annonc.2023.09.2870

147P Non-small cell lung cancer: Artiﬁcial intelligence enables the identiﬁcation of survival signatures complementary to an Immunologically active gene expression signature involving previous therapies

P. Saintigny1, P. Iriso2, M. Afshar2, V.K. Attignon3, J. Auclair4, J. Boulahfa2,M. Boussageon4, J. Fayette4, J-P. Foy5, A. Karabajakian3, M. Kindermans2,M. Lamkhioued1, S. Lantuejoul6, L. Michon6, S. Ortiz-Cuaran7, F. Parmentier2,M. Pérol4, A. Swalduz4, T. Turcat8

1CRCL Department, Centre Léon Bérard, Lyon, France; 2Data Science, Ariana Pharma,Paris, France; 3Translational Research Department, Centre Léon Bérard, Lyon, France;4Medical Oncology, Centre Léon Bérard, Lyon, France; 5Medical Oncology, Assistance Publique - Hopitaux De Paris, Paris, France; 6Medicine Dept, Centre Léon Bérard, Lyon,France; 7Cancer Cell Plasticity, Centre Léon Bérard, Lyon, France; 8Oncology, OmiCure,Paris, France

Background: Non-small cell lung cancer (NSCLC) is one of the most prevalent cancers worldwide. Centre Léon Bérard, Lyon, France has developed a 27-gene expressionbased HOT score that predicts outcome in patients with advanced stage treated with immunotherapy. Yet, this signature could be complemented with additional models involving a smaller set of genes. In this study, we used KEM (Knowledge Extraction and Management) explainable Artiﬁcial Intelligence platform, a tool that systematically extracts relations within the variables of a database, to reﬁne the HOT score,shortening the signature and improving performances.

Methods: Starting from GEO warehouse (GSE161537), 2,568 variables were aggregated into a consolidated database with 82 NSCLC patients. Analysis focused on the associations between combinations of genes, previous treatment lines and overall survival (OS): KEM extracted 194,349 relations that were ﬁltered on the number survival (OS): KEM® extracted 194,349 relations that were filtered on the number ofof involved genes, statistical signiﬁcance and speciﬁcity.

|Table: 148P |Table: 148P |Table: 148P |Table: 148P |Table: 148P | |---|---|---|---|---|

||Central ISH |Central ISH |Central ISH |Central ISH |

|Detected |32 |7 |9 |48 |

|Not detected |44 |136 |32 |212 |

|N/A |2 |2 |3 |7 |

|Total |78 |145 |44 |267 |

||PPA (95% CI): 42% (31e54%) |NPA (95% CI): 95% (90e98%) |||

||Central HER2* |status |||

|Plasma HER2amp |HER2+ |HER2- |N/A |Total |

|Detected |35 |7 |6 |48 |

|Not detected |54 |140 |18 |212 |

|N/A |3 |2 |2 |7 |

|Total |92 |149 |26 |267 |

||PPA (95% CI): 39% (29e50%) |NPA (95% CI): 95% (90e98%) |NPA (95% CI): 95% (90e98%) |NPA (95% CI): 95% (90e98%) |

Results: We identiﬁed 5 genes, DKC1, HPGD, MLPH, ABCC4 and MVP, combined into two 4-gene signatures with similar performances that predicted survival with a signiﬁcant interaction between previous treatment lines and gene expression: patients who carry these signatures and that had undergone at least two treatment lines before immunotherapy showed an improved OS in both models (hazard ratio ¼ 0.45and 0.36). Compared to the HOT score, the number of genes retained was reduced from 27 to 4, and performances improved: balanced accuracy increases from 0.62(HOT score) to 0.78.

Conclusions: Our analysis enabled the preliminary identiﬁcation of signatures that complement the HOT score: the impact of previous lines of therapy was included into the model, the number of markers was reduced and performances increased. Theseﬁndings are currently being conﬁrmed using Cancer Research Institute iAtlas, a database that contains gene expression for over 1,100 cancer patients across ﬁve different tissue types. Speciﬁc adjustments may be required to account for differences in gene expression measurements between the training and testing tests.

https://doi.org/10.1016/j.annonc.2023.09.2871

148P

DESTINY-PanTumor02 study of trastuzumab deruxtecan(T-DXd) in patients (pts) with HER2-expressing solid tumors:Exploratory biomarker analyses of HER2 expression and gene ampliﬁcation in tissue and plasma

V. Makker1, J-Y. Lee2, D-Y. Oh3, A. Oaknin4, S.D. Puvvada5, F. Cecchi5, R. Mcewen6,F. Michelini7, F. Meric-Bernstam8

1Department of Medical Oncology, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical Center, New York, NY, USA; 2Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul, Republic of Korea; 3Department of Internal Medicine, Seoul National University Hospital Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; 4Gynaecologic Cancer Programme, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO),Barcelona, Spain; 5Translational Medicine, AstraZeneca, Gaithersburg, MD, USA;6Oncology, AstraZeneca - Oncology R&D, Cambridge, UK; 7Translational Medicine,Oncology R&D, AstraZeneca, Waltham, MA, USA; 8Department of Investigational Cancer Therapeutics, MD Anderson Cancer Center, University of Texas, Houston, TX,USA

Background: HER2 expression is prevalent in a range of solid tumors. Testing for HER2 is not routine outside breast and gastric cancers, and no HER2 assays are currently validated in all cancers. We evaluated the concordance between local and central HER2 immunohistochemistry (IHC) and between HER2 ampliﬁcation in tissue and in baseline plasma circulating tumor DNA (ctDNA).

Methods: In this open-label, multicenter, multicohort, phase 2 study (NCT04482309),T-DXd (5.4 mg/kg q3w) was evaluated in pts with HER2-expressing (IHC 2+/3+ by local or central testing) locally advanced or metastatic disease after 1 systemic Tx or central testing) locally advanced or metastatic disease after ≥1 systemic Tx ororwithout Tx options. HER2 IHC status was assessed centrally using HER2 HercepTest(DAKO) and scored according to gastric-speciﬁc criteria. HER2 ampliﬁcation was evaluated centrally using Ventana dual in situ hybridization (ISH) on archival tissue and detected in baseline plasma ctDNA using Guardant Health OMNI assay.

Results: Agreement between local and central HER2 IHC score was 59% for IHC 3+and 55% for IHC 2+. HER2 ampliﬁcation was 35% by ISH and 18% by ctDNA. The table shows concordance between HER2 status by ISH or IHC and ctDNA; agreement with HER2 focal ampliﬁcation detected in plasma was 42% and 39%, respectively.

*HER2+: IHC3+ and IHC2+/ISH+

HER2-: IHC2+/ISH- and IHC1+/0

PPA and NPA were calculated excluding N/A samples (failed/unproﬁled/undetectable ctDNA); CI calculated using Clopper-Pearson method CI, conﬁdence interval; HER2-amp, focal HER2 ampliﬁcation; N/A, not available; NPA, negative percent agreement;PPA, positive percentage agreement

Conclusions: The moderate concordance between local and central HER2 IHC results can be ascribed to multiple factors, including different assays/algorithms, tumor heterogeneity, and inter-pathologist variability, highlighting the need for a standardized method to score HER2 across indications. Detection of HER2 ampliﬁcation in plasma was accurate, as indicated by the low rate of false positives; however,sensitivity was poor. This suggests that ctDNA testing may help identify pts with HER2 ampliﬁcation but is not yet a substitute for tissue-based HER2 ISH and IHC testing.

Clinical trial identiﬁcation: NCT04482309.

Editorial acknowledgement: Under the guidance of authors and in accordance with GPP3, medical writing and editorial support was provided by Melanie Francis, MSc, of Helios Medical Communications, and was funded by AstraZeneca.

Legal entity responsible for the study: Daiichi Sankyo and AstraZeneca.

Funding: Daiichi Sankyo and AstraZeneca.

Disclosure: V. Makker: Financial Interests, Institutional, Funding, Study funding: Merck, Eisai,Clovis, Karyopharm, AstraZeneca; Financial Interests, Institutional, Funding, Study support: Zymeworks; Financial Interests, Institutional, Funding, Study Support: BMS, Duality, Faeth, Takeda; NonFinancial Interests, Principal Investigator: Merck; Non-Financial Interests, Advisory Role: Eisai, Clovis,Novartis, Lilly, Gsk, Karyopharm, Iteos, Faeth, Duality, ZYmeworks, Morphosys, Moreo. J. Lee:Financial Interests, Personal, Invited Speaker: AstraZeneca, Takeda, MSD, Roche; Financial Interests,Personal, Advisory Board: Eisai, GI Innovation; Financial Interests, Institutional, Local PI: Alkermes,AstraZeneca, BergenBio, Cellid, Clovis Oncology, Eisai, GI Innovation, ImmunoGen, Janssen, Merck,without Tx options. HER2 IHC status was assessed centrally using HER2 HercepTestTMMersana, MSD, Novartis, OncoQuest, Roche, Seagen, Synthon; Financial Interests, Personal and Institutional, Local PI: BeiGene; Financial Interests, Personal, Steering Committee Member: AstraZeneca, OncoQuest, Seagen, ImmunoGen, MSD; Financial Interests, Institutional, Research Grant:ONO, Takeda. D. D. Oh: Financial Interests, Personal, Advisory Board: AstraZeneca, Novartis, Genentech/Roche, Merck Serono , Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene,Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA, MSD; Financial Interests, Institutional,Research Grant: AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, Handok. A. Oaknin:Financial Interests, Personal, Advisory Board: AstraZeneca, Clovis Oncology, Deciphera Pharmaceuticals, Genmab, GSK, Immunogen, Mersana Therapeutics, PharmaMar, Merck Sharps & Dohme de España, SA, Agenus, Sutro, Corcept Therapeutics, EMD Serono, Novocure, Sattucklabs, Itheos, Eisai,F. Hoffmann-La Roche, Seagen, OneXerna Therapeutics, Inc, Regeneron, Sutro Biopharma; Financial Interests, Personal, Other, Travel and accomodation: AstraZeneca, PharmaMar, Roche; Financial Interests, Institutional, Funding: Amgen, AbbVie Deutschland, Advaxis Inc., Aeterna Zentaris, Aprea Therapeutics AB, Regeneron Pharmaceuticals, Clovis Oncology Inc, EISAI limited LTD, F. Hoffmann e La Roche LTD, Immunogen Inc, Merck, Sharp & Dohme de España SA, Millennium Pharmaceuticals Inc, PharmaMar SA, Tesaro Inc., Bristol Myers Squibb; Non-Financial Interests, Leadership Role, on behalf of GEICO: GCIG; Non-Financial Interests, Ofﬁcer, Chair of Gynaecological Track ESMO 2019 .

Scientiﬁc Track Member Gynaecological Cancers ESMO 2018 , ESMO 2020 , ESMO 2022 . Member of Gynaecological Cancers Faculty and Subject Editor Gyn ESMO Guidelines: ESMO; Non-Financial Interests, Leadership Role, ESMO GYN Co-Chair 2023 - 2025: ESMO; Non-Financial Interests, Leadership Role, Chair de Cervix Committee. 2022-2024: GCIG; Non-Financial Interests, Member: ESMO,ASCO, GCIG, SEOM, GOG. S.D. Puvvada: Financial Interests, Personal, Full or part-time Employment:AstraZeneca. F. Cecchi: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. R.

Mcewen: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. F. Michelini:Financial Interests, Personal, Full or part-time Employment: AstraZeneca. F. Meric-Bernstam:Financial Interests, Personal, Other, Consultant: AstraZeneca, F. Hoffman-La Roche Ltd., Zymeworks,OnCusp Therapeutics; Financial Interests, Personal, Advisory Board, Advisory Board/Consultant:Seagen; Financial Interests, Personal, Advisory Board: Zentalis, Karyopharm, Biovica, Eisai, Protai,TheraTechnologies; Financial Interests, Personal, Other, Consulting: Tallac Therapeutics, Lengo Therapeutics, LOXO-Oncology, Black Diamond, Inﬁnity Pharmaceuticals, AbbVie, GT Aperion, Ecor1;Financial Interests, Personal, Other, Consutling: Menarini Group; Financial Interests, Institutional,Other, Local PI / Research Grant: Aileron Therapeutics, Bayer Healthcare, CytomX Therapeutics Inc.,Daiichi Sankyo Co. Ltd., eFFECTOR Therapeutics, Taiho Pharmaceutical Co.; Financial Interests,Institutional, Other, Local PI / Research Grant / Coordinating PI: AstraZeneca; Financial Interests,Institutional, Local PI: Calithera Biosciences, Curis Inc., Debiopharm International, Guardant Health Inc., Klus Pharma, Novartis; Financial Interests, Institutional, Other, Local PI / Steering Committee Member: Genentech Inc.; Financial Interests, Institutional, Research Grant: Takeda Pharmaceutical Co., Puma Biotechnology Inc., Repare; Other, Travel Support: Cholangiocarcinoma Foundation; Other,

S239

Travel support: European Organisation for Research and Treatment of Cancer (EORTC), European Society for Medical Oncology (ESMO).

https://doi.org/10.1016/j.annonc.2023.09.2872

149P

Assessing the effect of single dose trastuzumab and

pertuzumab (HP) on biological changes and pathological complete response (pCR) in ERBB2+ Breast Cancer: Results from the neoadjuvant BionHER study

N. Gomez Serra1, F. Brasó-Maristany2, B. Fullana Grimalt3, R. Ortega4, A. Petit5,M. Vicente4, C. Falo6, A. Stradella7, M. Bañuls8, L. Pare Brunet9,

M. Marín-Aguilera10, A. Fernandez Ortega11, A. Vethencourt6, D. Cordero12,A. Iserte13, P. Galván14, C.M. Perou15, P. Villagrasa Gonzalez9, A. Prat16,

S. Pernas Simon17

1Medical Oncology Department, ICO - Institut Català d’Oncologia - Hospital Duran i Reynals, Hospitalet De Llobregat, Spain; 2Oncology Department, IDIBAPS - Fundació de Recerca Clinic Barcelona - Institut d’Investigacions Biomediques August Pi i Sunyer/SOLTI, Barcelona, Spain; 3Breast unit, ICO - Institut Català d’Oncologia - Hospital Duran i Reynals, Hospitalet De Llobregat, Spain; 4Radiology, Hospital Universitari de Bellvitge, Hospitalet De Llobregat, Spain; 5Pathology, Hospital Universitari de Bellvitge, Hospitalet De Llobregat, Spain; 6Breast Cancer Unit, ICO - Institut Català d’Oncologia l’Hospitalet (Hospital Duran i Reynals), L’Hospitalet De Llobregat, Spain;7Medical Oncology Department, Institut Català d’Oncologia, L’Hospitalet De Llobregat, Spain; 8IDIBELL, ICO - Institut Català d’Oncologia - Hospital Duran i Reynals,Hospitalet De Llobregat, Spain; 9Scientiﬁc Department, Reveal Genomics, S.L. , Barcelona, Spain; 10Scientiﬁc Department, Hospital Clinic y Provincial de Barcelona,Barcelona, Spain; 11Oncology, ICO - Institut Català d’Oncologia l’Hospitalet (Hospital Duran i Reynals), Hospitalet De Llobregat, Spain; 12Unit of Bioinformatics for Precision Oncology, Institut Català d’Oncologia l’Hospitalet (Hospital Duran i Reynals), L’Hospitalet De Llobregat, Spain; 13Clinical Trials Unit, IDIBELL - Bellvitge Biomedical Research Institute, Hospitalet De Llobregat, Spain; 14Translational Genomics and Targeted Therapies in Solid Tumors Lab, IDIBAPS - Fundació de Recerca Clinic Barcelona - Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain;15Department of Genetics, UNC - Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA; 16Medical Oncology Department, Hospital Clinic y Provincial de Barcelona, Barcelona, Spain; 17Medical Oncology Breast Unit, ICO - Institut Català d’Oncologia l’Hospitalet (Hospital Duran i Reynals), L’Hospitalet De Llobregat, Spain

Background: HER2 blockade in ERBB2+ BC can boost the immune system and inhibit cell proliferation and survival. Here, we aimed to identify early molecular changes following a single dose of HP and its association with subsequent pCR following neoadjuvant HP-based chemotherapy.

Methods: Patients (pts) with stage I-III ERBB2+BC were treated with neoadjuvant pertuzumab+trastuzumab+paclitaxel (THP)x16w. Paired tumor biopsies were obtained at baseline (D1) and at day 8 (D8) following a loading-dose of HP, prior to weekly paclitaxel addition. HER2DX gene expression signatures and the expression of 185 genes were evaluated in both timepoints. Paired SAM analyses (FDR<5%) and t-tests determined signiﬁcant changes between D1-D8. Logistic regression analyses identi-ﬁed associations with pCR (ypT0/isN0).

Results: Gene expression was evaluated in paired samples in 49 out of 52 pts (94%).

cT1-2 disease represented 85% of cases, cN0 59%, and 67% were HR+. The overall pCR rate was 45.6% and 55.3% when ypT1miN0 was considered. In all pts, HP induced a signiﬁcant decrease in HER2DX proliferation, HER2 amplicon, pCR, risk and ERBB2 scores, and in 81 (43.8%) genes including KRT18, SPDEF, MUCL1 or FOXA1; and a signiﬁcant increase in the HER2DX IGG signature and 84 (45.4%) genes including GPNMB, CD68, CD86 or CD4. At D8, the HER2DX IGG signature (p¼0.002) and 61(33.0%) genes including LY9 (p<0.001), CD8A (p<0.001), CD27 (p<0.001) or GZMA(p<0.001) were signiﬁcantly associated with pCR. At D1, pCR rates in HER2DX IGGhigh, medium and low were 71.4%, 22.2% and 25.0%, respectively. At D8, pCR rates in HER2DX IGG-high, medium and low were 81.0%, 33.3% and 6.3%, respectively. The ratio between D8 and D1 of HER2DX pCR (p¼0.006) and risk (p¼0.026) scores and 38(20.5%) genes including S100A9 (p¼0.006), TRPV6 (p¼0.008), GPNMB (p¼0.013) orLY9 (p¼0.016) were signiﬁcantly associated with pCR.

Conclusions: In early-stage ERBB2+ BC, a single dose of HP induces signiﬁcant biological changes that may better predict pCR. At day 8, pts with high expression of HER2DX immune signature and immune-related genes have a higher probability of achieving a pCR following THP.

Funding: Reveal Genomics S.L.

https://doi.org/10.1016/j.annonc.2023.09.2873

150P Validation of a genomic assay in early-stage HER2+ breast cancer (BC) treated with trastuzumab and pertuzumab (HP):A correlative analysis from PHERGain phase II trial

A. Llombart Cussac1, J.M. Pérez-García2, L. Pare Brunet3, G. Villacampa Javierre3,F. Brasó-Maristany4, M. Gion Cortes5, P. Schmid6, M.A. Colleoni7, M. Ruiz Borrego8,P. Galván9, J. Parker10, C.M. Perou11, P. Villagrasa Gonzalez3, J.A. Guerrero12,

M. Sampayo-Cordero13, M. Mancino14, A. Prat15, J. Cortés16

1Medical Oncology Department, Hospital Arnau de Vilanova; MEDSIR - Medica Scientia Innovation Research, Valencia, Spain; 2Medical Oncology, International Breast Cancer Center (IBCC), Pangaea Group; MEDSIR - Medica Scientia Innovation Research,Barcelona, Spain; 3Scientiﬁc Department, Reveal Genomics, S.L., Barcelona, Spain;4Oncology Department, IDIBAPS - Fundació de Recerca Clinic Barcelona - Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain; 5Medical Oncology Department, Hospital Universitario Ramon y Cajal, Madrid, Spain; 6Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, London, UK; 7Senology, IEO - Istituto Europeo di Oncologia, Milan, Italy;8Oncology, Hospital Universitario Virgen del Rocio, Seville, Spain; 9Translational genomics and targeted therapies in solid tumors lab, IDIBAPS - Fundació de Recerca Clinic Barcelona - Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona,Spain; 10Bioinformatics, UNC - Lineberger Cancer Center, Chapel Hill, NC, USA;11Lineberger Comprehensive Cancer Center, UNC, Chapel Hill, NC, USA; 12MEDSIR -Medica Scientia Innovation Research, Barcelona, Spain; 13Scientiﬁc, MEDSIR - Medica Scientia Innovation Research, Barcelona, Spain; 14Operations and Scientiﬁc Departments, MEDSIR - Medica Scientia Innovation Research, Barcelona, Spain;15Medical Oncology Department, Hospital Clinic y Provincial de Barcelona, Barcelona,Spain; 16Department of Medicine, Oncology Department, International Breast Cancer Center (IBCC), Madrid, Spain

Background: HER2DX is a prognostic (risk-score) and predictive (pathological complete response [pCR]-score) genomic assay in early-stage HER2+ BC. Here, we evaluated the ability of HER2DX following (neo)adjuvant HP-based therapy.

Methods: HER2DX was evaluated on baseline FFPE tumors from PHERGain(NCT03161353). Patients (pts) with newly diagnosed stage I-IIIA HER2+ BC and PET evaluable lesions were randomized (1:4) to receive either docetaxel (T), carboplatin(C), (C), and HP (group A) or HP ±endocrine therapy (ET) (group B). PET was performedand HP (group A) or HP endocrine therapy (ET) (group B). PET was performedprior to randomization and after 2 cycles. Group A received TCHPx6 regardless of on treatment PET response. Group B received HP ETx2 and PET-responder (RX) treatment PET response. Group B received HP ± ETx2 and PET-responder (RX) ptsptscontinued with HP ETx6, while PET-non-RX pts received TCHPx6. After surgery, continued with HP±ETx6, while PET-non-RX pts received TCHPx6.After surgery, PET-PET-RX without a pCR received TCHPx6. All pts completed HPx18. Primary objective was the association of HER2DX with pCR (ypT0/is ypN0). Secondary objective was the association of HER2DX risk-score with invasive disease-free survival (iDFS).

Results: HER2DX was evaluated in 292 (82.0%) pts. Clinical T2-4 and node-negative disease represented 84.6% and 49.3%, respectively, and 66.4% of tumors were hormone receptor (HR) positive. The overall pCR rate was 38.0% (56.4% in group A and

33.8% in group B). In the multivariable analysis, HER2DX pCR-score (as a continuous variable) was signiﬁcantly associated with pCR (odds ratio [OR] per 10-unit increase¼1.29 (1.5-1.8), p<0.001), after adjusting for treatment and clinicopatho-logical factors such as HR status, treatment group, or PET response. In the overall population, the pCR rates in HER2DX pCR-high, med, and low groups were 50.4%,

35.8%, and 23.2% (pCR-high vs pCR-low OR¼3.37, p<0.001), respectively. HER2DXlow-risk showed a numerically better 3-year iDFS than HER2DX high-risk pts (100% vs

93.5%; hazard ratio¼ 0.37 [0.1-1.7]) after adjusting by pCR status. Eight out of 9 ptswith metastatic progression had HER2DX high-risk prognostic score.

Conclusions: HER2DX predicts pCR following neoadjuvant HP-based therapy (with or without chemotherapy) and identiﬁes pts with a higher risk of recurrence. This assay might help individualize HP-based therapy in early HER2+ BC.

Clinical trial identiﬁcation: NCT03161353.

Legal entity responsible for the study: MEDSIR.

Funding: Reveal Genomics, MEDSIR.

Disclosure: L. Pare Brunet: Financial Interests, Institutional, Full or part-time Employment: Reveal Genomics S.L.; Financial Interests, Institutional, Other, Patent pending: In vitro method for the prognosis of patients suffering from HER2-positive breast cancer - 905333: Reveal Genomics S.L. G.

Villacampa Javierre: Financial Interests, Personal, Invited Speaker, Invited speaker in a course: MSD;Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Invited speaker in an internal training: Pierre Fabrer, GSK; Financial Interests, Personal,Invited Speaker, Internal discussion about the interpretation of some published results: Pﬁzer;Financial Interests, Personal, Other, Collaborations with speciﬁc projects: Reveal Genomics. F. BrasóMaristany: Financial Interests, Personal, Advisory Board: Reveal Genomics. M. Gion Cortes: Financial Interests, Personal, Invited Speaker: Roche, Daiichi Sankyo, Novartis; Financial Interests, Personal,Other, Travel expenses: Roche, Pﬁzer; Financial Interests, Personal, Advisory Board: Gilead; Financial Interests, Personal, Full or part-time Employment: MEDSIR. P. Schmid: Financial Interests, Personal,Advisory Board: AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Pﬁzer, Puma, Roche,Gilead, Eisai, MSD, Seagen, Amgen, Celgene, Lilly; Financial Interests, Institutional, Research Grant:Astellas, AstraZeneca, Genentech, Novartis, Oncogenex, Roche, Medivation. M. M.A. Colleoni: Financial Interests, Institutional, Research Grant: Roche; Non-Financial Interests, Leadership Role, CO-Chair Scientiﬁc Committee: International Breast Cancer Study Group. P. Galván: Financial Interests, Personal, Full or part-time Employment: Reveal Genomics. J. Parker: Financial Interests, Personal, Other,Advisory: Reveal Genomics, Bristol Myers Squibb; Financial Interests, Personal, Full or part-time Employment: LifeEdit Therapeutics; Financial Interests, Personal, Ownership Interest: Reveal Genomics, GeneCentric; Financial Interests, Personal, Royalties: Veracyte. C.M. Perou: Financial Interests, Personal, Member of Board of Directors: GeneCentric Therapeutics; Financial Interests,Personal, Stocks/Shares: GeneCentric Therapeutics, Bioclassiﬁer LLC, Reveal Genomics; Financial Interests, Personal, Royalties, from PAM50 licensing: Bioclassiﬁer LLC; Financial Interests, Personal,Royalties: GeneCentric Therapeutics; Non-Financial Interests, Advisory Role: GeneCentric

Therapeutics, Bioclassiﬁer LLC, Reveal Genomics. P. Villagrasa Gonzalez: Financial Interests, Personal,Full or part-time Employment, CEO and co-founder of the company: Reveal Genomics S.L.; Financial Interests, Personal, Ownership Interest: Reveal Genomics S.L.; Financial Interests, Personal, Royalties, PCT/EP2021/086493 - In Vitro method for the prognosis of patients suffering from HER2-positive breast cancer: Reveal Genomics S.L. A. Prat: Financial Interests, Personal, Invited Speaker:Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pﬁzer, Oncolytics Biotech,Guardant Health, Peptomyc; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Institutional, Other, Contracted research: Boehringer Ingelheim, Medica Scientia inno. Research; Financial Interests, Personal, Advisory Board: AstraZeneca, 1TRIALSP, S.L.;Financial Interests, Personal, Member of Board of Directors, Leadership role: Reveal Genomics, SL.;Financial Interests, Personal, Stocks/Shares: Reveal Genomics, Oncolytics Biotech; Financial Interests,Personal, Royalties: Reveal Genomics, International Oncology Bureau, S.L.; Financial Interests,Institutional, Local PI: Roche, AstraZeneca; Financial Interests, Personal and Institutional, Steering Committee Member: Daiichi Sankyo; Financial Interests, Institutional, Coordinating PI: Novartis;Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation, Actitud Frente al Cáncer Foundation; Non-Financial Interests, Personal, Other, Asociación Española de Investigación sobre el Cáncer: ASEICA. J. J. Cortés: Financial Interests, Personal, Advisory Board: Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex,Polyphor, Lilly, Merck Sharp& Dohme, GSK, Leuko, Bioasis, Clovis oncology, Boehringer Ingelheim,Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics; Financial Interests, Personal, Invited Speaker: Roche, Novartis, Celgene, Eisai, Pﬁzer, Samsung Bioepis, Lilly,Merck Sharp & Dohme, Daiichi Sankyo; Financial Interests, Personal, Other, Consulting/advisor:Expres2ion Biotechnologies; Financial Interests, Personal, Stocks/Shares: MEDSIR, Nektar Therapeutics; Financial Interests, Institutional, Research Grant: Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer Healthcare, Eisai, Guardanth health, Merck Sharp &Dohme , Pﬁzer, Piqur Therapeutics, Puma B, Queen Mary University of London; Other, Travel cost and expenses: Roche, Novartis, Eisai, Daiichi Sankyo, Pﬁzer, Gilead, AstraZeneca. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2874

151P

Mut, mu

Baseline circulating tumor DNA (ctDNA) biomarker analysis of patients with human epidermal growth factor receptor 2(HER2)-overexpressing metastatic nonesmall cell lung

cancer (NSCLC) treated with trastuzumab deruxtecan

(T-DXd)

E.F. Smit1, E. Felip2, D. Uprety3, M. Nagasaka4, K. Nakagawa5, L. Paz-Ares6,J. Pacheco7, B.T. Li8, D. Planchard9, C.S. Baik10, Y. Goto11, H. Murakami12,

K.M.C. Pereira13, A. Taguchi14, M. Kogo14, Y. Kuwahara13, M. Zou13, W. Feng13,Z. Tsuchihashi13, P.A. Jänne15

1Department of Pulmonary Diseases, University Medical Centre, Leiden, Netherlands;2Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona,Spain; 3Medical Oncology, Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA;4Medicine, University of California Irvine School of Medicine, Orange, CA, USA;5Medical Oncology, Kindai University Hospital, Osaka, Japan; 6Medical Oncology,Clinical Universidad de Navarra, Madrid, Spain; 7Medical Oncology/Internal Medicine,University of Colorado Cancer Center, Aurora, IL, USA; 8Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 9Medical Oncology, Gustave Roussy,Villejuif, France; 10Medical Oncology, University of Washington, Seattle, WA, USA;11Thoracic Oncology Department, National Cancer Center Hospital, Tokyo, Japan;12Medical Oncology, Shizuoka Cancer Center, Shizuoka, Japan; 13Oncology, Daiichi Sankyo, Inc., Basking Ridge, NJ, USA; 14Oncology, Daiichi Sankyo Co., Ltd., Tokyo,Japan; 15Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston,MA, USA

Background: DESTINY-Lung01 (NCT03505710) showed encouraging and consistent antitumor activity for T-DXd in heavily pretreated patients with HER2-overexpressing(immunohistochemistry [IHC] 3+/2+) NSCLC. We investigated associations between baseline gene mutations using ctDNA and clinical outcomes in these patients (data cutoff, May 2021).

Methods: Among 90 patients in the DESTINY-Lung01 HER2-overexpressing cohorts, 85 had baseline ctDNA samples analyzed at Guardant Health OMNI. Activating mutations in key oncogenes (EGFR, RAS, BRAF) and other genes of interest at baseline were assessed for their association with clinical efﬁcacy (objective response rate [ORR] and progression-free survival [PFS]) with T-DXd treatment (cohort 1, 6.4 mg/kg [N ¼ 49];cohort 1a, 5.4 mg/kg [N ¼ 41] every 3 weeks); analyses were not adjusted forbaseline characteristics.

Results: The 85 evaluable patients had an ORR of 27.1% (95% CI, 18.0-37.8) and a median PFS (mPFS) of 5.9 months (95% CI, 4.5-7.4). Activating mutations were

tant; WT, wild-type.aKRAS/NRAS. bTop 4 genes based on log rank test signiﬁcance

identiﬁed in EGFR (15 patients [17.6%]: 7 T790M, 7 L858R, 1 S768I, 4 E746_A750del, 2 G719A), KRAS (20 patients [23.5%]), NRAS (1 patient [1.2%]), and BRAF (1 patient[1.2%]). 13 of the 15 patients with EGFR-activating mutations had prior EGFR tyrosine kinase inhibitor treatment. No clear effects of EGFR- and RAS-activating mutations on ORR and mPFS were observed; however, mutations in STK11 and KEAP1 were associated with signiﬁcantly shorter mPFS (Table).

Conclusions: Baseline ctDNA analysis showed that the presence of activating mutations in EGFR, KRAS, or NRAS did not impact the clinical efﬁcacy of T-DXd in patients with HER2-overexpressing NSCLC whereas mutations in STK11 and KEAP1 were associated with shorter mPFS. Updated results will be presented (data cutoff,December 2021).

Clinical trial identiﬁcation: NCT03505710.

Editorial acknowledgement: Under the guidance of authors, assistance in medical writing and editorial support was provided by Brian Brennan, PhD, and Sara Duggan,PhD, of ApotheCom, and was funded by Daiichi Sankyo, Inc.

Legal entity responsible for the study: Daiichi Sankyo, Inc., and AstraZeneca.

Funding: Daiichi Sankyo, Inc., and AstraZeneca.

Disclosure: E.F. Smit: Financial Interests, Institutional, Advisory Board: AstraZeneca, Daiichi Sankyo, MSD, Boehringer Ingelheim, Roche, Eli Lilly, Takeda, Sanoﬁ, Janssen, BMS; Financial Interests,Personal, Invited Speaker: Daiichi Sankyo, Boehringer Ingelheim; Financial Interests, Personal,Advisory Board: Merck Seranno; Financial Interests, Institutional, Other, DSMB member: DSI;Financial Interests, Institutional, Local PI: Pﬁzer, AZ, Genmab, DSI, Sanoﬁ. E. Felip: Financial Interests,Personal, Advisory Board: AstraZeneca, AbbVie, Amgen; Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Touch Oncology, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche,Janssen, Medical Trends, Medscape, Merck Serono, Bayer, Merck Sharp & Dohme, Peervoice, Pﬁzer,Sanoﬁ, Takeda, Seom; Financial Interests, Personal, Other, Independent member ofthe board: Grifols;Financial Interests, Personal, Other, Member of the Nominating Commitee and Compliance Committee: :ESMO; Financial Interests, Personal, Other, Member of Scientiﬁc Committee: ETOP. D.

Uprety: Financial Interests, Personal, Advisory Board: Daiichi Sankyo, AstraZeneca; Financial Interests, Personal, Invited Speaker: Sanoﬁ; Financial Interests, Advisory Board: Jazz Pharmaceuticals .

M. Nagasaka: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Novartis,EMD Serono, Pﬁzer, Lilly, Genentech; Financial Interests, Personal, Other, Consulting for tumor board: Caris Life Sciences; Financial Interests, Personal, Speaker’s Bureau: Takeda, Janssen, Mirati,Blueprint Medicines; Financial Interests, Other, Travel support: AnHeart Therapeutics. K. Nakagawa:Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co., Ltd., Eli Lilly Japan K.K.,AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., MSD K.K., Pﬁzer Japan Inc., Nippon Boehringer Ingelheim Co., Ltd., Taiho Pharmaceutical Co.,Ltd., Bayer Yakuhin, Ltd., Incyte biosciences Japan,Merck Biopharma Co., Ltd., Janssen Pharmaceutical K.K., Bristol Myers Squibb Company, Medical Mobile Communications co., Ltd, Novartis Pharma K.K., Daiichi Sankyo Co., Ltd.; Financial Interests,Personal, Advisory Board: Ono Pharmaceutical Co.,Ltd., Eli Lilly Japan K.K.; Financial Interests, Personal, Writing Engagement: Yodosha Co., Ltd.; Financial Interests, Institutional, Research Grant:Amgen Inc., Bristol Myers Squibb K.K., Chugai Pharmaceutical Co.,Ltd., EP-CRSU CO., LTD., EPS Corporation., Eisai Co., Ltd., GSK K.K., IQVIA Services Japan K.K., Janssen Pharmaceutical K.K.,Kobayashi Pharmaceutical Co., Ltd., MSD K.K., Nippon Boehringer Ingelheim Co.,Ltd., Nippon Kayaku Co.,Ltd., PRA HEALTHSCIENCES, SRL Medisearch Inc., Syneos Health Clinical K.K., Sanoﬁ K.K., Taiho Pharmaceutical Co.,Ltd., Takeda Pharmaceutical Co.,Ltd., CMIC CO., Ltd., Pﬁzer R&D Japan G.K.,Labcorp Development Japan K.K., Pﬁzer Japan Inc., Shionogi & Co., Ltd., Otsuka Pharmaceutical Co.,Ltd., Astellas Pharma Inc., Ascent Development Services, Eisai Inc., Bayer Yakuhin, Ltd. L. L. Paz-Ares:Financial Interests, Personal, Advisory Board, Speaker fees: Roche, MSD, BMS, AstraZeneca, Lilly,Pharmamar, BeiGene, Daichii, Medscape, PER; Financial Interests, Personal, Advisory Board: Merck Serono, Pﬁzer, Bayer, Amgen, Janssen, GSK, Novartis, Takeda, Sanoﬁ, Mirati; Financial Interests,Personal, Other, Board member: Genomica, Altum sequencing; Financial Interests, Institutional,Coordinating PI: Daiichi Sankyo, AstraZeneca, Merck Sharp & Dohme corp, BMS, Janssen-cilag international NV, Novartis, Roche, Sanoﬁ, Tesaro, Alkermes, Lilly, Takeda, Pﬁzer, Pharmamar; Financial Interests, Personal, Coordinating PI: Amgen; Financial Interests, Other, Member: AACR, ASCO, ESMO;Financial Interests, Other, Foundation Board Member: AECC; Financial Interests, Other, President.

ASEICA(Spanish Association of Cancer Research): ASEICA; Financial Interests, Other, Foundation president: ONCOSUR; Financial Interests, Other, Member: Small Lung Cancer Group. J. Pacheco:Financial Interests, Personal, Other, Consulting Fees: Silverback therapeutics, Blueprint Medicines,AstraZeneca, Jazz Pharmaceuticals. B.T. Li: Financial Interests, Institutional, Funding, Clinical trial funding: Daiichi Sankyo, Amgen, Bolt Biotherapeutics, Genentech, Hengrui, Lilly; Financial Interests,Institutional, Funding, Clinical trial funding, uncompensated advisory: AstraZeneca; Financial Interests, Institutional, Invited Speaker, Academic travel support: Amgen. D. Planchard: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Novartis, GSK, NOVARTIS, Janssen, AbbVie,Roche, Pﬁzer, MSD, Gilead, Seagen, Pierre Fabre; Financial Interests, Personal, Invited Speaker:Daiichi Sankyo. C.S. Baik: Financial Interests, Institutional, Principal Investigator: Rain , AbbVie,Nuvalent, Blueprint, Turning Point, BMS, Lilly, AstraZeneca, Jansen, Daiichi, Spectrum, Pﬁzer, Loxo;Financial Interests, Personal, Advisory Board: Daiichi, Boehringer Ingelheim, Janssen, Regeneron,Silverback, Pﬁzer, AstraZeneca, Guardant, TurningPoint, Takeda. Y. Y. Goto: Financial Interests, Personal,Advisory Board: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, Guardant Health Inc., Illumina, MSD, Novartis, Ono Pharmaceutical, Pﬁzer, Taiho, Johnson and Johnson, D3bio; Financial Interests, Personal, Invited Speaker: AstraZeneca, Boehringer Ingelheim,Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, MSD, Merck, Novartis, Ono Pharmaceutical,Pﬁzer, Taiho, Thermo Fischer; Financial Interests, Institutional, Local PI: Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Preferred Network; Financial Interests, Personal and Institutional, Coordinating PI:

|Table:151P Efﬁcacy according to mutation status |Table:151P Efﬁcacy according to mutation status |Table:151P Efﬁcacy according to mutation status |Table:151P Efﬁcacy according to mutation status |Table:151P Efﬁcacy according to mutation status |Table:151P Efﬁcacy according to mutation status | |---|---|---|---|---|---|

|Key oncogenes ||||||

|EGFR |15 |27.1 (17.2-39.1) |26.7 (7.8-55.1) |6.7 (4.5-7.5) |4.6 (1.3-NA) |

|RASa |21 |26.6 (16.3-39.1) |28.6 (11.3-52.2) |6.7 (4.2-7.5) |4.6 (1.4-NA) |

|Otherselected genesb ||||||

|STK11 |11 |29.7 (19.7-41.5) |9.1 (0.2-41.3) |7.0 (5.4-8.3) |1.2 (0.5-2.8) |

|KEAP1 |11 |29.7 (19.7-41.5) |9.1 (0.2-41.3) |6.7 (5.4-8.3) |1.4 (0.6-2.4) |

|ARID2 |11 |29.7 (19.7-41.5) |18.2 (2.3-51.8) |6.7 (5.4-10.5) |3.1 (1.2-6.7) |

|LRP1B |32 |26.4 (15.3-40.3) |28.1 (13.7-46.7) |7.2 (5.4-15.5) |4.2 (1.5-6.7) |

for PFS.

S241

Chugai, Novartis, Pﬁzer; Financial Interests, Institutional, Research Grant: Prefered Network;Financial Interests, Institutional, Coordinating PI: Guardant Health. H. Murakami: Financial Interests,Personal, Advisory Board: Chugai Pharma, Taiho Pharmaceutical, AstraZeneca, Lilly Japan, Ono Pharmaceutical, Bristol Myers Squibb Japan, MSD, Takeda, Novartis, Daiichi Sankyo, Eisai, Nihonkayaku, Pﬁzer, Amgen, Chugai Pharma, Daiichi Sankyo, GAIA BioMedicine, Taiho Pharmaceutical,Amgen; Financial Interests, Institutional, Research Grant: Chugai Pharma, AstraZeneca, Takeda,Daiichi Sankyo, AbbVie, IQVIA, Bayer, Taiho Pharmaceutical. K.M.C. Pereira, A. Taguchi, M. Kogo, Y.

Kuwahara, M. Zou, W. Feng, Z. Tsuchihashi: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. P.A. Jänne: Financial Interests, Personal and Institutional, Funding: AstraZeneca, Boehringer Ingelheim, Eli Lilly Pharmaceuticals, Daiichi Sankyo, Takeda Oncology; Financial Interests, Personal, Advisory Board: Pﬁzer, Roche/Genentech, Chugai Pharmaceuticals, SFJ Pharmaceuticals, Voronoi, Biocartis, Novartis, Sanoﬁ, Mirati Therapeutics, Transcenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Esai, Allorion Therapeutics, Accutar Biotech, AbbVie, Monte Rosa,Scorpion Therapeutics, Merus, Frontier Medicines, Hongyun Biotechnology, Duality; Financial Interests, Personal, Stocks/Shares: Gatekeeper Pharmaceuticals; ; Financial Interests, Institutional,Funding: PUMA; Financial Interests, Personal, Invited Speaker: Revolution Medicines; Financial Interests, Personal, Royalties: LabCorp.

https://doi.org/10.1016/j.annonc.2023.09.2875

152P

*Other t

Efﬁcacy of olaparib in advanced cancers with germline or somatic tumor mutations in BRCA1, BRCA2, CHEK2 and ATM:A Belgian precision tumor-agnostic phase II study

S.R. Joris1, H. Denys2, J.J. Collignon3, M. Rasschaert4, D. T’Kint de Roodenbeke5,F.P. Duhoux6, J-L. Canon7, S. Tejpar8, J. Mebis9, L. Decoster10, P.G. Aftimos11,J. De Grève12

1Medical Oncology Department, UZ Brussel - Universitair Ziekenhuis Brussel, Liedekerke, Belgium; 2Medical Oncology Department, UZ Gent - University Hospital Ghent,Gent, Belgium; 3Department of Medical Oncology, CHU Liège Sart-Tilman-Service d’Oncologie, Liège, Belgium; 4Oncology Department, UZA - University Hospital Antwerp, Edegem, Belgium; 5Medical Oncology Department, Institute Jules Bordet,Anderlecht, Belgium; 6Medical Oncology Department, Cliniques Universitaires SaintLuc (UCLouvain Saint-Luc), Woluwe-Saint-Lambert, Belgium; 7Department of Oncology-Hematology, GHdC - Grand Hopital de Charleroi - Site Notre Dame, Charleroi, Belgium; 8Gastro-Enterology, UZ Leuven - University Hospitals Leuven - Campus Gasthuisberg, Leuven, Belgium; 9Medical Oncology Department, Jesse Ziekenhuis -Campus Virga Jesse, Hasselt, Belgium; 10Department of Medical Oncology, UZ Brussel

- Universitair Ziekenhuis Brussel, Jette, Belgium; 11Clinical Trials Conduct Unit, Institute Jules Bordet, Anderlecht, Belgium; 12Medical Oncology Department, Vrije Universiteit Brussel - Faculty of Medicine & Pharmacy, Brussels, Belgium

Background: The Belgian Precision initiative aims to maximize the implementation of tumor-agnostic NGS in patients with advanced cancer and enhance access to molecularly-guided treatment options (MGTOs). Academic tumor-agnostic basket phase 2 studies are part of this initiative. The current investigator-driven trial aimed to investigate olaparib efﬁcacy in advanced cancers with a pathogenic or likely pathogenic mutation (germline or somatic) in a gene that plays a role in homologous recombination (HR).

Methods: Open-label multi-cohort phase 2 study that examines the efﬁcacy of olaparib in patients with an HR gene mutation in their tumor and failed SoC. Patients with a somatic or germline mutation in the same gene deﬁne a cohort. For each cohort, a Simon minimax two-stage design was used. If a response was observed in the ﬁrst 13 patients, 14 additional patients were included (type I error rate of 5% and a power of 80% when the true response rate is 20%). Here, we report the results on four completed cohorts: patients with a BRCA1, BRCA2, CHEK2 or ATM mutation.

Results: The overall objective response rate across different tumor types was 11% in the BRCA1 (N¼27) and 21% in the BRCA2 (N¼27) mutated cohorts. Partial responseswere seen in pancreatic cancer, gallbladder cancer, endocrine carcinoma of the pancreas and parathyroid cancer. One patient with a BRCA2 germline mutated colon cancer has an ongoing CR with 19+ months on treatment. mPFS in responding patients is 14+ months (5-34+ months). The clinical beneﬁt rate was 63% in the BRCA1 and 46% in the BRCA2 mutated cohorts. No clinical activity was observed in the ATM(N¼13) and CHEK2 (N¼14) cohorts. Safety data were consistent with the knownproﬁle of olaparib.

Conclusions: Olaparib showed efﬁcacy in different cancer types harboring somatic or germline mutations in the BRCA1/2 genes but not in ATM and CHEK2. Patients with

|Table:153P |Table:153P |Table:153P |Table:153P |Table:153P |Table:153P |Table:153P |Table:153P |Table:153P |Table:153P |Table:153P ||| |---|---|---|---|---|---|---|---|---|---|---|---|---|

||BRCA 1 |BRCA 1 |BRCA 1 |BRCA 1 ||BRCA 2 |BRCA 2 |BRCA 2 |BRCA 2 |BRCA 2 ||TOTAL |

||RING |DBD |BRCT |Others ||Total |PALB2-BD |RAD51 |DBD |Others |Total ||

|Healthy carrier |3 |21 |41 |38 ||103 |2 |55 |5 |19 |81 |184 |

|Breast |1 |2 |20 |13 ||36 |1 |17 |3 |7 |28 |64 |

|Ovarian |1 |2 |7 |8 ||18 |0 |6 |2 |4 |12 |30 |

|Pancreas |0 |0 |1 |0 ||1 |0 |1 |0 |2 |3 |4 |

|Othertumors* |0 |1 |0 |0 ||1 |0 |6 |0 |1 |7 |8 |

|Total |5 (3.1%) |26 (16.4%) |69 (43.4%) |59 |(37.1%) |159 |3(2.3%) |85 (64.9%) |10 (7.6%) |33 (25.2%) |131 |290 |

|Meanage at diagnosis |53 |63 |44 |43.9 ||46 |51 |51 |43 |49 |49 |47 |

umors: cholangiocarcinoma, medulloblastoma, urotelial, astrocitoma, cervical and

any cancer type harboring BRCA1/2 mutations should have access to olaparib with real-world documentation of efﬁcacy in a retrospective register.

Clinical trial identiﬁcation: NCT03967938.

Legal entity responsible for the study: Belgian Society of Medical Oncology (BSMO).

Funding: Kom op tegen Kanker , Fondation contre le Cancer, AstraZeneca and MSD(unrestricted grant, olaparib).

Disclosure: S.R. Joris: Non-Financial Interests, Institutional, Advisory Role: AstraZeneca; NonFinancial Interests, Institutional, Sponsor/Funding: AstraZeneca, MSD. H. Denys: Non-Financial Interests, Institutional, Advisory Role: pﬁzer, Roche, PharmaMar, AstraZeneca, Eli Lilly, Novartis,Amgen, GSK, Seagen, MSD, Gilead. P.G. Aftimos: Non-Financial Interests, Institutional, Research Grant: Roche; Non-Financial Interests, Institutional, Other, Consulting: Boehringer Ingelheim, Macrogenics, Roche, Novartis, Amcure; Financial Interests, Institutional, Other, Consulting: Servier, G1 therapeutics, Radius, Deloitte; Financial Interests, Institutional, Other, Honoraria: Synthon, Amgen,Novartis; Financial Interests, Institutional, Other, Honoraria: Gilead, Lilly, Daiichi Sankyo. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2876

153P

melanom

Descriptive analysis of the location of point mutations in BRCA and the risk of breast or ovarian cancer diagnosis

P. Torres-Mozas, F. Galvez Montosa, N. Luque Caro, F.J.G. Verdejo,

A.L.O. Ortega Granados, J. Requena Aguilar, J.Z. Benoit Perejón, R. Garcia Munoz,G.P. Vinueza Hidalgo, I. Fernández Ros, P. Sanchez-Rovira

Medical Oncology, Hospital Universitario de Jaén, Jaén, Spain

Background: Within BRCA carriers, there are data suggesting that not all alterations confer the same risk of breast or ovarian cancer. In addition, the localization of the mutation as a biomarker of response to targeted therapies such as iPARP is in the process of being validated. The distribution of mutations according to the functional domain in which they are located may be a good method for establish their role in cancer risk.

Methods: We included all carriers from the registry of the Hereditary Cancer Unit.

Functional domains (dom) of BRCA1 were deﬁned as: Really Interesting New Gene(RING) from aa 8-96; DNA-binding dom (DBD) from aa 452-1092; and BRCA1 C terminal (BRCT) from aa 1650-1863 Functional doms of BRCA2 were deﬁned as: PALB2-BD dom from aa 21-39, RAD51-binding dom (RAD51-BD) from aa 900-2000, and DBD from aa 2459-3190.

Results: 284 carriers were located. 66% women, 55% BRCA1 mutation carriers (mc).

Of these, 63% healthy carriers (hc), half of whom were women. Among the BRCA1 muts, 55% of breast cancer (bc) were associated with BRCT muts compared with 5.5%in DBD. In the BRCT dom, the mean age at diagnosis (dx) of bc was 44 years, with 35%of luminal tumors. Among hc, only 33% were older than the mean age at dx. Among the BRCA2 muts, 61% of the cases with bc were associated with the RAD51-BD dom compared to 10% in the DBD dom. In the RAD51-BD dom, the mean age at dx of bc was 51 years, with 11% of cases being Her-2 positive and 29% triple negative. Among hc, only 40% were older than the median age at dx. As for ovarian cancer, a more heterogeneous pattern was observed, although again, the doms with the most cases were BRCT and RAD51-BD.

Conclusions: The characterization of the mut population can provide data for the personalization of follow-up. In our population, the age of hc is shown as a bias for the deﬁnition of risk, so more follow-up and multicenter studies are needed to validate the results.

https://doi.org/10.1016/j.annonc.2023.09.2877

a, all with 1 case reported.

154P

Highly sensitive serum volatolomic biomarkers for pancreatic cancer diagnosis and prognosis

A. Martínez1, A. Martín-Carnicero2, M.T. Tena3, M.P. Martínez-Moral1

1Oncology, Center for Biomedical Research of La Rioja (CIBIR), Logroño, Spain;2Medical Oncology, Hospital San Pedro, Logrono, Spain; 3Department of Chemistry,Universidad de la Rioja, Logroño (La Rioja), Spain

Background: Pancreatic adenocarcinoma (PAC) is one of the most lethal kinds of cancer. PAC is usually diagnosed very late, thus limiting treatment options and leading to low survival rates. Volatile organic compounds (VOCs) are ﬁnal metabolism products that can be detected in a number of ﬂuids. Our goal was to identify and validate diagnostic and prognostic PAC biomarkers in serum samples.

Methods: Twenty PAC patients and a sex/age matched control group (n¼19) wererecruited. A second group of 5 patients and 5 healthy volunteers was used for validation. IRB approval was provided by “Comité de Ética de Investigación con Medicamentos de La Rioja (CEImLar)” and all subjects signed the informed consent. A Varian CP-3800 gas chromatographer coupled to a Saturn 2200 ion trap mass spectrometer was used for the non-targeted analysis of VOCs. Surrogate standards were added to all serum samples, that were heated at 50C and VOCs were collected into added to all serum samples, that were heated at 50°C and VOCs were collected into aa 50/30 mm CAR/PDMS/DVB ﬁber (Supelco). Desorption was done at 250C for 50/30 μm CAR/PDMS/DVB fiber (Supelco). Desorption was done at 250°C for 3030 seconds in the injection port. MassHunter software (Agilent) was used for chromatogram processing including deconvolution of the signals.

Results: The volatolomic proﬁle identiﬁed 433 VOCs in serum. Of these, 40 were able to distinguish cases from controls (diagnostic biomarkers). Unsupervised PCA and heatmaps, as well as supervised PLS-DA, showed a clear separation of cases vs controls. ROC curves indicated that 19 VOCs showed excellent predictive potential,with AUC > 0.90. The validation cohort conﬁrmed the predictive value of 11 VOCs.

Prognostic VOCs were identiﬁed by comparing patients that survived more than one year after diagnosis with those who did not. Sixteen VOCs showed prognostic discrimination and 3 of them had ROC with AUC > 0.86. Furthermore, the chemical structure of 4 of the main VOCs was conﬁrmed by comparison with standards.

Conclusions: We have identiﬁed a panel of VOCs that correctly classify patients from controls and predict patient survival with high speciﬁcity and sensitivity. Reliable biomarkers may open the door to new technologies and the early detection of PAC.

Funding: ADER (Project Hequipa, 2018-I-IDD-00059).

https://doi.org/10.1016/j.annonc.2023.09.2878

155P Exploring the utility of serum anti-tNASP antibodies as a screening biomarker in prostate, pancreatic, and ovarian cancer

O. Alekseev1, X. Yi2, M. Kasmenn2, S. Kundu2, M. Rogers2, Z. Vaskalis2

1Physiology and Pathophysiology Department, Campbell University, Buies Creek, NC,USA; 2CUSOM, Campbell University School of Osteopathic Medicine, Lillington, NC,USA

Background: Nuclear auto-antigenic sperm protein (NASP) is a histone chaperone and a facilitator of chromatin assembly. One of two NASP splice variants, tNASP, is speciﬁc to the testis, where it is sequestered by the blood-testis barrier and also present in cancer cells. Exposure of tNASP from the cancer cells to the immune system induces a robust humoral immune response. We hypothesized that the autoantibodies produced against tNASP may be used as a supplementary diagnostic marker for prostate,pancreatic, and ovarian cancer.

Methods: Sera from patients with pancreatic cancer (74), prostate cancer (63), and ovarian cancer (19) were tested for the presence of antibodies against tNASP using enzyme-linked immunosorbent assay (ELISA) with a recombinant tNASP fragment as bait. Correlation analysis was used to determine correlations between anti-tNASP antibody level and the age, ethnicity, TMN staging, and diagnostic marker levels (PSA in the prostate cancer and CA19-9 in pancreatic cancer).

Results: Level of anti-tNASP antibody in prostate cancer patients ranged from 426 to 3810 mg/mL and was signiﬁcantly higher compared to healthy individuals (p<0.01).

The cutoff for anti-tNASP antibody thus was established at 400 mg/mL. Combined analysis of anti-tNASP and PSA tests demonstrated that 18% of PC patients with PSA higher than 4 ng/mL had a low level of anti-tNASP antibody (false positive PSA,supported by negative biopsy); 11.4% of PC patients with PSA lower than 4 ng/mL had high levels of anti-tNASP antibodies (false negative PSA, proved histologically).

Level of anti-tNASP antibody in pancreatic cancer patients ranged from 564 to 2751 mg/mL and was signiﬁcantly higher compared to healthy individuals (p<0.01). Correlations between expression of tNASP antibody and levels of CA19-9 are not conclusive. There is a signiﬁcant difference in tNASP antibody concentrations between serum from patients with ovarian cancer and serum from the control group of patients.

Conclusions: Expression of serum anti-tNASP antibody is not a speciﬁc screening marker for prostate, pancreatic, or ovarian cancer. Combined use of PSA with anti34 - Issue S2 - 2023

tNASP antibody analysis reveals signiﬁcant elimination of false positive and false negative PSA test results.

Funding: Campbell University, USA.

https://doi.org/10.1016/j.annonc.2023.09.2879

156P The association between ﬁbrotic endotypes, determined by pre-treatment serum levels of collagen metabolites, and survival outcomes in patients with pancreatic cancer

R.S. Pedersen1, J. Thorlacius-Ussing2, N.I. Nissen2, A. Johansen3, I. Chen3, C. Jensen2,C. Hansen4, M. Karsdal2, J.S. Johansen3, N. Willumsen2

1Department of Biomedical Sciences, Copenhagen University, Copenhagen, Denmark;2Biomarkers and Research, Nordic Bioscience A/S, Herlev, Denmark; 3Department of Oncology, Herlev and Gentofte Hospital, Herlev, Denmark; 4Department of Surgery,Rigshospitalet, Copenhagen, Denmark

Background: Abnormal collagen ﬁber architectures in tumor ﬁbrosis affect prognosis and treatment response in pancreatic cancer (PC) patients. Increased ﬁbrotic activity releases collagen metabolites into the bloodstream. The aim was to explore these metabolites to cluster PC patients into tumor ﬁbrosis endotypes and evaluate overall survival (OS).

Methods: Serum was collected from patients with PC prior to chemotherapy or resection and included in the BIOPAC Study (ID: NCT03311776) (stage I (n¼15), StageII (n¼201), stage III (n¼164) and stage 4 (n¼434)). Principal component analysis wasperformed on the levels of ﬁve collagen metabolites (Table) measured by ELISAs. Kmeans clustering was used to discover clusters and Kaplan-Meier curves and the cox proportional hazards model used to dicover associations with OS.

|Table: 156P || |---|---|

|Biomarker |name collagen metabolite |

|C3M |Neo-epitope of MMP-9 mediated degradation of type III collagen |

|PRO-C3 |Released N-terminal pro-peptide of type III collagen |

|PRO-C5 |Released C-terminal pro-peptide of type V collagen |

|PRO-C6 |C-terminal of released C5 domain of type VI collagen a3 c (endotrophin) |

|PRO-C11 |Released N-terminal pro-peptide of type XI collagen |

hain

Results: Three putative endotypes (cluster A, B, C) were identiﬁed. Patients in cluster B had higher C3M, PRO-C5 and PRO-C11 levels compared to cluster A, whereas patients in cluster C had higher PRO-C3 and PRO-C6 levels compared to cluster A. Patients with endotype A had a median OS of 332 days vs. 185 and 144 days for endotype B and C (p<0.001). Compared to endotype A, both endotype B (HR¼1.56,95% CI 1.28e1.91, p<0.001) and endotype C (HR¼1.69, 95% CI 1.26e2.26, p<0.001)were predictors of poor OS when corrected for age, sex, performance status, body mass index, diabetes, cachexia, stage, number of metastatic sites, and CA19-9.

Conclusions: Clustering of patients with PC based on ﬁve collagen-derived metabolites measured in serum identiﬁes 3 distinct endotypes that were associated with poor OS independent of other common risk factors. These ﬁndings indicate that noninvasive collagen biomarkers can be used to identify ﬁbrotic endotypes in patients with PC and that such endotypes may inform on patient prognostication.

Funding: The Danish Research Foundation.

Disclosure: J. Thorlacius-Ussing, N.I. Nissen, C. Jensen, M. Karsdal, N. Willumsen: Financial Interests, Institutional, Full or part-time Employment: Nordic bioscience A/S. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2880

S243

157P

S244

CLDN18 fusions rather than expression is a biomarker

related to the efﬁcacy of paclitaxel in patients with ovarian metastasis of gastric cancer

P. Yu1, Y. Cao1, X. Chen1, W. Wu2, Q. Xu3, J. Fang1, X. Huang1, X. Shi4, W. Zhizheng4,Z. Ye1, F. Pang5, Y. Du6, X. Cheng1

1Department of Gastric Surgery, Cancer Hospital of the University of Chinese Academy of Sciences/ Zhejiang Cancer Hospital, Hangzhou, China; 2Department of Pathology,Cancer Hospital of the University of Chinese Academy of Sciences/ Zhejiang Cancer Hospital, Hangzhou, China; 3Department of Oncology, Cancer Hospital of the University of Chinese Academy of Sciences/ Zhejiang Cancer Hospital, Hangzhou, China;4Medical Products Department, Shanghai OrigiMed Co., Ltd., Shanghai, China;5Medical Department, OrigiMed, Shanghai, China; 6Department of Gastric Surgery,Zhejiang Cancer Hospital - Cancer Research Institute, Hangzhou, China

Background: Paclitaxel inhibits cellular microtubule depolymerisation and has antitumor effects in patients with ovarian metastases from gastric cancer. CLDN18 is aberrantly expressed in gastric cancer and plays an important role in tumor invasion and metastasis. However, the relationship between CLDN18 and the efﬁcacy of paclitaxel is lacking in research.

Methods: A total of 74 GC patients with ovarian metastasis treated with paclitaxel were included in the study. 65 primary gastric and 73 ovarian metastatic tumor samples were collected from the enrolled patients, including 64 pairs of matched primary gastric and metastatic ovarian tumor samples. WES was performed with a mean coverage depth of 187x (range: 108-344x) for tumor samples. Immunohistochemistry (IHC) was performed on tissue samples to detect CLDN18 expression.

Results: Of 74 patients, 41 responded to paclitaxel (the "effective" group), while 33 did not respond (the "ineffective" group). Statistical analysis revealed that mutations in RHOA (p ¼ 0.037), AFF2 (p ¼ 0.028), PIK3CD (p ¼ 0.028), and TAF1L (p ¼ 0.028)were associated with the ineffectiveness of paclitaxel treatment, while mutations in SALL4 (p ¼ 0.036), CCDC105 (p ¼ 0.018), and CLDN18 (p ¼ 0.036) were associatedwith a positive response to paclitaxel treatment. IHC was performed on six CLDN18 fusion patients and twelve patients with different responses to paclitaxel. Of CLDN18 fusion patients, four were CLDN18-positive and two were CLDN18-negative, indicating that CLDN18 fusion did not correlate with CLDN18 expression. CLDN18 expression was positive in nine patients who responded to paclitaxel treatment and four patients who did not, and negative in two patients who responded and three who did not.

Statistical analysis indicated that there was no signiﬁcant correlation between the effect of paclitaxel treatment and the expression of CLDN18 (9/11 vs. 4/7, p ¼ 0.17).

Conclusions: We have identiﬁed potential biomarkers, including CLDN18, that could predict the efﬁcacy of paclitaxel treatment based on the differential response to treatment. We have also conﬁrmed that CLDN18 fusion is a potential predictive biomarker for paclitaxel treatment response, independent of CLDN18 expression.

https://doi.org/10.1016/j.annonc.2023.09.2881

158P In silico analysis of HER2 enriched subtype and a HER2 index based on transcriptomic data of breast cancer compared to gastric and uterine serous carcinomas

A. Gonzalez-Vilanova1, T.C. Fleitas2, L. Gaba Garcia3, S. Zuniga-Trejos1,J.A. Perez Fidalgo4

1Biostatistics, INCLIVA Instituto de Investigación Sanitaria, Valencia, Spain; 2Medical Oncology Department, Hospital Clinico Universitario de Valencia, Valencia, Spain;3Dept. Medical Oncology, Hospital Clinic y Provincial de Barcelona, Barcelona, Spain;4Dept. Medical Oncology, Hospital Clinico Universitario de Valencia, Valencia, Spain

Background: In Breast cancer (BC) PAM50 platform has identiﬁed a HER2-enriched(HER2E) subgroup with predictive and prognosis implications. Our study aimed to perform an in-silico analysis to conﬁrm the prognostic role and the association of two genomic signatures (HER2E and HER2index) with the HER2 expression in gastric (GC)and Uterine serous carcinoma (USC) in comparison to BC.

Methods:We extracted clinical, transcriptomic, and proteome data of primary tumors from 3 publicly available databases: 1) TCGA-BRCA of BC (n¼1095), 2) TCGA-STAD ofGC (n¼412), and 3) TCGA-UCEC (serous subtype) of USC (n¼138). Patients wereclassiﬁed according to the PAM50 deﬁnition of breast cancer. Moreover, we calculated the correlation of the tumor expression proﬁles with the HER2 index signature(Li et al 2020 ). The association of the HER2-related, expression-based biomarkers with overall survival was calculated with independent Cox Proportional Hazard models,separately for each TCGA cohort.

Results: In the BC dataset, HER2E subtype was positively correlated with HER2mRNA and HER2protein (HER2p) (p<0.001 ) with a trend towards a correlation with HER2phospoprotein (pp). HER2 index in BC was correlated with HER2pp (p<0.001)and non-signifcantly with HER2mRNA (p¼0.069), and HER2p (p¼0.087). Both HER2Eand HER2index showed an impaired survival in BC (p¼0.032 and p¼0.002 respec-tively). In GC cohort, no correlation was found between HER2E and HER2mRNA. HER2 index was correlated only with HER2mRNA (p<0.001). HER2E and HER2 index were

not associated with survival. For the USC cohort, HER2E and HER2index were not correlated with HER2mRNA, HER2p, or HER2p, although HER2E showed a trend towards a positive association with HER2mRNA and HER2p (p¼0.059 and 0.053respectively). These signatures were not prognostic in terms of PFS in the USC cohort(HER2E p¼0.284 and HER2 index p¼0.771).

Conclusions: HER2E subtype of PAM50 and HER2 index signatures showed signiﬁcant correlations with HER2 expression and survival in BC, however when these signatures were applied to other HER2 tumors such as GC or USC the prognostic role and correlation with the HER2 protein expression is limited.

Legal entity responsible for the study: INCLIVA.

Disclosure: T.C. Fleitas: Financial Interests, Personal, Invited Speaker, Update on the ongoing treatment strategies for GEA: Servier; Financial Interests, Personal, Invited Speaker, The clinical impact of NRTK strategies in GI tumors: Bayer; Financial Interests, Personal, Invited Speaker, Invited as a speaker in an educational session.: Bristol, Amgen; Financial Interests, Personal, Invited Speaker,Invited speaker in an educational session: Bristol, MSD, Lilly, Roche; Non-Financial Interests, Principal Investigator, PI of SURPASS-2 study: Adapt Immune; Non-Financial Interests, Principal Investigator, PI of a clinical trial in GEA tumors: Daichii Sankyo; Non-Financial Interests, Principal Investigator, PI of a clinical trial: BeiGene. J.A. Perez Fidalgo: Financial Interests, Personal, Advisory Board: AstraZeneca,MSD, GSK, PharmaMar, Eisai, Clovis; Financial Interests, Personal, Invited Speaker: AstraZeneca, GSK,PharmaMar; Financial Interests, Institutional, Research Grant: GSK, AstraZeneca, PharmaMar. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2882

159P Better performance of pan-claudin18 antibodies on claudin18.2 detection in gastric adenocarcinoma than claudin18.2 speciﬁc antibody

S. Ni1,W. Sheng1,W. Su2, H. Lu3, Q. Yan3, J. Xu3, C. Hua3, Z. Huang2, L. Ruan3, C. Zhu2

1Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai,China; 2Department of Translational Medicine, Amoy Diagnostics Co., Ltd., Xiamen,China; 3Department of Research and Development, Amoy Diagnostics Co., Ltd., Xiamen, China

Background: The claudin18 isoform 2 (CLDN18.2), a member of the tight junction protein family, is a highly selective target for development of novel therapies in various primary malignant tumors. Due to the interference of CLDN18.1, which is highly homologous to CLDN18.2, selection of appropriate antibodies still need to be further identiﬁed.

Methods: Expression of CLDN18.2 was evaluated in a total of 66 gastric adenocarcinoma samples by immunohistochemistry(IHC) using the pan-CLDN18 antibodies(clone 43-14A and clone MM02), which recognizes both CLDN18.2 and CLDN18.1, and the CLDN18.2-speciﬁc antibody (clone EPR19202-244). The results were further veriﬁed by qPCR and CLDN18.1-speciﬁc antibody respectively.

Results: The CLDN18.2 expression evaluated by 43-14A and MM02 showed highly consistentat in different eligibility criterions ( 2+ membrane staining intensity in consistentat in different eligibility criterions (≥ 2+ membrane staining intensity in≥40% or ≥75% of tumor cells) with 95.45% and 90.91% overall percent agree-40% or 75% of tumor cells) with 95.45% and 90.91% overall percent agree-ments(OPA) respectively. While EPR19202-244 showed low sensitivity (84.38%)compared with 43-14A, even after readjusting the optimal threshold according to the ROC curve and Youden index. CLDN18, CLDN18.1 and CLDN18.2 mRNAs were further measured via quantative real-time PCR and IHC for CLDN18.1 was applied. It was veriﬁed that all those samples determined to be negative for CLDN18.2 by EPR19202-244 but positive for CLDN18 by pan-CLDN18 antibodies should be identiﬁed as true positive for CLDN18.2.

|Table: 159P Comparison of clone 43-14A, clone MM02, and clone |Table: 159P Comparison of clone 43-14A, clone MM02, and clone |Table: 159P Comparison of clone 43-14A, clone MM02, and clone |Table: 159P Comparison of clone 43-14A, clone MM02, and clone |Table: 159P Comparison of clone 43-14A, clone MM02, and clone |Table: 159P Comparison of clone 43-14A, clone MM02, and clone |Table: 159P Comparison of clone 43-14A, clone MM02, and clone |Table: 159P Comparison of clone 43-14A, clone MM02, and clone |EPR19202-244 | |---|---|---|---|---|---|---|---|---|

||43-14A/MM02/EPR19202-244 |43-14A/MM02/EPR19202-244 |43-14A/MM02/EPR19202-244 |43-14A/MM02/EPR19202-244 |43-14A/MM02/EPR19202-244 |43-14A/MM02/EPR19202-244 |43-14A/MM02/EPR19202-244 ||

||+/+/+ |+/+/- |+/-/- |-/+/- |-/-/+ |-/+/+ |-/-/- |Total |

|Samples |29 |7 |0 |2 |2 |1 |25 |66 |

|Samples were veriﬁed |20 |5 |/ |2 |1 |0 |9 |37 |

|qPCR pan-CLDN18 |19 |4 ||2 |0 |/ |1* ||

|CLDN18.2 |19 |4 ||2 |0 ||0 ||

|CLDN18.1 |0 |0 ||0 |0 ||1* ||

|IHC CLDN18.1-speciﬁc |0 |0 ||0 |0 ||0 ||

Note: ≥2+ intensity in ≥40% tumor cells defined as CLDN18.2-positive for 43-14A2+ intensity in 40% tumor cells deﬁned as CLDN18.2-positive for 43-14Aand and MM02, and ≥2+ ≥25% for EPR19202-24. *: Possibly due to technical differ-MM02, and 2+ 25% for EPR19202-24. *：Possibly due to technical differ-ences in qPCR and IHC

Conclusions: Our results clarify the differences between EPR19202-244, 43-14A and MM02, and suggesting a higher sensitivity and speciﬁcity of pan-claudin18 antibodies,which should be used for the dectction of CLDN18.2.

Disclosure: W. Su, H. Lu, Q. Yan, J. Xu, C. Hua, Z. Huang, L. Ruan, C. Zhu: Financial Interests,Personal, Full or part-time Employment: Amoy Diagnostics. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2883

160P

Real-world practices and physician perspectives on

biomarker testing and treatment patterns in patients with locally advanced unresectable or metastatic (La/m) gastric/gastroesophageal junction (G/GEJ) adenocarcinoma in the US

K. Lewis1, R. Fuldeore2, S. Braun3, G. Gourgioti4, A. Lambert1, G. Thomason1,K. Bernacki2, J. Yang5

1Oncology and Rare Diseases, Adelphi Real World, Bollington, UK; 2Medical Affairs,Astellas Pharma Global Development, Inc., Northbrook, IL, USA; 3Medical Affairs, US Oncology, Astellas Pharma Global Development, Inc., Northbrook, IL, USA; 4Biostatistics, Astellas Pharma Europe Ltd, Addlestone, UK; 5Department of Medicine, Memorial Sloan Kettering Cancer Center,Weill Cornell Medical College, New York, NY, USA

Background: Human epidermal growth factor receptor 2 (HER2)-targeted therapy and immunotherapy have improved survival outcomes for patients with La/m G/GEJ adenocarcinoma. Biomarker testing for mismatch repair (MMR) or microsatellite instability (MSI), HER2, and programmed-death ligand 1 (PD-L1) is critical for determining appropriate therapy. We describe real-world data on testing and treatment patterns using the Adelphi Disease Speciﬁc Program (DSP).

Methods: Data was collected using the Adelphi’s DSP, a cross-sectional survey of US physicians taken between Sept 2022 and Feb 2023. Patients included those diagnosed with La/m G/GEJ adenocarcinoma on or after Jan 2021. Current biomarker testing treatment patterns, and physician attitudes were analyzed descriptively.

Results: Of the 438 pt records received from 60 treating physicians, 338 pts (77%) had La/m G/GEJ adenocarcinoma. Most pts had de novo (85%) disease, 71% were on ﬁrstline (1L) therapy and 29% on second line. Fluorouracil-based regimens were most common in 1L. MSI/MMR testing increased over time. Regardless of disease stage,almost all physicians (97%) reported biomarker testing at initial diagnosis to be“important” to “extremely important”. However, only a subset of patients had testing performed (Table): HER2 (69%), PD-L1 (51%), and MSI/MMR (44%); 18% had no biomarker testing.

|Table: 160P Biomarker testing patterns |Table: 160P Biomarker testing patterns |Table: 160P Biomarker testing patterns |Table: 160P Biomarker testing patterns |Table: 160P Biomarker testing patterns |Table: 160P Biomarker testing patterns |Table: 160P Biomarker testing patterns |Table: 160P Biomarker testing patterns |Table: 160P Biomarker testing patterns |Table: 160P Biomarker testing patterns | |---|---|---|---|---|---|---|---|---|---|

||||2021 |2021 |2022 ||2023 |2023 ||

|Overall |338 ||44 ||207 ||17 |||

|HER2 |234 |(69) |24 |(55) |157 |(76) |11 |(65)|(65) |

|PD-1 |110 |(33) |8 |(18) |70 |(34) |9 |(53) ||

|PD-L1 |172 |(51) |16 |(36) |115 |(56) |8 |(47)|(47) |

|MSI/MMR IHC |148 |(44) |11 |(25) |103 |(50) |9 |(53) ||

|VEGFR-2 |54 |(16) |4 |(9) |34 |(16) |5 |(29) ||

|CDH-1 |35 |(10) |3 |(7) |18 |(9) |5 |(29) ||

|CLDN 18.2 |25 |(7) |2 |(5) |15 |(7) |5 |(29)|(29) |

|NTRK gene fusion |60 |(18) |4 |(9) |40 |(19) |5 |(29) ||

|EBV |48 |(14) |6 |(14) |32 |(15) |5 |(29) ||

|NTRK |58 |(17) |4 |(9) |39 |(19) |5 |(29)|(29) |

|FGFR2 |61 |(18) |3 |(7) |40 |(19) |5 |(29)|(29) |

|FGFR2b |46 |(14) |3 |(7) |31 |(15) |5 |(29) ||

|No biomarker/genetic tests conducted |60 |(18) |9 |(20) |31 |(15) |5 |(29)|(29) |

34 - IssueS2 - 2023

Conclusions: This study describes potential gaps in biomarker testing in real-world practice for pts with La/m G/GEJ adenocarcinoma. Despite most physicians reporting biomarker testing to be important at the time of diagnosis, only a subset of patients had testing reported. This outcome highlights a need to understand barriers to testing in clinical practice and to establish routine testing as standard of care.

Editorial acknowledgement: Medical writing support was provided in accordance with the Good Publication Practice 2022 Update ( GPP 2022) and the International Committee of Medical Journal Editors (ICMJE) guidelines by George Pellegrino, MD,PhD, of Oxford PharmaGenesis Inc., Newtown, PA, USA, and was funded by Astellas Pharma, Inc.

Legal entity responsible for the study: This study, utilizing Adelphi Real World’s DSPTM was sponsored by Astellas Pharma, Inc. Data collection was undertaken by Adelphi Real World as part of an independent survey, entitled the “Adelphi Real World Advanced Gastric Cancer DSP.” The DSP is a wholly owned Adelphi Real World product. Astellas were one of multiple subscribers to the DSP.

Funding: This study, utilizing Adelphi Real World’s DSPTM was sponsored by Astellas Pharma, Inc. Data collection was undertaken by Adelphi Real World as part of an independent survey, entitled the “Adelphi Real World Advanced Gastric Cancer DSP.”The DSP is a wholly owned Adelphi Real World product. Astellas were one of multiple subscribers to the DSP.

Disclosure: K. Lewis, A. Lambert, G. Thomason: Financial Interests, Personal, Full or part-time Employment: Adelphi Real World. R. Fuldeore, S. Braun, K. Bernacki: Financial Interests, Personal,Full or part-time Employment: Astellas Pharma Global Development, Inc. G. Gourgioti: Financial Interests, Personal, Full or part-time Employment: Astellas Pharma Europe, Ltd. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2884

161P Biomarkers of neoadjuvant combinational therapy for locally advanced gastric or gastroesophageal junction adenocarcinoma

Y. Wang1, J. Yang1, X. Zhou2, Q. Liu1, Y. Yang1, W. Guan3, B. Liu1, J. Wei1

1The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, China;2The Comprehensive Cancer Centre, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine,Nanjing, China; 3General Surgery Department, Medical School of Nanjing University &Clinical Cancer Institute of Nanjing University, Nanjing, China

Background: Gastric or gastroesophageal junction (G/GEJ) cancers is one of the most common lethal malignancies in the world. Nearly half of the G/GEJ cancers are locally advanced at diagnosis and with poor prognosis. Several clinical trials demonstrated that perioperative anti-PD-1 therapy in combination with concurrent chemoradiotherapy (cCRT) for locally advanced G/GEJ cancers could raise the pCR rate over 30%. However, the biomarkers for patients with pCR are nor clear.

Methods: 34 patients with locally advanced G/GEJ cancer received neoadjuvant sintilimab in combination with cCRT followed by gastrectomy and adjuvant sintilimab and chemotherapy in our center. Baseline tumor biopsies and post-treatment surgical tissues were collected for multiplex immunoﬂuorescence (mIF), next-generation sequencing (NGS) and mass cytometry (CyTOF).

Results: Our results met the pre-speciﬁed primary endpoint, with a pCR rate of 38.2%and median DFS of 17.0 months. Biomarker analysis by mIF showed that patients with positive PD-L1 expression showed a numerically higher pCR rate. Also, higher levels of inﬁltrating CD3+T cells, CD4+T cells, and CD56+natural killers (NKs) were found in patients achieving pCR than those not achieving pCR (non-pCR). Moreover, the proportion of CD127+CD27+HLA-DR-CD38-CD4 TCM deﬁned by CyTOF was signiﬁcantly lower in pCR patients. Also, tumor mutation burden (TMB) analyzed by NGS was signiﬁcantly higher in the pCR group. Clone evolution can explain the therapy efﬁcacy,and could be deployed to overcame therapy resistance. Deletion of cytoband 7q35,where TPK1 locates, was signiﬁcantly enriched in pCR groups while deletion of 11q14.3, which TRIM family sitting, was signiﬁcantly enriched in non-pCR groups.

Conclusions: It is consistent with the acknowledged prognostic biomarker of immunotherapy that positive PD-L1 expression, higher T cell inﬁltration and TMB could be predictive biomarkers of perioperative anti-PD-1 therapy in combination with cCRT for locally advanced G/GEJ. Furthermore, we found a new TCM subtype deﬁned with CD127+CD27+HLA-DR-CD38-and deletion of cytoband 7q35 or 11q14.3 could be novel biomarkers.

Clinical trial identiﬁcation: The study protocol was published previously. Wei, J. et al.

Efﬁcacy and Safety of Sintilimab in Combination with Concurrent Chemoradiotherapy for Locally Advanced Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma(SHARED): Study Protocol of a Prospective, Multi-Center, Single-Arm Phase 2 Trial.

Cancer Manag Res 14, 2007-2015, https://doi.org/10.2147/CMAR.S355687 (2022).

https://doi.org/10.1016/j.annonc.2023.09.2885

162P MR imaging biomarkers proﬁles in patients with prostate cancer treated with androgen deprivation therapy

A.L. Sanchez Iglesias1, V. Morillo Macías1, A. Nogué Infante2, M. Domingo2,V. Aznar1, R. Yebana2, C. Puerto Frances1, A. Fuster-Matanzo2, P. Plaza Ortega1,F. Bellvis Bataller2, R. Muelas Soria1, A. Alberich Bayarri2, C. Ferrer Albiach1

1Radiation Oncology, Consorcio Hospitalario Provincial De Castellon, Castellon, Spain;2Quibim - Quantitative Imaging Biomarkers in Medicine, Valencia, Spain

Background: Radiomics has emerged as a potential tool to predict clinical outcomes in prostate cancer (Pca ). MRI has a fundamental role in staging and radiotherapy planning, being affected in the case of receiving prior androgen deprivation treatment(ADT). The aim of this study was to determine imaging biomarker proﬁles that allow to identify patients with a worse prognosis and a higher risk of biochemical relapse(BQR).

S245

|Table: 163P Pts with molecular response and correlation between baseline biomarker status and radiographic response |Table: 163P Pts with molecular response and correlation between baseline biomarker status and radiographic response |Table: 163P Pts with molecular response and correlation between baseline biomarker status and radiographic response |Table: 163P Pts with molecular response and correlation between baseline biomarker status and radiographic response |Table: 163P Pts with molecular response and correlation between baseline biomarker status and radiographic response |Table: 163P Pts with molecular response and correlation between baseline biomarker status and radiographic response |Table: 163P Pts with molecular response and correlation between baseline biomarker status and radiographic response | |---|---|---|---|---|---|---|

||All pts |All pts |CRC pts |CRC pts |CRC pts ||

|N (pts with both ctDNA and radiographic response data) |45 |45 |22 |22 |22 ||

|Pts with conﬁrmed PR, n/N (%) |11/45 (24) |11/45 (24) |4/22 (18) |4/22 (18) |4/22 (18) ||

|Pts with molecular response, n/N (%) |14/29a (48) |14/29a (48) |8/17b (47) |8/17b (47) |8/17b (47) ||

||HighHigh |HighHigh |HighHighKRAS |HighHighKRAS |HighHighKRAS |BRAF |

||TMBMSI |TMBMSI |TMBMSImut |TMBMSImut |TMBMSImut |mut |

|Pts with conﬁrmed PR with |3/200/3 |3/200/3 |3/130/12/16 |3/130/12/16 |3/130/12/16 |1/3 |

|biomarker positivity, n/N (%) |(15) |(0) |3/130/12/16 |3/130/12/16 |3/130/12/16 |1/3 |

Methods: A single-center, retrospective, observational study was designed. Baseline MRIs (T2w, DWI and/or DCE sequences) from PCa patients treated with ADT and radiotherapy were included. Using Quibim’s QP-Prostate solution, radiotherapy were included. Using Quibim's QP-Prostate solution, subregionssubregions(Transition + Central Zone [TZ + CZ], Peripheral zone [PZ] and seminal vesicles [SV])were automatically segmented. For each subregion and for the whole prostate (WP),computed using the weighted biomarkers averaging, 105 radiomic features (shape and textures) from T2w, apparent diffusion coefﬁcient (ADC) variables from DWI and perfusion parameters from DCE were extracted.

Results: As of 3 April 2023, 57 pts were efﬁcacy evaluable, including 27 pts with CRC.

The objective response rate was 25% (14/57; all conﬁrmed partial responses [cPR]) in all pts and 22% in pts with CRC (6/27; all cPR). Most prevalent gene alterations were TP53 (67%), LRP1B (43%), APC (41%), and KRAS (41%) mutations and PTPRT (45%) and TOP1 (43%) ampliﬁcations. The table shows the correlation between response and select biomarkers (at baseline) in the 45 pts (22 CRC) who had both ctDNA and radiographic response data. A molecular response was observed in 48% (14/29) of all evaluated pts and 47% (8/17) of pts with CRC; median change from baseline tumor size was -22.5% and -20.3%, respectively.

J. Powderly:Financial Interests, Personal, Other, Consulting: Boxer Capital; Financial Interests, Personal, Writing Engagement, Consulting: Aavocyte; Financial Interests, Personal, Member of Board of Directors,Founder and Owner: Carolina BioOncology Institute, PLLC, BioCytics Inc.; Financial Interests, Personal, Ownership Interest, Founder and Owner: BioCytics Inc. Therapeutics, Calico Life Sciences, Apros, Jounce Therapeutics, Atreca, Sequenom,Repertoire Immune Medicines, Molecular Templates, I-MAB Pharma, NexCure, Xilio Therapeutics,Immune-Onc, Trethera, Zenshine Pharma, Adagene, BJ BioScience, Fate Therapeutics, Conjupro BioTherapeutics, PEEL Therapeutics, CUE BioPharma, Pieris Pharmaceuticals, RiboScience, Moderna TX, Phanes Therapeutics, SK Life Science, Harbour BioMed, Simcere, Allarity, Aulos, GI Innovation,IGM BioSciences, Aptevo, Medikine, IconOVir Bio, Qurgen; Financial Interests, Institutional, Funding:Precision for Medicine, MT Group, STEMCELL Technologies, Replimmune, Merck, Xilis; Financial Interests, Personal and Institutional, Funding: PIOMA; Financial Interests, Personal and Institutional,Local PI, Also funding for contract laboratory services: Nuvation; Financial Interests, Personal and Institutional, Funding, Wugen is sponsor of contract laboratory translational research: Wugen;Financial Interests, Personal and Institutional, Other, AavoCyte & AavoBioCytics are jointly

A. Kramer1, M.J. Greuter1, S. Schraa2, G.R. Vink2, J. Phallen3, V. Velculescu3,G. Meijer4, D. Van Den Broek5, M. Koopman2, J.M.L. Roodhart2, R. Fijneman4,V.P. Retel6, V. Coupé1

1Epidemiology & Data Science, Amsterdam UMC, Locatie VUmc, Amsterdam,Netherlands; 2Medical Oncology Department, University Medical Center Utrecht(UMCU), Utrecht, Netherlands; 3Medical Oncology, Johns Hopkins Medicine - The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; 4Pathology, NKIAVL - Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam,Netherlands; 5Department of Laboratory Medicine, NKI-AVL - Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands; 6Psychosocial Research and Epidemiology, NKI-AVL - Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands

Background: After curative surgery for stage II colon cancer (CC-II), only patients with high-risk features (pT4 tumor and MSS status) are offered adjuvant chemotherapy(ACT) in the Netherlands. Nevertheless, 15% of CC-II patients develop a recurrence.

Post-operative circulating tumor DNA (ctDNA) is a prognostic biomarker that could improve selection of patients that may beneﬁt from ACT. We performed an early evaluation of the effectiveness and cost-effectiveness of ctDNA-guided selection for ACT in CC-II in the Netherlands.

Methods: The validated PATTERN model, which simulates the course of disease from diagnosis till death in CC-II, was supplemented with data on the prognostic value of ctDNA from the Dutch PLCRC-MEDOCC study. Five strategies for selecting patients for ACT were evaluated: current guideline strategy (pT4 and MSS), ctDNA-only strategy,and three combination strategies of ctDNA in addition to pT4 and MSS status. For each strategy, we estimated costs, (quality-adjusted) life-years (QALYs), recurrences and CC deaths. The impact of uncertainty concerning strategy adherence, treatment effect of ACT, costs of ctDNA testing, and test performance on cost-effectiveness was assessed in sensitivity analyses.

Results: Model predictions showed that the ctDNA-only strategy was less effective(more recurrences, less QALYs) and that the combination strategies were more effective (less recurrences, more QALYs) than the current guideline strategy. From the viewpoint of cost-effectiveness, using a willingness-to-pay threshold of V50.000/QALY, the current guideline strategy was most favorable. Sensitivity analyses showed that the combination strategies could be cost-effective if the costs of ctDNA testing are lower than V1500, and/or if ACT is more effective in ctDNA+ than in ctDNApatients. Improved ctDNA test had limited impact on the cost-effectiveness.

M. Koopman: Financial Interests, Institutional,Advisory Board, advisory board and speaker: Pierre Fabre; Financial Interests, Institutional, Advisory Board: MSD, Bayer; Financial Interests, Institutional, Advisory Board, Advisory Board, Speaker:Servier; Financial Interests, Institutional, Invited Speaker: Merck, BMS; Financial Interests, Institutional, Trial Chair: servier; Financial Interests, Institutional, Research Grant: Servier, Roche, Bayer,Bristol Myers Squibb, Merck, Personal Genomics Diagnostics, Sirtex, Pierre Fabre; Financial Interests,Institutional, Funding: Pierre Fabre, Amgen, Nordic Farma, Novartis, Merck, Servier, BMS; NonFinancial Interests, Leadership Role, Vice-Chair of DCCG: Dutch Colorectal Cancer Group; NonFinancial Interests, Advisory Role, Member of KWF scientiﬁc board: KWF; Non-Financial Interests,Other, ESMO faculty member for the Gastro-Intestinal Tumours e colorectal cancer: ESMO; Non34 - Issue S2 - 2023

Financial Interests, Advisory Role, expert member of committee “regie op registers dure geneesmiddelen” ZINNL: ZiNNL; Non-Financial Interests, Advisory Role, CRC expert on Kanker.nl platform for answering online CRC questions of CRC (non) patients: Patient respresentative organisation(Kanker.nl); Non-Financial Interests, Leadership Role, chair of RWD & DH working group: ESMO;Other, PI of the Dutch Prospective Colorectal Cancer Cohort study: PLCRC project. J.M.L. Roodhart:Financial Interests, Institutional, Sponsor/Funding: Bayer, BMS, Merck Serono, Pierre Fabre, Servier,HUB 4 organoids, Cleara Biotech. R. Fijneman: Financial Interests, Institutional, Sponsor/Funding:Cergentis BV, Personal Genome Diagnostics, Delﬁ Diagnostics, MERCK BV; Other, Personal and Institutional, Other, has several patents pending: Other. V.P. Retel: Financial Interests, Personal and Institutional, Funding: Intuitive BV. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2888

1Medical Oncology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain;2Medical Oncology Department, IOR - Instituto Oncologico Dr. Rosell, Dexeus University Hospital, Quironsalud Group, Barcelona, Barcelona, Spain; 3Medical Oncology,International Breast Cancer Center (IBCC), Pangaea Group; MEDSIR - Medica Scientia Innovation Research, Barcelona, Spain; 4Department of Pathology, Vall d’Hebron University Hospital, Barcelona, Spain; Spanish Biomedical Research Network Centre in Oncology (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain; 5Operations and Scientiﬁc Departments, MEDSIR - Medica Scientia Innovation Research, Barcelona,Spain; 6Department of Oncology and Hemato-Oncology, IEO - Istituto Europeo di Oncologia and University of Milan, Milan, Italy; 7Molecular Oncology, Hospital Arnau de Vilanova, Catholic University, Valencia, Spain; 8Medical Oncology Department,Hospital Arnau de Vilanova; MEDSIR - Medica Scientia Innovation Research, Valencia,Spain; 9Oncology Department, International Breast Cancer Center (IBCC), Pangaea Group; Universidad Europea de Madrid, Faculty of Biomedical and Health Sciences,Department of Medicine; MEDSIR - Medica Scientia Innovation Research, Madrid,Spain

Background: Trop-2 is a transmembrane calcium signal transducer widely expressed in multiple tumor types on the membrane surface of epithelial cells. Antibody-drug conjugates targeting Trop-2 are currently being developed for the treatment of breast cancer. However, there is little data regarding the therapeutic implications of Trop-2 expression in HER2-positive breast cancer.

Results: A total of 41 pts were included. Of these, 31.7% (13/41) had node-positive disease and 63.4% (26/41) were estrogen receptor-positive. 68.3% (28/41) of the tumors showed Trop-2 expression (low [29.3%]; medium [17.1%]; and high [21.9%]).

No relationship was found between Trop-2 expression and different clinicopathologic features, but there was a trend toward higher progesterone receptor negativity among Trop-2-expressing tumors (p ¼ 0.098). pCR was achieved in 63.4% (26/41) ofthe pts. According to Trop-2 expression, pCR rates were 50.0% (14/28) and 92.3% (12/13) in pts with and without Trop-2 expression, respectively (p¼0.015).

Conclusions: Trop-2 expression by IHC was identiﬁed in approximately two thirds of HER2-positive EBC pts. Trop-2 appears to be a potential mechanism of resistance in this patient population and may become a strategic target for future combinations.

S247

University of London; Other, Travel cost and expenses: Roche, Novartis, Eisai, Daiichi Sankyo, Pﬁzer,Gilead, AstraZeneca. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2889

166P

Metabolomic prediction of breast cancer treatment toxicities

M. Piffoux1, J. Jacquemin2, M. Petera3, S. Boyault4, A-L. Martin5, S. Everhard6,F. André7, B. Pistilli8, M. Fournier9, P. Rouanet10, A. Dhaini Merimeche11,

B. Sauterey12, M. Campone13, C. Tarpin14, M.A. Mouret Reynier15, O. Rigal16,T. Petit17, E. Pujos Guillot18, Y. Drouet2, O. Tredan1

1Medical Oncology Department, Centre Léon Bérard, Lyon, France; 2Direction de la Recherche Clinique et de L’innovation, Centre Léon Bérard, Lyon, France; 3Unité de Nutrition Humaine, Inrae, Aubière, France; 4Cancer Genomic, Centre Léon Bérard,Lyon, France; 5Biostatistics, Unicancer Paris, France; 6UCBG, Unicancer, Paris, France;7Breast Cancer Unit, Medical Oncology Department, Gustave Roussy - Cancer Campus,Villejuif, France; 8Breast Cancer Group, Institut Gustave Roussy, Villejuif, France;9Medical Oncology, Institute Bergonié - Centre Régional de Lutte Contre le Cancer(CLCC), Bordeaux, France; 10Medical Oncology, CRLC Val d’Aurelle, La Défense, France;11Medical Oncology, Institut de Cancérologie de Lorraine - Alexis Vautrin, Vandoeuvrelès-Nancy, France; 12Medical Oncology, ICO - Institut de Cancerologie de l’Ouest - Site Paul Papin, Angers, France; 13Medical Oncology Department, ICO Institut de Cancerologie de l’Ouest René Gauducheau, Saint-Herblain, France; 14Medical Oncology, IPC -Institut Paoli-Calmettes, Marseille, France; 15Medical Oncology, Jean Perrin Center,Clermont-Ferrand, France; 16Medical Oncology, Centre Henri Becquerel, Rouen,France; 17Medical Oncology, Centre Paul Strauss Centre de Lutte contre le Cancer,Strasbourg, France; 18Plateforme d’Exploration du Métabolisme, Metabohub, INRAE,Aubière, France

Background: Long term treatment related toxicity is a major issue for breast cancer patients in the adjuvant setting. Predicting toxicities may allow us to adapt the treatment strategy. We assessed whether the metabolomic proﬁle of patients may predict long-term toxicities.

Methods: High-resolution untargeted metabolomics was performed at baseline for 857 ER-positive, HER2- breast cancer patients from the CANTO prospective cohort.

Four metabolomic proﬁles per patient were produced: (i) shared and annotated metabolites (n¼224), (ii) annotated but not always common metabolites (n¼456), (iii)annotated but not always shared metabolites (n¼766) and (iv) all metabolites(n¼1693, FullMet). Samples were split into a discovery and validation set. Webenchmarked algorithms adapted for high dimensional analysis (LASSO, Adaptive LASSO, machine learning, and deep learning) in order to select best models for prediction.

Results: 30.0% of patients were >65 years old, 24.4% <50 years old, 20.4% had BMI>30, 12.7% had previous history of neurological disorders, 6.1% had diabetes.

69.6% presented with pT1, 25.7% with pT2 and 3.4% with pT3; 11.1% had lymph node involvement. Among all benchmarked, adaptive LASSO was the most interesting statistical method with limited optimism bias. It also allows the selection of a subset of metabolites of particular interest. The addition of rare metabolites as well as nonannotated metabolites signiﬁcantly increase the predictive power of models. Metabolic toxicity prediction mainly relied on endogenous metabolites while neurological toxicities were partly predicted using exogenous/environmental metabolites. In the validation set, compared to clinical data alone (AUC 0.50-0.54), addition of metabolomics data shows moderate (AUC ¼ 0.55-0.60) but signiﬁcant (p<0.05 adjusted formultiple comparison) predictive ability for neurological and metabolic toxicities.

Conclusions: Breast cancer patient metabolomic proﬁle at baseline improves toxicity prediction after adjuvant chemotherapy, similar to what is reported for genomicﬁngerprints. Untargeted metabolomics allows the achievement of higher performance by taking into account environmental exposure, metabolites linked to microbiota as well as rare and uncommon metabolites.

Clinical trial identiﬁcation: NCT01993498.

Funding: CANTO consortium.

https://doi.org/10.1016/j.annonc.2023.09.2890

167P A tumor immune microenvironment-based model for

prediction of everolimus efﬁcacy in premenopausal women with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer:

Preliminary results from MIRACLE trial

T. Yujing1, Y. Guan2, Y. Chen1, D. Ji1, J. Wang1, F. Ma1, Y. Luo1, P. Zhang1, X. You3,W. Xi3, Y. Song3, B. Xu1, Y. Fan1

1Medical Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College - National Cancer Center, Cancer Hospital, Beijing, China; 2Oncology, Beijing Chao-Yang Hospital, Beijing, China; 3Bioinformatics, Jiangsu Simcere Diagnostics Co.,Ltd, Nanjing, China

Background: Everolimus (EVE), a mammalian target of rapamycin (mTOR) inhibitor,has has been proven beneficial for patients with HR*/HER2, advanced breast cancerbeen proven beneﬁcial for patients with HR+/HER2, advanced breast cancer(ABC) with endocrine resistance. Preclinical studies showed mTOR has close relationships with the tumor immune microenvironment (TME). Therefore, this study aimed to identify TME-related markers to predict efﬁcacy of EVE in patients with HR+/HER2HER2 ABC.ABC.

Methods: Tumor tissues of patients from Miracle trial receiving EVE were collected for NanoString RNA expression analysis. TME cell type and TME signatures associated with efﬁcacy were identiﬁed using the 289-immuno-gene panel of NanoString nCounter platform. Multiple statistical approaches were applied for enrichment analyses, survival estimation and validation.

Results: Mast cell scores signiﬁcantly increased in patients who did not respond to EVE (P ¼ 0.031) and those who had progression-free survival (PFS) < 6 months (P ¼0.029). CD8 T cells were highly inﬁltrated in tumor tissue from patients with PFS < 1 year (P ¼ 0.035). Patients with PFS > 1 year had lower scores of chemokines (P ¼0.032) and Teff (P ¼ 0.028) than those with PFS < 6 months did. Histidine decar-boxylase (HDC), TNF receptor superfamily member 1A (TNFRSF1A), and RAD51 correlated with PFS and EVE response. Patients with HDC (P ¼ 0.013) or TNFRSF1A (P¼ 0.0031) overexpression showed shorter PFS, whereas patients with RAD51 over-expression showed prolonged PFS (P ¼ 0.049). A predictive model comprising HDC,TNFRSF1A, and RAD51 was established, and the receiver operating characteristic curve demonstrated its superiority (AUC ¼ 0.96). The results also showed that pa-tients whose tumors were non-responsive to EVE (P ¼ 0.00021) or whose PFS waspoor (P ¼ 0.0025) were at a higher risk in the model.

Conclusions: The immune-related gene model consisting of HDC, TNFRSF1A, and RAD51 could potentially predict the efﬁcacy of EVE in premenopausal patients with HR+/HER2ABC with endocrine resistance, which could help stratify responders HR/HER2 ABC with endocrine resistance, which could help stratify responders toto EVE and guide the choice of EVE in clinical practice.

https://doi.org/10.1016/j.annonc.2023.09.2891

168P HUWE1 inhibition has tumor suppressive effect in triplenegative breast cancer cell lines by modulating glycolytic and immune modulatory markers

S. Kahol, S. Mathur

Department of Pathology, AIIMS - All India Institute of Medical Sciences, New Delhi,India

Background: The E3 ligase HUWE1 is a key regulator of the DNA damage response,transcription, autophagy, apoptosis and metabolism in a variety of cancers. Due to its pivotal role in conferring substrate speciﬁcity, HUWE1 has attracted enormous attention as a promising anticancer drug target. In this study, we have studied the role of HUWE1 in triple-negative breast cancer (TNBC) cell lines and evaluated its role on aerobic glycolysis which is upregulated in cancer cells and immune modulatory markers for their roles in immunotherapy. TNBC subtype neither express hormone receptors nor Her2/neu. TNBC are highly aggressive, with poor prognosis and no welldeﬁned treatment regimen. Therefore, considering HUWE1 as an oncogene its role has been explored on glucose metabolism and immune modulation in TNBC cell lines.

Methods: Two TNBC cell lines i.e. MDA-MB-231 and MDA-MB-468 were used in the present study. These cell lines were treated with HUWE1 inhibitor: BI8622 for 24 h and the effect of inhibition was seen on its substrate (c-myc), aerobic glycolytic (HK-2,GLUT-1) and immune checkpoint markers (PDL-1, CD-47) using western blotting approach. Wound healing assays and clonogenic assays were also performed in BI8622 treated cells to check the effects of HUWE1 inhibition on migration and colony forming ability of TNBC cells in both the cell lines.

Results: As expected, there was a decrease in the protein expression levels of c-myc after the HUWE1 inhibition. Furthermore, there was decrease in protein expression of glycolytic markers i.e. HK-2 and GLUT-1 as well as immuno modulatory markers i.e.

PDL-1 and CD-47. Additionally, the HUWE1 inhibition in TNBC cells was positively associated with the inhibition of migration and clonogenic potential.

Conclusions: In this study for the ﬁrst time, we have demonstrated that HUWE1 acts as a tumor suppressor in TNBC by regulating the glucose metabolism and immune

checkpoint inhibitors. HUWE1 inhibition could functionally suppress TNBC development possibly by regulating aerobic glycolysis and immune checkpoints through cmyc.

Editorial acknowledgement: ICMR- Indian Council of Medical Research, New Delhi,India

Legal entity responsible for the study: Shruti Kahol, Sandeep Mathur.

Funding: Indian Council of Medical Research, ICMR, New Delhi.

https://doi.org/10.1016/j.annonc.2023.09.2892

169P

Integration of metabolomics and transcriptomics to reveal potential biomarkers associated with treatment response of neoadjuvant therapy in HER2+ breast cancer

N. Zhang, Y. Xiang, Z. Jing, F. Yu, J. Zeng, X. Pan, W. Zhou, X. Liang, Y. Yue, H. Zhang,Y. Deng, S. Deng, S. Mo, X. Jiang, X. Zeng

Breast Cancer Center, Chongqing University Cancer Hospital, Chongqing, China

Background: This study aimed to explore potential indicators associated with neoadjuvant efﬁcacy of TCbHP regime (taxane, carboplatin, trastuzumab and pertuzumab) in HER2+ breast cancer.

Methods: LC-MS and GC-MS platform-based untargeted metabolomics were performed to determine the metabolic proﬁles of plasma samples from HER2+ breast cancer patients, who received and completed neoadjuvant therapy (NAT) with TCbHP regime and subsequent surgery at Chongqing University Cancer Hospital. Random forest (RF) was used to establish predictive models based on pre-therapeutic metabolic traits. Transcriptome analysis was performed in available samples to identify differentially expressed genes (DEGs) before treatment. Metabolic and transcriptomic data were integrated to uncover signiﬁcantly perturbed pathways potentially involved in drug resistance.

Results: From July 20, 2020 to May 28, 2021, a total of 40 HER2+ breast cancer patients with 120 plasma samples were eligible and recruited for this study. Of whom 21 (52.5%)patients achieved pCR and 19 (47.5%) achieved non-pCR. There were signiﬁcant differences in plasma metabolic proﬁles between non-pCR and pCR groups before and during treatment. A total of 100 differential metabolites were identiﬁed between pCR and non-pCR patients at pre-therapeutic period, which were signiﬁcantly enriched in 40 metabolic pathways. Four key metabolites [sophorose, N-(2-acetamido)iminodiacetic acid, taurine and 6-hydroxy-2-aminohexanoic acid] were selected by RF analysis. The AUC value to discriminate pCR and non-PCR group to NAT of the single potential metabolite or combined panel of these metabolites were more than 0.910. 18 metabolites had potential value in monitoring effect. A total of 163 DEGs were identiﬁed between biopsy tissue samples from pCR and non-pCR patients. 39 altered pathways aberrantly expressed at both metabolic and transcriptional levels.

Conclusions: Metabolomics integrated with transcriptomics analysis could assist for gaining more insights into biochemical pathophysiology and facilitate the development of novel therapeutic targets for insensitive patients.

Funding: Science and Technology Research Program of Chongqing Municipal Education Commission (Grant No. KJZD-K202000104); Chongqing Science and Health Joint Medical Research Project (Grant No.2021MSXM085, 2021MSXM291, 2022MSXM004);Talent Program of Chongqing (Grant No. CQYC20200303137). Beijing Science and Technology Science and Technology Research Program of Chongqing Municipal Education Commission (Grant No. KJZD-K202000104); Chongqing Science and Health Joint Medical Research Project (Grant No.2021MSXM085, 2021MSXM291,2022MSXM004); Talent Program of Chongqing (Grant No. CQYC20200303137); Beijing Science and Technology Innovation Medical Development Foundation (Grant No.

KC2021-JF-0167-05).

https://doi.org/10.1016/j.annonc.2023.09.2893

170P Clinical signiﬁcance and functional role of GPR56 (ADGRG1)in breast cancer

H. Chen1, X. Hu1, W. Ouyang1, D. Wang2, Y. Wang1, Y. Yu1, H. Yao1

Background: The clinical signiﬁcance and functional role of adhesion G proteincoupled receptors (aGPCRs) in breast cancer remain largely unknown. We aimed to comprehensively analyze the prognostic potential of aGPCRs in breast cancer, identify the key prognostic GPCRs, and comprehend their functional roles.

Results: A total of 128 T2w, 107 DWI and 62 DCE MRIs from 128 PCa patients (32[25%] low or favourable intermediate risk [group 1] and 96 (75%) high or unfavourable intermediate risk [group 2]) were included, of whom 20 (16%) experienced BQR (18 [19%] from group 2). According to risk stratiﬁcation, patients from group 1 presented more homogeneous textures in PZ and WP than group 2. Regarding BQR,the ADC mean was higher in the TZ in those who did not relapse, while patients with greater major axis length in the PZ, WP and SV were more likely to relapse. In SV and WP heterogenicity-related feature values were signiﬁcantly higher in BQR. In group 2,diffusion parameters and shape variables in the SV were signiﬁcantly different in those experiencing BQR.

Conclusions: Imaging biomarker proﬁles in this PCa population may help to better stratify patients at risk based on baseline MRIs. High-risk patients may be identiﬁed by the heterogeneity of textures. Diffusion and texture parameters may determine a higher probability of relapse.

https://doi.org/10.1016/j.annonc.2023.09.2886

163P

S246

Genomic alterations in circulating tumor DNA (ctDNA) and response to ABBV-400 treatment in patients with advanced solid tumors

J. Bar1, M.R. Sharma2, Y. Kuboki3, R. Perets4, D. Sommerhalder5, N. Yamamoto6,J. Powderly7, J.H. Strickler8, M. Li9, A. Luo10, G. Morrison-Thiele11,

M.R. Neagu Aristide12, A. Vasilopoulos13, D.R. Camidge14

1Institute of Oncology, Chaim Sheba Medical Center, Ramat Gan, Israel; 2Medical Oncology Dept., START Midwest, Grand Rapids, MI, USA; 3Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan;4Oncology, Clinical Research Institute at Rambam, Rambam Medical Center, Haifa,Israel; 5Oncology, NEXT Oncology, San Antonio, TX, USA; 6Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan; 7Oncology, Carolina BioOncology Institute PLLC, Huntersville, NC, USA; 8Division of Medical Oncology, Duke University Medical Center, Durham, NC, USA; 9Companion Diagnostic Strategy, AbbVie Inc. - Headquarters, North Chicago, IL, USA; 10Statistics, AbbVie Inc. - Headquarters,North Chicago, IL, USA; 11Oncology Early Discovery, AbbVie Inc. - Headquarters, North Chicago, IL, USA; 12Oncology Early Development, AbbVie, Redwood City, CA, USA;13Precision Medicine and Clinical Biomarker, Oncology, AbbVie Inc. - Headquarters,North Chicago, IL, USA; 14Medical Oncology, University of Colorado Cancer Center Anschutz Cancer Pavilion, Aurora, CO, USA

Background: Several solid tumors, including colorectal cancer (CRC), overexpress cMet. The antibody-drug conjugate ABBV-400 comprises the c-Metetargeting antibody telisotuzumab conjugated to a potent topoisomerase 1 inhibitor payload. ABBV-400 is being evaluated in a phase 1 trial (NCT05029882) in patients (pts) with advanced solid tumors.We analyzed correlations between genomic alterations and response of pts in this study.

Methods: Adults with advanced solid tumors and no validated treatment option were enrolled. Intravenous ABBV-400 was administered once every 3 weeks. ctDNA was isolated from plasma and analyzed using the GuardantINFINITY assay that evaluated various parameters including single-nucleotide variants and insertion-deletion mutations (753 genes), ampliﬁcations (415 genes), tumor mutational burden (TMB), and microsatellite instability (MSI) status. Molecular response (based on ctDNA variant allele frequencies) and radiographic response (RECIST v1.1) were assessed.

Volume 34-Issue S2 -

a29 pts were evaluable for molecular response.b17 CRC pts were evaluable for molecular response. CRC, colorectal cancer; MSI, microsatellite instability; mut,mutations; PR, partial response; pts, patients; TMB, tumor mutational burden.

Conclusions: ABBV-400 showed promising preliminary efﬁcacy, with molecular and radiographic responses in pts with advanced solid tumors with heterogeneous genomic proﬁles, including in pts with high TMB and KRAS mutations.

Clinical trial identiﬁcation: NCT05029882.

Editorial acknowledgement: Medical writing support was provided by Joanne Franklin, PhD, CMPP, from Aptitude Health, The Hague, the Netherlands, and funded by AbbVie.

Legal entity responsible for the study: AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing,and approval of the abstract. All authors had access to relevant data and participated in the drafting, review, and approval of this abstract. No honoraria or payments were made for authorship.

Funding: AbbVie funded this study and participated in the study design, research,analysis, data collection, interpretation of data, reviewing, and approval of the abstract. All authors had access to relevant data and participated in the drafting, review,and approval of this abstract. No honoraria or payments were made for authorship.

Disclosure: J. Bar: Financial Interests, Personal, Advisory Role: AbbVie, AstraZeneca, Bayer, BMS,Causalis, Eisai, MSD, Novartis, Roche, Takeda; Financial Interests, Personal, Research Funding:ImmuneAI, OncoHost, MSD, AstraZeneca. M.R. Sharma: Financial Interests, Personal, Advisory Role:Pliant Therapeutics; Financial Interests, Personal, Stocks or ownership: AbbVie, Biogen, Bristol Myers Squibb, Lilly, Merck, Pﬁzer, Regeneron, Amgen, Gilead Sciences, Johnson & Johnson, Janssen,Moderna Therapeutics, Vertex, West Pharmaceutical; Financial Interests, Personal, Research Funding: Ascentage Pharma, AstraZeneca, Bolt Biotherapeutics, BMS, Compugen, Constellation Pharmaceuticals, CytomX Therapeutics, Exelixis, Ikena Oncology, Inhibrx, Jounce Therapeutics, KLUS Pharma, Loxo, MacroGenics, Merck, Pﬁzer, Regeneron, Symphogen, Syros Pharmaceuticals, Astellas Pharma, Celgene, Treadwell Therapeutics, PureTech, GSK/Tesaro, Seattle Genetics, Shattuck Labs,Sapience Therapeutics, Epizyme, Odonate Therapeutics, Tempest Therapeutics, Mersana, NGM Biopharmaceuticals, Samumed, Onconova Therapeutics, Gilead Sciences, AbbVie, Agenus, Alkermes,Alpine Immune Sciences, Alexo Therapeutics, Johnson & Johnson/Janssen, Seven and Eight Biopharmaceuticals, Cullinan Oncology, Debiopharm Group, Palleon Pharmaceuticals, Helsinn Therapeutics, Kinnate Biopharma, KSQ Therapeutics, Repare Therapeutics, SK Life Sciences,Theratechnologies, Tizona Therapeutics Inc. Y. Y. Kuboki: Financial Interests, Personal, Research Funding: Taiho, Astellas, Lilly, Takeda, Daiichi Sankyo, AstraZeneca, Boehringer Ingelheim, Chugai,Genmab, GSK, Incyte, AbbVie, Amgen; Financial Interests, Personal, Advisory Role: Takeda, Amgen,Boehringer Ingelheim; Financial Interests, Personal, Other, Honoraria: Taiho, Lilly, Bristol Myers Squibb. R. Perets: Financial Interests, Personal, Advisory Role: Galmed Pharmaceuticals, Gilboa Therapeutics, 1E Therapeutics; Financial Interests, Personal, Other, Honoraria: MSD. D. Sommerhalder: Financial Interests, Personal, Other, Employee: Texas Oncology, US Oncology; Financial Interests, Personal, Other, Honoraria: Syneos; Financial Interests, Personal, Research Funding: AbbVie,ADC Therapeutics, Ascentage Pharma Group, Astellas, Biomea Fusion, Boehringer Ingelheim, BJ Bioscience, BioNTech, Fate Therapeutics, Gilead Sciences, Immuneering, Kura Oncology, Monopteros Therapeutics, Navire Pharma Inc, Nimbus Saturn Inc, NGM Biopharmaceuticals, Parthenon, Pﬁzer,isolated from plasma and analyzed using the GuardantINFINITYIM assay that evaluatedRevolution Medicines, Mirati Therapeutics, Symphogen, Teon Therapeutics, Medilink Therapeutics,ZielBio Inc. N. Yamamoto: Financial Interests, Personal, Research Grant: Astellas, Chugai, Eisai, Taiho,BMS, Pﬁzer, Novartis, Eli Lilly, AbbVie, Daiichi Sankyo, Bayer, Boehringer Ingelheim, Rakuten Medical,Kyowa Kirin, Takeda, Ono, Janssen Pharma, Merck Sharp & Dohme, Merck, GSK, Sumitomo Pharma,Chiome Bioscience, Otsuka, Carna Biosciences, Genmab, Shionogi, Toray, Kaken, AstraZeneca, Cimic,InventisBio, Rakuten Medical; Financial Interests, Personal, Other, Personal fees: Ono Pharmaceutical, Chugai, Daiichi Sankyo, Eisai, Takeda, Otsuka, Boehringer Ingelheim, Cimic, Healios. J. ; Financial Interests, Personal,Ownership Interest, Founder and Owner of phase 1 cancer research clinic: Carolina BioOncology Institute, PLLC; Financial Interests, Personal, Other, Founder and Owner, developing intellectual property for cellular therapies: BioCytics Inc; Financial Interests, Personal and Institutional, Local PI:Bristol Myers Squibb, Cullinan, Genentech/Roche, AstraZeneca/MedImmune, EMD Serono, Macrogenics, InCyte, Top Alliance BioSciience, Seattle Genetics, AbbVie, FLX Bio, Alkermes, Arcus BioSciences, Tempest Therapeutics, Calico Life Sciences, Apros, Jounce Therapeutics, Atreca, Sequenom,Repertoire Immune Medicines, Molecular Templates, I-MAB Pharma, NexCure, Xilio Therapeutics,Immune-Onc, Trethera, Zenshine Pharma, Adagene, BJ BioScience, Fate Therapeutics, Conjupro BioTherapeutics, PEEL Therapeutics, CUE BioPharma, Pieris Pharmaceuticals, RiboScience, Moderna TX, Phanes Therapeutics, SK Life Science, Harbour BioMed, Simcere, Allarity, Aulos, GI Innovation,IGM BioSciences, Aptevo, Medikine, IconOVir Bio, Qurgen; Financial Interests, Institutional, Funding:Precision for Medicine, MT Group, STEMCELL Technologies, Replimmune, Merck, Xilis; Financial Interests, Personal and Institutional, Funding: PIOMA; Financial Interests, Personal and Institutional,Local PI, Also funding for contract laboratory services: Nuvation; Financial Interests, Personal and Institutional, Funding, Wugen is sponsor of contract laboratory translational research: Wugen;Financial Interests, Personal and Institutional, Other, AavoCyte & AavoBioCytics are jointly

developing cellular therapies with BioCytics Human Applications Lab for point of care manufacturing: AavoCyte; Other, As Founder and Owner of BioCytics Inc. developing immune cellular therapy: BioCytics Inc. J.H. Strickler: Financial Interests, Personal, Other, Consulting: AbbVie,Amgen, AstraZeneca, Bayer, BeiGene, Daiichi Sankyo, Eli Lilly, GSK, Natera, Pﬁzer, Pionyr Immunotherapeutics, Roche/Genentech, Seagen, Silverback Therapeutics, Takeda, Viatris, Zentalis; Financial Interests, Personal, Research Funding: AbbVie, Amgen, AStar D3, Bayer, BeiGene, Curegenix, Daiichi Sankyo, Eli Lilly, Erasca, Gossamer Bio, Leap Therapeutics, Nektar, Roche/ Genentech, Seagen,Silverback Therapeutics. M. Li, A. Luo, G. Morrison-Thiele, M.R. Neagu Aristide, A. Vasilopoulos:Financial Interests, Personal, Stocks/Shares, Employee and may own stock: AbbVie Inc. D.R.

Camidge: Financial Interests, Personal, Other, Honoraria: AbbVie, Amgen Astellas BioPharma,AnHeart Therapeutics, Apollomics, AstraZeneca, BeiGene, Bio-Thera, Blueprint Medicines, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Elevation Oncology, EMD Serono, GSK, Helsinn Therapeutics,Hengrui Pharmaceutical, Janssen, Kestrel Labs, Lilly, Mersana, Nuvalent, Inc., OnKure, Pﬁzer, Puma Biotechnology, Qilu Pharmaceutical, Ribon Therapeutics, Roche, Sanoﬁ, Seattle Genetics, Takeda,Turning Point Therapeutics; Financial Interests, Personal, Research Funding: Inivata (Inst).

https://doi.org/10.1016/j.annonc.2023.09.2887

164P

Early evaluation of effectiveness and cost-effectiveness of ctDNA-guided selection for adjuvant chemotherapy in stage II colon cancer

Conclusions: Selecting patients based on ctDNA status in addition to pT4 and MSS status for ACT can improve patient selection in terms of effectiveness, and can also potentially become a cost-effective strategy. However, more research is needed to investigate the prognostic and predictive value of ctDNA to accurately evaluate the(cost)effectiveness.

Legal entity responsible for the study: Amsterdam UMC.

Funding: ZonMW.

Disclosure: G.R. Vink: Financial Interests, Institutional, Sponsor/Funding: BMS, Merck, Servier,Personal Genome Diagnostics, Bayer, Sirtex, Pierre Fabre, Lilly, Delﬁ Diagnostics. V. Velculescu:Financial Interests, Personal and Institutional, Member of Board of Directors, Stockholder and consultant: Personal Genome Diagnostics, Delﬁ Diagnostics. G. Meijer: Financial Interests, Personal and Institutional, Member of Board of Directors: CRCbioscreen BV; Financial Interests, Institutional,Research Funding: CZ health insurances; Financial Interests, Institutional, Product Samples, provide materials, equipment and/or sample/genomic analyses: Exact Sciences, Sysmex, Sentinel Ch. SpA,Personal Genome Diagnostics, Delﬁ, Hartwig Medical Foundation; Other, Personal and Institutional,Other, has several patents pending/issued: Other. D. Van Den Broek: Financial Interests, Institutional,Speaker, Consultant, Advisor: Roche diagnostics. M. 165P Correlation between trophoblast cell-surface antigen-2(Trop-2) expression and pathological complete response(pCR) in HER2-positive early breast cancer (EBC): A sub analysis of PHERGain trial

M. Gion Cortes1, J.J. Garcia Mosquera2, J.M. Pérez-García3, V. Peg Cámara4,J.A. Guerrero5, L. López-Montero5, M. Mancino5, J. Rodríguez Morató5,G. Antonarelli6, L. Fernández-Murga7, L. Serrano García7, V. Puglia7,

A. Llombart Cussac8, J. Cortés9

Methods: Trop-2 expression, as determined by immunohistochemistry (IHC) and its relationship with clinicopathologic features and pCR, was retrospectively analyzed in patients (pts) with HER2-positive EBC treated with upfront neoadjuvant docetaxel,carboplatin, trastuzumab, and pertuzumab in the PHERGain study (Pérez-García et al,Lancet Oncol 2021). Trop-2 expression was classiﬁed into low, medium, and high groups according to a histochemical score (H-score) based on staining intensity and percentage of stained cells.

Legal entity responsible for the study: MEDSIR - Medica Scientia Innovation Research.

Funding: Fundación Contigo.

Disclosure: M. Gion Cortes: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Other, Travel expenses: Roche, Pﬁzer. J.M. Pérez-García: Financial Interests, Personal, Advisory Role: Lilly, Roche, Eisai, Daichii Sankyo, AstraZeneca, Seattle Genetics, Gilead;Financial Interests, Personal, Other, travel expenses: Roche; Financial Interests, Personal, Full or parttime Employment: MEDSIR. J.A. Guerrero, L. López-Montero, M. Mancino, J. Rodríguez Morató:Financial Interests, Personal, Full or part-time Employment: MEDSIR. A. Llombart Cussac: Financial Interests, Institutional, Research Funding: Roche, Agendia, Lilly, Pﬁzer, Novartis, Merck Sharp &Dohme, Gilead, Daichii Sankyo; Financial Interests, Personal, Speaker, Consultant, Advisor: Lilly,Roche, Pﬁzer, Novartis; Financial Interests, Personal, Speaker’s Bureau: Lilly, AstraZeneca, Merck Sharp & Dohme; Financial Interests, Personal, Other, Travel support: Roche, Pﬁzer, AstraZeneca;Financial Interests, Personal, Stocks or ownership: MEDSIR, Initia-Research. J. J. Cortés: Financial Interests, Personal, Advisory Board: Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp & Dohme, GSK, LEUKO, Bioasis, Clovis oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics; Financial Interests, Personal, Invited Speaker: Roche, Novartis, Celgene,Eisai, Pﬁzer, Samsung Bioepis, Lilly, Merck Sharp & Dohme, Daiichi Sankyo; Financial Interests,Personal, Other, Consulting/advisor: Expres2ion Biotechnologies; Financial Interests, Personal,Stocks/Shares: MedSIR, Nektar Therapeutics; Financial Interests, Institutional, Research Grant:Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer Healthcare, Eisai,Guardanth Health, Merck Sharp & Dohme, Pﬁzer, Piqur Therapeutics, Puma B, Queen Mary

0.84 [95% CI, 0.73-0.97], respectively), while those carrying hazardous HLA alleles have higher risk of MPC (HR, 1.31 [95% CI, 1.09-1.57] and HR, 1.55 [95% CI, 1.25-1.93], respectively). HLA alleles are associated with organ-speciﬁc MPC occurrence.

Lower animal fat intake subsided (HR, 0.46 [95% CI, 0.26-0.82]) while unqualiﬁed vegetable fat intake increased MPC risk (HR, 2.23 [95% CI, 1.22-4.07]) for male cancer patients carrying hazardous HLA alleles. Lower free sugar intake subsided the risk of MPC for female patients carrying hazardous HLA alleles (HR, 0.34 [95% CI, 0.15-0.74]).

Conclusions: HLA alleles might help to understand the predisposition and organspeciﬁc incidence of MPC. Intervention on diet could counteract the risk.

Legal entity responsible for the study: Zhongyi Dong.

https://doi.org/10.1016/j.annonc.2023.09.2904

181P GeNeo: Agnostic comprehensive genomic proﬁling versus limited panel organ-directed next-generation sequencing within the Belgian PRECISION initiative

P.G. Aftimos1, K. Punie2, L. Decoster3, C. Van Marcke de Lummen4, A. Hebrant5,G. Raicevic5, E. Van Valckenborgh5, B. Maes6, J. Maetens5, J.J. Collignon7,

T.F.A. van den Mooter8, J. Fried-Vermeij9, W. Demey10, S. Tejpar11, M. Peeters12,J-L. Canon13, W. Lybaert14, J. Mebis15, S. Rottey16, J. De Grève17

1Clinical Trials Conduct Unit, Institute Jules Bordet, Anderlecht, Belgium; 2General Medical Oncology Dept., UZ Leuven - University Hospitals Leuven - Campus Gasthuisberg, Leuven, Belgium; 3Department of Medical Oncology, UZ Brussel - Universitair Ziekenhuis Brussel, Jette, Belgium; 4Medical Oncology, Cliniques Universitaires Saint-Luc (UCLouvain Saint-Luc), Woluwe-Saint-Lambert, Belgium;5Cancer Centre, Sciensano, Brussel, Belgium; 6Laboratory, Jessa Ziekenhuis - Campus Salvator, Hasselt, Belgium; 7Department of Medical Oncology, CHU Liège Sart-TilmanService d’Oncologie, Liège, Belgium; 8Medical Oncology Department, GZA Ziekenhuizen Campus Sint-Augustinus, Wilrijk, Belgium; 9Department of Medical Oncology, ZNA

- Ziekenhuis Netwerk Antwerpen - Middelheim, Antwerpen, Antwerp, Belgium;10Medical Oncology Dept., A.Z. Klina, Brasschaat, Belgium; 11GI Oncology, UZ Leuven -University Hospitals Leuven - Campus Gasthuisberg, Leuven, Belgium; 12Medical Oncology, UZA - University Hospital Antwerp, Edegem, Belgium; 13Department of Oncology-Hematology, GHdC - Grand Hopital de Charleroi - Site Notre Dame, Charleroi, Belgium; 14Medical Oncology, AZ Nikolaas Hospital, Sint-Niklaas, Belgium;15Medical Oncology Department, Jesse Ziekenhuis - Campus Virga Jesse, Hasselt,Belgium; 16Department of Medical Oncology, UZ Gent - University Hospital Ghent,Gent, Belgium; 17Medical Oncology Department, Vrije Universiteit Brussel - Faculty of Medicine & Pharmacy, Brussels, Belgium

Background: Several targeted therapies are available through reimbursed organspeciﬁc next-generation sequencing (NGS). Agnostic comprehensive genomic proﬁling(CGP) covering all classes of genomic alterations could improve access to molecularlyguided therapies (MGTs).

Methods: PRECISION is an initiative launched by the Belgian Society of Medical Oncology (ESMO Open. 2022 Aug;7(4):100524). In the prospective GeNeo trial, CGP(FoundationOne CDx or Heme) was centrally done on tumor samples for patients with advanced solid tumors (NCT04641676). In parallel, organ-directed NGS panel testing was mandatory if reimbursed. Patients with no tissue sample were enrolled with a liquid biopsy. Results were discussed at a national molecular tumor board (MTB).

Reasons for non-initiation of the recommended treatment were recorded. Clinical and genomic data are stored in the PRECISION database, with prospective follow-up up to 2 years.

Results: From October 2020 to April 2022, 1000 patients were enrolled at 13 sites.

CGP results were available for 937 (843 tissue and 94 liquid biopsies) patients, out of which 918 were discussed at the MTB. The largest cohorts were breast (n¼137),colorectal (n¼128) and rare cancers (n¼100). Turnaround-time from sample receivedto to MTB recommendation was ≤28 days for 45% of cases and ≤37 days for 80%. 576MTB recommendation was 28 days for 45% of cases and 37 days for 80%. 576patients (63%) received at least one recommendation for CGP-based therapy. Cohorts with most treatment recommendations (>75% of cases) were bladder, biliary tract,skin and thyroid cancers. 72% of 469 patients who also had an organ-directed NGS test received at least one additional treatment recommendation based on CGP testing. Among the patients who received at least one MTB recommendation, 123(21%) were treated accordingly. Reasons for non-compliance include patient ineligibility (26%), physician decision (23%) and treatment unavailability (22%). Follow-up continues.

Conclusions: Tumor-agnostic CGP provides more treatment options to patients with advanced solid tumors when compared to organ-directed NGS panel testing. The national MTB provides recommendations within a clinically relevant timeframe and enhances the uptake of MGTs.

Clinical trial identiﬁcation: NCT03873103.

Funding: Roche, Fondation contre le Cancer, Kom op tegen Kanker.

Disclosure: P.G. Aftimos: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim,Macrogenics, Roche, Novartis, Amcure, Servier, G1 Therapeutics, Radius, Deloitte, Menarini, Gilead,Novartis, Eisai, Lilly; Financial Interests, Personal, Invited Speaker: Synthon, Amgen; Financial Interests, Institutional, Research Grant: Roche. K. Punie: Financial Interests, Institutional, Advisory Board: AstraZeneca, Novartis, Roche, Vifor Pharma, Eli Lilly, Pierre Fabre, McCann Health, Roularta,Teva, Gilead Sciences, Pﬁzer, Gilead, MSD; Financial Interests, Institutional, Invited Speaker: Pﬁzer,Roche, Novartis, Eli Lilly, Mundi Pharma, MSD, Medscape, MSD; Financial Interests, Institutional,Other, Consultancy: Roche; Financial Interests, Personal, Other, Consultancy: Gilead, Novartis, MSD,Roche; Financial Interests, Personal, Invited Speaker: Sanoﬁ, AstraZeneca, Exact Sciences, Focus Patient, Pﬁzer, Gilead Sciences; Financial Interests, Personal, Advisory Board: Seagen, AstraZeneca,Pﬁzer; ;Financial Interests, Personal, Ownership Interest: Need Inc.; Financial Interests, Institutional,Funding: Sanoﬁ; Non-Financial Interests, Other, Committee member: ESMO Young Oncologists Committee; Non-Financial Interests, Leadership Role, Vice President: Belgian Society of Medical Oncology BSMO; Non-Financial Interests, Other, Committee Member: ESMO Resilience Task Force;Non-Financial Interests, Leadership Role: EORTC Breast Cancer Task Force Steering Committee Member; Non-Financial Interests, Institutional, Product Samples, Drug provision for academic research: Gilead Sciences; Non-Financial Interests, Advisory Role: Commission personalized medicine Federal Government Belgium; Non-Financial Interests, Advisory Role, External Scientiﬁc Advisor:European Medicine Agency. L. L. Decoster: Financial Interests, Institutional, Advisory Board: AstraZeneca, BMS, MSD; Financial Interests, Institutional, Invited Speaker: BMS, MSD, Roche, Servier, Sanoﬁ;Financial Interests, Institutional, Research Grant, conduct of academic trial: Boehringer Ingelheim;Non-Financial Interests, Leadership Role, member of board: European Cancer Organisation; NonFinancial Interests, Leadership Role, Board member: International Society of Geriatric Oncology(SIOG). C. Van Marcke de Lummen: Financial Interests, Institutional, Advisory Board: Eli Lilly,

Novartis, AstraZeneca; Non-Financial Interests, Member of Board of Directors: BSMO. A. Hebrant:Financial Interests, Personal, Full or part-time Employment: Sciensano. G. Raicevic: Financial Interests, Personal, Full or part-time Employment: Sciensano. E. Van Valckenborgh: Financial Interests,Personal, Full or part-time Employment: Sciensano. B. Maes: Financial Interests, Personal, Advisory Board: Servier, AstraZeneca, Illumina; Financial Interests, Personal, Invited Speaker: Pﬁzer, Illumina;Financial Interests, Institutional, Invited Speaker: Illumina, SeqOne; Non-Financial Interests, Principal Investigator: BSMO. J. Maetens: Financial Interests, Personal, Full or part-time Employment: Sciensano. J.J. Collignon: Financial Interests, Personal, Full or part-time Employment: Sciensano. S.

Tejpar: Financial Interests, Institutional, Advisory Board: Roche, Boehringer Ingelheim, Bayer, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Amgen, Merck Serono. J. Canon: Financial Interests, Institutional, Research Grant: Roche. S. Rottey: Financial Interests, Institutional, Advisory Board: Pﬁzer, Merck, Roche, Ipsen, BMS; Financial Interests, Institutional, Invited Speaker: Ipsen,BMS, Astellas; Financial Interests, Institutional, Research Grant: MSD, Roche, BMS; Non-Financial Interests, Principal Investigator, It is my main task in the hospital to attract and perform clinical trials in oncology phase I-III: all companies performing clinical trials in oncology in Europe. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2905

182P

ALK fusion detection by RNA next-generation sequencing(NGS) compared to DNA in a large, real-world non-small cell lung cancer (NSCLC) dataset

W. Iams1, R. Ben-Shachar2, L. Gai3, K. Beauchamp4, N. Sharma5, S. Islam6,J. Guinney7, H. Nimeiri8, R.D. Gentzler9, E. Cohen10

1Hematology/Oncology, Vanderbilt Ingram Cancer Center, Nashville, TN, USA; 2Clinical Development, Tempus Labs, Inc., Chicago, IL, USA; 3AI & Data Science, Tempus Labs,Inc., Chicago, IL, USA; 4Tempus Labs, Inc., Chicago, IL, USA; 5Systems Biology, Tempus Labs, Inc., Chicago, IL, USA; 6Translational Research, Tempus Labs, Inc., Chicago, IL,USA; 7Research and Development, Tempus Labs, Inc., Chicago, IL, USA; 8Oncology Department, Robert. H. Lurie Cancer Center of Northwestern University, Chicago, IL,USA; 9Hematology/Oncology, University Hospital of Virginia (UVA), Charlottesville, VA,USA; 10Medicine Department, Moores Cancer Center - UC San Diego Health, La Jolla,CA, USA

Background: While DNA NGS can detect clinically actionable fusions in tumors,technical and biological limitations may lead to false negatives, preventing patients from receiving approved therapies associated with outcome beneﬁt. RNA NGS is recommended by ESMO guidelines to maximize fusion detection but is not widely used clinically. In a large, real-world dataset, we quantify the beneﬁt of RNA concurrent with DNA NGS for ALK fusion detection in NSCLC.

Methods: We retrospectively analyzed de-identiﬁed stage IIIB-C and IV NSCLC samples sequenced with the Tempus xT assay (DNA and whole-exome capture RNA NGS).

ALK fusion prevalence was compared to public DNA-seq-based data from Dana Farber Cancer Institute (DFCI, N¼4,497) and Memorial Sloan Kettering Cancer Center(MSKCC, N¼5,317) with one-sided proportion tests. ALK fusions were limited toknown oncogenic partners detectable by FISH or IHC (EML4, KIF5B, KLC1, and PICALM). Therapeutic adoption was analyzed in cases with 90 days of ﬁrst-line ALM).Therapeutic adoption was analyzed in cases with ≥90 days of first-line medi-medi-cation data.

Results: Among 7,428 NSCLC patients, 2.9% had ALK fusions (n¼217), with 83%(n¼180) detected by both DNA and RNA, 15% (n¼33) from RNA alone, and 2% (n¼4)from DNA alone. ALK fusion prevalence in the Tempus Database was higher than the combined MSKCC and DFCI rate (2.4%, n¼236/9,814, P¼0.036). To investigate RNA vsDNA discordance, we examined exonic EML4-ALK breakpoint locations (n¼32). Mostcases had canonical breakpoints in RNA (n¼26), where 18 had no DNA support inthese breakpoints, suggesting complex ALK rearrangements in DNA. The remaining 8 had limited DNA support but were below the clinical threshold for reporting. Of those with medication data (n¼7), 6 patients with EML4-ALK fusions detected by RNA alonereceived targeted therapy post-testing and 5 remained on therapy for 100 received targeted therapy post-testing and 5 remained on therapy for ≥100 days.days.

Conclusions: This large, real-world dataset demonstrates that RNA NGS increases ALK fusion detection by 18% over DNA alone for patients with advanced NSCLC. This increase is likely to translate to a larger number of patients matched to and receiving targeted therapy. Consequently, RNA NGS should be considered for more widespread adoption in the clinic.

Funding: Tempus Labs.

Disclosure: W. Iams: Financial Interests, Personal, Advisory Board: Tempus, EMD Serono, Amgen,Sanoﬁ, NovoCure, Genentech, AstraZeneca, Catalyst, Jazz Pharma, Elevation Oncology, Bristol Myers Squibb, Janssen, Takeda, Mirati, G1 Therapeutics; Financial Interests, Personal, Other, Funding:Tempus. R. Ben-Shachar: Financial Interests, Personal, Full or part-time Employment: Tempus Labs;Financial Interests, Personal, Stocks/Shares: Tempus Labs, Myriad Genetics. L. Gai: Financial Interests, Institutional, Full or part-time Employment: Tempus Labs Inc. K. Beauchamp: Financial Interests, Personal, Full or part-time Employment: Tempus Labs, Inc; Financial Interests, Personal,Stocks/Shares: Tempus Labs, Inc. N. Sharma: Financial Interests, Personal, Full or part-time Employment: Tempus labs; Financial Interests, Personal, Stocks/Shares: Tempus labs. S. Islam:Financial Interests, Personal, Full or part-time Employment: Tempus Labs; Financial Interests, Personal, Stocks/Shares: Tempus Labs. J. Guinney: Financial Interests, Institutional, Full or part-time Employment: Tempus Labs; Financial Interests, Institutional, Stocks/Shares: Tempus Labs. H. H. Nimeiri:Financial Interests, Personal, Full or part-time Employment: Tempus; Financial Interests, Personal,Stocks/Shares: Tempus, AbbVie. R.D. Gentzler: Financial Interests, Personal, Advisory Board:AstraZeneca, Takeda, Gilead, Janssen, Mirati, Daiichi Sankyo, Sanoﬁ, Oncocyte, Jazz Pharmaceuticals;Financial Interests, Personal, Invited Speaker: Clinical Care Options, OncLive, Targeted Oncology,Society for Immunotherapy of Cancer (SITC); Financial Interests, Institutional, Local PI: Janssen,Mirati, Daiichi Sankyo, Bristol Myers Squibb, AstraZeneca, Jounce Therapeutics, Takeda, Bristol Myers Squibb, Merck, Chugai, Amgen; Financial Interests, Institutional, Research Grant: Pﬁzer;Financial Interests, Institutional, Coordinating PI: Mirati; Non-Financial Interests, Leadership Role:

Hoosier Cancer Research Network; Non-Financial Interests, Principal Investigator: NCI ETCTN; NonFinancial Interests, Other, Member of Lung Cancer Scientiﬁc Review Committee: American Society of Clinical Oncology, Scientiﬁc Review Committee; Non-Financial Interests, Other, Committee Member:NCI Investigational Drug Steering Committee; Non-Financial Interests, Ofﬁcer, Associate Editor:Journal of Thoracic Oncology, ASCO Meeting Abstracts; Non-Financial Interests, Personal, Other,Travel support for attending meetings for invited speaker: International Association for the Study of Lung Cancer (IASLC). E. Cohen: Financial Interests, Personal, Other, Consulting: Eisai, Merck, MSD,Nectin Tx, Pangea Therapeutics, Roche, Adagene, Astellas, Cidara, Genmab, Gilboa, iTeos, Eli Lilly,Novartis, Nykode, PCI Biotech, Replimune, Soteria, Viracta; Financial Interests, Personal, Other,DSMB: Kura; Financial Interests, Personal, Other, BOD: Akamis Bio; Financial Interests, Personal,Stocks/Shares: Kinnate Biophama, Primmune Therapeutics.

https://doi.org/10.1016/j.annonc.2023.09.2906

183P Frequency of actionable fusions in 7,735 patients with solid tumors

K.J. McDonnell1, J.R. Hoag2, C. Flannery2, D. Hall3, M.C. Evans4, A. Akkunuri4,S. Thakkar3, J.R. Lobello3, G.D. Basu3, R.F.L. Baehner3, J.D. Bonner1, S.S. Lindsey1,C. Hong1, X. Xia1, S. Gray1, S.B. Gruber1

1Center for Precision Medicine, City of Hope Comprehensive Cancer Center, Duarte, CA,USA; 2Clinical Biostatistics, Exact Sciences Corporation, Madison, WI, USA; 3Precision Oncology, Exact Sciences Corporation, Redwood City, CA, USA; 4Bioinformatics, Exact Sciences Corporation, Madison, WI, USA

Background: Identifying rare oncogenic gene fusions can be challenging. Comprehensive genomic proﬁling (CGP) approaches that include RNA sequencing can improve fusion detection versus exome or targeted DNA sequencing alone. Here, we characterize gene fusions in solid tumors detected with the OncoExTraTMtumornormal, whole-exome (WES), whole-transcriptome (WTS) CGP assay.

Methods: The study included oncology patients with solid tumor samples tested with the OncoExTra assay between May 2018 and November 2022. We quantiﬁed the frequency of all potentially clinically-relevant fusions, including those with therapeutic, clinical trial eligibility, prognostic or diagnostic implications, and the subset of these with FDA-approved therapies at the time of testing.

Results: Overall, 7,735 patients and 33 tumor types were included. We identiﬁed 931(12.0%) patients with clinically-relevant fusions, 224 (2.9%) of whom had a fusion associated with an FDA-approved therapy, with large variation in frequency across tumor types (Table). Sarcomas had one of the highest proportions (34.4%) of fusions identiﬁed, many of which are diagnostic or prognostic: PAX3/7-FOXO1 (n¼17), SS18-SSX (n¼10), CIC-DUX4 (n¼8), and MDM2 (n¼6). We also detected fusions in 189(9.5%) breast (including 43 with ESR1, 13 with ERBB2, 12 with FGFR family), 33 (3.4%)colorectal (including 5 RSPO, 3 RET), and 29 (9.9%) non-small cell lung (including 10 ALK, 5 RET, 3 ERBB2) cancer patients. Across all cancers, ERG (3.0%) was the most common fusion partner, found predominantly in prostate cancer patients. Other notable fusions involved ESR1 (n¼64); RAF family (n¼30); NTRK family (n¼27); andRSPO family (n¼12).

Conclusions: Oncogenic gene fusions, including those with FDA-approved therapies,were identiﬁed with varying frequency across solid tumors. Sarcomas had a high proportion of fusions, including those with therapeutic, diagnostic and prognostic relevance.

g those with therapeutic, diagnostic and prognostic relevance.

|Table: 183P Gene fusions in select tumor types |Table: 183P Gene fusions in select tumor types |Table: 183P Gene fusions in select tumor types |Table: 183P Gene fusions in select tumor types | |---|---|---|---|

|Breast |1989 (25.7%) |189 (9.5%) |65 (3.3%) |

|Colorectal |975 (12.6%) |33 (3.4%) |9 (0.9%) |

|Prostate |582 (7.5%) |277 (47.6%) |7 (1.2%) |

|Ovary |389 (5.0%) |21 (5.4%) |4 (1.0%) |

|Sarcoma |326 (4.2%) |112 (34.4%) |16 (4.9%) |

|NSCLC |293 (3.8%) |29 (9.9%) |18 (6.1%) |

|Brain |274 (3.5%) |41 (15.0%) |22 (8.0%) |

|Bladder |197 (2.5%) |14 (7.1%) |6 (3.0%) |

|Thyroid |132 (1.7%) |17 (12.9%) |15 (11.4%) |

|Biliary |93 (1.2%) |16 (17.2%) |11 (11.8%) |

|All Cancers |7735 (100.0%) |931 (12.0%) |224 (2.9%) |

Legal entity responsible for the study: Exact Sciences Corporation.

Funding: Exact Sciences Corporation.

Disclosure: J.R. Hoag, C. Flannery, D. Hall, M.C. Evans, A. Akkunuri, S. Thakkar, J.R. Lobello, G.D.

Basu: Financial Interests, Personal, Full or part-time Employment: Exact Sciences. S.B. Gruber:Financial Interests, Personal, Ownership Interest: Brogent International. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2907

184P

Patient-speciﬁc HLA-I genotypes predict response to immune checkpoint blockade

Methods: We retrospectively analyzed 193 ALC patients for Programmed Death -Ligand 1 (PD-L1) and EGFR expression on CTCs from. CTCs were isolated from Drug Controller General of India-approved OncoDiscover technology based on immunomagnetic targeting using anti EpCAM antibody, and immuno-staining with anti EGFR and PD-L1 antibodies. CTCs were detected based on the expression of CKs, absence of CD45, and prominent DAPI-stained nuclei. The presence or absence of EGFR and PDL1 was determined with automated immunoﬂuorescence microscopy.

Results: Among the evaluated cohort, 67 % patients showed the presence of CTCs with a mean value of 4.2 (Range: 1 to 62, SD ¼10.65). The absence of CTCs from theremaining 33 % of patients could be due to the therapy response of the clinically stable disease. From all patients showing the presence of CTCs, 66 % showed the detectable expression of PD-L1, while 42 % showed a strong expression of EGFR. The presence of PD-L1 was a signiﬁcant association with CTCs. Similarly, the expression of EGFR among the detected CTCs showed high signiﬁcance compared to the reported data on tissue biopsy from the literature.

Conclusions: Detection of therapeutic targets on CTCs obtained from ALC strongly indicate these patients qualify for anti-EGFR and PD-L1 therapies. Systematic studies with larger samples are required to strengthen the liquid biopsy-based detection of actionable targets. This could immensely help ALC patients showing progressive disease on chemo/radiotherapy.

Legal entity responsible for the study: Actorius Innovations and Research.

Funding: Actorius Innovations and Research.

https://doi.org/10.1016/j.annonc.2023.09.2897

174P Frequency and prognostic value of circulating tumor cells in cancer of unknown primary

M. Pouyiourou1, S. Riethdorf2, T. Bochtler3, C. Coith2, B. Kraft1, T. Hielscher4,cirDNA into undetectable (30%),low (≤1% ratio; 38.1%), and high (>1% ratio;31.6%).A. Stenzinger5, K. Pantel2, A. Krämer6

1Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg,Heidelberg, Germany; 2Institute for Tumor Biology, UKE Universitätsklinikum Hamburg-Eppendorf KMTZ, Hamburg, Germany; 3Medical Oncology, NCT - Nationales(≥1%) had lowest proportion in low T-cirDNA/cirDNA (17%) contrary to undetectableZentrum für Tumorerkrankungen, Heidelberg, Germany; 4Division of Biostatistics,German Cancer Research Center (DKFZ), Heidelberg, Germany; 5Institute of Pathology,University Hospital Heidelberg, Institute of Pathology, Heidelberg, Germany; 6Clinical Operation Unit Molecular Hematology/Oncology, German Cancer Research Center(DKFZ) and University of Heidelberg, Heidelberg, Germany

Background: Cancer of unknown primary (CUP) is deﬁned as a primary metastatic malignancy, where the primary tumor remains elusive in spite of a comprehensive diagnostic workup. Patients with CUP have a poor prognosis, making the need for the development of novel therapeutic and prognostic tools urgent. The frequency and prognostic value of circulating tumor cells (CTCs), which are considered to be the source of metastasis, has not yet been systematically evaluated in CUP.

Methods: 92 patients with a conﬁrmed diagnosis of CUP according to the ESMO guidelines, who presented to our clinic between 07/2021 and 03/2023 provided blood samples for CTC enumeration using CellSearch methodology. CTC counts were correlated with demographic, clinical and molecular data generated by comprehensive genomic proﬁling of tumor tissue.

Results: CTCs were detected in 35% of all patients. The highest CTC frequency was observed among patients with unfavorable CUP (18/53, 34%), while patients with single-site/oligometastatic CUP harbored the lowest CTC frequency (4/28, 14%).

Disease burden and the number of affected organs had no signiﬁcant effect on the CTC detection rate (P¼0.251 and P¼0.805). CDKN2A alterations were slightly morecommon in CTC-negative patients (P¼0.086). High CTC levels (5 CTCs/7.5 ml) pre-dicted for adverse overall survival (OS) compared to negative or low counts (median 74 vs. 19 months; Log-rank P¼0.002; HR 3.73; 95% CI 1.54-9.00). Progression-freesurvival was also affected by CTC status, the effect did not, however, reach statistical signiﬁcance (median 7.4 vs 3.6 months, Log-rank P¼0.1). CTC dynamics over thecourse of the disease were prognostic for OS, with patients that were either consistently CTC-negative or turned negative during treatment demonstrating the best prognosis.

Conclusions: The number of CTCs is a predictor of survival in patients with CUP.

Measurement of CTCs provides a useful prognostic tool in the management of these patients.

Funding: German Cancer Research Center.

Disclosure: A. Stenzinger: Financial Interests, Personal, Advisory Board: Aignostics, AstraZeneca,Janssen, Bayer, Seattle Genetics, Pﬁzer, MSD, Eli Lilly, Illumina, Thermo Fisher, Amgen; Financial

Interests, Institutional, Advisory Board: BMS, Takeda, Novartis; Financial Interests, Personal, Invited Speaker: Roche, Incyte; Financial Interests, Institutional, Research Grant: Bayer, Chugai, BMS, Incyte.

K. Pantel: Financial Interests, Personal, Advisory Board: Menarini/Silicon Biosystems. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2898

175P

Table:Featu

Vesse 1stbin 12thb 2ndbi

Vesse

Radiomic biomarker of vessel tortuosity for monitoring treatment change: Preliminary ﬁndings in prospective evaluation of ECOG-ACRIN EA5163

P. Mutha1, F. Duan2, V.S. Viswanathan1, M. Khorrami1, N. An3, V. Velcheti4,

A. Gupta5, S.S. Ramalingam6, K. Kelly7, K. Sandler8, H. Borghaei9, A. Madabhushi1

1Wallace H. Coulter Department of Biomedical Engineering at Emory University and Georgia Tech, Emory University, Atlanta, GA, USA; 2Department of Biostatistics, Brown University, Providence, RI, USA; 3Center for Statistical Sciences, Brown University,Providence, RI, USA; 4Thoracic Oncology, NYU Langone Medical Center and School of Medicine, New York, NY, USA; 5Department of Radiology, Case Western Reserve University / University Hospitals, Cleveland, OH, USA; 6Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine,Atlanta, GA, USA; 7Hematology Oncology Department, UC Davis Comprehensive Cancer Center, Sacramento, CA, USA; 8Department of Radiology, Vanderbilt University Medical Center, Nashville, TN, USA; 9Hematology/Oncology Department, Fox Chase Cancer Center - Main Campus, Philadelphia, PA, USA

Background: EA5163 is a phase 3 randomized trial investigating ﬁrst-line mono immunotherapy (IO) or IO with chemotherapy in advanced non-small cell lung cancer(NSCLC). Previous work has retrospectively validated a CT based radiomic signature of tumor associated quantitative vessel tortuosity (QVT) for prognosticating outcomes in IO treated NSCLC (Alilou et al. Sci Adv 2022 ). In this study, we report initial results of evaluating QVT in assessing IO related treatment changes in EA5163, speciﬁcally associating changes in QVT (D-QVT) with changes in tumor volume (D-TV) between baseline (B) and 6 week post-treatment scans (TP1).

Methods: CT scans from 29 patients enrolled in EA5163 with measurable lung lesions at B and TP1 were included. Vasculature was automatically segmented in a 25mm region around manually annotated tumors in CT using MATLAB R2022b. 84 QVT features measuring tortuosity, curvature and angle statistics were extracted. No information on outcomes, survival, or treatment arm assignment was available due to the ongoing nature of the trial. Spearman correlation and false discovery rate corrected p-values were computed to associate D-QVT with D-TV in an unsupervised setting. A risk score (QRS) was generated as the output of a classiﬁer previously trained on 5 D-QVT features prognostic of RECIST v1.1 response.

Results: 14 D-QVT features were signiﬁcantly (p<0.05) correlated with D-TV with an absolute range of 0.45 and 0.76. 4 features in the QRS signature were signiﬁcantly correlated with D-TV (Table). QRS based stratiﬁcation showed net decrease in TV in low risk patients, whereas a net increase in high-risk patients at TP 1 (p<0.001). The D-QVT features were not associated with baseline tumor volume.

Correlation

p-value

l volume

0.71

<0.001

of tortuosity histogram

0.65

0.002

in of angles histogram

0.61

0.004

n of curvature histogram

l volume to tumor volume ratio

-0.48

0.053

Conclusions: This study demonstrated an association between CT derived radiomic biomarker D-QVT and D-TV in an ongoing prospective clinical trial. Validation of these results upon interim analyses or trial completion is warranted.

Clinical trial identiﬁcation: NCT03793179.

Funding: This study was coordinated by the ECOG-ACRIN Cancer Research Group(Peter J. O’Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute (NCI) of the National Institutes of Health(NIH) under the following award numbers: U10CA180820, U10CA180794,UG1CA233234, UG1CA233270, and UG1CA233247. This study was also supported by an NCI grant NIH 1 R01CA257612-01A1. The content is solely the responsibility of the authors and does not necessarily represent the ofﬁcial views of the National Institutes of Health.

Disclosure: V. Velcheti: Financial Interests, Personal, Advisory Board: ITeos Therapeutics, Bristol Myers Squibb, Merck, AstraZeneca/MedImmune, GSK, Amgen, Elevation Oncology, Merus, Taiho Oncology; Financial Interests, Institutional, Research Funding: Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantWorks, Genoptix, Altor BioScience, Merck, Bristol Myers Squibb, Atreca,Heat Biologics, Leap Therapeutics, RSIP Vision, GSK. A. Gupta: Financial Interests, Personal, Other,Consultancy for future development of AI tools on chest radiographs: GE Healthcare; Financial Interests, Personal, Stocks/Shares, Own shares of the company presently valued at 56 dollars: Picture Health; Financial Interests, Institutional, Funding, Research support for ongoing AI projects around chest radiography: GE Healthcare. S.S. Ramalingam: Financial Interests, Personal, Other, Editor in Chief, Cancer journal: American Cancer Society; Financial Interests, Research Grant: Merck, AstraZeneca, Advaxis, BMS, Amgen, Takeda, Genmab, GSK. K. Kelly: Financial Interests, Personal, Royalties, Primary reviewer for the small cell lung cancer chapter: UPTODATE. H. Borghaei: Financial

Interests, Personal, Advisory Board: BMS, Genentech, Eli Lilly, Merck, EMD-serono, AstraZeneca,Novartis, Genmab, Regeneron, Amgen, Takeda, PharmaMar, Jazz Pharma, Mirati, Daiichi, Guardant,Natera, Oncocyte, BeiGene, iTeo, Boehringer Ingelheim, Puma, BerGenbio, Janssen; Financial Interests, Personal, Other, Training discussion: Pﬁzer; Financial Interests, Personal, Other, DSMB:Novartis; Financial Interests, Institutional, Other, Clinical trial support: BMS, Amgen; Financial Interests, Personal, Stocks/Shares, Options for scientiﬁc advisory role: Sonnetbio; Financial Interests,Personal, Stocks/Shares, Options for scientiﬁc advisory board: Nucleai, Inspira (Rgenix); Financial Interests, Institutional, Trial Chair, Investigator initiated trial support: BMS; Financial Interests,Institutional, Coordinating PI, Investigator initiated trial support: Amgen, Lilly; Financial Interests,Personal and Institutional, Trial Chair, Chair steering committee: Miratti; Financial Interests, Personal and Institutional, Steering Committee Member: Amgen, AstraZeneca; Financial Interests, Personal,Steering Committee Member, Also trial support: BMS; Other, DSMB: Novartis, Takeda, Incyte,Springworks. A. Madabhushi: Financial Interests, Personal, Advisory Board, Serve on SAB and consult: SimbioSys; Financial Interests, Personal, Advisory Board: Aiforia, Picture Health; Financial Interests, Personal, Full or part-time Employment: Picture Health; Financial Interests, Personal,Ownership Interest: Picture Health, Elucid Bioimaging, Inspirata Inc; Financial Interests, Personal,Royalties: Picture Health, Elucid Bioimaging; Financial Interests, Institutional, Funding: AstraZeneca,Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2899

176P Enhancing immunotherapy response prediction via

multimodal integration of radiology and pathology deep learning models

M. Ligero1, O.S.M. El Nahhas2, O. Prior Palomares1, V. Navarro3, I. Sansano4,G. Serna5, S. Mauchanski5, R.D.A. Toledo6, R. Dienstmann7, S. Ramon y Cajal4,E. Garralda8, P.G. Nuciforo5, J.N. Kather2, R. Perez Lopez9

1Radiomics Group, Vall d’Hebron Institute of Oncology, Barcelona, Spain; 2Clinical AI,EKFZ - Else Kröner Fresenius Zentrum für Digitale Gesundheit, Dresden, Germany;3Oncology Data Science (ODysSey) Group, Vall d’Hebron Institute of Oncology (VHIO)-Cellex Center, Barcelona, Spain; 4Pathology Department, Vall d’Hebron University Hospital, Barcelona, Spain; 5Molecular Oncology Group, Vall d’Hebron Institute of Oncology (VHIO)-Cellex Center, Barcelona, Spain; 6Medical Oncology Department, Vall d’Hebron Institute of Oncology (VHIO)-Cellex Center, Barcelona, Spain; 7Oncology Data Science (ODysSey) Group group, Vall d’Hebron Institue of Oncology, Barcelona, Spain;8Early Drug Development Unit, Hospital Universitario Vall d’Hebron, Barcelona, Spain;9Radiomics Group, Vall d’Hebron Institute of Oncology (VHIO)-Cellex Center, Barcelona, Spain

Background: The growing need for better predictive biomarkers in immunotherapy has driven the development of AI models across various ﬁelds. Despite this progress,most studies focus on single modalities, such as pathology or radiology. This study emphasizes the importance of multimodal biomarkers, combining radiology and pathology data, to optimize treatment outcomes and advance personalized medicine in immunotherapy.

Methods: We developed weakly-supervised deep learning (DL) models for CT and PDL1-stained immunohistochemistry (IHC) images. We trained a CT-based model to predict immunotherapy clinical beneﬁt (PFS > 5 months) in a pan-cancer cohort from VHIO(n¼369). Simultaneously, we trained a DL method to predict PD-L1 status fromIHC images in an open source NSCLC cohort (n¼233), validated in a pan-cancer cohortfrom VHIO (n¼106). The model predictions of both modalities were aggregated andutilized for patient stratiﬁcation in immunotherapy response. In the overlapping subset with both modalities’ data (n¼75), we explored the association between PFSand the combination of predicted clinical beneﬁt by CT and predicted PDL1 status by IHC using Cox regression and log-rank test.

Results: The CT-based and IHC-based DL models exhibited effective performance in predicting PFS for immunotherapy response in the pan-cancer cohort, with hazard ratios (HR) of 0.62 [95% CI 0.5-0.78], p <0.05 and 0.66 [95% CI 0.44-1], p <0.05,respectively. In the multi-modal data subsets, patients classiﬁed as clinical beneﬁt prediction by the CT-based model and PDL1 high by the IHC-based model (n ¼ 20)exhibited better immunotherapy response (HR 0.44 [0.25-0.78], p <0.05) with longer PFS (median PFS 4.08 [2.70-10.91] months) compared to the rest (median PFS 1.81[1.68-2.96] months).

Conclusions: Integrating radiology and pathology data improves response prediction compared to single modality models, emphasizing the potential of a multimodal approach for better patient stratiﬁcation in immunotherapy.

Funding: CRIS Foundation Talent Award (TALENT19-05).

Disclosure: R. Dienstmann: Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca,Boehringer Ingelheim, Ipsen, Libbs, Lilly, Merck Sharp & Dohme, Roche, Sanoﬁ, Servier, GSK, Takeda,Janssen, Foundation Medicine; Financial Interests, Personal, Advisory Board: Bayer, Roche; Financial Interests, Personal, Full or part-time Employment, Oncoclínicas is a private healthcare provider in Brazil. I work part time as Medical Director of the Precision Medicine and Big Data Initiative. We develop molecular tests (pathology and genomics) that are offered to patients treated in the organisation as part of support programs sponsored by pharmaceutical companies and I coordinate research activities with real-world clinico-genomics cohorts: Oncoclínicas; Financial Interests, Personal, Stocks/Shares: Trialing; Financial Interests, Personal, Research Grant: Merck. E. Garralda:Financial Interests, Personal, Advisory Board: Roche, Ellipses Pharma, Boehringer Ingelheim, Janssen Global Services, Seattle Genetics, Alkermes, Thermo Fisher, MabDiscovery, Anaveon, Hengrui, F-Star Therapeutics, Sanoﬁ, Incyte; Financial Interests, Personal, Invited Speaker: MSD, Lilly, Roche, Thermo Fisher, Novartis, Seagen; Financial Interests, Personal, Full or part-time Employment: NEXT Oncology;Financial Interests, Institutional, Funding: Novartis, Roche, Thermo Fisher, AstraZeneca, Taiho;Financial Interests, Institutional, Research Grant: BeiGene, Janssen. P.G. Nuciforo: Financial Interests,

S251

Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: MSD Oncology,Bayer; Financial Interests, Personal, Other, Consultant: Targos Molecular Pathology GmbH. J.N.

Kather: Financial Interests, Personal, Invited Speaker: Fresenius, Eisai, MSD; Financial Interests,Personal, Advisory Board: Owkin, DoMore Diagnostics, Panakeia, London, UK. R. Perez Lopez:Financial Interests, Personal, Full or part-time Employment, VHIO staff (team leader of the Radiomics Group): VHIO; Financial Interests, Institutional, Research Grant, Co-PI of 3 research studies.:AstraZeneca; Financial Interests, Institutional, Research Grant, PI of a research study: Roche. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2900

177P

Methods: A total of 1593 breast patients were analyzed using RNA-seq and clinical data from four independent public datasets, including 1064 patients from TCGA, 198 from GSE7390, 327 from GSE20685, and 104 from GSE42568. We also analyzed the mutated landscape based on exome and copy number alteration data from TCGA. In addition, single-cell RNA-seq (scRNA-seq) data from three breast cancer patients from GSE198745, and data on mammary gland tissue from the Tabula Muris, were used to measure the variation of the candidate GPCRs across diverse cell types. The CellMiner database was used to examine drug sensitivity.

Results: Among the 33 aGPCRs, GPR56 was the only signiﬁcant prognostic factor in all four datasets. High GPR56 expression was signiﬁcantly lined to worse relapse-free survival and overall survival. GPR56 expression was higher in younger, high-grade, and triple-negative breast cancers. GPR56-related genes were involved in several pathways, including cell division, DNA replication, cell cycle, protein binding, and others.

GPR56 also participated in the activation of multiple cancer signaling pathways. High GPR56 expression was correlated with higher levels of several immune cells, immune checkpoints, and immune-related scores. scRNA-seq analysis revealed that GPR56 was mainly expressed in tumor cells, tumor stem cells and endothelial cells. In normal breast tissues, GPR56 expression was higher in basal cell subsets than in luminal epithelial cell subsets, suggesting that GPR56 may interact with breast stem cells. In addition, there were some differences in the mutant landscape between the high and low GPR56 expression groups. Furthermore, GPR56 was signiﬁcantly associated with sensitivity to multiple antitumor drugs.

Conclusions: GPR56 was signiﬁcantly linked to the molecular pathology and prognosis of breast cancer. GPR56 may serve as a promising novel therapeutic target in breast cancer.

Funding: This study was supported by grants 82273204, 81972471 and 82073408 from the National Natural Science Foundation of China, grant 2023A1515012412 and 2023A1515011214 GuangDong Basic and Applied Basic Research Foundation, grant 2023A03J0722, 202206010078 and 202201020574 from the Guangzhou Science and Technology Project, grant 2018007 from the Sun Yat-Sen University Clinical Research 5010 Program, grant SYS-C-201801 from the Sun Yat-Sen Clinical Research Cultivating Program, grant A2020558 from the Guangdong Medical Science and Technology Program, grant 7670020025 from Tencent Charity Foundation , grant YXQH202209 from the Scientiﬁc Research Launch Project of Sun Yat-Sen Memorial Hospital, grant HL2021012 from the nursing research project of Sun Yat-Sen Memorial Hospital.

https://doi.org/10.1016/j.annonc.2023.09.2894

171P Combined expression of MKI67, FOXC1 and PDL1 is a pantumor tissue-agnostic predictor of PD1/PDL1 inhibitor

efﬁcacy in metastatic renal cell cancer: Validation in

checkmate 009, 010 and 025 clinical trial cohorts

P.S. Ray1, T. Ray2, C. Taylor3, R. Hussa2

1Surgical Oncology, Onsite Healthcare, Lincolnwood, IL, USA; 2Research & Development, Onconostic Technologies, Inc., Evanston, IL, USA; 3Pathology, Keck School of Medicine - University of Southern California USC, Los Angeles, CA, USA

Background: Accurate prediction of PD1/PDL1 inhibitor therapeutic efﬁcacy (TE) as well as any resultant durable clinical beneﬁt (improved progression-free survival(PFS), overall survival (OS)) is not consistently achieved with existing biomarkers like PDL1 or tumor mutational burden(TMB). We hypothesized that a multi-marker (MM)predictive biomarker strategy that tracks plasticity using FOXC1 expression, in parallel to tumor proliferation and immune evasion, using expression of MKI67 and PDL1,respectively, may demonstrate superior TR prediction, and also enable accurate prediction of risk for hyperprogressive disease (HPD).

Methods: Metastatic renal cell carcinoma (mRCC) patients enrolled in Checkmate(CM) 009, 010 and 025 clinical trials (n¼35, 168, 803) with available pre-treatmenttumor RNA-Seq data (n¼16, 45, 250 respectively) were analysed for FOXC1, MKI67and PDL1 expression, and correlated with overall response rate (ORR), PFS, OS and HPD, the latter deﬁned as time-to-treatment-failure <¼2 months post-treatmentinitiation. Optimized biomarker cut-off values based on model area-under-curve were leave-one-out cross validated and prediction algorithms derived to predict Predicted Responders (PR) and Non-Responders (NR). The unmodiﬁed strategy was then validated in independent datasets.

Results: In CM025 ORR prediction by MM was speciﬁc to the Nivolumab arm [ITT CR%¼22.5%, PR CR%¼41.8%, NR CR%-3.6% OR¼19.4 (4.3- 87.8)95%CI, p<0.0001,n¼111] and not the Everolimus arm [ITT CR%¼4.6%, PR CR%¼3.3%, NR CR%¼ 5.4%,n¼109]. This was conﬁrmed further in combined CM009+CM010 cohorts (OR¼9.63(0.98-94.54) 95%CI, p¼0.03). MM-predicted PR consistently displayed superior PFS(p<0.0001) and OS (p¼0.03) compared to predicted NR who displayed either Pro-gressive Disease or Hyperprogressive Disease, and were superior to results with PDL1.

Conclusions: Tracking multiple dimensions of cancer biology using our MM approach again proved its superiority in predicting PD1/PDL1 inhibitor efﬁcacy in advanced/metastatic tumors, this time in mRCC patients. This approach merits further testing in prospective clinical trials.

Clinical trial identiﬁcation: NCT01358721 - October 28, 2021 NCT01354431 - May 12,2022 NCT01668784 - August 9, 2022.

S249

Legal entity responsible for the study: Partha S. Ray, MD.

Disclosure: P.S. Ray: Non-Financial Interests, Institutional, Advisory Board: Onconostic Technologies Inc.; Financial Interests, Institutional, Stocks/Shares: Onconostic. T. Ray, R. Hussa: Financial Interests, Institutional, Stocks/Shares: Onconostic Technologies Inc. C. Taylor: Non-Financial Interests,Institutional, Advisory Board: Onconostic Technologies Inc.; Financial Interests, Institutional, Stocks/Shares: Onconostic Technologies Inc.

https://doi.org/10.1016/j.annonc.2023.09.2895

172P

T cell-derived circulating DNA and tumour inﬂammatory microenvironment in EGFR-mutant advanced non-small cell lung cancer: Correlation with the outcome of EGFR TKI

treatment

N. Zungsontiporn1, S. Santisukwongchote2, P. Sitthideatphaiboon1,

N. Leelayuwatanakul3, K. Korphaisarn4, P. Chantranuwat2, V. Sriuranpong1,C. Vinayanuwattikun1

1Division of Medical Oncology, Department of Medicine, King Chulalongkorn Memorial Hospital - Thai Red Cross Society, Bangkok, Thailand; 2Department of Pathology, King Chulalongkorn Memorial Hospital - Thai Red Cross Society, Bangkok, Thailand; 3Division of Pulmonary and Critical Care Medicine, Department of Medicine, King Chulalongkorn Memorial Hospital - Thai Red Cross Society, Bangkok, Thailand; 4Division of Medical Oncology, Department of Medicine, Faculty of Medicine Siriraj Hospital,Mahidol University, Bangkok, Thailand

Background: We previously reported paradoxical impact of T-cell derived circulating

DNA (T-cirDNA) in-term of prognosis marker in advanced non-small cell lung cancer

(NSCLC). Longer durability of EGFR tyrosine kinase inhibitor (EGFRi) was correlated

with undetectable T-cirDNA/cirDNA. This study aimed to conﬁrm the ﬁnding in a

larger cohort, correlated with tumor immune microenvironment (TIME).

Methods: Pretreatment plasma of patients with advanced EGFR-mutant NSCLCs who

received EGFRi were collected. The semi-quantitative T-cirDNA /cirDNA was conducted by multiplex real-time polymerase chain reaction. Correlation with clinical

outcome and TIME, including programmed cell death ligand-1 (PD-L1 clone 22C3),

CD8 tumor inﬁltration lymphocyte (TIL), and Treg/FOXP3 were conducted.

Results: One-hundred and thirty-nine patients were divided according to T-cirDNA/

cirDNA into undetectable (30%), low (1% ratio; 38.1%), and high (>1% ratio; 31.6%).The median progression-free survival (PFS) was 13.1 [95% CI 8.8 e 17.4], 9.0 [95% CI

6.7 e 12.5], and 13.2 [95% CI 8.8 e 19.3] months respectively, which was longest in

undetectable and high T-cirDNA/cirDNA. Sixty-eight available tissue blocks for TIME

study revealed decremental proportion of high PD-L1 (15% TPS) in high (21%), study revealed decremental proportion of high PD-L1 (≥15% TPS) in high (21%), lowlow(13%) and undetectable T-cirDNA/cirDNA (4%). While high intra-tumoral CD8 TIL

(1%) had lowest proportion in low T-cirDNA/cirDNA (17%) contrary to undetectable(36%) and high T-cirDNA/cirDNA (47%). Multivariate cox-regression analysis revealed

that high PD-L1 and high intra-tumoral CD8 TIL were independent factors correlated

with shortened PFS. Good ECOG performance status (0-1) and undetectable T-cirDNA/

cirDNA were solely independent prognostic factor to overall survival.

Conclusions: Undetectable T-cirDNA/cirDNA represents inactivated naïve T-cell and

indicated favorable prognosis in EGFR-mutant NSCLCs who received EGFRi. Inﬂammatory TIME including high PD-L1 and high intra-tumoral CD8 indicated shorted

disease control with EGFRi. The interaction of active T-lymphocyte and TIME in EGFR

alteration advanced NSCLC received EGFRi is warranted.

Funding: The Health Systems Research Institute (Thailand).

Disclosure: N. Zungsontiporn: Financial Interests, Personal, Invited Speaker: AstraZeneca, Roche,blood samples for CTC enumeration using CellSearch methodology. CTC counts Takeda. P. Sitthideatphaiboon: Financial Interests, Personal, Advisory Board: AstraZeneca, Janssen,

Merck, Pﬁzer, Roche; Financial Interests, Personal, Invited Speaker: AstraZeneca, Bristol Myers

Squibb, Novartis, Pﬁzer, Roche, Takeda; Financial Interests, Institutional, Local PI: AstraZeneca,

Roche, Merck, Novartis. K. Korphaisarn: Financial Interests, Personal, Invited Speaker: Roche, Amgen,

AstraZeneca, MSD; Non-Financial Interests, Principal Investigator: MSD, Roche. V. Sriuranpong:

Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Novartis, MSD, Pﬁzer, Amgen;

Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Novartis, MSD, Amgen; Financial

Interests, Institutional, Research Funding: Roche, AstraZeneca, Novartis, MSD, Amgen. All other

authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2896

173P Expression of programmed death-ligand 1 and EGFR on circulating tumour cells in advanced lung cancer patients

J. Khandare1, G. Aland1, M. Garbhe2, S. Gosavi2, G. Khutale3, M. Patil2, V. Tulpule2,P. Lokhande2, A. Ashturkar2, V. Jadhav2, A. Vasudevan2, S. Jayant2, A. Bharde4

1CTC, Actorius Innovations and Research, Pune, India; 2CTC, Actorius Innovations and Research USA and India, Pune, India; 3CTC, OneCell Dx, Pune, India; 4CTC, OneCell Diagnostics India Pvt Ltd, Pune, India

Background: Targeted molecular therapy and immunotherapy have revolutionized the treatment of advanced lung cancer (ALC). Although therapeutically signiﬁcant, the outcome of ICI or TKI is dependent on the presence of their respective targets in

tumor cells. Evaluating targets based on solid biopsy may be often misleading,particularly in progressive patients despite therapy administration. Additionally, tissue biopsy provides a static signature of a target protein expression from the evolving tumor. The unmet need for dynamic detection and monitoring of actionable targets could be addressed by circulating tumor cells (CTCs). Here we report on the utility of CTCs to detect actionable targets from advanced lung cancer (ALCs) patients.

Revealing differences in radiosensitivity of advanced nonsmall cell lung cancer (NSCLC)through single-cell

sequencing data

P. You1, H. Zhou2, Q. Li2, D. Xie2, L. Yao2, S. Liu3

1Radiotherapy, Nanchang University, Nanchang, China; 2Department of Thoracic Surgery, Guangdong Province People’s Hospital, Guangzhou, China; 3Guangdong Province People’s Hospital, Southern Medical University Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou, China

Background: Radiotherapy resistance is a major therapeutic difﬁculty for advanced NSCLC patients because not all patients can beneﬁt from radiation therapy. Identifying disparities in radiosensitivity of advanced lung cancer and antagonizing the radiotherapy resistance are the challenges for clinical oncologists.

Methods: We analyzed the scRNA-seq transcriptome data of 42 patients with advanced NSCLC, including lung adenocarcinoma and lung squamous cell carcinoma,used the radiosensitivity index (RSI) to calculate the radiosensitivity intensity (RSIhigh and RSIlow) of each cell of 11 cell types, and drew the radiosensitivity difference map of different cell types in the system. The core role of malignant cells in radiosensitivity differences in advanced NSCLC was revealed using cell cycle inference, tumor cytoTRACE score, GO/KEGG enrichment, cell-cell interactions, cellular metabolic activity,and quasi temporal trajectory joint analysis, all in accordance with the "4R" principle of radiobiology (Repair, Reoxygenation, Redistribution, Regeneration).

Results: Malignant cells differ signiﬁcantly from other types of radiosensitive cells in processes such as cell cycle, aging, apoptosis, chromosomal alterations, and cellular metabolic activity. RSIhighcells make up the majority of cells in the G2/M and S phases, and the quantity and intensity of RSIhighcell ligand receptors increases considerably. RSIlowcells, as an exposure factor, tend to shift from epithelial to malignant cells, leading in alterations in ligand receptor input and output patterns.

Furthermore, we discovered considerable changes in the metabolic activity of RSIlow cells in lung squamous cell carcinoma.

Conclusions: Our ﬁndings show that radiosensitivity varies in advanced NSCLC. RSIlow cells could be a subset of malignant cells with radiotherapy resistance, driving clinical researchers to delve deeper into the detailed mechanism of advanced NSCLC.

https://doi.org/10.1016/j.annonc.2023.09.2901

178P Explainable radiomics, machine and deep learning models to predict immune-checkpoint inhibitor treatment efﬁcacy in advanced non-small cell lung cancer patients

L. Provenzano1, M. Favali2, L. Mazzeo3, A. Spagnoletti3, C. Giani4, G. Calareso5,M. Ruggirello5, F.G. Greco5, R. Vigorito5, M. Occhipinti4, M. Brambilla3,

S. Manglaviti3, C. Proto3, G. Lo Russo6, F. Trovò2, F.G.M. De Braud7, M. Ganzinelli3,A. Pedrocchi2, V. Miskovic8, A. Prelaj9

1Oncologia Medica 1, Istituto Nazionale dei Tumori di Milano - Fondazione IRCCS,Milan, Italy; 2Biomedical Engineering, Politecnico di Milano, Milan, Italy; 3Medical Oncology Department, Istituto Nazionale dei Tumori di Milano - Fondazione IRCCS,Milan, Italy; 4Oncology Dept., Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan,Italy; 5Radiology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan,Italy; 6Dipartimento Oncologia Toraco-Polmonare, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy; 7Medical Oncology & Haemathology Department,Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy; 8Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano, Milan, Italy; 9Oncologia Medica Toracica Dept., Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan,Italy

Background: IO revolutionized NSCLC treatment paradigm, but only a relatively small proportion of pts shows beneﬁts. Since available biomarkers demonstrated only limited predictive efﬁcacy, novel models are urgently needed. Radiomics, through machine learning (ML) and deep learning (DL) techniques, allows to extract features from raw images to build predictive models. This study aimed to develop and test 2 type of radiomics models in predicting IO efﬁcacy on advanced NSCLC, one ML-based,other through an end-to-end DL pipeline.

Methods: We collected CT scans and RWD from 295 consecutive pts with advanced NSCLC pts receiving any-line anti-PD(L)1 therapy either alone or in combination with

CHT at our Institution from 23/04/2013 to 12/05/2022 within APOLLO 11 study. ML workﬂow consisted of image preprocessing, feature extraction, 3 step feature selection, correlation, algorithm training and evaluation of 6 ML classiﬁers. ML models were trained using radiomics +/- RWD. Models were evaluated on independent test set and SHAP values used to explain model predictions. We compared developed model with novel DL end-to-end model, a 3D convolutional neural network.

Results: 15 image features were selected to build radiomic model, achieving ACC of

0.61 and AUC of 0.58. Combining it with additional RWD features, accuracy and AUC of LR reached 0.71 and 0.76. SHAP analysis for best-performing models showed RW(ECOG PS, therapy line, concomitant CHT, PDL1) and radiomics features (tumor shape and intensity/distribution of gray-level values) that most inﬂuenced models. DL model achieved an ACC of 0.69 and a Loss value of 0.773. A high proportion of higher GLSZM and a high value of large area size zones were associated to a higher response to therapy.

Conclusions: The developed and validated ML-based model includes radiomic and RW features, demonstrating ability to predict IO efﬁcacy and potential future applicability for treatment selection. We ﬁrstly demonstrated that a radiomics-based DL model outperform the all radiomics ML-based models highlighting the importance of this approach in image data. SHAP analysis provided valuable insights to explore features that most inﬂuenced the models’ predictions

Legal entity responsible for the study: Fondazione IRCCS Istituto Nazionale Tumori di Milano.

Disclosure: F.G.M. De Braud: Financial Interests, Personal, Advisory Role: Roche. A. Prelaj:Financial Interests, Funding: Roche, AstraZeneca, BMS. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2902

179P Molecular tumor board directed treatment for patients with advanced stage solid tumors: A case-control study

D. Bansal1, M.T. Roth1, C. Ward1, L. Douglass1, B. Buzard1, B. Gustafson1, T. Pluard1,J. Subramanian2

1Medical Oncology, Saint Luke’s Cancer Institute, Kansas City, MO, USA; 2Thoracic Oncology Center for Precision Oncology, Suite 4000, Saint Luke’s Primary Care Plaza,Kansas City, MO, USA

Background: Interpreting next-generation sequencing (NGS) results and directing treatment based on those results can be challenging. Molecular tumor boards (MTBs)can help by establishing collaborative frameworks to deliver patient care plans with the appropriate incorporation of genomic data.

Methods: This retrospective observational study evaluates the impact of MTB on the outcomes of adult patients diagnosed with advanced-stage cancer. Patients were grouped into those who received at least one treatment recommended by MTB or those who did not receive treatment recommended by MTB. Kaplan- Meier analysis was performed for overall survival (OS) and progression-free survival (PFS). Cox proportional hazard model was ﬁt for PFS, OS, and time on treatment (ToT) with multivariate adjusting for age, stage, line of therapy, and primary site of diagnosis.

Results: Of 238 evaluable patients, 138 (58%) received at least one treatment recommended by MTB. Patient characteristics were well balanced between the cohorts except for a statistically signiﬁcantly higher proportion of lung adenocarcinoma (33%v 14%, p¼0.0009) & melanoma (9% v 2%, p¼0.030) in the matched cohort and moreglioblastoma in the unmatched cohort (8% v 1%, p¼0.017) (Table). Median ToT was4.3 months for patients on matched treatment versus 2.8 months for patients who received therapy of provider’s choice (HR 0.58, 95% CI [0.41-0.83], p¼0.0027). Me-dian PFS was 9.7 months versus 4.3 months for MTB-matched treatment versus provider’s choice of treatment (HR 0.64, 95% CI [0.42-0.97],p¼0.035). Median OS was18.5 months for patients on MTB-recommended therapy versus 9.1 months for patients who received therapy of provider’s choice (HR 0.64, 95% CI [0.43-0.96],p¼0.030).

Conclusions: MTB treatment recommendations improved survival outcomes for patients with cancer even after correcting for imbalances between the two cohorts. Ourﬁndings show that MTBs in community cancer centers are feasible and valuable in cancer care.

unity cancer centers are feasible and valuable in cancer care.

|Table: 179P Histology |Matched |Matched |Unmatched |Unmatched | |---|---|---|---|---|

||No. |(%) |No. |(%) |

||138 ||100 ||

|Lung Adenocarcinoma |45 |(33%) |14 |(14%) |

|Colorectal Adenocarcinoma |10 |(7%) |14 |(14%) |

|Breast Carcinoma |8 |(6%) |12 |(12%) |

|Melanoma |12 |(9%) |2 |(2%) |

|Lung Squamous Cell Carcinoma |7 |(5%) |7 |(7%) |

|Prostatic Adenocarcinoma |5 |(4%) |6 |(6%) |

|Glioblastoma |2 |(1%) |8 |(8%) |

|Esophagogastric Adenocarcinoma |5 |(4%) |5 |(5%) |

|Pancreatic Adenocarcinoma |2 |(1%) |6 |(6%) |

|Cholangiocarcinoma |6 |(4%) |1 |(1%) |

|Non-cutaneous Squamous |6 |(4%) |1 |(1%) |

|Cell Carcinoma |||||

|Lung Small Cell Carcinoma |2 |(1%) |4 |(4%) |

|Endometrial Carcinoma |3 |(2%) |1 |(1%) |

|Sarcoma |1 |(1%) |3 |(3%) |

|Urothelial Carcinoma |1 |(1%) |2 |(2%) |

|Appendiceal Adenocarcinoma |2 |(1%) |1 |(1%) |

|Other Histologies |21 |(15%) |13 |(13%) |

Funding: Saint Luke’s Foundation.

https://doi.org/10.1016/j.annonc.2023.09.2903

180P An HLA-diet-oriented system unveiling organ-speciﬁc

occurrence of multiple primary cancers (MPC) with

prevention strategy: A large cohort study of 47,550 cancer patients

Z. Rong, Z. Dong, S-C. Ma, J. Lin, D. Han, X. Cai

Department of Radiation Oncology, Southern Medical University Nanfang Hospital,Guangzhou, China

Background: Along with the prolonged survival of cancer patients in recent years comes another dilemma, multiple primary cancers (MPC), which rob cancer patients of their privilege to optimal treatments. Nonetheless, understanding the hereditary and postnatal predisposition of MPC is still in its infancy.

Methods: We included 47,550 cancer patients in UK Biobank. Hazardous and protective HLA alleles concerning MPC were recognized leveraging stepwise logistic regression, which was further validated by log-rank test and Cox proportional hazard model. Logistic regression was used to investigate the organ-speciﬁc association between HLA and MPC. Cox proportional hazard model was used to explore potential interventions.

Results: Two protective (DPA1*02:02 and DRB1*04:03) and four hazardous (A*26:01,A*24:03, DPB1*20:01 and DQB1*06:01) HLA alleles are signiﬁcantly associated with MPC risk for male, whereas one protective (DRB5*01:01) and four hazardous(A*03:02, DRB1*08:03, DQB1*05:04, and DPB1*11:01) for female. Compared with patients without MPC-related HLA alleles, both male and female patients carrying protective HLA alleles have lower risk of MPC (HR, 0.67 [95% CI, 0.53-0.83] and HR,

K.S. Shohdy1, J. Atherton2, J. Longland2, J.L.E. Allison2, M. Pillai2, F. Thistlethwaite1

1Division of Cancer Sciences, The Christie NHS Foundation Trust and The University of Manchester, Manchester, UK; 2Experimental Cancer Medicine Team, The Christie NHS Foundation Trust, Manchester, UK

Background: Speciﬁc shared HLA Class 1 alleles have been linked to the response to immune checkpoint blockade (ICB). In this study, we aimed to identify the HLA-A subtypes associated with maximum beneﬁt from ICB.

Methods: We compiled a prospectively maintained clinical dataset of patients who underwent CLIA-approved germline HLA status testing as part of various advanced immune and cell therapy trials undertaken at the Christie NHS Foundation Trust. The probability of overall survival (OS) or progression-free survival (PFS) was estimated by the Kaplan-Meier method, and their associations with the HLA-A alleles were tested with Cox regression analysis.

Results: A total of 285 patients from 11 immune and cell therapy clinical trials were eligible for ﬁnal analysis. The median age at diagnosis was 57 years (range: 19 e 82).

The tumor categories were NSCLC (n¼93), melanoma (n¼60), and other cancers (n¼123). We identiﬁed 15 HLA-A subtypes, the most common alleles being HLA-A02(42.2%), HLA-A01 (35.4%), and HLA-A03 (26.0%). A total of 145 patients received ICB either as ﬁrst-line (56.5%) or as second or later-line (43.5%). Of these, 136 patients had evaluable clinical response status. 24.2% were positive for HLA-A02:01 and were eligible for screening for our HLA-speciﬁc trials. Patients with the HLA-A01 and HLAA30 subtypes were signiﬁcantly associated with a higher likelihood of clinical response to ICB (odds ratio ¼ 2.58, 95%CI: 1.20 e 5.62, p ¼ 0.017 and 1.80, 95% CI: 1.58-2.18,p¼ 0.011, respectively). In the NSCLC subgroup, patients with HLA-A01 subtypes weresigniﬁcantly associated with better OS (hazard ratio (HR): 0.42, 95%CI: 0.22-0.81, p¼0.010); meanwhile, HLA-A02 was associated with worse OS (HR: 1.95, 95%CI: 1.09-3.49, p¼ 0.024). In the other cancers subgroup, HLA-A11 and A24 were associatedwith better OS (HR: 0.20, 95%CI: 0.05-0.85, p¼ 0.030 and HR: 0.31, 95% CI: 0.10-0.89,p¼ 0.029, respectively).

Conclusions: HLA-A status predicted clinical outcomes of patients receiving ICB. HLA genotyping could be incorporated early into the diagnostic work-up of patients with solid cancers as a predictive and selective biomarker.

Legal entity responsible for the study: The Christie NHS Foundation Trust.

https://doi.org/10.1016/j.annonc.2023.09.2908

185P Real-world data analysis of genomic proﬁling-matched targeted therapy outcomes in patients with fusion-positive NSCLC

J. Patel1, R. Ben-Shachar2, K. Nadhamuni3, M. Carty3, R. Pelossof4, I. Klein5,H. Nimeiri6, C. Aggarwal7, R.D. Gentzler8

1Hematology and Oncology, Northwestern University Feinberg School of Medicine,Chicago, IL, USA; 2Clinical Development, Tempus Labs, Inc., Chicago, IL, USA; 3Data Science, Tempus Labs, Camarillo, CA, USA; 4Tempus Labs, Inc., Chicago, IL, USA;5Medical Affairs, Tempus Labs, Inc., Chicago, IL, USA; 6Oncology Department, Robert.

H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA; 7Medicine -Hematology/Oncology Department, University Of Pennsylvania, Philadelphia, PA, USA;8Hematology/Oncology, University Hospital of Virginia (UVA), Charlottesville, VA, USA

Background: While clinical oncology societies such as ESMO have recommended the use of Comprehensive Genomic Proﬁling (CGP) to identify patients eligible for targeted treatment, full utilization of the potential beneﬁts of CGP has not yet occurred in routine clinical practice. Here we assess the compliance to ESMO targeted therapy recommendations and associated outcomes for CGP-based ALK, RET, ROS1, and NTRK fusions detected in a large real-world, observational dataset of advanced NSCLC patients.

Methods: We retrospectively analyzed de-identiﬁed stage IV or metastatic NSCLC records from the Tempus database which encompasses molecular and clinical data from hundreds of clinics across the United States sequenced with the Tempus xT assay (DNA and whole-exome capture RNA NGS) from 2018-2022. Therapeutic adoption was analyzed in cases with 30 days of medication data post-sequencing.Real-world overall survival (rwOS) was deﬁned as the interval from start of medication prescribed after sequencing to date of death, censored on the last known physician encounter. A cox proportional hazards model was ﬁt to evaluate the relationship between matched targeted therapy compliance and rwOS in fusion-positive patients.

Results: Among 1,950 patients that met study inclusion criteria, N¼ 65 (3.3%) had afusion detected by CGP (N¼38 ALK fusions, N¼15 RET fusions, N¼11 ROS1 fusionsand N¼ 1 NTRK fusion). The overall compliance rate of targeted therapy was 82%(N¼53). The median time from sequencing to start of targeted therapy was < 1month. Fusion-positive patients receiving matched therapy had signiﬁcantly longer rwOS than those that did not receive matched therapy (HR¼0.13, p<0.001). ALK34 - Issue S2 - 2023

positive patients receiving matched therapy had signiﬁcantly longer rwOS than those that did not receive matched therapy, (HR¼0.12, p<0.05).

Conclusions: This study demonstrates that in a real-world, retrospective cohort, most oncologists utilized CGP to timely treat patients with ESMO-recommended targeted therapy for fusion-positive advanced NSCLC. More importantly, CGP-matched guideline-recommended treatment is associated with improved rwOS. Future studies are needed to understand the gap in compliance with matched targeted therapy.

Disclosure: J. Patel: Financial Interests, Personal, Advisory Board: AstraZeneca, Takeda. R. BenShachar: Financial Interests, Personal, Full or part-time Employment: Tempus Labs; Financial Interests, Personal, Stocks/Shares: Tempus Labs, Myriad Genetics. K. Nadhamuni: Financial Interests,Institutional, Full or part-time Employment: Tempus Labs; Financial Interests, Institutional, Stocks/Shares: Tempus Labs; Financial Interests, Institutional, Other, Full time employee: Tempus Labs. M.

Carty: Financial Interests, Institutional, Full or part-time Employment: Tempus Labs; Financial Interests, Institutional, Stocks/Shares: Tempus Labs; Financial Interests, Institutional, Advisory Board:Tempus Labs. R. Pelossof: Financial Interests, Personal, Full or part-time Employment: Tempus;Financial Interests, Personal, Other, RSUs: Tempus. I. Klein: Financial Interests, Institutional, Full or part-time Employment, Full time employee, also granted shares in the company with potential future value: Tempus Labs, Inc.; Financial Interests, Institutional, Stocks/Shares, Granted as part of overall compensation, may have future value.: Tempus Labs, Inc.; Non-Financial Interests, Member of Board of Directors, This is a not for proﬁt organization (503c) that advocates for appropriate medication oversight and usage in the US healthcare system, based on literature regarding waste and medical error in today’s system: Get the Meds Right. H. H. Nimeiri: Financial Interests, Personal,Full or part-time Employment: Tempus; Financial Interests, Personal, Stocks/Shares: Tempus, AbbVie. C. Aggarwal: Financial Interests, Personal, Advisory Board: AstraZeneca, Celgene, Genentech,Lilly, Merck, Bluprint, Daiichi/Sankyo, Sanoﬁ, Eisai, BeiGene, Shionogi, Turning Point, Pﬁzer, Janssen,Boehringer Ingelheim. R.D. Gentzler: Financial Interests, Personal, Advisory Board: AstraZeneca,Takeda, Gilead, Janssen, Mirati, Daiichi Sankyo, Sanoﬁ, Oncocyte, Jazz Pharmaceuticals; Financial Interests, Personal, Invited Speaker: Clinical Care Options, OncLive, Targeted Oncology, Society for Immunotherapy of Cancer (SITC); Financial Interests, Institutional, Local PI: Janssen, Mirati, Daiichi Sankyo, Bristol Myers Squibb, AstraZeneca, Jounce Therapeutics, Takeda, Bristol Myers Squibb,Merck, Chugai, Amgen; Financial Interests, Institutional, Research Grant: Pﬁzer; Financial Interests,Institutional, Coordinating PI: Mirati; Non-Financial Interests, Leadership Role: Hoosier Cancer Research Network; Non-Financial Interests, Principal Investigator: NCI ETCTN; Non-Financial Interests, Personal, Other, Travel support for attending meetings for invited speaker: International Association for the Study of Lung Cancer (IASLC); Non-Financial Interests, Other, Member of Lung Cancer Scientiﬁc Review Committee: American Society of Clinical Oncology, Scientiﬁc Review Committee; Non-Financial Interests, Other, Committee Member: NCI Investigational Drug Steering Committee; Non-Financial Interests, Ofﬁcer, Associate Editor: Journal of Thoracic Oncology, ASCO Meeting Abstracts.

https://doi.org/10.1016/j.annonc.2023.09.2909

186P Pooled efﬁcacy and safety data of alectinib (A) vs. crizotinib(C) from the randomized phase III ALEX and J-ALEX trials

M. Tagliamento1, M. Bruzzone2, M. Ceppi2, C. Genova3, F.G. Dall’Olio4, M. Aldea5,F. Spagnolo3, E. Blondeaux2, F. Poggio6, M. Brandão7, J. Remon Masip8,

L. Del Mastro3, L. Hendriks9, F. Barlesi9, D. Planchard8, M. Lambertini3, B. Besse9

1Cancer Medicine Department, Gustave Roussy (France) and University of Genova(Italy), Villejuif, France; 2Department of Statistics, IRCCS Policlinico San Martino Hospital, Genoa, Italy; 3Department of Oncology and Hematology, University of Genova and IRCCS Policlinico San Martino Hospital, Genoa, Italy; 4Medical Oncology Department, AOU Policlinico S. Orsola-Malpighi, Bologna, Italy; 5Cancer Medicine Department, Gustave Roussy and Paris-Saclay University, Villejuif, France; 6Department of Oncology and Hematology, IRCCS Policlinico San Martino Hospital, Genoa,Italy; 7Medical Oncology Department, Institute Jules Bordet e Hôpital Universitaire de Bruxelles, Brussels, Belgium; 8Cancer Medicine Department, Gustave Roussy, Villejuif,France; 9Pulmonary Diseases Department, Maastricht University Medical Center(MUMC), Maastricht, Netherlands

Background: Among patients (pts) with ALK+ advanced non-small cell lung cancer(NSCLC) naïve to ALK-inhibitors, A signiﬁcantly prolonged progression-free survival(PFS) over C. We present results of a post-hoc patient-level pooled analysis at interim data cut-off of the randomized phase III trials ALEX (NCT02075840) and J-ALEX(JapicCTI-132316), exploring new prognostic factors.

Methods: In both studies, the primary endpoint was PFS by RECIST v1.1. Treatment crossover was only allowed in the J-ALEX trial. Multivariate analysis was performed by Cox’s model, the independence of the two trial data sets was managed by random effects models. Survival outcomes were correlated with baseline characteristics including high tumor burden (hTB, i.e. > median sum of diameter of target lesions)adoption was analyzed in cases with ≥30 days of medication data post-sequencing.and body mass index (BMI).

Results: The pooled set included 500 pts (A¼249, C¼251) with data available forsurvival and safety analysis. There was no imbalance between A and C groups in age(median 58 vs 56), sex (female 58% vs 59%), brain metastases (29% vs 34%), BMI (<25 70% vs 67%). At a median follow-up of 17.1 months, A provided prolonged PFS over C(median not reached vs. 10.2 months, HR 0.41, 95% CI 0.31-0.55, p<0.001), with median OS not reached in any arm (HR 0.80, 95% 0.50-1.28, p¼0.353). In themultivariate analysis with correction for ethnicity, hTB (>55mm) was linked to worse PFS regardless of the treatment received (HR 1.66, 95% CI 1.26-2.20, p<0.001), and BMI BMI ≥25 was correlated with better OS compared to BMI <25 (HR 0.50, 95% 0.29-25 was correlated with better OS compared to BMI <25 (HR 0.50, 95% 0.29-0.88, p¼0.025). Treatment effectiveness in subgroups is shown in table. Signiﬁcantinteraction between treatment and TB (p¼0.002) was found in subgroup PFS analysis.

S255

Grade 3 adverse events occurred in 36% of pts with A vs 51% with C, 15% of Grade ≥3 adverse events occurred in 36% of pts with A vs 51% with C, 15% of ptsptsdiscontinued A vs 20% C.

|Table: 186P Subgroup analysis |Table: 186P Subgroup analysis |Table: 186P Subgroup analysis |Table: 186P Subgroup analysis |Table: 186P Subgroup analysis | |---|---|---|---|---|

||HR for PFS A vs C (95% CI) |p value for PFS |HR for OS A vs C (95% CI) |p value for OS |

|Ref. A vs C whole cohort |0.41 (0.31-0-55) |<0.001 |0.80 (0.50-1.28) |0.353 |

|Sum diam <55mm |0.25 (0.16-0.41) |<0.001 |0.79 (0.35-1.80) |0.572 |

|Sum diam >55mm |0.52 (0.36-0.76) |0.001 |0.87 (0.49-1.55) |0.645 |

|BMI <25 |0.44 (0.32-0.62) |<0.001 |0.99 (0.58-1.71) |0.976 |

|BMI >25 |0.35 (0.19-0.63) |0.001 |0.39 (0.12-1.21) |0.103 |

Conclusions: hTB is a prognostic and predictive factor in patients with advanced ALK+NSCLC under ALK-inhibitors, while a BMI 25 is linked to a reduced risk of NSCLC under ALK-inhibitors, while a BMI ≥25 is linked to a reduced risk of death.death.Escalation strategies could be explored for hTB.

Clinical trial identiﬁcation: This is a pooled analysis of ALEX (NCT02075840) and JALEX (JapicCTI-132316) trials. This abstract is based on research using data from data contributor F. HoffmanneLa Roche that has been made available through Vivli, Inc.

Vivli has not contributed to or approved, and is not in any way responsible for, the contents of this publication.

Legal entity responsible for the study: Marco Tagliamento (Study PI) and IRCCS Policlinico San Martino Hospital.

Disclosure: M. Tagliamento: Non-Financial Interests, Member, International Lung Cancer Foundation Fellow: IASLC; Non-Financial Interests, Member, Lung Cancer Group: EORTC; Other, Travel and accommodation expenses: Eli Lilly. C. Genova: Financial Interests, Personal, Invited Speaker,Speaker’s Bureau (scientiﬁc meeting): AstraZeneca, Bristol Myers Squibb, Merck-Sharp-Dohme, Eli Lilly, Novartis; Financial Interests, Personal, Advisory Board, Advisory board: Amgen, Sanoﬁ; Financial Interests, Personal, Advisory Board, Advisory Board: Roche, Takeda; Financial Interests, Institutional,Funding, Funding for support of translational study: Bristol Myers Squibb; Financial Interests,Institutional, Funding, Funding in support of translational study: AstraZeneca; Financial Interests,Institutional, Research Grant, Research Grant for translational study: Italian Ministry of Health; NonFinancial Interests, Principal Investigator, Local PI for clinical trials: AstraZeneca, Roche; NonFinancial Interests, Member, Scientiﬁc society membership: ASCO, AIOM, FONICAP, AIOT, IASLC, ISLB.

E. Blondeaux: Financial Interests, Institutional, Research Grant, Research grant to my Institution for a research project: Gilead Science. M. Brandão: Financial Interests, Personal, Invited Speaker, Speaker at a symposium at the AORTIC Conference 2019 : Roche; Financial Interests, Institutional, Invited Speaker, December 2021 : Janssen; Financial Interests, Institutional, Advisory Board, 03/2023: Sanoﬁ;Financial Interests, Institutional, Invited Speaker, 01/2023: Takeda; Financial Interests, Institutional,Invited Speaker, 05/2023: Pﬁzer; Financial Interests, Institutional, Local PI: AstraZeneca, Roche,Boehringer Ingelheim, Sanoﬁ; Non-Financial Interests, Leadership Role, EORTC Lung Cancer Group -Young and Early Career group Chair (since January 2022): EORTC. J. Remon Masip: Financial Interests, Personal, Invited Speaker: Roche, MSD, Boehringer Ingelheim; Financial Interests, Personal,Writing Engagement: Pﬁzer; Financial Interests, Personal, Advisory Board: AstraZeneca, OSE Immunotherapeutics, BMS, Jansse, Takeda, Sanoﬁ; Financial Interests, Institutional, Invited Speaker:Merck Portugal; Non-Financial Interests, Principal Investigator, PI of PECATI trial in Thymic malignancies endorsed by a grant by MSD: MSD; Non-Financial Interests, Other, Co-PI of APPLE trial(EORTC-1525): AstraZeneca; Non-Financial Interests, Member, Secretary of the Lung Cancer Group at the EORTC: EORTC. L. L.ests, Personal, Invited Speaker, Educational meetings: Accademia Nazionale Medicina;Financial Interests, Personal, Writing Engagement, Author for BC text: Pensiero Scientiﬁco Editore;Financial Interests, Personal, Advisory Board, Breast cancer: Uvet; Financial Interests, Personal,Other, Author slide kits and interviews: Think2it; Financial Interests, Personal, Advisory Board, Palbociclib: Pﬁzer; Financial Interests, Personal, Invited Speaker, Breast cancer: Aristea, Meeting SrL;Financial Interests, Personal, Other, Author slide kits: Forum service; Financial Interests, Personal,Other, Author text about biosimilars: Edizioni Minerva Medica; Financial Interests, Personal, Other,consultant: Kardo srl; Financial Interests, Personal, Invited Speaker, Breast cancer meetings: Delphi international, Over srl; Financial Interests, Personal, Invited Speaker: Prex Srl, Editree; Financial Interests, Personal, Advisory Board: Uvet, Collage SpA, Daiichi Sankyo, AstraZeneca, Agendia, Gilead;Financial Interests, Personal, Other, Interview: Infomedica srl; Financial Interests, Personal, Other,Consultant: Sharing progress in cancer care - Switzerland; Financial Interests, Personal, Other,Consultancy: Eli Lilly; Financial Interests, Institutional, Funding, National coordinating PI: Roche;Financial Interests, Institutional, Funding, Local PI: AstraZeneca, Roche, Eli Lilly, Daiichi Sankyo,Novella Clinical, Novartis; Non-Financial Interests, Institutional, Product Samples, Genomic Test:FoundationOne. Del Mastro: Financial Interests, Personal, Invited Speaker, Educational meeting:Novartis, Symposia, Andromeda E20, Vyvamed srl; Financial Interests, Personal, Invited Speaker,Lecture: Ipsen; Financial Interests, Personal, Advisory Board, Her2+ and TN breast cancer: Roche;Financial Interests, Personal, Writing Engagement, Consultancy for TNBC text: Roche; Financial Interests, Personal, Advisory Board, denosumab: Amgen; Financial Interests, Personal, Advisory Board,Early and metastatic BC: Eli Lilly; Financial Interests, Personal, Invited Speaker, CDK4-6 inhibitors: Eli Lilly; Financial Interests, Personal, Advisory Board, tucatinib: Seagen Int; Financial Interests, Personal,Advisory Board, Oncotype dx: Exact sciences, Havas life; Financial Interests, Personal, Advisory Board, Neratinib: Pierre Fabre; Financial Interests, Personal, Invited Speaker, Internal training: MSD;Financial Interests, Personal, Invited Speaker, Educational meetings: Accademia Nazionale Medicina;Financial Interests, Personal, Writing Eng ts and interviews: Think2it; Financial Interests, Personal, Advisory Board, Palbociclib: Pﬁzer; Financial Interests, Personal, Invited Speaker, Breast cancer: Aristea, Meeting SrL;Financial Interests, Personal, Other, Author slide kits: Forum service; Financial Interests, Personal,Other, Author text about biosimilars: Edizioni Minerva Medica; Financial Interests, Personal, Other,consultant: Kardo srl; Financial Interests, Personal, Invited Speaker, Breast cancer meetings: Delphi international, Over srl; Financial Interests, Personal, Invited Speaker: Prex Srl, Editree; Financial Interests, Personal, Advisory Board: Uvet, Collage SpA, Daiichi Sankyo, AstraZeneca, Agendia, Gilead;Financial Interests, Personal, Other, Interview: Infomedica srl; Financial Interests, Personal, Other,Consultant: Sharing progress in cancer care - Switzerland; Financial Interests, Personal, Other,Consultancy: Eli Lilly; Financial Interests, Institutional, Funding, National coordinating PI: Roche;Financial Interests, Institutional, Fu L. Hendriks: Financial Interests, Institutional, Advisory Board: Amgen, Boehringer Ingelheim, Lilly, Novartis, Pﬁzer, Takeda, BMS, Merck, Janssen, MSD; Financial Interests, Personal,Other, mentorship with key opinion leaders funded by AstraZeneca: AstraZeneca; Financial Interests,Institutional, Invited Speaker, for educational webinar: AstraZeneca, Lilly; Financial Interests, Institutional, Invited Speaker, educational webinar/interview: Bayer; Financial Interests, Institutional,Invited Speaker, educationals: MSD; Financial Interests, Personal, Invited Speaker, for webinars:Medtalks; Financial Interests, Institutional, Advisory Board, one time also personal: Roche; Financial Interests, Institutional, Other, performing interviews at conference: Roche; Financial Interests, Personal, Other, travel support: Roche; Financial Interests, Institutional, Other, podcast on brain metastases: Takeda; Financial Interests, Personal, Invited Speaker, payment for post ASCO round table discussion: VJOncology; Financial Interests, Personal, Invited Speaker, payment for post ASCO/ESMO/WCLC presentations, educational committee member: benecke; Financial Interests, Institutional, Invited Speaker, payment for post ESMO/ASCO discussion: high5oncology; Financial Interests,

Institutional, Other, educational webinar: Janssen; Financial Interests, Personal, Other, member of the committee that revised these guidelines: Dutch guidelines NSCLC, brain metastases and leptomeningeal metastases; Financial Interests, Institutional, Research Grant, for IIS: Roche, Boehringer Ingelheim, AstraZeneca, takeda; Financial Interests, Institutional, Local PI: AstraZeneca, GSK,Novartis, Merck Serono, Roche, Takeda, Blueprint Medicines, Mirati, AbbVie, MSD, Gilead; Financial Interests, Institutional, Research Grant, donation for health care improvement project: Merck;Financial Interests, Institutional, Research Grant, funding for healthcare improvement project: Pﬁzer;Non-Financial Interests, Other, Chair metastatic NSCLC for lung cancer group: EORTC; Non-Financial Interests, Other, secretary NVALT studies foundation: NVALT. F. Barlesi: Financial Interests, Institutional, Advisory Board: AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. HoffmanneLa Roche Ltd, Novartis, Merck, Mirati, MSD, Pierre Fabre, Pﬁzer, Sanoﬁ Aventis, Seattle Genetics, Takeda, AbbVie, ACEA, Amgen, Eisai, Ignyta; Non-Financial Interests,Principal Investigator: AstraZeneca, BMS, Merck, Pierre Fabre, F. Hoffmann-La Roche Ltd., Innate Pharma, Mirati. D. Planchard: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS,Merck, Novartis, Pﬁzer, Roche, Samsung, Celgene, AbbVie, Daiichi Sankyo, Janssen, Seagen, Gilead,Pierre Fabre; Financial Interests, Personal, Invited Speaker: AstraZeneca, Novartis, Pﬁzer, priME Oncology, Peer CME, Samsung, AbbVie, Janssen; Non-Financial Interests, Principal Investigator,Institutional ﬁnancial interests: AstraZeneca, BMS, Merck, Novartis, Pﬁzer, Roche, Daiichi Sankyo,Sanoﬁ-Aventis, Pierre Fabre; Non-Financial Interests, Principal Investigator: AbbVie, Sanoﬁ, Janssen.

M. Lambertini: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Lilly, Novartis,Pﬁzer, Exact Sciences, MSD, Seagen, Gilead; Financial Interests, Personal, Invited Speaker: Takeda,Sandoz, Ipsen, Libbs, Knight, Daiichi Sankyo, Lilly, Pﬁzer, Novartis, Roche; Financial Interests, Personal, Other, Travel grant to attend ASCO 2022: Gilead; Financial Interests, Institutional, Coordinating PI, 2-year research grant paid to my Institution: Gilead. B. Besse: Financial Interests, Institutional,Funding: 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines,Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, GSK, Janssen,Onxeo, OSE immunotherapeutics, Pﬁzer, Roche-Genentech, Sanoﬁ, Takeda, Tolero Pharmaceuticals;Financial Interests, Institutional, Research Grant: Genzyme Corporation, Chugai pharmaceutical,EISAI, Inivata, IPSEN, Turning Point Therapeutics. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2910

187P Ipatasertib and atezolizumab in cancers with increased PI3KAKT pathway activity: First results from the CRAFT trial

C.E. Heilig1, M. Singh2, M-V. Teleanu1, A. Desuki3, T. Kindler3, M. Bitzer4, B.D. Baier5,V. Kunzmann6, N. von Bubnoff7, H. Süsse8, L. Heiligenthal8, K. Steindorf9,

A. Benner10, S. Kreutzfeldt1, C. Heining11, P. Horak1, D. Hübschmann12, H. Glimm11,S. Fröhling1, R.F. Schlenk13

1Department of Translational Medical Oncology, National Center for Tumor Diseases(NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany,Heidelberg, Germany; 2Medical Oncology Department, NCT - Nationales Zentrum für Tumorerkrankungen, Heidelberg, Germany; 3University Cancer Center - Hematology and Medical Oncology, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz, Germany; 4Internal Medicine I, Universitaetsklinikum Tuebingen Medizinische Universitaetsklinik, Tuebingen, Germany; 5Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Würzburg, Germany; 6Department of Internal Medicine II, Medical Oncology and Comprehensive Cancer Center Mainfranken, University Hospital Würzburg,Wuerzburg, Bavaria, Germany; 7Department of Hematology and Oncology and University Cancer Center, UKSH - Universitätsklinikum Schleswig-Holstein - Campus Lübeck, Lübeck, Germany; 8Clinical Trial Center, National Center for Tumor Diseases (NCT), Heidelberg, Germany; 9Physical Activity Division,Prevention and Oncology Dept., German Cancer Research Center - National Center for Tumor Diseases (NCT), Heidelberg, Germany; 10Biostatistics Department, DKFZ -German Cancer Research Center, Heidelberg, Germany; 11Translational Medical Oncology, NCT / UCC - National Center for Tumor Diseases Dresden, Dresden, Germany; 12Computational Oncology, Molecular Precision Oncology Program, DKFZ -German Cancer Research Center, Heidelberg, Germany; 13Clinical Trial Center and Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany

Background: CRAFT (Continuous ReAssessment with Flexible ExTension in Rare Malignancies) is an open-label, 7-arm, cross-entity phase 2 trial investigating the efﬁcacy of combinations of molecularly targeted agents and PD-L1 inhibition with atezolizumab in cancers with targetable molecular alterations (PMID: 34808524). We report the interim efﬁcacy analysis of ipatasertib and atezolizumab in cancers with increased PI3K-AKT pathway activity.

Methods: Adult patients with locally advanced/metastatic cancer refractory to ≥1Adult patients with locally advanced/metastatic cancer refractory to 1medical treatment and selected molecular tumor characteristics (arm 1: BRAF V600E/K mutations; arm 2: ERBB2 ampliﬁcation/overexpression, activating ERBB2 mutations;arm 3: ALK rearrangements/ALK mutations; arm 4: aberrations predicting increased PI3K-AKT pathway activity; arm 5: activating PIK3CA mutations; arm 6: aberrations predicting increased RAF-MEK-ERK pathway activity; arm 7: alterations predicting anti-PD-L1/anti PD-1 sensitivity) were eligible. Main exclusion criteria were hematologic/primary brain cancers. In arm 4, ipatasertib 400 mg q.d. was given in a 21-dayson/7-days-off schedule, and atezolizumab was administered every 3 weeks. Statistics are based for each arm on a Simon’s optimal 2-stage design with 14 patients accrued in in stage 1 and 11 additional patients if ≥4 patients achieve the primary endpoint, i.e.,stage 1 and 11 additional patients if 4 patients achieve the primary endpoint, i.e.,disease control (complete/partial remission [PR] or stable disease [SD]) at day 110.

Results: Until 04/2023, 51 patients were registered, and 28 were treated. Thirteen patients with various cancers and PI3K-AKT-activating alterations (PTEN deletion/lossof-function mutation: n¼8; activating PIK3CA mutation: n¼2; activating AKT1 mu-tation: n¼3) were enrolled in arm 4. One patient with breast cancer and a homo-zygous AKT1 E17K and one patient with prostate cancer and PTEN loss achieved a PR and SD, respectively. None of the remaining 11 patients reached the endpoint.

Toxicity was mainly gastrointestinal and manageable.

Conclusions: Ipatasertib and atezolizumab were ineffective in this patient population with PI3K-AKT-altered tumors. More stringent molecular selection criteria and an addition trial arm were implemented (arm 5).

Clinical trial identiﬁcation: :NCT04551521, EudraCT 019-003192-18.

Legal entity responsible for the study: German Cancer Research Center, Heidelberg,Germany.

Funding: The trial is supported by the NCT Proof-of-Concept Clinical Trial Program and the NCT Molecular Precision Oncology Program. Study drugs are provided free of charge by Roche Pharma AG.

Disclosure: C.E. Heilig: Financial Interests, Institutional, Research Funding: AstraZeneca, Pﬁzer,PharmaMar, Roche. A. Desuki: Financial Interests, Personal, Advisory Board: Roche, BMS, Novartis,MSD. B.D. Baier: Financial Interests, Personal, Advisory Role: Lilly. K. Steindorf: Financial Interests,Personal, Invited Speaker: Adviva, Audi Health Insurance, Murgpark Fitness, Pierre Fabre, Takeda;Financial Interests, Personal, Expert Testimony: Swiss Group for Clinical Research. C. Heining:Financial Interests, Personal and Institutional, Research Funding: Boehringer Ingelheim ; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Speaker’s Bureau: Roche, Novartis. P. Horak: Financial Interests, Personal, Advisory Board: Platomics; Financial Interests, Personal, Other, Honoraria: Platomics, Roche, Trillium. S. Fröhling: Financial Interests,Personal, Advisory Board: Bayer, Illumina, Roche; Financial Interests, Personal, Invited Speaker:Amgen, Eli Lilly, Illumina, PharmaMar, Roche. R.F. Schlenk: Financial Interests, Personal and Institutional, Research Funding: AstraZeneca, Boehringer Ingelheim, Pﬁzer, PharmaMar, Roche, Daiichi Sankyo; Financial Interests, Personal, Speaker’s Bureau: Daiichi Sankyo, Pﬁzer, AbbVie, Astellas;Financial Interests, Personal, Advisory Board: AbbVie, Daiichi Sankyo, Jazz, Pﬁzer. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2911

188P

The landscape of SMARCA2 genomic alterations in Chinese cancer patients

C. Jiaqi1, Y. Dong2, T. Han2, D. Guo2, R. Kong2, M. Wang2, S. Chen3, R. Ding2,W. Deng3, F. Bu4

1Department of Medical Oncology, The Second Afﬁliated Hospital of Zhejiang University College of Medicine, Hangzhou, China; 2The Medical Department, Jiangsu Simcere Diagnostics Co., Ltd., Nanjing, China; 3Bioinformatics Department, Jiangsu Simcere Diagnostics Co., Ltd., Nanjing, China; 4Operations Department, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, China

|Table: 189P Demographics |Overall (6361) | |---|---|

|Mean Age (SD) |65.5 (8.3) |

|Sex, n (%) ||

|Female |3579 (56.3%) |

|Male |2782 (43.7%) |

|Race, n (%) ||

|White |5198 (81.7%) |

|Black/African American |817 (12.8%) |

|American Indian/Alaska Native |29 (0.5%) |

|Asian |203 (3.2%) |

|Multiracial |13 (0.2%) |

|Native Hawaiian/Other Paciﬁc Islander |6 (0.1%) |

|Unknown |95 (1.5%) |

|Ethnicity, n (%) ||

|Hispanic/Latino |828 (13.0%) |

|Not Hispanic/Latino |5452 (85.7%) |

|Unknown |81 (1.3%) |

|Region, n (%) ||

|Midwest |1184 (18.6%) |

|Northeast |833 (13.1%) |

|South |3059 (48.1%) |

|West |1069 (16.8%) |

|Outside US |93 (1.5%) |

|Unknown |123 (1.9%) |

|Cigarette Smoking Status, n (%) ||

|Current |801 (12.5%) |

|Former |1756 (27.6%) |

|Never |3787 (59.5%) |

|Unknown |17 (0.3%) |

Background: Alterations of the SMARCA2 gene primarily promote cell proliferation and tumorigenesis by impacting the function of the SWI/SNF complex and activating multiple oncogenic signaling pathways. Previous studies have shown that selective inhibition of SMARCA2 can induce death of tumor cells with SMARCA4 mutations,providing a theoretical basis for SMARCA2 as a therapeutic target for tumors. In addition, differences in mutation proﬁles in pan-cancer can help understand pathogenesis, identify targets for therapy and promote precision medicine.

Methods: We retrospectively analyzed genomic DNA alterations in tissue samples from 21206 patients by next-generation sequencing (NGS). The SMARCA2 alterations were divided into functional or unfunctional mutations according to the OncoKB database.

Results: In total, 2.79% (592/21206) of pan-cancer patients carried SMARCA2 mutations. A total of 710 SMARCA2 alterations were identiﬁed in 592 patients, including missense mutations (60.56%), nonsense (4.51%), frameshifts (1.83%), splicing(21.83%), copy number variations (7.04%), non frameshift mutations (4.23%).

Compared the genomic landscape among the SMARCA2-functional (S-F), SMARCA2-unfunctional (S-UNF) and SMARCA2-wide type (S-WT) patients. The results showed the S-F group have higher TMB (55.82 vs. 27.78 vs. 6.33, p<0.05) and higher proportion of MSI-H patients (31.15% vs. 22.48% vs. 1.72%, p<0.05). Additionally,

13.34% (n¼79) of patients carried 2 (n¼57) or more than 2 (n¼22) SMARCA2 mu-tations. Compared with carriers of single mutation, they presented signiﬁcantly higher TMB (141.40 vs 27.18) and higher proportions of MSI-H (73.42% vs. 34.62%). It is worth noting that in the SMARCA2 mutation cohort, 24.16% of patients also carried SMARCA4 mutation, and patients with co-mutation have signiﬁcantly higher TMB(105.52 vs. 21.78) and a higher proportion of MSI-H (59.44% vs. 22.80%). Based on our results, immunotherapy may be an alternative strategy, which needs more clinical explorations.

Conclusions: SMARCA2 mutations are diverse, and patients with multiple SMARCA2 mutations or both SMARCA2-SMARCA4 mutations tumors had higher TMB and a higher proportion of MSI-H may more sensitive to immunotherapy, which may enable new therapeutic options in the future.

https://doi.org/10.1016/j.annonc.2023.09.2912

189P Design and enrollment for a classiﬁer development study for a blood-based multi-cancer early detection (MCED) test

C. Douville1, L. Hogstrom2, V. Gainullin2, H.J. Hwang3, S. Chowbina2, Y. Zhang2,M. Gray3, C. Nobles2, M. Kumar2, M. Manesse3, F. Zhuang3, V. Fa3, X. Chen2,J. Garces4, A. Mcelhinny3, G. Cerqueira2, G.A. Silvestri5, S. Rego6, T.M. Beer7,F. Diehl3

1Oncology, Johns Hopkins Medicine - The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; 2Bioinformatics, Exact Sciences Corporation, Madison,WI, USA; 3Research & Development, Exact Sciences Corporation, Madison, WI, USA;4Science Ofﬁce, Exact Sciences Corporation, Madison, WI, USA; 5Medicine, Medical University of South Carolina, Charleston, SC, USA; 6Clinical Affairs, Exact Sciences Corporation, Madison, WI, USA; 7Medical Affairs, Exact Sciences Corporation, Madison, WI, USA

Background: The aim of the Ascertaining Serial Cancer patients to Enable New Diagnostic 2 (ASCEND 2) case-control study is to develop a classiﬁer algorithm for a reﬁned version of a multi-analyte blood-based MCED test. Here, we report the study design, enrollment, and sample selection from this large, multi-center, prospective,case-control study of clinically characterized participants.

Methods: The ASCEND 2 study engaged 151 sites within the US and Europe for subject enrollment. Samples consisted of blood collected using LBgard tubes Samples consisted of blood collected using LBgard tubes forfor plasma and buffy samples. The study population includes male and female subjects 50 years old with known cancer, suspicion of cancer, and controls without cancer. ≥50 years old with known cancer, suspicion of cancer, and controls without cancer. AllAllsubjects provided informed consent and were assessed for study participation eligibility.

Results: Over 11,000 subjects were enrolled in this study. A subset of 6361 samples was selected to develop and reﬁne a multi-analyte cancer detection classiﬁer. The subset includes 1440 cancer subjects, from more than 18 organ sites reﬂective of US cancer incidence by tumor type, and 4921 age-matched subjects without suspicion of cancer. Demographics are reported in in the table. Cancer cases include stage I (388),stage II (301), stage III (374), stage IV (317), stage unknown (60). The samples will be partitioned into training and independent test sets. The performance of one or more locked cancer detection models developed in the training phase will be tested.

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L. Borras: Financial Interests, Personal, Full or part-time Employment: CDR-Life; Financial Interests,Personal, Leadership Role: CDR-Life; Financial Interests, Personal, Stocks/Shares: CDR-Life. S. Biswas:Financial Interests, Personal, Full or part-time Employment: CDR-Life. R. Leidner: Financial Interests,Personal, Advisory Role: Bristol Myers Squibb; Financial Interests, Personal, Project Lead: Bristol Myers Squibb, Incycte. E. Calvo: Financial Interests, Personal, Advisory Board: Adcendo, Amunix,Anaveon, AstraZeneca, BMS, Janssen, MonTa, MSD, Nanobiotix, Nouscom, Novartis, Servier, TargImmune, T-knife, Chugai, Elevation Oncology, Ellipses Pharmacy, SyneosHealth, Genmab, Diaccurate; Financial Interests, Personal, Invited Speaker: OncoDNA, PharmaMar, Roche/Genentech;Financial Interests, Personal, Full or part-time Employment, Director, Clinical Research: HM Hospitales Group; Financial Interests, Personal, Full or part-time Employment, Medical Oncologist. Clinical Investigator. Director, Clinical Research: START Madrid - CIOCC (Centro Integral Oncológico Clara Campal); Financial Interests, Personal, Member of Board of Directors, External Independent member of Board of Directors: PharmaMar; Financial Interests, Personal, Ownership Interest: START, Oncoart Associated; Financial Interests, Personal, Steering Committee Member, Member of Data Monitoring Committee: BeiGene, Sanoﬁ, Merus; Financial Interests, Personal, Steering Committee Member:Novartis; Non-Financial Interests, Other, Non-for-proﬁt Foundation. President and co-founder:INTHEOS (Investigational Therapeutics in Oncological Sciences) non-for-proﬁt Foundation; NonFinancial Interests, Advisory Role: PsiOxus; Non-Financial Interests, Other, Chair of the Independent Data Monitoring Committee: EORTC IDMC; Non-Financial Interests, Member of Board of Directors,Non-for-proﬁt Foundation, trustee member: Non-for-proﬁt Foundation PharmaMar; Non-Financial Interests, Advisory Role, Non-for-proﬁt foundation: CRIS Cancer Foundation, non-for-proﬁt ; NonFinancial Interests, Member: ASCO, ESMO, SEOM, EORTC.

https://doi.org/10.1016/j.annonc.2023.09.2923

201P

Afatinib for EGFR, HER2 or HER3 mutated solid tumors: A phase II Belgian precision study

L. Decoster1, P.G. Aftimos2, S. Rottey3, H. Prenen4, J.J. Collignon5, J. Mebis6,J-L. Canon7, V. Fastenaekels8, N. Cappoen8, S.R. Joris8, J. De Grève9

Results: A total of 45 pts were included in the trial with median age 62 years. The EGFR cohort comprised 7 pts: 2 pancreas, 1 head and neck, 1 breast, 1 endocrine tumor, 1 cervix and 1 kidney. The HER2 cohort comprised 30 pts: 11 NSCLC, 8 breast, 3 cervix, 2 colorectal, 2 head and neck, 1 bladder, 1 kidney, 1 liver and 1 pancreas. The HER3 cohort comprised 8 pts: 2 breast, 2 pancreas, 1 colorectal, 1 head and neck, 1 esophagus and 1 stomach. ORR and DCR were respectively 28.6% and 42.9% in the EGFR cohort, 3% and 49% in the HER2 cohort and 0% and 62.5% in the HER3 cohort.

Partial responses were observed in a HER2-mutated NSCLC (1/11) with a DOR of 8.5 months, an EGFR-mutated breast cancer (1/1) with a DOR of 6.6 months and an EGFRmutated pancreas cancer (1/2) with a DOR of 15.4 months. PFS and OS data will be presented at the meeting Safety data were consistent with the known safety proﬁle of afatinib.

Conclusions: Although three pts demonstrated a clinical meaningful beneﬁt, afatinib did not result in a signiﬁcant ORR improvement in the HER2 cohort, which completed accrual. Recruitment was hampered by a lack of systematic agnostic NGS sequencing and the COVID epidemic. Broader and more systematic agnostic NGS would enable further exploration of HER inhibition in solid tumors

Clinical trial identiﬁcation: EudraCT 2016-003411-34 Protocol No: 120.264 release date 26/09/2016.

Legal entity responsible for the study: Department Medical Oncology, UZ Brussel.

Funding: Kom op tegen kanker.

Disclosure: L. Decoster: Financial Interests, Institutional, Advisory Board: AstraZeneca, BMS, MSD;Financial Interests, Institutional, Invited Speaker: BMS, MSD, Roche, Servier, Sanoﬁ; Financial Interests, Institutional, Research Grant, conduct of academic trial: Boehringer Ingelheim; Non-Financial Interests, Leadership Role, member of board: European Cancer Organisation; Non-Financial Interests, Leadership Role, Board member: International Society of Geriatric Oncology (SIOG). P.G.

Financial Interests, Personal, Invited Speaker: Synthon, Amgen; Financial Interests, Institutional,Research Grant: Roche. S. Rottey: Financial Interests, Institutional, Advisory Board: Pﬁzer, Merck,Roche, Ipsen, BMS; Financial Interests, Institutional, Invited Speaker: Ipsen, BMS, Astellas; Financial Interests, Institutional, Research Grant: MSD, Roche, BMS; Non-Financial Interests, Principal Investigator, It is my main task in the hospital to attract and perform clinical trials in oncology phase I-III:all companies performing clinical trials in oncology in Europe. H. Prenen: Financial Interests, Institutional, Advisory Board: Amgen, Roche, AstraZeneca; Financial Interests, Institutional, Invited Speaker: Bayer, Ipsen, Sanoﬁ. J. Canon: Financial Interests, Institutional, Research Grant: Roche. J. De Grève: Financial Interests, Institutional, Invited Speaker: Roche. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2924

202P Participant perceptions and mammography adherence from DETECT-A: The ﬁrst prospective interventional trial of a multi-cancer early detection (MCED) blood test

N. Papadopoulos1, A.M. Lennon1, P. Elias2, S. Rego2, O. Choudhry2, D. Flake3,J. Cohen1, C. Douville1, A. Honushefsky4, I. Kinde5, A. Klein1, Z. Salvati4,

C. Tomasetti6, E. Wagner4, C. Walter4, E. Fishman1, K. Kinzler1, B. Vogelstein1,T.M. Beer7, A. Buchanan4

1Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore,MD, USA; 2Clinical Affairs, Exact Sciences Corporation, Madison, WI, USA; 3Clinical Biostatistics, Exact Sciences Corporation, Madison, WI, USA; 4Department of Genomic Health, Geisinger Medical Center, Danville, VA, USA; 5Technology Assessment, Exact Sciences Corporation, Madison, WI, USA; 6Center for Cancer Prevention and Early Detection, City of Hope Comprehensive Cancer Center, Duarte, CA, USA; 7Medical Affairs, Exact Sciences Corporation, Madison, WI, USA

Background: MCED tests may improve early cancer detection, but the impact of MCED testing on anxiety and standard of care (SOC) screening adherence is unknown.

The DETECT-A trial evaluated the CancerSEEK MCED test in 9,911 women without a cancer history (Science, 359:6499, 2020). DETECT-A participants without a cancer diagnosis were invited to a follow-up observational study involving annual surveys.

Here we report on participant satisfaction, anxiety, intent to adhere to SOC cancer screening, and adherence to breast cancer screening.

Methods: The survey, conducted approximately 3 years after DETECT-A enrollment,assessed: a) whether participants regretted DETECT-A participation or would participate again, b) how likely they were to adhere to routine cancer screenings, and c)how participation affected their anxiety. Adherence to biennial mammography screening was assessed at the month of survey completion for screening-eligible participants with evaluable medical records.

Results: Of the 7573 DETECT-A participants contacted, 3,870 (51%) completed a survey. Of the 3,788 respondents who answered all survey questions, 96.9% indicated no participation regret, 98.8% would participate again, 99.5% reported being equally or more likely to adhere to SOC screening, and 98.7% reported no change in or reduced anxiety. Of 1,053 participants eligible for mammography with available health records, 93.4% (n¼984) were adherent with mammography screening. 94.3%of participants with false positive (FP) results who completed a survey (n ¼ 35) re-ported no change or a reduction in anxiety; 5.7% (95%CI 1.6%-18.6%) reported an increase in anxiety compared to 1.3% (95% CI 0.9%-1.7%) of participants with true negative results (p ¼ 0.07).

Background: Recent advances have transformed care for HER2-positive gastrointestinal cancer. However, the clinical utility of NGS-based techniques for determining HER2 status in GI cancer has been limited. Here, we detail our experience regarding the assessment of HER2 alterations in GI cancer.

Methods: 626 colorectal cancer (CRC) samples, 80 esophageal cancer (ESCA) samples,153 esophagogastric junction cancer (EGJC) samples, and 286 gastric cancer (GC)samples were collected from August 2021 to April 2023. Among them, there were 82 CRC plasma samples, 33 GC plasma samples, 7 ESCA plasma samples, and 22 EGJC plasma samples. All specimens were detected by OncoDrug-Seq 603-gene panel assay through NGS using Illumina NovaSeq 6000. For plasmas, HER2 ampliﬁcation deﬁned as HER2 copy number >2.22 was identiﬁed. For tissues, HER2 ampliﬁcation deﬁned as HER2 copy number >6.00 was identiﬁed.

Results: For tissue samples, ERBB2 ampliﬁcation was detected in 0.74% of CRCs,

3.56% of GCs, 1.37% of ESCAs, and 3.05% of EGJCs. Only 2 GC cases (6.06%) were found to have ERBB2 ampliﬁcation for plasma samples. No ERBB2-ampliﬁed CRCs showed mismatch-repair deﬁciency. ERBB2 ampliﬁcation is anti-correlated with RAS/RAF mutations in CRCs (p¼0.047). Interestingly, ERBB2 ampliﬁcation was associatedwith microsatellite stability in GCs (p¼0.00078). Other driver alterations were notpresent in the ERBB2-ampliﬁed cases that currently have targeted therapies approved by the FDA including NTRK fusion, RET fusion, and BRAF V600E mutation.

Conclusions: The proportions of ERBB2 ampliﬁcation in GCs and EGJCs were relatively high. The high positive rate in GC plasma samples is worthy of attention. The mutational landscape of ERBB2-ampliﬁed cases provides novel insights that can help guide further patient-personalized therapy.

https://doi.org/10.1016/j.annonc.2023.09.2921

199P Novel machine learning (ML) algorithm to predict

immunotherapy response in small cell (SCLC) and non-small cell (NSCLC) lung cancer

L. Sharma1, S. Choi1, V. Balaji2, A. Joshi3, I. Mporas4, J. Shi5, Y. Zhao3, V. Tailor6,G. Powell2, D. Alrifai7, R. Shah8, J.S.C. Waters9, O.M. Adeleke2

1GKT School of Medical Education, King’s College London, London, UK; 2Curenetics Ltd,London, UK; 3School of Medicine, Imperial College London - Hammersmith Campus,London, UK; 4School of Physics, Engineering & Computer Science, University of Hertfordshire, Hatﬁeld, UK; 5Department of Oncology, St George’s Hospital NHS Trust,London, UK; 6CurenX, Precision Health, Atlanta, GA, USA; 7Cancer Department, Guys and St Thomas NHS Trust, London, UK; 8Medical Oncology, Maidstone Hospital,Maidstone, Kent, UK; 9Kent Oncology Centre, Maidstone Hospital - Maidstone and Tunbridge NHS Trust, Maidstone, UK

Background: Immune checkpoint inhibitors (ICI) are used to manage patients with SCLC and NSCLC lung cancer. Yet, response rates are often low and identifying patients that will beneﬁt from ICIs can be challenging. Accurate and accessible tools that predict ICI responses could enable a precision medicine approach that improves patient outcomes. This study aimed to use ML to predict response to ICI therapies in patients with lung cancer based on clinically available data.

Methods: 334 eligible records were reprocessed using one hot encoding. 161 patients had complete datasets available. Differences in data distribution were handled using the Synthetic Minority Oversampling Technique. Six ML algorithms were trained,including Linear regression, Support Vector Classiﬁer, XGBoost Classiﬁer, Random Forest, Decision Tree and Gaussian Naïve Bayes Classiﬁer. The algorithms used 80% of the training data, were tested on 20% of validation data and used the Grid Search Cross-Validation technique for hyperparameter optimization.

Results: Of the 161 patients, 9% had SCLC and 80% had NSCLC. Patients receiving Pembrolizumab, Nivolumab and Atezolizumab comprised 62%, 11% and 25%respectively. XGBoost Classiﬁer predicted response with the most accuracy, 64%. The artiﬁcial intelligence (AI) algorithm predicted and stratiﬁed ICI response better than PD-L1 levels alone (Table). The model showed good performance status, female gender and adenocarcinoma sub-type predicted response to ICI. Conversely, M1, N2 staging, male gender, squamous cell carcinoma sub-type and receiving Atezolizumab were predictive of disease progression.

Conclusions: Multiple novel ML models, developed using clinically available data,showed that ICI type, histopathology sub-type and TMN staging impact ICI response in lung cancer. Future studies will seek to include more SCLC cases and compare the prediction accuracy among the three ICIs.

Editorial acknowledgement: Jane Webb for data access from electronic medical records Denny Wong for data cleaning and pre-processing.

Disclosure: V. Balaji: Financial Interests, Personal, Full or part-time Employment: Curenetics. V.

Tailor: Financial Interests, Personal, Full or part-time Employment: CurenX. G. Powell: Financial Interests, Personal, Full or part-time Employment: Curenetics. R. Shah: Financial Interests, Personal,Advisory Role: Boehringer Ingelheim, AstraZeneca , Roche, Bristol Myers Squibb, MSD, Pﬁzer, Lilly,Novartis, Takeda, Bayer, BeiGene, Guardant Health, Sanoﬁ, EQRx. O.M. Adeleke: Financial Interests,Personal, Stocks or ownership: Curenetics. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2922

200P Precise tumor & patient selection for CDR404: A bispeciﬁc &bivalent MAGE-A4 T cell engager

G. Giacomazzi1, M. Liivrand2, R. Hieta2, N. Dupuis3, D. Rondas4, P. Swatkowski5,M. Vrohlings6, D. Lenherr-Frey7, L. Borras8, S. Biswas9, R. Leidner10, E. Calvo11

1Assay Development, CellCarta, Antwerpe, Belgium; 2Bioinformatics Core, Genevia Technologies, Tampere, Finland; 3Scientiﬁc Business Development, CellCarta, Antwerpe, Belgium; 4Clinical Operations, CellCarta, Antwerpe, Belgium; 5Global Regulatory Affairs, CellCarta, Naperville, IL, USA; 6Translational Science, CDR-Life Inc.,Horgen, Switzerland; 7Project Management, CDR-Life, Horgen, Switzerland; 8Research,CDR-Life, Horgen, Switzerland; 9Clinical, CDR-Life Inc., Horgen, Switzerland; 10Earle A Chiles Research Institute, Providence Cancer Institute, Southﬁeld, MI, USA; 11Dept.

Early Clinical Drug Development, Hospital Madrid Norte San Chinarro - Centro Integral Oncologico Clara Campal, Madrid, Spain

Background: A phase 1 trial of CDR404, an antibody-based T-cell engager (TCE) targeting MAGE-A4, is planned for 2024. CDR404 binds to a MAGE-A4 peptide presented on cancer cell surface HLA-A2. There are no validated assays to measure HLA peptide presentation. RNA sequencing or immunohistochemistry (IHC) for total MAGE-A4 can be used as surrogates. To identify tumors for trial inclusion and enable precise patient selection, we performed bioinformatic analyses and compared two IHC antibodies.

Methods: 32 solid tumors were selected from the TCGA dataset and ranked based on MAGE-A4 mRNA prevalence and expression (high to low). To assess protein expression, we compared speciﬁcity of two commercial MAGE-A4 antibodies for patient selection: an anti-rabbit E7O1U clone and an anti-mouse OTI1F9 clone. Cross reactivity to MAGE-A family members was conﬁrmed using IHC of individually transfected HEK293 cells.

Results: In ranking order, we identiﬁed 6 (RNAHIGH) tumors: squamous lung (LUSC),squamous head & neck (HNSC), bladder (BLCA), uterine carcinosarcoma (UCS),testicular germ cell (TGCT) and squamous cervical (CESC), which had both MAGE-A4 mRNA highest prevalence and median expression. Both parameters were positively correlated (R2¼0.64, p¼0.00012). Mean RNA levels were different for the RNAHIGHgroup compared to the remaining 26 tumors (RNALOW group), which consisted mainly of adenocarcinomas (p¼9.1e-120). Of interest, human papillomavirus (HPV) negative(-VE) HNSC had higher RNA levels vs. HPV-positive (+VE) tumors (p¼0.0046). In vitroover-expression experiments demonstrated that E7O1U only bound to MAGE-A4 whereas OTI1F9 cross-reacted widely with MAGE-A3, -A6, -A8, -A10, -A11 and -A12.

Conclusions: Squamous cell carcinomas were enriched in the MAGE-A4 RNAHIGH group. Trial screening efﬁciency can be optimized by enrolling RNAHIGHtumors especially LUSC and HPV -VE HNSC, two cancers with high unmet medical need. Lack of response reported in another MAGE-A4 TCE trial (NCT03973333) where tumor screening in ovarian cancer was absent conﬁrms that IHC selection will be essential for RNALOW tumors. In this regard, we have identiﬁed E7O1U as a highly speciﬁc MAGE-A4 antibody for precise IHC patient selection in the CDR404 trial.

Legal entity responsible for the study: CDR-Life.

Funding: CDR-Life.

Disclosure: G. Giacomazzi, N. Dupuis, D. Rondas, P. Swatkowski: Financial Interests, Personal, Full or part-time Employment: CellCarta. M. Liivrand, R. Hieta: Financial Interests, Personal, Full or parttime Employment: Genevia Technologies. M. Vrohlings: Financial Interests, Personal, Full or parttime Employment: CDR-Life; Non-Financial Interests, Member: ESMO. D. Lenherr-Frey: Financial

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Interests, Personal, Full or part-time Employment: CDR-Life; Other, Personal, Project Lead: CDR-Life.

1Department of Medical Oncology, UZ Brussel - Universitair Ziekenhuis Brussel, Jette,Belgium; 2Clinical Trials Conduct Unit, Institute Jules Bordet, Anderlecht, Belgium;3Department of Medical Oncology, UZ Gent - University Hospital Ghent, Gent,Belgium; 4Oncology Department, UZA - University Hospital Antwerp, Edegem,Belgium; 5Department of Medical Oncology, CHU Liège Sart-Tilman-Service d’Oncologie, Liège, Belgium; 6Medical Oncology Department, Jesse Ziekenhuis - Campus Virga Jesse, Hasselt, Belgium; 7Department of Oncology-Hematology, GHdC - Grand Hopital de Charleroi - Site Notre Dame, Charleroi, Belgium; 8Medical Oncology, UZ Brussel - Universitair Ziekenhuis Brussel, Jette, Belgium; 9Medical Oncology Department, Vrije Universiteit Brussel - Faculty of Medicine & Pharmacy, Brussels, Belgium

Background: The Belgian Precision initiative aims to implement tumor-agnostic NGS in advanced cancer patients (pts) and enhance access to genotype-matching drugs.

The current study aimed to investigate the efﬁcacy of afatinib in advanced pre-treated solid cancers with an EGFR (excluding non-small cell lung cancer (NSCLC)), HER2 or HER3 mutation.

Methods: Open-label phase 2 study including 3 cohorts for previously treated advanced cancers: EGFR, HER2 and HER3 mutated. The primary endpoint for each cohort was objective response rate (ORR). Response assessment was performed every 8 weeks. For each cohort, a Simon two-stage design was used. The null hypothesis that the true ORR is 10%, was tested against a one-sided alternative that the true ORR is 30%. If two or more ORR were observed in the ﬁrst ten pts, 19 additional pts were included (type I error 5% and power 80%) Secondary endpoints were disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS) and safety.

Conclusions: The ASCEND 2 study selected cancer types in an incidence-targeted manner, including rare and common cancers and evenly distributed stages. By enrolling a racially, ethnically, and geographically diverse cohort, the current study enables MCED test development with a representative cohort.

Disclosure: C. Douville: Financial Interests, Personal, Advisory Role: Exact Sciences Corporation;Financial Interests, Personal, Royalties: Johns Hopkins University. L. Hogstrom, V. Gainullin, H.J.

Hwang, S. Chowbina, Y. Zhang, M. Gray, M. Kumar, M. Manesse, F. Zhuang, V. Fa, X. Chen, A.

Mcelhinny, G. Cerqueira, S. Rego, F. Diehl : Financial Interests, Personal, Full or part-time Employment: Exact Sciences Corporation; Financial Interests, Personal, Stocks/Shares: Exact Sciences Corporation. J. Garces: Financial Interests, Personal, Full or part-time Employment: Exact Sciences

Corporation; Financial Interests, Personal, Stocks/Shares: Exact Sciences Corporation; Financial Interests, Personal, Ofﬁcer, CSO: Exact Sciences Corporation. G.A. Silvestri: Financial Interests, Personal, Other, Honoraria: AstraZeneca; Financial Interests, Personal, Advisory Role: Olympus Medical Systems, Biodesix, AstraZeneca, Daiichi Sankyo; Financial Interests, Institutional, Research Funding:Olympus, Biodesix, Seer, Amgen. T.M. Beer: Financial Interests, Personal, Full or part-time Employment: Exact Sciences Corporation; Financial Interests, Personal, Stocks/Shares: Exact Sciences Corporation, Arvinas, Salarius Pharmaceuticals; Financial Interests, Personal, Advisory Role: AbbVie,Amgen, Arvinas, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Constellation Pharmaceuticals, Dantari Pharmaceuticals, GSK, GRAIL, Janssen, Pﬁzer, Sanoﬁ, Sapience Therapeutics;Financial Interests, Institutional, Research Funding: Alliance Foundation Trials, Astellas Pharma,Bayer, Boehringer Ingelheim, Corcept Therapeutics, Endocyte, Freenome, GRAIL, Harpoon Therapeutics, Janssen R&D, Medivation, Sotio, Theraclone Sciences, Zenith Epigenetics.

https://doi.org/10.1016/j.annonc.2023.09.2913

190P

S258

Quantitative serum tumor markers (CEA, CA19-9, and CA125) are independently predictive of survival in patients with appendiceal adenocarcinoma

J.P. Y-C. Shen1, A. Yousef1, M.M.G. Yousef1, M. Zeineddine1, S. Chowdhury1,

M. Knaﬂ2, K. Raghav1, M.G. White3, K. Alfaro-Munoz1, B. Helmink4, K.F. Fournier4,M.J. Overman1

1Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center,Houston, TX, USA; 2Biostatistics, The University of Texas MD Anderson Cancer Center,Houston, TX, USA; 3Colon & Rectal Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 4Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Background: Although grade is strongly predictive of survival, no other prognostic or predictive biomarkers have been validated to help guide therapeutic decision making in Appendiceal adenocarcinomas (AA). Here we investigated the clinical utility of the serum tumor markers CEA, CA19-9, and CA-125 by association with survival and tumor molecular features.

Methods: The MD Anderson patient database was queried to identify a total of 1,322 patients diagnosed with of AA between 1997 to 2022 with at least one TM measured.

Elevation of TM deﬁned as above laboratory ULN (CEA > 3 ng/mL, CA 19-9 > 37 U/mL, and CA-125 > 37 U/mL, highly elevated deﬁned as top 10thpercentile (CEA >

|Table: 191P Resulting number of medical oncologist assessors prescribing the optimal treatment choice based on reported results |Table: 191P Resulting number of medical oncologist assessors prescribing the optimal treatment choice based on reported results |Table: 191P Resulting number of medical oncologist assessors prescribing the optimal treatment choice based on reported results |Table: 191P Resulting number of medical oncologist assessors prescribing the optimal treatment choice based on reported results |Table: 191P Resulting number of medical oncologist assessors prescribing the optimal treatment choice based on reported results |Table: 191P Resulting number of medical oncologist assessors prescribing the optimal treatment choice based on reported results |Table: 191P Resulting number of medical oncologist assessors prescribing the optimal treatment choice based on reported results |Table: 191P Resulting number of medical oncologist assessors prescribing the optimal treatment choice based on reported results | |---|---|---|---|---|---|---|---|

||Lab ID |||||||

|Sample ID |2 3 |4 |5 |6 |7 |8 |Gold Standard Treatment |

|1 |3 3 |0 |3 |3 |3 |3 |Immune Checkpoint Inhibitor |

|2 |3 0 |3 |3 |3 |3 |3 |Anti-EGFR mAb |

|3 |3 2 |2 |3 |2 |2 |3 |BRAF Inhibitor + Anti-EGFR mAb |

|Turnaround Time (Days) |24 63 |86 |20 |29 |21 |6 |14 Days |

100.4 ng/mL, CA 19-9 > 337.5 U/mL, and CA-125 > 41.8 U/mL).

Results: CEA, CA19-9 and CA125 were elevated in 56%, 34%, and 37% of patients,respectively, 63.8% had at least one elevated. The proportion of patients with elevation of each TM did not differ in high- vs low-grade tumors or by histologic subtype (mucinous, colonic, goblet, signet ring). CEA stratiﬁed patients by survival with median not-yet-reached for patients with normal CEA vs 182 mo for those with elevated CEA vs 96 mo for those with highly elevated CEA (log-rank p < 0.0001), 5-year OS was 95% vs 82% vs 61% for normal, elevated, and highly elevated, respectively. The prognostic effect of CEA was independent of grade, with 5-year OS (99%,93%, 69%, log-rank p < 0.0001) for low-grade and (91%, 73%, 55%, log-rank p <

0.0001). Similar survival stratiﬁcation was seen for CA19-9 (92%, 84%, 66%, log-rank p< 0.0001) and CA-125 (93%, 70%, 60%, log-rank p < 0.0001). CEA was more correlated with CA-19-9 (pearson r ¼ 0.62) than CA-125 (r ¼ 0.29). Elevation of multipleTM was associated with worse prognosis; HR relative to patients with no TM elevated was 4.9 (p ¼ 6.0e-6), 8.9 (p ¼ 6.5e-12), and 16.2 (p ¼ 8.0e-16), for 1, 2, or all 3 TM inmultivariate cox model of survival including gender, race, age, grade, and histologic subtype.

Conclusions: Elevation of CEA, CA19-9 and CA125 are independently associated with poor prognosis in patients with appendiceal cancer, all three should be measured.

Future efforts to evaluate incorporation of TM into clinical staging are warranted.

Funding: University of Texas MD Anderson Cancer Center, Cancer Prevention Research Institute of Texas.

Disclosure: J. P. Y-C. Shen: Financial Interests, Personal, Other, general consultation and expert testimony: ShenJPMD Inc; Financial Interests, Personal, Other, advisory board: Engine Biosciences,NaDeNo Nanosciences; Financial Interests, Institutional, Coordinating PI, research project: Celsius Therapeutics; Financial Interests, Institutional, Other, research funding for pilot project: BostonGene.

M.J. Overman: Financial Interests, Personal, Advisory Board: Roche, BMS, MedImmune, Merck,Amgen, Takeda, Janssen, Pﬁzer, Array, Gritstone, Nouscom, Atreca, Bayer; Financial Interests, Institutional, Coordinating PI: Roche, Lilly, Merck, BMS, Phanes, Nouscom. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2914

191P Novel approach to proﬁciency testing demonstrates wide gaps in biomarker quality for colon cancer treatment

K.R. Bisson1, A. Beharry1, M.D. Carter2, S. Dudani3, J.G. Garratt4, J.M. Loree5,S. Snow6, S. Yip7, J.R. Won4, B.S. Shefﬁeld1

1Department of Laboratory Medicine, William Osler Health System - Brampton Civic Hospital, Brampton, ON, Canada; 2Department of Pathology and Laboratory Medicine, Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada; 3Division of Medical Oncology, William Osler Health System - Brampton Civic Hospital, Brampton,ON, Canada; 4Department of Molecular Pathology, Canadian Pathology Quality Assurance - Assurance Qualité Canadienne en Pathologie (CPQA-AQCP), Richmond,BC, Canada; 5Division of Medical Oncology, BC Cancer, Vancouver Centre, Vancouver,BC, Canada; 6Division of Medical Oncology, Queen Elizabeth II Health Sciences Centre,Halifax, NS, Canada; 7Department of Pathology, Vancouver General Hospital, Vancouver, BC, Canada

Background: Biomarkers are fundamental to oncology, closely tying this practice to that of laboratory medicine. Results are required to be accurate, timely, comprehensive, and comprehendible. External proﬁciency testing is a key tool in maintaining quality. Traditional schemes test analytic accuracy. Here, we demonstrate the feasibility and utility of a novel end-to-end proﬁciency testing exercise examining the entire process of biomarker testing.

Methods: Challenge specimens were made using resected colon cancer tissue, each paired with a clinical vignette and distributed to participating labs. Participants were asked to provide all molecular testing required, which could include pre-analytic preparation, immunohistochemistry, gene sequencing, or other methodologies, and to draft and return a ﬁnal report for each case upon completion. Reports were redistributed to an assessor team including oncologists, who chose therapy based on each lab’s biomarker report. Finally, participants were graded based on their ability to guide oncologists to the most appropriate treatment. Gold standard treatments for each case were decided by assessors prior to the exercise, based on reference results and clinical vignettes.

Results: Eight laboratories participated. Three laboratories were found to have suboptimal results, two leading oncologists to incorrect therapeutic prescriptions (Table)and one withdrawn. Turnaround time ranged from 6-86 days (median 24).

Conclusions: This is the ﬁrst report of end-to-end proﬁciency testing, providing valuable insights into biomarker quality beyond analytic accuracy, including specimen management, communication, and turnaround time. Here, signiﬁcant quality gaps were identiﬁed, generating opportunities for improvement. This paradigm shift in quality assurance to focus on the complete specimen journey is a promising tool in assessing and improving modern cancer care.

Legal entity responsible for the study: Canadian Pathology Quality Assurance -Assurance qualité canadienne en pathologie (CPQA-AQCP).

Funding: Canadian Pathology Quality Assurance - Assurance Qualité en Pathologie Canadienne (CPQA-AQPC) with funding from Pﬁzer.

Disclosure: M.D. Carter: Financial Interests, Personal and Institutional, Other, Honoraria: Amgen,Bayer, Merck, Novartis, Pﬁzer, Incyte. S. Dudani: Financial Interests, Personal and Institutional,Advisory Board: Bristol Myers Squibb, Eisai, Ipsen, Merck, Pﬁzer, Taiho; Financial Interests, Personal and Institutional, Other, Honoraria: AstraZeneca, Ipsen, Merck, Pﬁzer. J.M. Loree: Financial Interests,Personal and Institutional, Other, Consulting: Ipsen, Novartis, Amgen, SAGA Diagnostics, Taiho;Financial Interests, Personal and Institutional, Research Grant: Foundation Medicine, Amgen, Ipsen,Personalis. S. Snow: Financial Interests, Personal and Institutional, Other, Advisory Boards/Consulting: Amgen, Bayer, BeiGene, Boehringer Ingelheim, Astellas, AstraZeneca, BMS, Janssen, Knight,Lilly, Merck, MSD, Novartis, Pﬁzer, Roche, Sanoﬁ, Taiho, Takeda; Financial Interests, Personal and Institutional, Member of Board of Directors: Lung Cancer Canada; Financial Interests, Institutional,Other, Research Trials (Institutional Funding): Amgen, AstraZeneca, BMS, Merck, Novartis, Sanoﬁ. S.

Yip: Financial Interests, Personal and Institutional, Advisory Board: Amgen, AstraZeneca, Bayer,Incyte, Pﬁzer, Roche. B.S. Shefﬁeld: Financial Interests, Personal and Institutional, Other, Consulting/Advisory Boards/Honoraria/Research Support: Amgen, AstraZeneca, Bayer, Biocartis, Boehringer Ingelheim, Cell Marque, Elevation Oncology, Eli Lily, EMD Serono, Incyte, Janssen, Merck, Novartis,Pﬁzer, Roche, ThermoFisher, Turning Point Therapeutics. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2915

192P

Impact of oncogenic ﬁbroblast growth factor receptor

(FGFR) alterations in patients with advanced solid tumors in a real-world setting

H. Sweiti1, L. Demirdjian2, S. Triantos1, K. Standish2, S. Thomas3, J. Greshock2,Q. Xia4, J. Paone5, P. Sheridan5, S. Pant6, C. Massard7, D.A. Reardon8, Y. Loriot9,M.H.H. Schuler10

1Oncology, Janssen R&D, Springhouse, PA, USA; 2Data Sciences, Janssen Pharmaceutical Companies of Johnson & Johnson, Titusville, NJ, USA; 3Translational Research Department, Johnson & Johnson Pharmaceutical - Research and Development, Spring House, PA, USA; 4Statistics, Janssen R&D, Springhouse, PA, USA; 5Delivery, Aetion, Inc,New York, NY, USA; 6Gastrointestinal Medical Oncology, MD Anderson Cancer Center,Houston, TX, USA; 7DITEP, Gustave Roussy - Cancer Campus, Villejuif, France; 8Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA; 9Cancer Medicine Department, Institut Gustave Roussy, Villejuif, France; 10Department of Medical Oncology, WTZ - Westdeutsches Tumorzentrum Essen, Essen, Germany

Background: Selective FGFR inhibitors are approved for treatment (tx) of FGFR+advanced urothelial cancer (UC) and cholangiocarcinoma (CCA). The prognostic FGFR+impact in solid tumors shows mixed results for select solid tumor types (TT). This study assessed the real-world (RW) prognostic impact of FGFR+ on overall survival(OS) of patients (pts) in a tumor agnostic (TA) setting.

Methods: This retrospective study used the Flatiron/Foundation Medicine, Inc Clinico-genomic database (FMI), including data from w280 US cancer centers. Pts (age 18 ≥18 y) had advanced/metastatic (adv/met) disease (except UC), evidence of FGFRy) had advanced/metastatic (adv/met) disease (except UC), evidence of FGFRtesting, and started ﬁrst-line (1L) systemic tx in the adv/met setting. All pts had FMI’s tissue-based genomic proﬁling. Pts with prior selective FGFR inhibitor tx were excluded. FGFR+ was deﬁned as 1 of 81 prespeciﬁed FGFR oncogenic mutations excluded. FGFR+ was defined as ≥1 of 81 prespecified FGFR oncogenic mutations ororany FGFR fusion involving an intact kinase domain. Pts with wildtype FGFR (FGFR-)were matched 3:1 with pts with FGFR+ on TT, age, sex, date of adv/met disease diagnosis, and FMI test version. The statistically powered primary objective assessed differences in TA RW OS from 1L tx initiation in pts with FGFR+ vs FGFR- adv/met disease treated with standard of care systemic tx. Secondary objectives assessed differences in tumor speciﬁc RW OS and in time to tx discontinuation or to next tx.

Delayed entry models and covariate-adjusted stratiﬁed Cox models were used to mitigate bias.

Results: Data from 253 FGFR+ and 759 FGFR- pts were analyzed. Demographics,baseline disease and clinical characteristics were balanced between groups. There were no signiﬁcant differences in TA RW OS from 1L between groups (HR, 0.97[FGFR+ vs FGFR-]; p¼0.78). Median RW OS from initiation of 1L tx was 1.13 y (95% CI,0.92-1.52) and 1.01 y (95% CI, 0.89-1.15) for FGFR+ and FGFR- pts, respectively. There were no signiﬁcant differences in RW OS between groups in tumor-speciﬁc comparisons, including CCA, breast cancer, and NSCLC.

Conclusions: There was no statistically signiﬁcant difference in RW OS between pts with FGFR+ or FGFRadv/ met solid tumors, with a median OS of w1 year in both groups. These results highlight the poor prognosis and high unmet need for novel,targeted tx.

Editorial acknowledgement: Frank Derosa, Parexel.

Legal entity responsible for the study: Janssen Research and Development.

Funding: Janssen Research and Development.

Disclosure: H. Sweiti: Financial Interests, Institutional, Stocks or ownership: Janssen R&D; Financial Interests, Institutional, Full or part-time Employment: Janssen R&D. L. Demirdjian: Financial Interests, Institutional, Full or part-time Employment: Janssen Research and Development; Financial Interests, Institutional, Stocks/Shares: Janssen Research and Development; Financial Interests,Institutional, Other, Patent: Janssen Research and Development; Non-Financial Interests, Project Lead: Janssen Research and Development. S. Triantos: Financial Interests, Institutional, Full or parttime Employment: Janssen R&D; Financial Interests, Institutional, Stocks or ownership: Janssen R&D.

K. Standish: Financial Interests, Institutional, Full or part-time Employment: Johnson and Johnson,Merck; Financial Interests, Institutional, Stocks or ownership: Johnson and Johnson, Merck, Eli Lilly;Financial Interests, Institutional, Research Funding: Johnson and Johnson; Financial Interests, Institutional, Other, Patent: Johnson and Johnson. S. Thomas: Financial Interests, Institutional, Full or part-time Employment: Janssen R&D; Financial Interests, Institutional, Stocks or ownership: Janssen R&D. J. Greshock: Financial Interests, Institutional, Full or part-time Employment: Janssen R&D;Financial Interests, Institutional, Stocks or ownership: Johnson and Johnson. Q. Xia: Financial Interests, Institutional, Full or part-time Employment: Janssen R&D, Geron; Financial Interests, Institutional, Stocks or ownership: Janssen R&D, Geron; Financial Interests, Institutional, Other, Travel,accomodations, expenses: Janssen R&D, Geron. J. J. Paone: Financial Interests, Institutional, Full or part-time Employment: Aetion Inc. P. Sheridan: Financial Interests, Institutional, Full or part-time Employment: Aetion Inc. S. Pant: Financial Interests, Institutional, Advisory Role: Zymeworks, Ipsen,Novartis, Janssen; Financial Interests, Institutional, Research Funding: Mirati Therapeutics, Mirati Therapeutics, Lilly, Xencor, Novartis, Rgenix, Bristol Myers Squibb, Astellas Pharma, Purple Biotech,4D Pharma, Boehringer Ingelheim, NGM Biopharmaceuticals, Janssen, Arcus Biosciences, Elicio Therapeutics. C. Massard: Financial Interests, Institutional, Speaker, Consultant, Advisor: Amgen,Astellas Pharma, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Celgene, Debiopharm Group,Genentech/Roche, Ipsen, Janssen R&D, Lilly, MSD, Novartis, Pﬁzer, Sanoﬁ, Orion, Taiho Pharmaceutical, Blueprint Medicines, Innate Pharma, PharmaMar, Faron Pharmaceuticals. D.A. Reardon:Financial Interests, Institutional, Advisory Role: Merck, Novocure, Regeneron, Bristol Myers Squibb,Oncorus, Agenus, EMD Serono, Merck KGaA, Taiho Pharmaceuticals, Delmar Pharmaceuticals,Advantagene, Bayer, Imvax, Medicenna, Vivacitas Oncology, Anheart Therapeutics, Ellipses Pharma,Genenta Science, Kintara Therapeutics, Kiyatec, Agios; Financial Interests, Institutional, Research Funding: Celldex, Incyte, Agenus, EMD Serono, Acerta Pharma, Omniox, Enterome; Financial Interests, Institutional, Other, Honoraria: Merck, Novocure, Regeneron, Bristol Myers Squibb, Oncorus,Agenus, EMD Serono, Merck KGaA, Taiho Pharmaceutical, Advantagene, Bayer, DelMar Pharmaceuticals, Imvax, Medicenna, Sumitomo Dainippon Pharma, Vivacitas Oncology, Anheart Therapeutics, Deciphera, Ellipses Pharma, Genenta Science, Inovio Pharmaceuticals, Kintara Therapeutics,Kiyatec, Neuvogen, Taiho Pharmaceutical, Y-mAbs Therapeutics. Y. Y. Loriot: Financial Interests, Personal, Advisory Board: Merck Kga, Pﬁzer, Gilead, Seattle Genetics, Tahio; Financial Interests,

Personal, Other, lectures, advisory boards: MSD, AstraZeneca, Astellas, Janssen; Financial Interests,Personal, Other, lectures, advisroy boards: Roche, BMS; Financial Interests, Institutional, Research Grant: Janssen, Sanoﬁ, MSD, Roche, Celsius; Financial Interests, Institutional, Steering Committee Member: Janssen; Financial Interests, Steering Committee Member: MSD, Astellas, Gilead/Immunomedics, Tahio; Financial Interests, Personal, Steering Committee Member: basilea; Financial Interests, Institutional, Local PI: Pﬁzer, MSD, Janssen, Exelexis, AstraZeneca, Pﬁzer, Merck Kga, BMS,Astellas, Gilead, Incyte; Financial Interests, Institutional, Coordinating PI: Janssen; Non-Financial Interests, Member: ESMO, ASCO, AACR; Non-Financial Interests, Other, scientiﬁc committee: ARC.

M.H.H. Schuler: Financial Interests, Institutional, Advisory Role: AstraZeneca, Boehringer Ingelheim,Bristol Myers Squibb, Novartis, Roche, Takeda, Amgen, GSK, Merck Serono, Sanoﬁ, Janssen Oncology; Financial Interests, Institutional, Research Funding: Bristol Myers Squibb, AstraZeneca;Financial Interests, Institutional, Other, Honoraria: Boehringer Ingelheim, Bristol Myers Squibb,Novartis, Amgen, Janssen-Cilag.

https://doi.org/10.1016/j.annonc.2023.09.2916

194P Early kinetics of C-reactive protein for cancer-agnostic prediction of therapy response and mortality in patients treated with immune checkpoint inhibitors: A multi-center cohort study

D. Barth1, F. Moik1, S.M. Steinlechner1, F. Posch2, V. Schlintl1, L. Koch3, N. John4,R. Wurm4, M. Pichler1, T. Bauernhofer1, P. Reimann5, C. Wohlkönig4, E. Richtig3,T. Winder5, M. Preusser6, P.J. Jost1, C. Ay7, A. Gerger1, A. Terbuch1, J.M. Riedl1

1Division of Oncology, Department of Internal Medicine, Medical University of Graz,Graz, Austria; 2Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; 3Department of Dermatology, Medical University of Graz, Graz, Austria; 4Division of Pulmonology, Department of Internal Medicine,Medical University of Graz, Graz, Austria; 5Oncology Department, Landeskrankenhaus Feldkirch, Feldkirch, Austria; 6Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria; 7Department of Medicine I, Clinical Division of Haematology and Haemostaseology, MedUni Wien - Medical University of Vienna,Vienna, Austria

Background: C-reactive protein (CRP) kinetics have recently been suggested as predictive biomarkers for the efﬁcacy of immune checkpoint inhibitor (ICI) therapy in selected cancer types. The aim of this study was to characterize early CRP kinetics as a tumor-agnostic biomarker for ICI treatment outcomes.

Methods: In this multicenter retrospective cohort study, two independent cohorts of patients with various cancer types undergoing palliative ICI treatment at Austrian academic centers served as the discovery (n¼562) and validation cohort (n¼474).Four different patterns of CRP-kinetics in the ﬁrst 3 months of ICI therapy were deﬁned (CRP-ﬂare responders, CRP-responders, CRP non-responders, patients with all-normal CRP). Objective response rate (ORR), progression-free- (PFS) and overall survival (OS) were deﬁned as co-primary endpoints. Uni-and multivariable logistic regression, Landmark analysis and Cox-regression including CRP kinetics as timedependent variable were performed.

Results: The ORR in patients with all-normal CRP, CRP responders, CRP ﬂare-responders and CRP non-responders was 41%, 38%, 31% and 12%, respectively. The median OS and PFS estimates were 24.5 months (95%CI 18.5 e not reached) and 8.2 months (95%CI 5.9-12.0) in patients with all-normal CRP, 16.1 months (95%CI 12.6-19-8) and 6.1 months (95%CI 4.9-7.2) in CRP-responders, 14.0 months (95%CI 8.5-19.4)and 5.7 months (95%CI 4.1-8.5) in CRP ﬂare-responders and 8.1 months (95%CI 5.8-9.9) and 2.3 months (95%CI 2.2-2.8) in CRP non-responders (log-rank p for PFS and OS<0.001). These ﬁndings prevailed in multivariable analysis and could be fully conﬁrmed in our validation cohort. Pooled subgroup analysis suggested a consistent predictive signiﬁcance of early CRP kinetics for treatment efﬁcacy and outcome independent of cancer type.

Conclusions: Early CRP kinetics represent a tumor-agnostic predictor for treatment response, progression risk and mortality in patients with cancer undergoing ICI therapy.

Disclosure: D. Barth: Financial Interests, Personal, Advisory Board: Roche, MSD, EISAI. F. Moik:Financial Interests, Personal, Advisory Board: Servier, BMS. L. Koch: Financial Interests, Personal,Advisory Board: BMS, MSD, Novartis, Pierre Fabre, Sanoﬁ Aventis. E. Richtig: Financial Interests,Personal, Speaker, Consultant, Advisor: Amgen, BMS, MSD, Merck, Novartis, Puerre Fabre, Sanoﬁ Aventis; Financial Interests, Personal, Steering Committee Member: Novartis. M. Preusser: Financial Interests, Personal, Speaker, Consultant, Advisor: Bayer, BMS, Novartis, Gerson Lehrman Group, CMC Contrast, GSK, Mundipharma, Roche, BMJ Journals, MedMedia, AstraZeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanoﬁ, MSD, Adastra, Tocagen, Gan & Lee Pharmaceuticals, Servier. J.M. Riedl:Financial Interests, Personal, Speaker, Consultant, Advisor: BMS, MSD. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2917

S259

195P

Identiﬁcation of biomarkers associated with checkpoint inhibitor pneumonitis based on serum proteomic approach and construction of an online interactive visual prediction model

X. Jia, H. Guo, Y. Zhang, Y. Li, X. Fu, X. Yu

Department of Medical Oncology, The First Afﬁliated Hospital of Xi’an Jiaotong University, Xi’ An, China

Background: Checkpoint inhibitor pneumonitis(CIP) is one of the most common fatal adverse events in the new era of immune checkpoint inhibitor(ICI). Screening the high risk group of CIP is a major clinical challenge to improve the safety of ICI therapy.

However, there are lack of effective biomarkers to predict CIP. The practical difﬁculties of early screening highlight the need to explore new biomarkers. The aim of this study is to determine predictive biomarkers of CIP through proteomics methods, and then build a prediction model, so as to improve the safety of ICI therapy.

Methods: This study prospectively recruited 98 tumor patients. Fasting peripheral blood was collected from patients before ICI therapy for the ﬁrst time. Patients were dynamically followed up and assessed for CIP. Serum protein spectrum was analyzed and identiﬁed by MALDI-TOF mass spectrometry(MALDI-TOF-MS) and LC-MS.

Conﬁrmatory studies were conducted by ELISA to quantitatively evaluate the expression of serum protein. R language is used to construct online interactive prediction model. This study was approved by the Ethics Committee of the First Afﬁliated Hospital of Xi’an Jiaotong University (XJTU1AF2021LSK-001).

Results: 31 patients with CIP constituted the case group. A total of 88 peptide peaks were detected by MALDI-TOF-MS. 15 protein polypeptides with the most signiﬁcant differences were selected for further identiﬁcation. After quantitative veriﬁcation by ELISA analysis, it was found that plasma serine protease inhibitor (SERPINA5), A-kinase anchor protein 6 (AKAP6), tubulin alpha-4A chain (TUBA4A) were signiﬁcantly highly expressed in CIP patients. Based on this, online interactive visual prediction model was constructed (https://mass-cip.shinyapps.io/DynNomapp/). Harrell’s Cindices of the training set and validation set were 0.974 and 0.968, respectively. The calibration curve and clinical decision curve showed satisfactory predicted value.

Conclusions: SERPINA5, AKAP6 and TUBA4A are considered useful biomarkers for predicting CIP. The predictive model has the potential to be a convenient, intuitive,and personalized clinical tool for assessing the risk of CIP.

https://doi.org/10.1016/j.annonc.2023.09.2918

196P Serum metabolomics to determine survival of

immunotherapy for advanced non-small cell lung cancer:Metabolomic analysis based on two cohorts

Y. Xu, K. Ding, Z. Peng, Y. Fan

Medical Thoracic Oncology, Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China

Background: Noninvasively collected samples are attracting signiﬁcant interest as new areas of biomarker study in immune checkpoint inhibitors (ICIs) ﬁeld, and metabolomics is one of these growing ones. We focused on the added value of the metabolomic proﬁle as a means of distinguishing long-term survival from short-term survival in NSCLC patients treated with ICIs.

Methods: We prospectively recruited 97 patients with stage IV NSCLC who were treated with anti-PD-1 inhibitor, including patients treated with monoimmunotherapy as second-line treatment (Cohort 1), and patients treated with combination immunotherapy as ﬁrst-line treatment (Cohort 2). Each cohort was divided into two groups,long-term survival and short-term survival. All blood samples were collected before beginning immunotherapy. Metabolomic proﬁling of serum was performed by UHPLCQ-TOF MS analysis. Multivariate data analysis, including Pareto-scaled principal component analysis (PCA) and orthogonal partial least-squares discriminant analysis(OPLS-DA), was performed.

Results: A total of 41 differential metabolites in Cohort 1 and 47 in Cohort 2 were screened. Among them, 8 common metabolites in ESI-mode and 11 in ESI+mode were signiﬁcantly associated with both PFS and OS in cohort 1. In cohort 2, 3 metabolites in ESI-mode and 6 in ESI+mode were signiﬁcantly associated with both PFS and OS. In cohort 1, the top 3 enriched KEGG pathways, as determined through signiﬁcant differential metabolic pathway analysis, were primary bile acid biosynthesis, african trypanosomiasis, and choline metabolism in cancer. In Cohort 2, the top 3 enriched KEGG pathways were the citrate cycle (TCA cycle), PPAR signaling pathway,and primary bile acid biosynthesis. The primary bile acid synthesis pathway had

signiﬁcant differences in the long-term survival and short-term survival groups in both Cohort 1 and Cohort 2.

Conclusions: Our study suggests that peripheral blood metabolomic analysis is critical for identifying metabolic biomarkers and metabolic pathways responsible for the NSCLC patients treated with ICIs, and the primary bile acid synthesis pathway may be the important one.

Legal entity responsible for the study: Zhejiang Cancer Hospital.

Funding: the Science and Technology Program for Health and Medicine in Zhejiang Province, China (Grant No. 2021KY541), and the Natural Scientiﬁc Foundation of Zhejiang Province, China (Grant No. LY19H160007).

https://doi.org/10.1016/j.annonc.2023.09.2919

197P Clinical beneﬁt of HER2-targeted therapies versus prior chemotherapy in refractory HER2 expressing and mutant gastrointestinal malignancies

V. Khanna1, A.S. Henry2, T.P. Johnson1, G. Heestand1, S. Shaheen1, C. Chong1,G.A. Fisher, Jr.1, C. Chen1

1Stanford Cancer Institute, Stanford Cancer Center Palo Alto, Palo Alto, CA, USA;2Department of Biomedical Data Science, Stanford University School of Medicine,Stanford, CA, USA

Background: HER2-directed drugs are established therapies for patients with advanced HER2+ gastroesophageal (GEJ) cancers. However, while various anti-HER2 agents including antibodies, antibody-drug conjugates, and tyrosine kinase inhibitors are active in non-GEJ HER2+ GI tumors, the optimal integration/sequencing of these agents with conventional chemotherapy is unclear.

Methods: We assessed the outcomes of patients with metastatic HER2-expressing or mutated non-GEJ GI cancers who received anti-HER2 drugs at our institution from 2010 e2021. We measured the growth modulation index (GMI) e the ratio of progression-free survival (PFS) of the anti-HER2 drug to the time-to-progression on the immediately prior therapy e for each line of HER2 therapy. GMI 1.3 is immediately prior therapy- for each line of HER2 therapy. GMI ≥1.3 is consideredconsideredmeaningful clinical beneﬁt, and we classiﬁed patients with GMI 2.6 as meaningful clinical benefit, and we classified patients with GMI ≥2.6 as exceptionalexceptionalbeneﬁters.

Results: Forty-one patients with adenocarcinomas (19 colorectal, 13 biliary tract, 3 intestinal, 3 pancreatic, 2 ampullary, and 1 appendiceal) were identiﬁed; 59% received 2 received ≥1 line of HER2-directed therapy were GMI evaluable. Fifty percent≥2 lines of therapy before their first anti-HER2 agent.Twenty-two patients wholines of therapy before their ﬁrst anti-HER2 agent. Twenty-two patients whoreceived 1 line of HER2-directed therapy were GMI evaluable. Fifty percentbeneﬁted from therapy and 36% derived exceptional beneﬁt. The median PFS to theﬁrst anti-HER2 therapy was 5.5 (0.4 e 53.0) months. All HER2 beneﬁters were either HER2-ampliﬁed, 3+ by IHC, or 2+/ISH+; none (0/3) with HER2 mutations derived beneﬁt. Three patients had exceptional beneﬁt to second-line HER2 drugs after deriving no beneﬁt on their ﬁrst HER2 therapy, with a median GMI of 4.9 (4.7 e 6.5)and a median PFS of 11.0 (4.3 e 13.7) months. One patient remains alive over 60 months since diagnosis and has received 5 lines of anti-HER2 therapy (median PFS of

8.8 months per agent).

Conclusions: Anti-HER2 drugs in later lines can provide durable beneﬁt relative to earlier-line chemotherapy in a large proportion of patients with HER2+ non-GEJ GI malignancies. Patients not beneﬁting from initial anti-HER2 drugs may still achieve sustained beneﬁt from subsequent HER2-directed regimens. Early and continued incorporation of anti-HER2 agents throughout a patient’s treatment course may optimize clinical outcomes.

Disclosure: T.P. Johnson: Financial Interests, Personal, Advisory Role: Servier. G. Heestand:Financial Interests, Personal, Advisory Role: Exelixis, Eisai, Elevation Oncology; Financial Interests,Personal, Other, Employment (Spouse): Genentech; Financial Interests, Personal, Other, Stock(Spouse): Roche. G.A. Fisher Jr: Financial Interests, Personal, Stocks/Shares: Seattle Genetics;Financial Interests, Personal, Other, Honoraria: Echina Health; Financial Interests, Personal, Advisory Role: Merck, Taiho Pharmaceutical, Ipsen, Roche/Genentech; Financial Interests, Institutional,Research Funding: Roche/Genentech, Merck; Financial Interests, Personal, Other: CytomX Therapeutics, Silenseed, AstraZeneca, Terumo Clinical Supply, Taiho Pharmaceutical, Hutchison MediPharma. C. Chen: Financial Interests, Personal, Other, Consultant: Boxer Capital, Guidepoint Global Advisors; Non-Financial Interests, Institutional, Local PI: ADC Therapeutics, Gilead Sciences, Kinnate Biopharma, Mersana, Oric Pharmaceuticals, Palleon, Pionyr, Rain Oncology, Ribosciences. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2920

198P

|Table: 199P |Table: 199P |Table: 199P |Table: 199P |Table: 199P |Table: 199P |Table: 199P |Table: 199P | |---|---|---|---|---|---|---|---|

|||Response (R) % |Stable Disease (SD) % |Disease Progression (DP) % |AI-predicted validation cohort % |AI-predicted validation cohort % |AI-predicted validation cohort % |

||||||R |SD |DP |

|Total N¼161 ||29 |8 |63 |33 |6 |61 |

|PD-L1 levels |<1% N¼23 |13 |9 |78 |33.3 |0 |66.6 |

||1-50% N¼19 |42 |0 |58 |66.6 |0 |33.3 |

||>50% N¼33 |33 |11 |56 50 14 |56 50 14 |56 50 14 |36 |

Detection of ERBB2 (HER2) ampliﬁcation by next-generation sequencing (NGS) in patients (pts) with gastrointestinal (GI)cancer

Y. Qi1, L. Huang2, Y. Jin3, F. Ruan2, H. He2

1Radiotherapy Center, Sichuan Cancer Hospital and Institute/The Afﬁliated Cancer Hospital School of Medicine, UESTC, Chengdu, China; 2Department of Medicine,Zhejiang Shaoxing Topgen Biomedical Technology Co., Ltd., Shanghai, China;3Department of Bioinformatics, Zhejiang Shaoxing Topgen Biomedical Technology Co.,Ltd., Shanghai, China

Funding: This research was supported by a research grant from AstraZeneca GmbH ,Bristol Myers Squibb GesmbH (BMS), Merck Sharp & Dohme Ges.m.b.H., Roche Austria GmbH and Sanoﬁ-aventis GmbH. The hypothesis of this study was not suggested by the the funding body, which had no role in the design, analysis, and publication of this study. MP (Matthias Preusser) gratefully acknowledges ﬁnancial support from the Austrian Federal Ministry for Digital and Economic Affairs, the Austrian National Foundation for Research, Technology and Development and the Christian Doppler Research Association.

Funding: This work was supported by Outstanding Youth Project of Shaanxi Province(2020JC-35), Research and development projects in Shaanxi Province (2022ZDLSF04-11), Natural Science Foundation of Shaanxi Province (2022JQ-796), Major project of innovation Fund of Chinese Society of Clinical Oncology-MSD (Y-MSD2020-024),Shaanxi Sanqin Scholars Innovation Team (2021-No. 32), Beijing Science Innovation Medical Development Fund (KC2021-JX-0186-5) and National Natural Science Foundation of China (No. 82272073).

Results: The TMB levels of BCOR-mutant (Mut) patients are higher than BCORwildtype (WT) patients in both TCGA (Median: 24.25 [0.55 - 245.56] vs. 2.78 [0.05 -1296.91], P < 0.001) and MSKCC (Median: 54.65 [2.95 - 203.64] vs. 6.14 [0.00 -93.04], P < 0.001) cohort. BCOR-Mut patients receiving ICIs achieve prolonged OS than BCOR-WT patients (median OS: 14 months vs. not reach; HR 95% CI: 0.28 (0.09-0.90); P ¼ 0.03); moreover, a multivariable analysis using Cox proportional-hazardsregression demonstrated that BCOR-Mut was associated with better OS (HR ¼ 0.29;95% CI: 0.092-0.93; P ¼ 0.036), after adjusting for age, gender, metastasis andtreatment. In TCGA cohort, there is no signiﬁcance in OS between BCOR-wildtype and BCOR-mutant patients (median OS: 55.4 vs 61.8 months, P ¼ 0.94). Based on theanalysis of immune cell inﬁltration status, the mechanism of the predictive value of BCOR mutation to ICIs efﬁcacy may be related to the greater abundance of activated CD4 memory T cell, CD8 T cell, follicular helper T cell and Macropghages M1, and lower abundance of Monocytes and CD4 memory resting cells in BCOR-mutant tumors.

Conclusions: Survival analysis of MSKCC shows BCOR mutation is an independent predictor of ICIs treatment in GC, rather than a prognostic factor, and may be associated with better immune cell inﬁltration.

https://doi.org/10.1016/j.annonc.2023.09.2931

209P Molecular atlas of copy number variation(CNV) in lung cancer with brain metastases

X. Zhang1, T. Han2, D. Guo2, R. Kong2, S. Chen3, R. Ding2, W. Deng3, F. Bu2

1Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China;2The Medical Department, Jiangsu Simcere Diagnostics Co., Ltd., Nanjing, China;3Bioinformatics Department, Jiangsu Simcere Diagnostics Co., Ltd., Nanjing, China

Background: Patients (pts) with lung cancer had high rates of brain metastasis (BM).

Genetic alterations were associated with the metastatic spread of lung cancer cells in recent study, lung cancer driver genes, such as EGFR, ALK, and RET are risk factors for brain metastasis in advanced lung cancer pts. The number of CNV regions was

markedly higher in the secondary metastatic tumor than the primary tumor in the lung. However, the precise mechanisms in BM were still unclear. In this study, we explored the clinical and molecular features of lung cancer with brain metastases in Chinese real word.

Methods: This study retrospectively analyzed the genomic alteration of Chinese lung cancer with brain metastases pts during 2019-2022. Next-generation sequencing(NGS) was performed to detect gene mutations in tumor. Lung cancer driver genes set, as EGFR, ALK, ROS1, BRAF, ERBB2, MET, KRAS and RET were evaluated in those pts.

Results: 193 lung cancer with brain metastases pts were enrolled. Male:Female ratio:128:65. Median age 61 years(Min-Max: 38-78). 79% of pts had CNV, and tumors with CNV had higher TMB values than those without CNV (7.7 vs. 2.8, p<0.001). The top3 ampliﬁcation genes were: EGFR(n¼25), MYC(n¼11), ERBB2(n¼10), and the threemost frequently deletion genes were: CDKN2A (n¼69), CDKN2B (n¼69), PTEN(n¼15). Among pts with TMB10, the proportion of pts with CNV was higher thanthat of pts without CNV (24% vs. 5%, c2¼7.22, p < 0.05). The numbers of pts withdriver gene mutation and pts without driver gene mutation were 145 and 48,respectively, and there was no signiﬁcant difference in age between the two groups.

Pts with CNV and no driver gene mutation had higher TMB values (average TMB¼9.6). The proportion of pts that carrying CNV in driver gene mutation tumorswas similar to those without driver gene mutation (82% vs. 68%).

Conclusions: 79% of pts with brain metastases had CNV. The top3 ampliﬁcation genes were: EGFR, MYC, ERBB2, and the three most frequently deletion genes were:CDKN2A, CDKN2B, PTEN. The proportion of pts that carrying CNV in driver gene mutation tumors was similar to those without driver gene mutation. Pts with CNV and no driver gene mutation had higher TMB values, indicating the pts may have more clinical beneﬁts from immunotherapy.

Legal entity responsible for the study: Xianfeng Zhang.

https://doi.org/10.1016/j.annonc.2023.09.2932

210P Lung tumour vascularity is a risk factor for survival in NSCLC patients undergoing surgery

A.R. Filippi1, F. Blistein2, F. Belmans2, S. Goffart2, L. Libert2, R. Narasimhan2,A. Corsi3, W. Vos2, M. Occhipinti3

1Department of Clinical, Surgical, Diagnostic and Paediatric Sciences, University of Pavia, Pavia, Italy; 2R&D, Radiomics SA, Liège, Belgium; 3Medical, Radiomics SA, Liège,Belgium

Background: Vascularization is known to be linked to tumour growth. We explored the potential of automated lung tumour vascularity assessment as risk factor for landmark survival.

Methods: 131 CT scans from the NSCLC Radiogenomics dataset were evaluated. All patients underwent surgery, with or without other therapies. Primary lung tumour(PLT) is segmented by a radiologist. Vessels segmentation (arteries and veins) is performed by an in-house deep learning segmentation model. Vascularity features extracted for the PLT include: amount of blood vessel connections, % of the tumour surface connected to vessels (%area), and basic statistics on the surface area of the connections. A generalized linear model (GLM) to predict landmark survival was trained with these features, tumour volume, and clinical factors. Stepwise feature reduction was performed to arrive to the ﬁnal model. We present the odds ratio (OR)as well as a combined risk score for the remaining independent predictors.

Results: Landmark survival was reached for 86/131 (66%) patients. GLM analysis showed 4 independent risk factors related to landmark survival: %area (OR¼ 1.69 for>2.5%), age (OR¼1.57 for >70 years), gender (OR¼2.10 for male) and radiationtherapy (OR¼1.51 for yes). Smoking status and tumor volume were not retained inthe ﬁnal model. We also showed that risk of dying before landmark survival increased with increased number risk factors (0%, 18%, 40%, 48% and 100% for 0, 1, 2, 3, 4 risk factors, respectively).

Conclusions: Lung tumour vascularity is an independent risk factor for landmark survival. We showed an approach were it can be used as additional prognostic factor to inform clinical decision making and therapy planning.

Editorial acknowledgement: Fabio Bottari, PhD, of Radiomics for providing medical writing support in accordance with Good Publication Practice ( GPP 2022) guidelines.

Disclosure: F. Blistein, F. Belmans, S. Goffart, L. Libert, R. Narasimhan, A. Corsi: Financial Interests,Personal, Full or part-time Employment: Radiomics. W. Vos: Financial Interests, Personal, Leadership Role: Radiomics. M. Occhipinti: Financial Interests, Personal, Financially compensated role: Radiomics. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2933

211P

Cost-efﬁcient detection of NTRK1, NTRK2 and NTRK3 gene rearrangements using the test for 5’/3’-end unbalanced expression: The analysis of 8075 patients

E. Imyanitov, A. Romanko, E. Preobrazhenskaya, V. Tiurin, A. Venina, R. Mulkidjan,A. Anuskina, A. Togo, A.O. Ivantsov, A.G. Iyevleva

Department of Tumor Growth Biology, N.N. Petrov National Medical Research Center of Oncology, St. Petersburg, Russian Federation

Background: The majority of NTRK1, NTRK2 and NTRK3 rearrangements result in the increased expression of the kinase portion of the gene due to its fusion to an actively transcribed gene partner. Consequently, the analysis of 5’-/3’-end expression imbalance is potentially capable of detecting the entire spectrum of NTRK gene fusions.

Methods: Formalin-ﬁxed tissue specimens were subjected to manual dissection of tumor cells, followed by DNA/RNA isolation and cDNA synthesis. 5’-/3’-end expression imbalance in NTRK genes was analyzed by real-time PCR. Further identiﬁcation of gene rearrangements was performed by variant-speciﬁc multiplexed PCR for 42 common NTRK fusions, and, whenever necessary, by RNA-based next-generation sequencing (NGS).

Results: The study initially included 8075 tissue specimens; 651 (8.1%) of these samples failed to pass the quality control. NTRK rearrangements were detected in 7/6436 (0.1%) lung carcinomas, 11/137 (8.0%) pediatric tumors, and 13/851 (1.5%)adult non-lung malignancies. The highest incidence of NTRK translocations was observed in pediatric sarcomas (7/39, 17.8%). Relatively high frequency of NTRK fusions was seen in microsatellite-unstable colorectal tumors (6/48, 12.5%) and salivary gland carcinomas (5/93, 5.4%). None of 1293 lung carcinomas with driver alterations in EGFR/ALK/ROS1/RET/MET oncogenes had NTRK 5’/3’-end expression imbalance. Variant-speciﬁc PCR was performed for 744 tumors with normal 5’/3’-end expression ratio: there were no rearrangements in 172 EGFR/ALK/ROS1/RET/METnegative lung cancers and 125 pediatric tumors, while NTRK fusions were detected in 2/447 (0.4%) non-lung adult malignancies.

Conclusions: This study describes a robust pipeline for the detection of NTRK1, NTRK2 and NTRK3 gene fusions, which may be considered as a cost-efﬁcient alternative to conventional methods of NTRK analysis.

Funding: Russian Science Foundation (grant number 17-75-30027).

https://doi.org/10.1016/j.annonc.2023.09.2934

212P Extracellular vesicle miRNA as effective biomarkers for predicting antitumor efﬁcacy in lung adenocarcinoma treated with chemotherapy and checkpoint blockade

S. Sun, H. Yu, X. Wu, X. Zhao, Z. Hu, J. Wang

Thoracic Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai,China

Background: Immune checkpoint inhibitors (ICIs) have improved the care of patients in metastatic lung adenocarcinoma (LUAD). However, PD-L1 status, high Tumor Mutational Burden (TMB), and mismatch repair deﬁciency are the only validated biomarkers of efﬁcacy for ICIs. These markers remain imperfect, and new predictive markers represent an unmet medical need. MicroRNAs (miRNAs) encapsulated within plasma-derived extracellular vesicles (EVs) may be suitable for use as noninvasive diagnostic biomarkers for aggressive malignancies, including LUAD. Here, we assessed the possibility of plasma EVs derived miRNAs as potential biomarkers for predicting and identifying the beneﬁciaries of combined immunochemotherapy.

Methods: A total of 31 patients with metastatic LUAD who received pembrolizumab combined with pemetrexed and carboplatin were enrolled. After efﬁcacy evaluation.

25 patients had durable clinical beneﬁts from combined immunochemotherapy, and the rest patients showed disease progression. MiRNA proﬁles of plasma-derived EVs from these patients were investigated using unsupervised hierarchical clustering.

Results: 46 differentially expressed miRNAs (DEMs) were identiﬁed between responders and non-responders. Interestingly, we found that miR-6815-5p, miR-15a-5p,miR-92a-3p, and miR-107 were obviously down regulated in non-responder group.

However, miR-769-5p, and miR-589-5p showed a trend of signiﬁcantly increased expression. In addition, all these ﬁndings were further conﬁrmed by clinical imaging assessment.

Conclusions: In conclusion, ,EVs miRNAs derived from patients with lung cancer showed promising application scenarios for effectively identifying true responders treated with combined immunochemotherapy.

Clinical trial identiﬁcation: NCT04427475, release date is June 11, 2020.

Legal entity responsible for the study: Fudan University Shanghai Cancer Center.

Funding: Shanghai "Science and Technology Innovation Action Plan" Natural Science Foundation (19ZR1410400).

https://doi.org/10.1016/j.annonc.2023.09.2935

213P Unlocking cancer treatment opportunities by populationbased advanced diagnostics in Norway

H.E.G. Russnes1, H.L. Nilsen2, M. Jebens3, E. Janssen4, R.M. Wold5,

L.A. Meza-Zepeda6, E. Hovig7, T. Lien1, V. Nygaard1, P. Niehusmann1, K.M. Ersland8,R. Forthun8, H.K. Haugland9, A.B. Wennerström2, T. Lüders2, U. Randen10, H.Y. Dai3,A.V.B. Granlund3, A.J. Skjulsvik3, R. Hovland8

1Dept. of Pathology, Oslo University Hospital, Oslo, Norway; 2Epigen, Akershus University Hospital HF, Lorenskog, Norway; 3Dept. of Pathology, St. Olavs Hospital,Trondheim, Norway; 4Dept. of Pathology, Stavanger University Hospital - Helse Stavanger HF, Stavanger, Norway; 5Dept. of Pathology, University Hospital of North Norway, Tromso, Norway; 6Dept. of Core Facilities, Oslo University Hospital - The Norwegian Radium Hospital, Oslo, Norway; 7Dept. of Tumor Biology, Oslo University Hospital - Radiumhospitalet, Oslo, Norway; 8Section for Cancer Genomics, Helse Bergen HF, Haukeland University Hospital, Bergen, Norway; 9Dept. of Pathology, Helse Bergen HF, Haukeland University Hospital, Bergen, Norway; 10Dept. of Pathology,Akershus University Hospital HF, Lorenskog, Norway

Background: Targeted cancer treatment has been developed at a rapid pace, but implementation of precision cancer medicine (PCM) has met several challenges. Key challenges are: 1) lack of clinical evidence within and across tumor groups 2) lack of predictive biomarker 3) access to medication and 4) regulatory and economic factors.

These are interconnected, and PCM trials are needed to address most of them. To meet the need for tailored diagnostics for PCM trials, we designed a national Infrastructure for Precision Diagnostics e InPreD-Norway.

Methods: In 2020, the CEOs of the four Norwegian health regions allocated funding to the six university hospitals to form a collaborative network, InPreD, with dedicated environments (nodes) at each site for implementing next-generation cancer diagnostics. The ﬁrst task has been to build a complete program for Comprehensive Gene Proﬁling (CGP), including a national virtual tumorboard, for patients eligible for experimental cancer treatment and trial inclusion.

Results: The InPreD nodes were gradually built at the six university hospitals. The largest hospital, Oslo University Hospital, was initiated ﬁrst, built a transdisciplinary environment and implemented a complete pipeline for CGP testing (TSO500). These solutions were used by the other nodes when they were initiated. In spring 2023, the InPreD nodes had completed CPG proﬁling of 1000 patient cases. A new treatment opportunity was found for 34% of the patients, where referral to the national PCM trial IMPRESS-Norway trial dominated (21%). The National molecular tumorboard meets virtually twice weekly to discuss the analysed cases with the InPreD nodes and the referring physicians, providing both an advisory but also and educational role.

InPreD now plan novel diagnostics such as drug sensitivity screening and digital pathology biomarkers for planned trials.

Conclusions: The national Infrastructure, InPreD, secures competence building and standardised service in CGP testing nationwide, providing new treatment opportunities for cancer patients. Beyond strengthening the ability to identify patients to clinical trials, it serves as a united interaction partner for national stakeholders such as governmental bodies, health authorities and industry.

Legal entity responsible for the study: The Norwegian regional health authorities.

Funding: The Norwegian regional health authorities and the involved hospitals.

Disclosure: H.E.G. Russnes: Financial Interests, Institutional, Invited Speaker, Speaker on Illumina satellite meeting ( ESMO 2022): Illumina; Financial Interests, Institutional, Advisory Board, Novartis satellite meeting, Nordic Lung Cancer meeting, 2022: Novartis; Financial Interests, Institutional,Other, Debate, precision medicine, Oslo 2022 : Merck; Financial Interests, Institutional, Other,Participation, round table, Cholangiocarcinoma; Nordic meeting 2021: Incyte; Financial Interests,Institutional, Coordinating PI, Funding of 500 FMliquid test to patients in the IMPRESS-Norway trial:Roche Norway; Financial Interests, Institutional, Coordinating PI, Funding of TSO500 liquid tests for 500 patients in the IMPRESS-Norway trial: Illumina; Non-Financial Interests, Leadership Role, InPreD is an establishment in the public health care, securing disciplinary work when implementing precision diagnostics for cancer.: National Infrastructure for Precision Diagnostics (InPreD); NonFinancial Interests, Leadership Role, A network structure established as part of the public health care system, to share knowledge, build competence and work with harmonisation and standardisation to implement precision medicine: National Competence Network for Precision Medicine; Non-Financial Interests, Leadership Role, Head of working group for molecular pathology and for the Norwegian association for molecular pathology: The Norwegian Association of Pathology. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2936

214P PESSA: A shiny app for pathway enrichment score-based survival analysis in cancer

Y. Shi, H. Yang, A. Lin, J. Zhang, P. Luo

Department of Oncology, Zhujiang Hospital of Southern Medical University, Guangzhou, China

Background: The activation levels of biologically signiﬁcant gene sets are innovative molecular markers for tumours and play an irreplaceable role in the diagnosis,staging, prognosis evaluation and treatment of tumours; however, there is still a scarcity of web-based tools for prognosis analysis that use gene set activation levels as molecular markers for tumours. We have developed a web-based tool for survival analysis using gene set activation levels.

S267

Methods: All data analysis within PESSA is implemented via R. Activation levels of MSigDB gene sets were assessed using the single-sample gene set enrichment analysis (ssGSEA) method based on microarray and high-throughput sequencing data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA).

PESSA was used to perform median and best cut-off dichotomous grouping of ssGSEA scores for each dataset, relying on the survival and survminer packages for survivalrelated analysis and visualisation. The web pages were built relying on Shiny.

Results: PESSA is an open-access online tool for visualising prognostic analysis based on the activation levels of biologically signiﬁcant gene sets as molecular markers of tumour prognosis. A total of 214 datasets from the GEO and TCGA covering 51 different cancer types and 13 different survival status types were included; 13,434 tumour-related gene sets were obtained from the MSigDB for pre-grouping. For survival analyses, the gene set of interest was selected; Kaplan‒Meier analyses and visualisation were conducted based on the median and best dichotomous cut-off, plus continuous variables were subjected to univariate Cox regression analyses.

Conclusions: PESSA (https://smuonco.shinyapps.io/PESSA/) is a large, interactive,easily accessible web-based analysis tool covering a large amount of data; it can creatively use predeﬁned gene set activation levels as molecular markers of tumours and facilitate survival analysis for cancer patients.

Funding: The Natural Science Foundation of Guangdong Province [2018A030313846,2021A1515012593]; the Science and Technology Planning Project of Guangdong Province [2019A030317020]; the National Natural Science Foundation of China[81802257, 81871859, 81772457, 82172750 and 82172811]; and the Guangdong Basic and Applied Basic Research Foundation (Guangdong - Guangzhou Joint Funds)[2022A1515111212].

https://doi.org/10.1016/j.annonc.2023.09.2937

215P

Identifying predictors of overall survival among TMB-low cancer patients treated with immune checkpoint inhibitors

C.B. Xavier1, G. Guardia2, J.P. Alves3, C.D.H. Lopes1, B. Awni1, E.F. de Campos1,A.A. Camargo2, D.L.F. Jardim1, P. Galante2

1Oncology Center, Hospital Sírio-Libanês, São Paulo, Brazil; 2Molecular Biology Center,Hospital Sírio-Libanês, São Paulo, Brazil; 3Data Science, Innovation Intelligence AI, San Francisco, CA, USA

Background: Dichotomizing tumors into tumor mutational burden (TMB)-high and TMB-low is common practice but may not determine which patients will beneﬁt from immune checkpoint inhibitors (ICI). This study examines the impact of somatic mutations on overall survival (OS) for TMB-low metastatic cancer patients (MCP) treated with ICI.

Methods: Genomic (MSK-IMPACT) and clinical data from 1,172 TMB-low (<10mut/Mb) MCP were collected. OS accordingly to single-genemutations was assessed by Kaplan-Meier (KM) method. For genes exhibiting a correlation with OS, we conducted a Cox multivariate analysis (CMA) stratiﬁed by TMB, sex, age, microsatellite instability(MSI), and histology. KM and CMA were also performed to investigate the relation between insertions and deletions (InDels) and OS. Linear regression (LR) investigated the relation between TMB and InDels burden. Decision tree modeling (DTM) aimed to predict whether patients that received ICI harbored OS shorter or longer than the median OS of 15 months. The discriminative features (DF) for DTM were TMB(continuous), gene mutations, sex, and histology.

Results: Mutations in 25 genes were related to OS. CMA conﬁrmed 9 genes associated with superior (VHL) and inferior (CTNNB1, DAXX, H3C2, HLA-A, IGF1R, KMT2D,SMARC4, TP53) OS (P < 0.05). MSI, age, and gender did not affect OS. Melanoma,bladder, and RCC endowed patients with better OS (P < 0.01). TMB and InDels exhibited a R-squared of 0.38 - low (or absent) relation. The InDels burden was unrelated to OS (P ¼ 0.21). VHL mutation was a predictor of better OS in uni- andmultivariate levels for RCC (N¼149; P < 0.01). At DTM, RCC histology was the ﬁrst DF(gini 0.492). For RCC patients, VHL mutation was the second (gini 0.349). For non-RCC patients, melanoma histology was the second. At the third layer, a TMB threshold of

5.095 mut/Mb for VHL wild-type patients and TP53 mutation for non-RCC and nonMelanoma patients were the following DF.

Disclosure: M. Rothe: Financial Interests, Institutional, Full or part-time Employment, I work as the Senior Biostatistician on the TAPUR Study at ASCO.: American Society of Clinical Oncology. P.K.

Mangat: Financial Interests, Institutional, Full or part-time Employment: American Society of Clinical Oncology. E. Garrett-Mayer: Financial Interests, Institutional, Full or part-time Employment: American Society of Clinical Oncology; Financial Interests, Personal, Royalties, Book: Principles of Anticancer Drug Development: Humana Press. K.F. Mileham: Financial Interests, Personal, Advisory Board: Regeneron, AstraZeneca, Mirati, Takeda, Genentech; Financial Interests, Personal, Invited Speaker: ACCC, Chest, OncLive, Merck. H.L. Duvivier: Financial Interests, Personal, Invited Speaker,Speakers Bureau: Guardant Health; Non-Financial Interests, Member: ASCO. M. Akce: Financial Interests, Personal, Advisory Board: Eisai, Ipsen, GSK, QED Therapeutics, Exelixis, AstraZeneca, Curio Science, Genentech, Isofol, Taiho, Incyte; Financial Interests, Institutional, Local PI: Tesaro, RedHill Biopharma, Polaris, Bristol Myers Squibb-Ono Pharmaceutical, Xencor, Merck Sharp & Dohme, Eisai,Pﬁzer, Bellicum Pharmaceuticals, Boehringer Ingelheim, Syros Pharmaceuticals, IMPAC Medical Systems, AstraZeneca; Financial Interests, Institutional, Trial Chair: Bayer; Financial Interests, Personal and Institutional, Steering Committee Member: AstraZeneca. D. D. behl: Financial Interests,Personal, Advisory Board, Member of invited advisory board on Adaura, Caspian and Poseidon trials:AstraZeneca; Financial Interests, Personal, Invited Speaker, Speaker for Tagrisso and Durva: AstraZeneca; Financial Interests, Personal, Advisory Board, Invited advisor discussion on IO: Lilly; Financial Interests, Personal, Advisory Board, Lonsurf: Taiho; Financial Interests, Personal, Invited Speaker,Panel discussion: Guardant; Financial Interests, Personal, Advisory Board, ad board member: Amgen;Financial Interests, Personal, Advisory Board, Amivantamab ad board: Janssen; Financial Interests,Personal, Advisory Board: BMS; Non-Financial Interests, Member of Board of Directors, Not a paid position: SCOPe ( phase 1 partnership with UCD). N. blinded and no connection to any health care ﬁrm: Guidepoint Global; Financial Interests, Personal and Institutional,Advisory Role, Participated in Ad board: Novartis; Financial Interests, Personal and Institutional,Advisory Board, Participated in Ad board: AstraZeneca/Daiichi Sankyo ; Financial Interests, Personal and Institutional, Advisory Board, Peer review through NCCN: Taiho Oncology ; Financial Interests,Personal and Institutional, Advisory Board, Participated in pharma sponsored Case discussion session: Tersera therapeutics ; Financial Interests, Personal and Institutional, Advisory Board, Ad board participation: Ipsen ; Financial Interests, Personal and Institutional, Advisory Board: ITM Isotope Technologies Munich ; Non-Financial Interests, Personal and Institutional, Advisory Board, DSMB member: RayzeBio ; Financial Interests, Personal and Institutional, Research Funding, research funding: Zymeworks , Bristol Myers Squibb/Medarex ; Financial Interests, Personal and Institutional,Research Funding, NCCN sponsored grant for clinical trial with Neratinib: Puma Biotechnology ;Financial Interests, Personal and Institutional, Research Funding, Research funding: Oryzon Genomics . Vijayvergia: Financial Interests, Personal,Financially compensated role, Participated in a few market research interviews - blinded and no connection to any health care ﬁrm: Guidepoint Global; Financial Interests, Personal and Institutional,Advisory Role, Participated in Ad board: Novartis; Financial Interests, Personal and Institutional,Advisory Board, Participated in Ad board: AstraZeneca/Daiichi Sankyo ; Financial Interests, Personal and Institutional, Advisory Board, Peer review through NCCN: Taiho Oncology ; Financial Interests,Personal and Institutional, Advisory Board, Participated in pharma sponsored Case discussion session: Tersera therapeutics ; Financial Interests, Personal and Institutional, Advisory Board, Ad board participation: Ipsen ; Financial Interests, Personal and Institutional, Advisory Board: ITM Isotope Technologies Munich ; Non-Financial Interests, Personal and Institutional, Advisory Board, DSMB member: RayzeBio ; Financial Interests, Personal and Institutional, Research Funding, research funding: Zymeworks , Bristol Myers Squibb/Medarex ; Financial Interests, Personal and Institutional,Research Funding, NCCN sponsored grant for clinical trial with Neratinib: Puma Biotechnology ;Financial Interests, Personal and Institutional, Research Funding, Research funding: Oryzon Genomics . A. Gaba: Financial Interests, Institutional, Local PI, Clincial trial. Payment to my institution:GSK; Non-Financial Interests, Member, Advocacy: Association of Clinical Oncology. F. F. Meric-Bernstam: Financial Interests, Personal, Other, Consultant: AstraZeneca, F. Hoffman-La Roche Ltd.,Zymeworks, OnCusp Therapeutics; Financial Interests, Personal, Advisory Board, Advisory Board/Consultant: Seagen; Financial Interests, Personal, Advisory Board: Zentalis, Karyopharm, Biovica,Eisai, Protai, TheraTechnologies; Financial Interests, Personal, Other, Consulting: Tallac Therapeutics,Lengo Therapeutics, LOXO-Oncology, Black Diamond, Inﬁnity Pharmaceuticals, AbbVie, GT Aperion,Ecor1; Financial Interests, Personal, Other, Consutling: Menarini Group; Financial Interests, Institutional, Other, Local PI / Research Grant: Aileron Therapeutics, Bayer Healthcare, CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., eFFECTOR Therapeutics, Taiho Pharmaceutical Co.; Financial Interests, Institutional, Other, Local PI / Research Grant / Coordinating PI: AstraZeneca; Financial Interests, Institutional, Local PI: Calithera Biosciences, Curis Inc., Debiopharm International, Guardant Health Inc., Klus Pharma, Novartis; Financial Interests, Institutional, Other, Local PI / Steering Committee Member: Genentech Inc.; Financial Interests, Institutional, Research Grant: Takeda Pharmaceutical Co., Puma Biotechnology Inc., Repare; Other, Travel Support: Cholangiocarcinoma

Foundation; Other, Travel support: European Organisation for Research and Treatment of Cancer(EORTC), European Society for Medical Oncology (ESMO). S.M. Schuetze: Financial Interests, Personal, Other, DSMC member: BioAtla; Financial Interests, Personal, Royalties: UpToDate; Financial Interests, Institutional, Local PI: Tracon, Adaptimmune, Boehringer Ingelheim, Shanghai Pharmaceuticals, Rain Therapeutics. A. Gregory: Financial Interests, Institutional, Full or part-time Employment: American Society of Clinical Oncology; Other, Family member works for Pﬁzer: Pﬁzer. S.

Halabi: Financial Interests, Personal, Other, Member of DSMB: Sanoﬁ, Aveo Oncology, BMS, Janssen;Financial Interests, Institutional, Funding: ASCO. R.L. Schilsky: Financial Interests, Personal, Advisory Board, Member, Clinical Advisory Board: Cellworks; Financial Interests, Personal, Advisory Board,Member, Mission Advisory Board: EQRx; Financial Interests, Personal, Advisory Board, Consultant:Illumina, Scandion Oncology, Clariﬁed Precision Medicine, Bryologyx; Financial Interests, Personal,Advisory Board, Clinical advisory board: Syapse; Financial Interests, Personal, Advisory Board, Scientiﬁc advisory board: ZephyrAI; Financial Interests, Personal, Member of Board of Directors: Leap Therapeutics; Financial Interests, Personal, Stocks/Shares, Stock options: Cellworks, Clariﬁed Precision Medicine, Bryologyx; Financial Interests, Personal, Stocks/Shares, Stock: EQRx; Financial Interests, Personal, Stocks/Shares, Stock ownership/Member, Board of Directors: Leap Therapeutics;Financial Interests, Institutional, Coordinating PI, Research grant to ASCO to support TAPUR clinical trial: AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Genentech, Lilly, Merck, Pﬁzer,Seagen; Financial Interests, Institutional, Coordinating PI, Research grant to ASCO to support TAPUR trial: Taiho; Non-Financial Interests, Leadership Role, Chairman: WIN Consortium; Non-Financial Interests, Member of Board of Directors, Board member: Alliance Clinical Trials Group, Friends of Cancer Research, Reagan Udall Foundation for FDA, EORTC; Non-Financial Interests, Advisory Role,Member, Strategic Executive Advisory Committee: Canadian Cancer Trials Group; Non-Financial Interests, Advisory Role, Chair, Scientiﬁc Advisory Board: Ontario Institute for Cancer Research. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2930

208P

Identiﬁcation of BCOR mutation as a novel predictor of immunotherapy efﬁcacy in gastrointestinal tumors

W. Wang1, Q. Zhang2, C. Zhu2, D. Chen2

1Department of Thoracic Surgery, Xi’an International Medical Center Hospital, Xi’an,China; 2The Medical Department, Jiangsu Simcere Diagnostics Co., Ltd., Nanjing, China

Background: Immune checkpoint inhibitors (ICIs) have become an important therapeutic option for gastrointestinal cancer (GC). BCOR (BCL6 Corepressor) is an epigenetic regulator, whose mutation has been found to be associated with the development of various tumors, while evidence in GC remains limited.

Methods: We analyze genomic data from 236 GC patients receiving immunotherapy from Memorial Sloan Kettering Cancer Center (MSKCC) to assess the relationship between BCOR mutation status and efﬁcacy of immunotherapy. The prognostic value and RNA mechanism exploration of BCOR mutations are explored in 914 GC samples from The Cancer Genome Atlas (TCGA) database. CIBERSORT is used to evaluate the inﬁltration status of 22 immune cell types in TCGA GC cohort. Survival is estimated by Kaplan-Meiercurves, with the P-values are determined by log-ranktest.

Conclusions: A follow-up study of MCED participant survey responses revealed high levels of participant satisfaction, intent to adhere to SOC screening, and mammography adherence. Most participants reported no change or a decrease in anxiety. This data suggest that MCED testing with imaging-based diagnostic resolution does not signiﬁcantly increase anxiety or negatively impact mammography adherence for most participants, including those with FP results.

Editorial acknowledgement: Medical writing and editorial support was provided by Carolyn Hall, PhD, and Feyza Sancar, PhD (Exact Sciences, Madison, WI).

Disclosure: N. Papadopoulos: Financial Interests, Personal, Advisory Role: Exact Sciences Corporation, Haystack Oncology; Financial Interests, Personal, Stocks or ownership: Exact Sciences Corporation, Haystack Oncology, ManaT Bio, Personal Genome Diagnostics, NeoPhore, CAGE Pharma;Financial Interests, Personal, Licencing Fees or royalty for IP, I receive royalties for Intellectual Property owned and managed by Johns Hopkins University: Johns Hopkins University. A.M. Lennon:Financial Interests, Personal, Licencing Fees or royalty for IP, I receive royalties for Intellectual Property owned and managed by Johns Hopkins University: Johns Hopkins University. P. Elias:Financial Interests, Personal, Full or part-time Employment: Exact Sciences Corporation; Financial Interests, Personal, Stocks/Shares: Exact Sciences Corporation. S. Rego: Financial Interests, Personal,Full or part-time Employment, travel/accommodation expenses: Exact Sciences Corporation;Financial Interests, Personal, Stocks/Shares: Exact Sciences Corporation. O. Choudhry: Financial Interests, Personal, Full or part-time Employment: Exact Sciences Corporation; Financial Interests,Personal, Stocks/Shares: Exact Sciences Corporation. D. Flake: Financial Interests, Personal, Full or part-time Employment: Exact Sciences Corporation; Financial Interests, Personal, Stocks/Shares:Exact Sciences Corporation. J. Cohen: Financial Interests, Personal, Stocks or ownership: Haystack Oncology; Financial Interests, Personal, Licencing Fees or royalty for IP, I receive royalties for Intellectual Property owned and managed by Johns Hopkins University: Johns Hopkins University. C.

Douville: Financial Interests, Personal, Advisory Role, Consulting and travel/accomodations expenses: Exact Sciences Corporation; Financial Interests, Personal, Licencing Fees or royalty for IP, I receive royalties for Intellectual Property owned and managed by Johns Hopkins University: Johns Hopkins University. A. Honushefsky: Financial Interests, Institutional, Research Funding: Freenome Holdings, Inc, Exact Sciences Corporation. I. Kinde: Financial Interests, Personal, Full or part-time Employment: Exact Sciences Corporation; Financial Interests, Personal, Stocks/Shares: Exact Sciences

Corporation; Financial Interests, Personal, Licencing Fees or royalty for IP, I receive royalties for intellectual property owned and managed by Johns Hopkins University: Johns Hopkins University. A.

Klein: Financial Interests, Personal, Advisory Role, consulting: Merck; Financial Interests, Personal,Advisory Board, consulting: OptumInsight; Financial Interests, Personal, Funding: OptumLabs. Z.

Salvati: Financial Interests, Institutional, Research Funding: Exact Sciences Corporation. C. Tomasetti:Financial Interests, Personal, Advisory Role: Haystack Oncology, PrognomIQ; Financial Interests,Personal, Stocks or ownership: Haystack Oncology, PrognomIQ; Financial Interests, Personal, Licencing Fees or royalty for IP, I receive royalties for intellectual property owned and managed by Johns Hopkins University: Johns Hopkins University. E. Wagner: Financial Interests, Institutional,Research Funding: Freenome Holdings, Inc, Exact Sciences Corporation. C.Walter: Financial Interests,Institutional, Research Funding: Freenome Holdings, Inc, Exact Sciences Corporation. E. Fishman:Financial Interests, Personal, Other, Honoraria: GE Healthcare, HipGraphics; Financial Interests,Institutional, Research Funding: GE Healthcare, HipGraphics, GE Healthcare; Financial Interests,Institutional, Other, Honoraria: Siemens Healthineers. K. Kinzler: Financial Interests, Personal,Advisory Role, I also own stock: Haystack Oncology, Exact Sciences Corporation, Cage Pharma,ManaT Bio, Neophore; Financial Interests, Personal, Advisory Board, I also own stock.: Personal Genome Diagnostics; Financial Interests, Personal, Licencing Fees or royalty for IP, I receive royalties for intellectual property owned and managed by Johns Hopkins University.: Johns Hopkins University. B. Vogelstein: Financial Interests, Personal, Advisory Role, I also own stock: Cage Pharma, Catalio Capital Management, NeoPhore; Financial Interests, Personal, Stocks or ownership: ManaT Bio,Haystack Oncology, Personal Genome Diagnostics, Exact Sciences Corporation; Financial Interests,Personal, Licencing Fees or royalty for IP, I receive royalties for intellectual property owned and managed by Johns Hopkins University: Johns Hopkins University. T. T.M. Beer: Financial Interests,Personal, Full or part-time Employment: Exact Sciences Corporation; Financial Interests, Personal,Stocks/Shares: Exact Sciences Corporation, Salarius Pharmaceuticals; Financial Interests, Personal,Advisory Role, I also own stock: Arvinas; Financial Interests, Personal, Advisory Role: AbbVie, Amgen,Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Constellation Pharmaceuticals, Dantari Pharmaceuticals, GSK, GRAIL, Janssen, Pﬁzer, Sanoﬁ, Sapience Therapeutics. A. Buchanan: Financial Interests, Personal, Full or part-time Employment: IMPACT Pharmaceuticals; Financial Interests,Institutional, Research Funding: Exact Sciences Corporation, Freenome Holdings, Inc; Financial Interests, Personal, Licencing Fees or royalty for IP: MeTree and You, Inc.

https://doi.org/10.1016/j.annonc.2023.09.2925

203P

Genomic characterization of sporadic MET ampliﬁed nonsmall cell lung cancer (NSCLC) and association with realworld outcomes

R.D. Gentzler1, N. Sharma2, A. Mitra3, R. Ben-Shachar3, M. Stein2, J. Guinney4,H. Nimeiri3, W. Iams5, C. Aggarwal6, J. Patel7

1Hematology/Oncology, University Hospital of Virginia (UVA), Charlottesville, VA, USA;2Systems Biology, Tempus Labs, Inc., Chicago, IL, USA; 3Clinical Development, Tempus Labs, Inc., Chicago, IL, USA; 4Cancer Genomics, Tempus Labs, Inc., Chicago, IL, USA;5Medical Oncology, Vanderbilt Ingram Cancer Center, Nashville, TN, USA; 6Medicine -Hematology/Oncology Department, University Of Pennsylvania, Philadelphia, PA, USA;7Medical Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL,USA

Background: MET copy-number ampliﬁcations (CNAs) are implicated as a resistance mechanism in patients treated with EGFR-targeted tyrosine kinase inhibitors and are associated with poor outcomes. However, data are limited on associations of immune biomarker and clinical outcomes among patients with sporadic MET CNAs d deﬁned as preceding ﬁrst-line (1L) therapy. This is the ﬁrst real-world dataset to assess the prevalence of sporadic MET ampliﬁcations and their association with real-world clinical outcomes.

Methods: We analyzed a de-identiﬁed, multimodal dataset of 3,998 NSCLC patients biopsied prior to or within 30 days after the start of 1L therapy. Samples underwent NGS testing with Tempus xT (DNA-seq of 595-648 genes, 500x coverage). MET CNAs were identiﬁed using a CN threshold of 4 copies and compared to patients were identified using a CN threshold of ≥4 copies and compared to patients thatthatwere copy-number neutral (CN-N); patients with MET exon14 skipping mutations were excluded.

Results: The prevalence of sporadic MET CNAs in NSCLC patients was 5.7% (n¼227).Patients with MET CNAs were more likely to harbor EGFR mutations compared to CNN patients (17.6% vs 12.3%; p¼0.02). In the subset of EGFR mutation-negative pa-tients with PD-L1 data (n¼2,230), a higher proportion of patients with MET CNAswere PD-L1-H (tumor proportion score 50%) compared to MET CN-N patients were PD-L1-H (tumor proportion score ≥50%) compared to MET CN-N patients (45%(45%vs 25.9%; p<0.001). Amongst EGFR mutation-negative patients (n¼3,494), MET CNA-H Hpatients were significantly enriched for High Tumor Mutational Burden (TMB-H,≥patients were signiﬁcantly enriched for High Tumor Mutational Burden (TMB-H, 10 Mut/Mb) compared to CN-N patients (21.4% vs 13.5%, p¼0.004). In the subset ofEGFR mutation-negative patients treated with 1L immune checkpoint inhibitors (ICIs,n¼1,464); there was no signiﬁcant difference in rwOS for patients with MET CNAs(median OS 21.5 months) vs CN-N patients (median OS 16.5 months), (HR¼0.81, CI¼[0.57, 1.14], p¼0.22).

Conclusions: The majority of treatment-naive patients with sporadic MET CNAs are EGFR mutation-negative and enriched with biomarkers that are predictive of immune therapy beneﬁt (PD-L1-H and TMB-H). Future clinical trials evaluating MET targeted therapy should account for this genomic heterogeneity and immunogenic therapeutic potential.

Legal entity responsible for the study: Tempus Labs, Inc.

Funding: Tempus Labs, Inc.

Disclosure: R.D. Gentzler: Financial Interests, Personal, Advisory Board: AstraZeneca, Takeda,Gilead, Janssen, Mirati, Daiichi Sankyo, Sanoﬁ, Oncocyte, Jazz Pharmaceuticals; Financial Interests,Personal, Invited Speaker: Clinical Care Options, OncLive, Targeted Oncology, Society for Immunotherapy of Cancer (SITC); Financial Interests, Institutional, Local PI: Janssen, Mirati, Daiichi Sankyo,Bristol Myers Squibb, AstraZeneca, Jounce Therapeutics, Takeda, Bristol Myers Squibb, Merck,Chugai, Amgen; Financial Interests, Institutional, Research Grant: Pﬁzer; Financial Interests,

Institutional, Coordinating PI: Mirati; Non-Financial Interests, Leadership Role: Hoosier Cancer Research Network; Non-Financial Interests, Principal Investigator: NCI ETCTN; Non-Financial Interests, Other, Member of Lung Cancer Scientiﬁc Review Committee: American Society of Clinical Oncology, Scientiﬁc Review Committee; Non-Financial Interests, Other, Committee Member: NCI Investigational Drug Steering Committee; Non-Financial Interests, Ofﬁcer, Associate Editor: Journal of Thoracic Oncology, ASCO Meeting Abstracts; Non-Financial Interests, Personal, Other, Travel support for attending meetings for invited speaker: International Association for the Study of Lung Cancer (IASLC). N. Sharma: Financial Interests, Personal, Full or part-time Employment: Tempus labs;Financial Interests, Personal, Stocks/Shares: Tempus labs. A. Mitra: Financial Interests, Personal,Stocks or ownership: Tempus Labs, Inc., Guardant Health. R. Ben-Shachar: Financial Interests, Personal, Stocks or ownership: Tempus Labs, Inc.; Financial Interests, Personal, Full or part-time Employment: TTempus Labs, Inc. M. M. Stein: Financial Interests, Personal, Full or part-time Employment: Tempus Labs. J. Guinney: Financial Interests, Institutional, Full or part-time Employment:Tempus Labs; Financial Interests, Institutional, Stocks/Shares: Tempus Labs. H. Nimeiri: Financial Interests, Full or part-time Employment: Tempus Labs, Inc.; Financial Interests, Stocks/Shares:Tempus Labs, Inc., AbbVie. W. Iams: Financial Interests, Personal, Advisory Board: Tempus, EMD Serono, Amgen, Sanoﬁ, NovoCure, Genentech, AstraZeneca, Catalyst, Jazz Pharma, Elevation Oncology, Bristol Myers Squibb, Janssen, Takeda, Mirati, G1 Therapeutics. C. Aggarwal: Financial Interests, Personal, Advisory Board: AstraZeneca, Celgene, Genentech, Lilly, Merck, Bluprint, Daiichi/Sankyo, Sanoﬁ, Eisai, BeiGene, Shionogi, Turning Point, Pﬁzer, Janssen, Boehringer Ingelheim. J. Patel:Financial Interests, Personal, Advisory Board: AstraZeneca, Takeda.

https://doi.org/10.1016/j.annonc.2023.09.2926

204P Performance assessment of a comprehensive genomic proﬁling (CGP) NGS kit across multiple study laboratories

J. Choi1, A. Fellowes2, E. Pikarsky3, M. Teixeira4, I. Vogl5, A. Ahmed1, K. Bi1,K. Kirkconnell1, C. Yin1, M. Shin1, N. Shrestha1, J. Blau1, S. Li1, Y. Li1, G. Kumar1,R. Chien1, S.E. Trabucco6, W. Wen1, M. Javey1, Z. Li1

1Molecular Labs, Roche Diagnostics Solutions, Pleasanton, CA, USA; 2Molecular Diagnostic Development, Peter MacCallum Cancer Center, Melbourne, VIC, Australia;3Department of Pathology, The Hebrew University of Jerusalem, Jerusalem, Israel;4Department of Pathology, Instituto Portugues de Oncologia do Porto Francisco Gentil,EPE, Porto, Portugal; 5Laboratory Operations, FMI GmbH, Penzberg, Germany;6Oncology Genomics Dept., Foundation Medicine, Inc, Cambridge, MA, USA

Background: Precision oncology is a rapidly evolving ﬁeld. Reliable tools are required for comprehensive genomic proﬁling (CGP) in clinical and research settings. NGS provides capabilities to detect multiple alterations, but complex workﬂows may be difﬁcult to implement. Roche Diagnostics and Foundation Medicine have developed the AVENIO Tumor Tissue CGP Kit, a streamlined and easy to implement ResearchUse-Only CGP assay to enable translational research labs.

Methods: The AVENIO Tumor Tissue CGP Kit proﬁles 324 genes for cancer alterations,tumor mutation burden (TMB), microsatellite instability (MSI), and genomic loss of heterozygosity (gLOH)). The kit contains reagents to create libraries. A software provides access to Foundation Medicine’s bioinformatics pipeline. Five laboratories tested 160 samples, consisting of cell line and formalin ﬁxed parafﬁn embedded(FFPE) tumor specimens. To assess reproducibility, 144 samples were evaluated across operators, lots, and instruments. To evaluate diagnostic sensitivity and speciﬁcity, 314 FFPE samples were tested and positive and negative predictive agreements determined against an orthogonal NGS method.

Results: Across ﬁve labs, pass rate was 98.1%. Sequencing quality metrics were high,with most samples reaching 1500x-2500x median coverage. Sites had 99.7% agreement for short variants. In the 144 sample reproducibility study, samples were highly uniform across variables, achieving >90% on-target rate. In the 314 sample concordance study, pass rate was 99.06%, with most samples achieving 2000x-2500x median coverage. Out of 314 samples, PPA to an orthogonal NGS-based method were: 98.3%short variants, 90.5% rearrangements, 94.8% copy number, 100% MSI, 100% TMB,and 96.8% gLOH. NPA reached 99.97% across short variants. Detected alterations included EGFR T7090M, BRAF V600E, KRAS 12/13 mutations, and EML4-ALK fusions.

Conclusions: CGP tests are being utilized in precision oncology, but NGS workﬂows and bioinformatics pipelines can be difﬁcult to implement. The AVENIO CGP Tumor Tissue Kit is highly reproducible across sites and operators, achieving high sequencing quality metrics and diagnostic sensitivity.

Legal entity responsible for the study: Roche Diagnostics Solutions.

Funding: Roche Diagnostics Solutions.

Disclosure: J. Choi, A. Ahmed, K. Bi, K. Kirkconnell, C. Yin, M. Shin, N. Shrestha, J. Blau, S. Li, Y. Li, G.

Kumar, R. Chien,W.Wen, Z. Li: Other, Institutional, Full or part-time Employment: Roche Diagnostics.

A. Fellowes, E. Pikarsky : Other, Institutional, Sponsor/Funding, Roche sponsored study: Roche Diagnostics. M. Teixeira: Other, Institutional, Sponsor/Funding, Roche Sponsored Study: Roche Diagnostics; Other,Speaker, Consultant, Advisor: AstraZeneca Produtos Farmacêuticos; Other, Speaker,Consultant, Advisor: Janssen Cilag Farmacêutica, Merck Sharp & Dohme, Novartis Farma Produtos Farmacêuticos, Roche Farmacêutica Química , Roche Sistemas De Diagnósticos Sociedade Unipessoal. I. Vogl, S.E. Trabucco: Other, Institutional, Full or part-time Employment: Foundation Medicine. M. Javey: Other, Institutional, Full or part-time Employment, Stocks: Roche Diagnostics.

https://doi.org/10.1016/j.annonc.2023.09.2927

S263

205P

A novel immunoprecipitation/PCR method for detection of plasma cfDNA fragments selectively occupied by CTCF in cancer

D. Pamart, J-V. Turatsinze, B. Cuvelier, M. Herzog, J. Micallef

Research and Development, Belgian Volition SRL, Isnes, Belgium

Background: CTCF-binding site (BS) occupancy is plastic, tissue speciﬁc and altered in cancer. This principle underlies some fragmentomics methods. We hypothesized that ChIP-Seq of plasma CTCF-cfDNA might identify CTCF-BSs selectively occupied in cancer and that, having removed all nucleosomes or other non-CTCF bound cfDNA by CTCF immunoprecipitation (IP), the presence of cfDNA fragments corresponding to sites selectively CTCF occupied in cancer may be tested for by PCR. We now report a novel liquid biopsy method, and initial results, based on this principle.

Methods: (i) Identiﬁcation of CTCF-BSs selectively occupied in cancer samples. Plasma samples were collected from healthy volunteers (n¼5), and patients with inﬂam-matory conditions (n¼5) or cancer (n¼5). IP was performed using anti-CTCF coatedmagnetic beads and immunoprecipitated cfDNA was extracted, ampliﬁed and sequenced on an Illumina platform. (ii) We developed speciﬁc qPCR assays for 10 CTCF-BS sequences that we observed to be preferentially bound in the plasma of cancer patients vs either inﬂammatory conditions or healthy subjects. The panel of qPCR assays was tested on CTCF associated cfDNA isolated from plasma samples (1ml)obtained from patients diagnosed with a variety of common solid cancer diseases(n¼48).

Results: We observed that speciﬁc CTCF IP resulted in isolation of cfDNA fragments with a frequency peak in the 30-80bp range that was not present in negative controls(mouse-IgG). These short cfDNA fragments included previously described CTCF binding sites. Moreover, CTCF binding sites were not randomly distributed on cfDNA fragments but located at the centre of each fragment. Among the CTCF occupied binding sites observed, we identiﬁed 29 sites that were signiﬁcantly differentially bound in cancer. We observed highly sensitive and speciﬁc qPCR test results for a number of common solid cancer diseases including high sensitivity at disease stage I and II.

Conclusions: This is the ﬁrst demonstration of IP of plasma CTCF-cfDNA. IP followed by multiplex PCR may form the basis of a rapid, low cost liquid biopsy method that obviates expensive library preparation and NGS.

Legal entity responsible for the study: Belgian Volition.

Disclosure: D. Pamart, J-V. Turatsinze, B. Cuvelier, J-V. Turatsinze: Financial Interests, Personal, Full or part-time Employment: Belgian Volition. M. Herzog: Financial Interests, Personal, Full or part-time Employment: Belgian Volition; Financial Interests, Personal, Stocks/Shares: VolitionRx. J. Micallef:Financial Interests, Personal, Ofﬁcer, Chief Scientiﬁc Ofﬁcer: VolitionRx Ltd; Financial Interests,Personal, Stocks/Shares: VolitionRx Ltd.

https://doi.org/10.1016/j.annonc.2023.09.2928

206PWAYFIND-R: A global, real-world database of patients (pts)with a solid tumour proﬁled with next-generation

sequencing (NGS)

J-Y. Blay1, A. Hackshaw2, C. Le Tourneau3, J. Geissler4, A. Ferro5, E. Schirgruber6,O. Skatkova7, R. Dienstmann8

1Medicine Department, Centre Léon Bérard, Lyon, France; 2Clinical Trials, Cancer Research UK & University College London Cancer Trials Centre, London, UK;3Department of Drug Development and Innovation (D3i), Institut Curie, Paris, France;4Patvocates Network, Patvocates GmbH, Riemerling (Hohenbrunn), Germany; 5RWD Oncology, PD Data Science, Roche Products Limited, Welwyn Garden City, UK; 6Global Product Development Medical Affairs, F. Hoffmann-La Roche Ltd, Basel, Switzerland;7Global Product Development Medical Affairs Operations, F. Hoffmann-La Roche AG -Switzerland, Basel, Switzerland; 8Oncoclínicas Precision Medicine, Oncoclínicas Group,Sao Paulo, Brazil

Background: WAYFIND-R is a global, multicentre, prospective pan-cancer registry collecting long-term data from pts diagnosed with a solid tumour proﬁled with NGS.

The goal is to advance precision medicine by providing high-quality real-world data(RWD) to researchers internationally.

Methods: WAYFIND-R data are electronically collected into a centralised database with standardised forms and high quality data management procedures. To ensure reliability/accuracy and a ﬁt-for-purpose data source, data are periodically evaluated.

Enrolment began in Sep 2020. Sites submit baseline pt, tumour, biomarker, NGS and molecular tumour board (MTB) decision making at enrolment, and treatment and outcome data at routine follow up.

Results: As of 31 Mar 2023, 855 pts had complete baseline data collection and cancerrelated information; 755 carried on to the next data collection, 119 had died and 18 had ended participation. Pts were enrolled at 61 sites across 23 countries, mostly at academic institutions/university hospitals. The median age was 65 years (range: 20e 93), 50% were female, 49% were retired and 62% had government insurance. WAYFIND-R had 109 cancer types and 160 subtypes (most common: adenocarcinoma [n ¼389]). The most commonly detected genes were TP53, KRAS, EGFR, BRAF and APC.

The most commonly screened non-NGS biomarkers were cytokeratin 7 (CK7/KRT7),PD-L1, CA19-9, CEA and Ki67. Table shows data for the most common cancer types in the registry.Many pts (n [ 341; 40%) had not been evaluated by an MTB. The most frequent MTB recommendation after NGS testing (n [213; 25%) was to start other treatment (chemotherapy: 63%; immunotherapy: 19%; targeted therapies: 18%).

Conclusions: The WAYFIND-R registry captures precision oncology data using a standardised approach globally. WAYFIND-R can enable further insights into clinical decision making, the timeliness of NGS testing and access to therapy.

Clinical trial identiﬁcation: NCT04529122, ﬁrst posted 27 August, 2020.

Editorial acknowledgement: Research support for third-party writing assistance for this abstract, furnished by Eleanor Porteous, MSc, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Legal entity responsible for the study: F. Hoffmann-La Roche Ltd.

Funding: F. Hoffmann-La Roche Ltd.

Disclosure: J. Blay: Financial Interests, Personal, Advisory Board: Bayer, Deciphera, GSK, Roche;Financial Interests, Personal, Invited Speaker: PharmaMar; Financial Interests, Institutional, Invited Speaker: MSD, MSD; Financial Interests, Personal, Other, member of the supervisory board: Innate pharma; Financial Interests, Institutional, Funding: MSD, BMS, Deciphera; Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, Bayer, GSK, Novartis, OSE pharma. A. Hackshaw:Financial Interests, Personal, Stocks/Shares: Illumina, Thermo Fisher; Financial Interests, Institutional, Research Grant: F. Hoffmann-La Roche Ltd., MSD Oncology, Takeda, BMS, Boehringer Ingelheim , Celgene; Financial Interests, Personal, Other, Honoraria: AbbVie, Boehringer Ingelheim,Takeda, AstraZeneca, Daiichi Sankyo, Merck Serono, Merck/MSD, USB, F. Hoffmann-La Roche Ltd;Financial Interests, Personal, Advisory Role: AbbVie, F. Hoffmann-La Roche Ltd, Grail, Inc.; NonFinancial Interests, Personal, Other, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd: F. Hoffmann-La Roche Ltd. C. Le Tourneau: Financial Interests, Personal,Advisory Board: BMS, MSD, Merck Serono, Nanobiotix, Roche, Rakuten, Seattle Genetics, GSK,Celgene, ALX Oncology, Exscientia. J. Geissler: Financial Interests, Institutional, Research Grant:Novartis, Incyte, Bristol Myers Squibb, Pﬁzer, Takeda; Financial Interests, Personal, Other, Travel:Amgen, Alnylam, BioMarin, Novartis, Pﬁzer, Roche, Servier, UCB; Non-Financial Interests, Personal,Advisory Role: Alnylam, Bayer, Boehringer Ingelheim, BioMarin, Daiichi Sankyo, Gilead, Janssen,Novartis, Pﬁzer, Roche, Servier, Sanoﬁ, Sobi, UCB; Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd: F. Hoffmann-La Roche Ltd. A. Ferro: Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd.;Financial Interests, Personal, Full or part-time Employment: Roche Products Limited; Non-Financial Interests, Personal, Other, Research funding: Support for third-party editing assistance from F.

Hoffmann-La Roche Ltd.: F. Hoffmann-La Roche Ltd. E. Schirgruber: Non-Financial Interests, Personal,

|Table:206P |Table:206P |Table:206P |Table:206P |Table:206P |Table:206P | |---|---|---|---|---|---|

||Lung (n [ 280) |Colon (n [ 92) |Pancreas (n [81) |Breast (n [ 54) |Ovarian (n [ 30) |

|Median age, years (range) |66 (38e90) |59 (24e88) |65 (34e88) |48 (25e81) |60 (28e78) |

|Female, n (%) |129 (46.1) |43 (46.7) |40 (49.4) |54 (100) |30 (100) |

|||||(CK7/KRT7) ||

|genes ||PIK3CA BRAF |TET2ATM |DNMT3A ERBB2 ||

|Table: 207P Demographics and efﬁcacy outcomes |Table: 207P Demographics and efﬁcacy outcomes |Table: 207P Demographics and efﬁcacy outcomes | |---|---|---|

||CDK4 (N[16) |CDK6 (N[15) |

|Median (Med) age, years (range) |61 (32-77) |64 (45-74) |

|Female, No. (%) |9 (56) |9 (60) |

|ECOG PS, No. (%) |ECOG PS, No. (%) |ECOG PS, No. (%) |

|0-1 |13 (81) |13 (81) |

|2 |3 (19) |3 (19) |

|Prior systemic regimens, No. (%) |Prior systemic regimens, No. (%) |Prior systemic regimens, No. (%) |

|0 |0 |1 (6) |

|1-2 |1-2 |4 (25) |

|3 |3 |11 (69) |

|DC rate, % (OR or SD16+)(1-sided 90% CI)|DC rate, % (OR or SD16+)(1-sided 90% CI)|13 (3, 100) |

|OR rate, % (95% CI) |OR rate, % (95% CI) |0 (0,21) |

|Med PFS, wks (95% CI) |Med PFS, wks (95% CI) |8 (8, 12) |

|Med OS, wks (95% CI) |Med OS, wks (95% CI) |36 (11, 71) |

|Tumor type |Tumor type ||

|Adrenal |Adrenal |1 |

|Biliary tract |Biliary tract |2 |

|Chordoma |Chordoma |1 |

|Colorectal |Colorectal |– |

|Esophagus |Esophagus |1 |

|Non-small cell lung |Non-small cell lung |4 |

|Ovarian |Ovarian |1 |

|Pancreatic |Pancreatic |1 |

|Prostate |Prostate |2 |

|Small intestine |Small intestine |– |

|Uterine |Uterine |3 |

Other, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.:F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Full or part-time Employment: F. HoffmannLa Roche Ltd.; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd. O. Skatkova:Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Full or part-time Employment: F.

Hoffmann-La Roche Ltd. R. Dienstmann: Financial Interests, Personal, Invited Speaker: Amgen,AstraZeneca, Boehringer Ingelheim, Ipsen, Libbs, Lilly, Merck Sharp & Dohme, Roche, Sanoﬁ, Servier,GSK, Takeda, Janssen, Foundation Medicine; Financial Interests, Personal, Advisory Board: Bayer,Roche; Financial Interests, Personal, Full or part-time Employment, Oncoclínicas is a private healthcare provider in Brazil. I work part time as Medical Director of the Precision Medicine and Big Data Initiative. We develop molecular tests (pathology and genomics) that are offered to patients treated in the organisation as part of support programs sponsored by pharmaceutical companies and I coordinate research activities with real-world clinico-genomics cohorts.: Oncoclínicas; Financial Interests, Personal, Stocks/Shares: Trialing; Financial Interests, Personal, Research Grant: Merck.

https://doi.org/10.1016/j.annonc.2023.09.2929

207P

Palbociclib (P) in patients (pts) with solid tumors with CDK4 or CDK6 ampliﬁcation (amp): Results from the Targeted Agent and Proﬁling Utilization Registry (TAPUR) study

M.F. Khalil1, M. Rothe2, P.K. Mangat2, E. Garrett-Mayer3, K.F. Mileham4, E.R. Ahn5,H.L. Duvivier6, L.C. Farrington7, M. Akce8, D. Behl9, P.J. Gold10, V.K. Chiu11,

N. Vijayvergia12, C. Calfa13, A. Gaba14, F. Meric-Bernstam15, S.M. Schuetze16,

A. Gregory2, S. Halabi17, R.L. Schilsky2

1Hematology Oncology, Lehigh Valley Hospital-Cedar Crest - Cancer Institute, Allentown, MA, USA; 2CENTRA - Tapur Study, American Society of Clinical Oncology (ASCO),Alexandria, VA, USA; 3Center for Research and Analytics, American Society of Clinical Oncology (ASCO), Alexandria, USA; 4Thoracic-Pulmonary, Levine Cancer Institute -Morehead, Charlotte, NC, USA; 5Medical Oncology, Cancer Treatment Centers of America-Chicago, part of the City of Hope, Zion, IL, USA; 6Oncology Department,Cancer Treatment Centers of America - Atlanta, part of City of Hope, Newnan, GA,USA; 7Oncology, Cancer Treatment Centers of America e Chicago, part of City of Hope,Chicago, IL, USA; 8Internal Medicine, Hematology and Oncology, The University of Alabama at Birmingham, Birmingham, AL, USA; 9Med onc, Sutter Institute for Medical Research, Sacramento, CA, USA; 10Medical Oncology, Swedish Cancer Institute -Medical Oncology - First Hill, Seattle, WA, USA; 11Internal Medicine (Med Onc), The Angeles Clinic and Research Institute, A Cedars-Sinai Afﬁliate, Los Angeles, CA, USA;12Hematology/Oncology, Fox Chase Cancer Center - Main Campus, Philadelphia, PA,USA; 13Oncology, University of Miami Sylvester Comprehensive Cancer Center/Hollywood, Hollywood, FL, USA; 14Medical Oncology and Hematology, Roger Maris Cancer Center Sanford Health, Fargo, ND, USA; 15Investigational Cancer Therapeutics Department, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;16Internal Medicine, University Hospital - Michigan Medicine, Ann Arbor, MI, USA;17Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA

Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with speciﬁc genomic alterations. Results from 2 cohorts of pts with solid tumors with CDK4 or CDK6 amp treated with P are reported.

Methods: Eligible pts had measurable disease, ECOG performance status (PS) 0-2,adequate organ function and no standard treatment (tx) options. Genomic testing was performed in CLIA-certiﬁed, CAP-accredited labs. Amp cut-offs were deﬁned per NGS providers. Recommended dosing was 125 mg P orally once daily for 21 days on followed by 7 days off, until disease progression. Low accruing histology-speciﬁc cohorts with CDK4 or CDK6 amp were collapsed into 2 histology-pooled cohorts for analysis. Primary endpoint was disease control (DC) deﬁned as investigator assessment of complete or partial response (PR) or stable disease (SD) of at least 16+ weeks(wks) duration (SD16+) per RECIST v1.1. The hypothesized null DC rate of 15% was evaluated by a 1-sided exact binomial test (a¼ 0.10; power 65% and 58%, respec-tively). Secondary endpoints were progression-free survival (PFS), overall survival(OS), objective response (OR), duration of response (DOR) and SD, and safety.

Results: Pts with solid tumors with CDK4 amp (N¼16) or CDK6 amp (N¼15) wereenrolled. 1 pt from each cohort was not evaluable for efﬁcacy. Table shows demographics and outcomes. For the CDK4 cohort, 2 pts had SD16+ for a DC rate of 13%(p¼0.72); the null DC rate was not rejected. Of pts with SD16+, duration of SD was 28(ovarian) and 52 (adrenal) wks. For the CDK6 cohort, 1 pt had a PR (pancreatic, DOR ¼8 wks) for a DC rate of 7% (p¼0.897) and OR rate of 7%; the null DC rate was notrejected. 6/31 pts had 1 tx-related grade 3-4 adverse or serious adverse event rejected. 6/31 pts had ≥1 tx-related grade 3-4 adverse or serious adverse event ofofneutropenia or thrombocytopenia.

Conclusions: P did not show antitumor activity in heavily pretreated pts with advanced solid tumors with CDK4 or CDK6 amp.

S265

Clinical trial identiﬁcation: NCT02693535 Study launched 14 March, 2016.

Legal entity responsible for the study: American Society of Clinical Oncology, Inc.

(ASCO).

Funding: AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly and Company, Genentech, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.,Rahway, NJ, USA, Pﬁzer, Seagen and Taiho Oncology.

Conclusions: Tumor histology, mutated genes, and a better adjusted TMB cutoff(5.095 mut/Mb) are important for predicting ICI treatment outcomes in TMB-low patients. Among RCC patients, VHL mutations predict better OS. Individualized proﬁling is needed for a tailored ICI treatment strategy.

https://doi.org/10.1016/j.annonc.2023.09.2938

216P PTCH1 mutation as a potential predictor of immune checkpoint inhibitors in gastrointestinal cancer

Y. Tang1, Q. Zhang2, Y. Qi2, D. Chen2

1Department of Surgical Oncology, The Second Aﬂiated Hospital Zhejiang University School of Medicine, Hangzhou, China; 2The State Key Lab of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing,China

Methods: We screened the following 3 cohorts: (1) MSKCC cohort (N¼236) of GC(including esophageal, gastric and colorectal cancers) who received ICIs. (2) Peking University Cancer Hospital (PUCH) GC cohort (N¼92) who received ICIs. (3) the TCGAcohort (N¼914) of GC. The patients were divided into PTCH1 mutant type (PTCH1-MT) group and PTCH1 wild type (PTCH1-WT) group. We analyzed the differences in overall survival (OS) and TMB between the two groups. Tumor immune microenvironment (TIME) was evaluated by calculating the cell inﬁltration score as the arithmetic mean analysis of the constituent genes.

Methods: Next-generation sequencing of 551-gene proﬁling was performed to analyze postoperative tissues from 22312 Chinese solid tumors in 2019-2022. Somatic mutations and copy number variations were detected following the standard operating procedure.

Results: PTCH1 mutations were present in 3.1% of patients with advanced solid tumors, a total of 791 PTCH1 somatic mutations were detected in 684 tumor samples.

The higher frequency cancer type contained lung cancer(n¼239), colorectal can-cer(n¼137), and stomach cancer(n¼60). Of 791 PTCH1 mutations, missense muta-tions(65%,n¼514) were more observed, and 25% were loss of function (LOF)mutations, including frameshift(n¼124), nonsense(n¼50), splicing(n¼23) mutations.Exon 23, exon1 and exon22 of PTCH1 were the main mutational hotspot regions found, with p.S1203Afs*52 (n¼26), p.R1308Efs*64 (n¼22), p.R602* (n¼11),p.Y1316Tfs*56 (n¼11) being the most frequent mutations in our study. There was asigniﬁcant statistical difference in TMB values that the PTCH1 mutant group was higher than the PTCH1 wild-type group (39 vs. 5, p < 0.001), and patients who presented with two or more PTCH1 mutations with higher compared with those patients carried only a single mutation (129 vs. 29, p < 0.001). TMB in PTCH1 frameshift_variant tumors (53, 0e672) was signiﬁcantly higher than TMB in PTCH1 splice

variant tumors (15, 0e60; P< 0.05). The proportion of PTCH1 alterations in MSI-H tumors was higher than those without mutations (22% vs. 1%, p < 0.001).

Conclusions: In our study, PTCH1 mutations are present in 3.1% of solid tumors, and mostly occurred in exon 23, exon1, and exon22. PTCH1 mutant tumors tended to be associated with higher TMB values (39 vs. 5), therefore, Hh pathway inhibitor combined immunotherapy may be considered in the future.

https://doi.org/10.1016/j.annonc.2023.09.2940

218P

Funding: This work was supported by the National Research Foundation of Korea[NRF] grants funded by the Korean government [MSIT] [NRF-2023R1A2C2004339 to HJC, NRF-2023R1A2C2006375 to CK].

Disclosure: C. Kim: Financial Interests, Personal, Advisory Board: Roche, ONO, MSD, BMS, Oncocross, Virocure. H. Chon: Financial Interests, Personal, Advisory Board: Eisai, Roche, Bayer, ONO,MSD, BMS, Celgene, Sanoﬁ, Servier, AstraZeneca, Sillajen, Menarini, GreenCross Cell. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2941

219P Multicentric evaluation of amplicon-based next-generation sequencing solution for local comprehensive molecular tumor proﬁling

E. Jantus Lewintre1, A. Rappa2, D. Ruano3, S. Gallach Garcia4, C.J.C. Camps Herrero5,L. Lacroix6, K. Kashofer7, T. van Wezel3, M. Barberis1

1Biotechnology, Universitat Politècnica de València, Valencia, Spain; 2Pathology, IEO -Istituto Europeo di Oncologia IRCCS, Milan, Italy; 3LUMC-Leiden University Medical Center, Leiden, Netherlands; 4Molecular Oncology Department, FIHGUV - Fundación de Investigación Hospital General Universitario de Valencia, Valencia, Spain;5Oncology, Hospital General Universitario Valencia, Valencia, Spain; 6Institute Gustave Roussy, Villejuif, France; 7Medical University of Graz, Graz, Austria

Background: Molecular proﬁling of tumors is an essential step in the management of cancer patients, enabling personalized treatment decisions. Oncomine Comprehensive Assay Plus (OCA+) is an amplicon-based next-generation sequencing solution that can detect multiple biomarkers, including complex biomarkers, in a single assay. Here,

we aimed to evaluate the sensitivity, speciﬁcity, and concordance of this comprehensive genomic proﬁling solution in detecting various types of biomarkers in a multicentric study using a cohort of 190 pre-characterized clinical tumor samples.

Results: OCA+ demonstrated a total success rate of 97.2%. High sensitivity and speciﬁcity were obtained in detecting multiple biomarkers, including complex biomarkers. The assay detected >95% of SNVs and indels with a variant allele frequency(VAF) (VAF) of ≥5%, and identified gene fusions, TMB, MSI and GIN with high concordanceof 5%, and identiﬁed gene fusions, TMB, MSI and GIN with high concordanceto orthogonal methods, 90%, 70%, 84% and 93% respectively.

Conclusions: OCA+ is a sensitive and speciﬁc platform for molecular tumor proﬁling,including the detection of complex biomarkers. The high concordance rate with orthogonal methods highlights the assay’s potential in guiding clinical decision-making for personalized cancer care. OCA+ may provide comprehensive genomic information for cancer management and may be a valuable tool for further implementing precision medicine in oncology.

Legal entity responsible for the study: Thermo Fisher.

Funding: Thermo Fisher.

https://doi.org/10.1016/j.annonc.2023.09.2942

220P Biomarker of blood age and inﬂammation in older cancer patients might predict outcome

M.H.F. Vetter1, C. Ewald2, E. Burri3, R. Rosenberg4, S. Subotic5, S. Mitrovic6,E.D. Chiru7, M. Knuﬁnke7

1Medical Oncology Hematology and Immunotherapy, KSBL - Kantonsspital Baselland Liestal, Liestal, Switzerland; 2Molecular Science, ETH Zurich - Inst. f. Molecular Health Sciences, Zurich, Switzerland; 3Gastroenterology, KSBL - Kantonsspital Baselland Liestal, Liestal, Switzerland; 4Surgical Oncology, Cancer Center, KSBL - Kantonsspital Baselland Liestal, Liestal, Switzerland; 5Urology, KSBL - Kantonsspital Baselland Liestal,Liestal, Switzerland; 6Lab Medicine, KSBL - Kantonsspital Baselland Liestal, Liestal,Switzerland; 7Oncology, KSBL - Kantonsspital Baselland Liestal, Liestal, Switzerland

Background: Two-thirds of all cancers are diagnosed in patients above the age of 65 years, often associated with worse outcomes. The aim of this cohort study was to identify the predictive value of blood markers of inﬂammation, cell activity, and aging in older patients with solid malignant tumors.

Methods: Patients diagnosed with solid tumors were included at the Cancer Center Baselland, ,Switzerland. We investigated the predictive value on overall survival of blood markers sampled by clinical routine, including CRP (C-reactive protein), NLR(Neutrophil-to-lymphocyte ratio), LDH (Lactate dehydrogenase), Albumin, and Vitamin B12 (Cobalamin). The study analyzed the median value of each blood marker in all patients diagnosed after January 1, 2018, and calculated the survival curves and hazard ratios.

Results: From Jan 2018 to Feb 2022, a total of 510 patients were included with a median age at diagnosis of 72 years (57-91 years). Among these patients, 246 had localized disease, and 262 had advanced disease at primary diagnosis. The diagnoses included NSCLC (n¼158, 31%), CRC (n¼98, 19%), breast cancer (n¼58, 11%), prostatecancer (n¼82, 16%), pancreas cancer (n¼42, 8%), urothelial cancer (n¼42, 8%) andSCLC (n¼30, 6%). Patients with abnormal median blood values had a signiﬁcantlyincreased risk of poor outcomes. NLR>4 (p<0.001, HR¼2.37), CRP >5mg/l (p¼0.021,HR¼1.6), CRP>10mg/l (p<0.001, HR¼4.0-6.6), Albumin<35g/l (p<0.001, HR¼3.05),LDH>250U/l (p<0.001. HR¼2.24), and Vitamin B12>810pmol/l (p<0.002, HR¼2.96)were associated with increased hazard ratios.

Conclusions: Older cancer patients with abnormal inﬂammation and aging markers had worse outcomes. This highlights the potential role of these blood markers in predicting outcomes in cancer patients with solid tumors. It is important to note that these blood markers are not cancer-speciﬁc, and their levels can be affected by other factors, such as infection, inﬂammation, and nutritional status. However, when used in conjunction with other clinical and pathological factors, they may provide additional information for risk stratiﬁcation and treatment planning. Overall, our study adds to the growing body of evidence on the potential role of blood biomarkers in predicting outcomes in cancer patients.

https://doi.org/10.1016/j.annonc.2023.09.2943

S269

221P

Methods: This study prospectively enrolled 106 patients with unresectable HCC treated with Ate/Bev (discovery cohort: 50 patients from one center; validation cohort: 56 patients) as the ﬁrst-line systemic treatment in three tertiary cancer centers in Korea. Baseline blood samples were analyzed using multiplex ﬂow cytometry.

Results: The optimal cut-off value for baseline peripheral T-cell activation phenotype(IFN-g+TNF-a+), 2.50%, was determined using maximally selected rank statistics. In the discovery cohort, the patients with high-peripheral T-cell activation phenotype at baseline had an increased objective response rate (ORR) than those with low activation levels (15.4% vs. 35.1%). Moreover, progression-free survival (PFS) and overall survival (OS) were signiﬁcantly longer in patients with high-peripheral T-cell activation phenotype than those with low levels (hazard ratio [HR], 0.37; 95% CI, 0.18e0.79; P¼0.008 for PFS; HR, 0.18; 95% CI, 0.07e0.41; P < 0.001 for OS). In the validation cohort, these ﬁndings were consistently observed. The patients with high-peripheral T cell activation phenotype at baseline were associated with a higher ORR (15.0% vs.

38.9%) and longer PFS (HR, 0.43; 95% CI, 0.22e0.85; P ¼ 0.012) and OS (HR, 0.41;95% CI, 0.18e0.96; P ¼ 0.035) compared with those with low activation levels.

Conclusions: Highly activated peripheral T-cell phenotype was associated with favorable clinical beneﬁt in patients with unresectable HCC treated with Ate/Bev.

Therefore, peripheral T-cell activation phenotypes could be used as a potential predictor of Ate/Bev treatment.

https://doi.org/10.1016/j.annonc.2023.09.2944

222P Therapeutic opportunities for porcupine inhibition in gastrointestinal cancer

N. Cook1, S. Wu2, C. Maksymiuk2, C. Phillips3, J. Robertson4, S.A. Woodcock3

1Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester,Cambridgeshire, UK; 2Clinical and Translational Research, Caris Life Sciences - Headquarters, Irving, TX, USA; 3Redx Oncology, Redx Pharma Plc, Macclesﬁeld, UK; 4Clinical Development Department, Redx Pharma Plc, Macclesﬁeld, UK

Background: Gastrointestinal (GI) cancer (Upper/Lower GI and Hepatobiliary) causes more cancer deaths than any other body system. Wnt pathway activation promotes common GI cancers, but safely targeting this pathway is challenging. Inhibition of Porcupine, an enzyme essential for Wnt ligand activity, has clinical potential to suppress Wnt in a safe and tolerated manner. Preclinically, GI tumors with upstream Wnt pathway variants (RNF43 loss of function (LoF), RSPO gain of function (GoF)) are Wnt ligand dependent and exquisitely sensitive to RXC004, a small molecule Porcupine inhibitor. Using Caris data, 278,649 human tumor samples (across all 58 solid tumor lineages) were analysed for the prevalence of upstream Wnt pathway variants and associated features.

Methods: Human tumors were analysed by next-generation sequencing of DNA (592 genes, NextSeq; WES, NovaSeq) and RNA (WTS, NovaSeq) by Caris. Molecular proﬁles and prevalence of RNF43_LoF and RSPO2/3_GoF cases were compared with negative(WT) cases using Fisher-Exact analysis. Real world overall survival was obtained from insurance claims data and Kaplan-Meier estimates were calculated for deﬁned cohorts from time of tissue collection to last contact.

Results: Prevalence of RNF43_LoF, RSPO2_GoF and RSPO3_GoF were 1.3%, 0.1% and

0.3% in all lineages; increasing to 3.6%, 0.2% and 0.9% in GI lineages. The top lineages by combined Wnt ligand dependent prevalence were GI: Small Bowel (9.6%), Colorectal (CRC; 5.9%), Pancreatic (5.4%) and Gastric (4.3%) cancers. Of 15,025 CRC cases,13,886 (92%) were Microsatellite stable (MSS). Within MSS CRC cases, prevalence of RNF43_LoF was 2.6% and RSPO2/3_GoF was 1.6%; hence total prevalence was 4.2%.

BRAF_V600E had high co-occurrence with Wnt ligand dependent (42%), compared to WT (3.4%), MSS CRC cases. In MSS CRC, upstream Wnt pathway variants were

associated with poor prognosis in either all cases (HR 1.64; p<0.0001) or BRAF_WT cases (HR 1.52; p<0.0001) versus WT cases.

Conclusions: Upstream Wnt pathway variants are enriched in GI cancer, in particular Small Bowel cancer, a rare subtype of high unmet need. In MSS CRC cancer, the poor prognosis and high BRAF_V600E co-occurrence with upstream Wnt pathway variants suggests beneﬁt of co-targeting Wnt and MAPK pathways in this population.

Background: The backbone chemotherapy of ﬁrst-line standard of care (SOC) for microsatellite stable (MSS) metastatic colorectal cancer (mCRC) combines 5-Fluorouracil to oxaliplatin and/or irinotecan. There are no biomarkers to predict response,which is complete or long-lasting (CR/LLR) in w25% of patients, while w15% are primary refractory. Our study aims at developing an accurate response predictor via a pathomics model based on Hematoxylin & Eosin (H&E)-stained digital slides (WSI).

Methods: We trained an unsupervised bag-of-words artiﬁcial intelligence (AI)-based model on 62 patients classiﬁed as response outliers as follow: i) super-sensitive if they achieved CR or LLR >10 months to any SOC (N¼20); ii) refractory if progressionoccurred at ﬁrst disease reassessment (N¼42). WSIs of the resected primary tumorswere tiled into patches of 224x224 pixel (0.5mm/pixel). First-order and texture features were subsequently extracted from all tumoral tiles, and grouped into homogenous clusters through a 3x3 self-organized map. For each patient, the percentage of tiles belonging to each tiles’ cluster was computed and used by a dendrogram to create clusters of similar patients. Patients’ survival was calculated by landmark analysis logrank test. Main clinicopathological features were matched to treatment response by Fisher’s exact test.

N. Saoudi Gonzalez: Financial Interests, Other, Travel expenses: Amgen, Merck; Financial Interests,Speaker, Consultant, Advisor: Amgen. C. Marchiò: Financial Interests, Advisory Board: Bayer, Roche,AstraZeneca, Daiichi Sankyo. S. Siena: Financial Interests, Personal, Advisory Board, Advisory Board Member: Agenus, AstraZeneca, BMS, Checkmab, Daiichi Sankyo, GSK, Novartis, Seagen, T-OneTherapeutics. A. Bardelli: Financial Interests, Speaker, Consultant, Advisor: Illumina, Inivata, Guardant Health; Financial Interests, Stocks/Shares: NeoPhore; Financial Interests, Research Grant:NeoPhore, AstraZeneca, Inivata; Financial Interests, Advisory Board: Neophore, Inivata, Roche Genentech. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2946

224P

Germline HLA-I/II is not associated with clinical outcome but the absence of HLA-A01 or the presence of HLA-B27

supertypes were correlated with improved clinical outcome among patients with NSCLC treated with pembrolizumab in combination with chemotherapy

A. Abed1, A. Reid2, M. Millward3, E.S. Gray4

1Centre for Precision Health, Edith Cowan University, Joondalup, WA, Australia;2Centre for Precision Health, Edith Cowan University, Perth, WA, Australia; 3School of Medicine, University of Western Australia, Perth, WA, Australia; 4School of Medical and Health Sciences, Edith Cowan University, Perth, WA, Australia

Background: Maximal heterozygosity on the human leukocyte antigen (HLA) loci was found to be associated with improved survival among NSCLC patients treated with immune checkpoint inhibitors (ICI). Here we aimed to investigate the effect of germline HLA-I/-II zygosity on clinical outcomes among NSCLC patients treated withﬁrst-line pembrolizumab in combination with chemotherapy. We explored the correlation between different HLA-A/-B supertypes and clinical outcome among the same cohort.

Background: The association between genetic alterations and beneﬁt of immunotherapy is well documented, but evidence for gastrointestinal cancer (GC) remains limited. Patched1 (PTCH1) mutation, a frequently altered gene in GC, lead to dysregulation of Hedgehog signaling. However, the efﬁcacy of PTCH1 mutations in immunotherapy in patients with GC remains unclear. Herein, we aimed to analyze the association between PTCH1 mutations and immune checkpoint inhibitors (ICIs) efﬁcacy in patients with GC.

Results: In MSKCC cohort, PTCH1-MT group (9.3%) had signiﬁcantly better OS(p¼0.017, median OS, 34m vs. 13m) and higher TMB (p<0.01). The results of themultivariate analysis showed that PTCH1 had a signiﬁcant effect on OS, with the PTCH1-MT group had better OS (p¼0.035; HR¼0.37; 95%CI: 0.15-0.93). Furthermore,we consistently observed in the PUCH cohort that the PTCH1-MT group (7.6%)signiﬁcantly prolonged OS (p¼0.036). Additionally, in the TCGA cohort, we similarlyobserved a trend towards longer OS (p¼0.63, mOS, 70.2m vs. 61.8m) and higher TMB(p<0.01) in PTCH1-MT group (5.8%). It shows that PTCH1 is a predictor, but not a prognostic factor. Subsequently, we assessed the abundance of 22 predeﬁned immune cells. The score of CD4 T cells, CD8 T cells, NK cells, mast cells, and M1 cells were all signiﬁcantly higher in the PTCH1-MT group (p<0.05). It shows that the PTCH1-MT group has a higher activation TIME.

Conclusions: Our study demonstrated that PTCH1 mutation could act as a potential predictor for ICIs therapy in GC. In the future, relevant prospective clinical trials need to be designed to verify this conclusion.

https://doi.org/10.1016/j.annonc.2023.09.2939

217P Clinical and molecular features of PTCH1 mutant in solid tumors

X. Li1, T. Han2, D. Guo2, R. Kong2, S. Chen3, R. Ding2, W. Deng3, F. Bu2

1Center for Integrative and Translational Medicine, Shandong Public Health Clinical Center, Jinan, China; 2The Medical Department, Jiangsu Simcere Diagnostics Co., Ltd.,Nanjing, China; 3Bioinformatics Department, Jiangsu Simcere Diagnostics Co., Ltd.,Nanjing, China

Background: PTCH1, a tumor suppressor and inhibitor of the hedgehog pathway. Hh signaling was reported to modulate the tumor microenvironment by increasing immune checkpoint expression and promoting an inﬂammatory environment. Mutations of PTCH1 are potential therapeutic targets, Hh pathway inhibitor has been developed as a treatment for patients with advanced solid tumors. It is thus important to understand the genomic landscape of PTCH1 mutation. Here, we explored PTCH1 mutation proﬁles in Chinese solid tumors.

Peripheral T cell activation phenotype is associated with clinical outcomes and immune-related adverse events of ipilimumab-nivolumab in advanced hepatocellular

carcinoma

W.S. Lee1, H. Yang1, S.J. Lee1, S.J. Kong1, B. Kang1, I. Kim2, H. Kim3, C. Kim1, H. Chon1

1Medical Oncology, CHA Bundang Medical Center, Seongnam, Republic of Korea;2Internal Medicine, Inje University Haeundae Paik Hospital, Busan, Republic of Kora;3Internal Medicine, Ulsan University Hospital, Ulsan, Republic of Korea

Background: Although combination immunotherapies have become a mainstay of treatment for patients with advanced hepatocellular carcinoma (HCC), studies of circulating biomarkers for immunotherapy in HCC are still limited. Therefore, we aimed to evaluate the peripheral T-cell activation phenotype as a biomarker for clinical outcomes of immunotherapies for HCC.

Methods: Baseline blood samples from 86 patients with advanced HCC in three tertiary cancer centers in Korea (ipilimumab-nivolumab [Ipi/Nivo], n¼55; nivolumab[Nivo], n¼31) were prospectively collected and analyzed.

Results: In the discovery cohort of the Ipi/Nivo group, the peripheral T-cell activation phenotype (IFN-g+TNF-a+) at baseline was signiﬁcantly higher in patients with partial response or stable disease compared with those with progressive disease. The cut-off value for high-peripheral T-cell activation phenotype was set to 5.55% using maximally selected rank statistics for optimally predicting survival outcomes. In both the discovery and validation cohorts, the patients with high-peripheral T-cell activation phenotypes showed an increased ORR and more favorable PFS (discovery cohort:hazard ratio [HR], 0.35; 95% CI, 0.16e0.74; P ¼ 0.004; validation cohort: HR, 0.22;95% CI, 0.04e1.11; P¼ 0.046) and OS (discovery cohort: HR, 0.44; 95% CI, 0.20e0.99;P ¼ 0.042; validation cohort: HR, 0.20; 95% CI, 0.04e1.02; P ¼ 0.036) than those withlow levels. These results were consistent in the Nivo cohort. Regarding immunerelated adverse events (irAEs), patients with high-peripheral T-cell activation phenotype showed higher incidence of irAEs compared with those with low levels(14.3% vs. 37.0%). Of note, comparing baseline peripheral blood cytokine levels according to irAEs, the patients with irAEs had signiﬁcantly lower serum levels of IL-6 at baseline.

Conclusions: Baseline peripheral T-cell activation phenotype was a predictor of clinical outcomes and irAEs in patients with advanced HCC receiving Ipi/Nivo immunotherapy. Patients with lower serum IL-6 levels at baseline might experience more frequent irAEs during Ipi/Nivo treatment in advanced HCC.

Methods: DNA and/or RNA were obtained from formalin-ﬁxed parafﬁn-embedded(FFPE) tumor samples from patients with different cancer types from 5 different centers. Samples studied addressed the complete variety of genomic alterations targeted by the Oncomine Comprehensive Assay Plus. OCA+ was used to generate libraries that were sequenced using the Ion S5 Prime system and analyzed using Ion Reporter Oncomine Comprehensive Plus - w3.0 workﬂow. Single nucleotide variants(SNVs), insertions/deletions (indels), copy number alterations (CNAs), gene fusions,tumor mutation burden (TMB), microsatellite instability (MSI) and Genomic instability(GIN related to HRD) results were compared to orthogonal and gold standard methods.

Peripheral T cell activation phenotype predicts clinical outcomes of atezolizumab-bevacizumab therapy in unresectable hepatocellular carcinoma

C. Kim1,W.S. Lee1, H. Yang1, S.J. Lee1, S.J. Kong1, B. Kang1, I. Kim2, H. Kim3, H. Chon1

1Medical Oncology, CHA Bundang Medical Center, Seongnam, Republic of Korea;2Internal Medicine, Inje University Haeundae Paik Hospital, Busan, Republic of Korea;3Internal Medicine, Ulsan University Hospital, Ulsan, Republic of Korea

Background: Atezolizumab plus bevacizumab (Ate/Bev) has demonstrated superior efﬁcacy to sorafenib, thereby becoming the new standard ﬁrst-line treatment in patients with unresectable hepatocellular carcinoma (HCC). However, there is a lack of reliable biomarkers that could predict clinical outcomes of Ate/Bev. In this study, we aimed to assess the clinical and immunological implications of peripheral T-cell activation phenotype as a biomarker in patients with HCC treated with Ate/Bev.

Legal entity responsible for the study: Redx Pharma PLC.

Funding: Redx Pharma PLC.

Disclosure: N. Cook: Financial Interests, Institutional, Invited Speaker: Roche; Financial Interests,Institutional, Local PI: Taiho, Roche, AstraZeneca, Avacta, Bayer, Eisai, UCB, Boeringher, Stemline,Ergomed; Financial Interests, Institutional, Coordinating PI: RedX, Orion, Starpharma; Non-Financial Interests, Advisory Role: Roche. S. Wu: Financial Interests, Personal, Full or part-time Employment:Caris Life Sciences. C. Maksymiuk: Financial Interests, Personal, Full or part-time Employment: Caris Life Sciences. C. Phillips, J. Robertson, S.A. Woodcock: Financial Interests, Personal, Full or part-time Employment: Redx Pharma PLC.

https://doi.org/10.1016/j.annonc.2023.09.2945

223P Artiﬁcial intelligence-based pathomics biomarker predict primary resistance to ﬁrst-line treatment in metastatic colorectal cancers

G. Mauri1, V. Giannini2, G. Nicoletti2, L. Lazzari3, A. Sartore Bianchi4, F. Marmorino5,G. Randon6, M. Nieva Munoz7, N. Saoudi Gonzalez8, A. Puccini9, E. Berrino10,C. Marchiò11, M. Di Como12, M.C. Aquilano12, S. Arena13, V. Torri14, S. Siena15,A. Bardelli16, D. Regge17, S. Marsoni3

1Oncology and Hemato-Oncology, IFOM ETS - The AIRC Institute of Molecular Oncology; Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, and Department of Hematology Oncology, and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, Milan, Italy; 2Surgical Sciences, University of Turin,Turin, Italy; 3Clinical Trial Unit, IFOM ETS - The AIRC Institute of Molecular Oncology,Milan, Italy; 4Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan,Italy; 5Dipartimento di Oncologia Medica, Università Degli Studi Di Pisa - Facoltà di Medicina e Chirurgia, Pisa, Italy; 6Dipartimento di Oncologia Medica, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy; 7Medical Oncology Department,Hospital del Mar - Parc de Salut Mar, Barcelona, Spain; 8Oncology Dept., Vall d’Hebron University Hospital, Barcelona, Spain; 9Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, Genoa, Italy; 10Pathology Unit, Candiolo Cancer Institute,FPO-IRCCS, Candiolo, Italy; 11Department of Medical Sciences, IRCCS - Istituto di Candiolo - FPO, Candiolo, Italy; 12Hematology Oncology, and Molecular Medicine,ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; 13Oncologia, Università degli Studi di Torino - Dipartimento di Oncologia - IRCCS Candiolo, Candiolo, Italy;14Oncology, Istituto Di Ricerche Farmacologiche Mario Negri - IRCCS, Milan, Italy;15Hemato-Oncology Dept., UNIMI - Università degli Studi di Milano Statale, Milan,Italy; 16Department of Oncology, University of Turin, Turin, Italy; 17Radiology Unit,IRCCS - Istituto di Candiolo - FPO, Candiolo, Italy

Results: Primary resistant patients had signiﬁcantly worse survival [logrank HR 4.2 95% CI (2.7-7.3)]. While outliers showed similar clinicopathological features (including stage, RAS/BRAF status, histotype and sidedness), pathomics signatures were significantly associated to primary resistance (p¼.005). According to the unsupervisedclustering, we classiﬁed as resistant patients belonging to four out of eight clusters obtaining an 88% (23/26) negative predictive value. We observed that patients classiﬁed as belonging to one of the four resistant clusters were predominantly characterized by a speciﬁc pattern of patches.

Conclusions: We demonstrated that a pathomics signature has the potential to predict resistance to SOC in MSS mCRC. Validation of these preliminary ﬁndings on a further cohort of 125 patients is ongoing.

Legal entity responsible for the study: IFOM ETS - The AIRC Institute of Molecular Oncology, Milan, Italy.

Funding: Fondazione AIRC under 5 per Mille 2018 - ID. 21091 program. Fondazione Oncologia Niguarda ONLUS.

Disclosure: G. Mauri: Financial Interests, Other, Honoraria: COR2ED. A. Sartore Bianchi: Financial Interests, Advisory Board: Amgen, Bayer, Novartis, Sanoﬁ, Servier. M. Nieva Munoz: Financial Interests, Other, Travel support: Merck; Financial Interests, Invited Speaker, Speaker honoraria: Merck.

Trial design: HAMLET.trans is a translational biosampling study of patients undergoing radical radiotherapy for NSCLC, H&N cancer or prostate cancer. Venous samples for ctDNA analysis and senescence-related proﬁling are collected together with dried blood spot samples before chemotherapy and radiotherapy at multiple time points during radiotherapy and post-treatment. Urine is collected from patients with prostate cancer. Patients are completing toxicity questionnaires during and after radiotherapy. Delivery dose per fraction is assessed based on imaging just before radiotherapy delivery. The trial aims to recruit at least 20 patients per arm. Patient samples are analysed for tumor-speciﬁc mutation, methylation proﬁling of cfDNA as well as cytokine assays to establish markers or response and toxicity and identify optimal sample timings for future studies. Blood spots are analysed for ctDNA tumour content to establish a less invasive way of frequent sampling on therapy. The results of HAMLET.trans will inform ongoing translational work.

Clinical trial identiﬁcation: NCT04060706.

Legal entity responsible for the study: Cambridge Cancer Trials Centre.

Funding: Cancer Research UK and the Medical Research Council UK.

https://doi.org/10.1016/j.annonc.2023.09.2958

236TiP Large-scale prospective observational study to develop a liquid-based detection system of minimal residual disease(MRD): LC-SCRUM-MRD

S. Kitagawa1, Y. Zenke1, K. Yoh1, J. Samejima2, K. Kunimasa3, S. Miyamoto4,

J. Sakakibara-Konishi5, R. Toyozawa6, M. Tachihara7, S. Niho8, K. Nosaki1, H. Izumi1,T. Sakai1, S. Umemura1, E. Sugiyama1, K. Murai1, S. Matsumoto1, M. Tsuboi1,

K. Goto1

1Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa,Japan; 2Department of Thoracic Surgery, National Cancer Center Hospital East,Kashiwa, Japan; 3Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan; 4Department of Medical Oncology, Japanese Red Cross Medical Center, Tokyo, Japan; 5Department of Respiratory Medicine, Faculty of Medicine Hokkaido University, Sapporo, Japan; 6Department of Thoracic Oncology,National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan; 7Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan; 8Pulmonary Medicine and Clinical Immunology Department, Dokkyo Medical University, Mibu, Japan

Background: MRD is a potential biomarker for predicting disease relapse or therapeutic response for lung cancer, and it is expected to establish a precise detection system by liquid biopsy. We have been conducting a prospective observational study to evaluate the clinical utility of MRD detection in lung cancer (LC-SCRUM-MRD) since August 2022, in parallel with a multicenter prospective genomic screening project in Japan (LC-SCRUM-Advantage).

Trial design: The main inclusion criteria are pathologically diagnosed treatment-naive lung cancer, 16 years of age or older, performance status 0-1, and normal organ function. A total of 10,680 patients in LC-SCRUM-Advantage/MRD will be enrolled over ﬁve years and assigned to one of six cohorts (A1 to B2) according to their histology, stage, and treatment (Table). In the MRD monitoring cohorts A2-B2 of 680 patients, we will analyze MRD every 1-6 months for up to 2 years, and computed tomography scans and serum tumor markers measurement will be performed at each time point. As for MRD analysis, we will perform tissue-based MRD detection systems that require sequencing of tumor tissue to create personalized plasma circulating tumor DNA (ctDNA) assay and liquid-based MRD detection systems that analyze plasma ctDNA by methylation proﬁling or urinary exosomal microRNA. The

S275

performance of these liquid-based MRD detection systems will be compared with tissue-based MRD detection systems to establish the optimal MRD detection system for lung cancer. As of April 2023, a total of 154 patients have been enrolled in LCSCRUM-MRD across 40 institutions, and preliminary results will be presented at this meeting.

Clinical trial identiﬁcation: UMIN000048977.

Legal entity responsible for the study: National cancer center.

Funding: Institutional funding.

Disclosure: Y. Zenke: Financial Interests, Personal, Invited Speaker: AstraZeneca, Lilly, chugai,Boheringer-ingelheim, Ono Pharmaceutical, Bristol-Meyers Squibb, Takeda Pharmaceutical, Taiho pharmaceutical, MSD, Novartis, Nippon-kayaku, Amgen, Kyowa-Hakko Kirin; Financial Interests,Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: AstraZeneca, MSD, Merck, Daiichi Sankyo, Amgen. K. Yoh: Financial Interests, Personal, Invited Speaker:AstraZeneca, Bristol Myers Squibb, Chugai, Daiichi sankyo, Lilly, Boehringer Ingelheim, Amgen,Takeda; Financial Interests, Institutional, Local PI: AstraZeneca, Lilly, Daiichi Sankyo, AbbVie, Taiho,MSD, Takeda, Amgen, Boehringer Ingelheim, Chugai; Financial Interests, Personal, Steering Committee Member: AstraZeneca. J. Samejima: Financial Interests, Personal, Writing Engagement: Taiho Pharmaceutical Co., Ltd, Shizenkagakusha, Stryker, Ziosoft; Financial Interests, Personal, Invited Speaker: B. Braun, Ziosoft, Johnson & Johnson, MiRXES, Taiho Pharmaceutical Co., Ltd; Financial Interests, Personal, Other, Providing surgical videos: Olympus, Johnson & Johnson. K. K. Kunimasa:Financial Interests, Institutional, Research Grant: Taiho Pharmaceutical Co., Ltd., AbbVie; Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai pharmaceutical, Nippon Boehringer Ingelheim, Eli Lilly Japan, Roche Diagnostics, Daiichi Sankyo, Novartis, Pﬁzer, Merk, Bristol Myers Squibb, Nippon Kayaku. R. Toyozawa: Financial Interests, Personal, Other, Honoraria: Chugai Pharmaceutical, Eli Lilly Japan, Taiho Pharmaceutical, Ono Pharmaceutical; Financial Interests, Personal,Other, honoraria: AstraZeneca, Takeda Pharmaceutical, MSD, Pﬁzer Japan; Financial Interests,Institutional, Local PI: AbbVie, Amgen, Takeda Pharmaceutical, Pﬁzer Japan, Daiichi Sankyo, Eli Lilly Japan, Novartis Pharma, AnHeart Therapeutics. M. Tachihara: Financial Interests, Personal, Invited Speaker: Eli Lilly Japan K.K., Chugai Pharmaceutical Co.,Ltd, AstraZeneca K.K, MSD K.K., Ono Pharmaceutical Co.,Ltd., Bristol Myers Squibb Co. Ltd.; Financial Interests, Personal and Institutional,Research Grant: AstraZeneca K.K. S. Niho: Financial Interests, Personal, Invited Speaker: AstraZeneca,Pﬁzer, Ono, Chugai, Eli Lilly, Takeda, Merck Biopharma, Eisai, Novartis, Kyorin, Boehringer Ingelheim,Kyowa Kirin, MSD, Nippon Kayaku, Daiichi Sankyo, Amgen; Financial Interests, Institutional, Funding:Taiho, GSK, Daiichi Sankyo, Chugai, Teijin, Eli Lilly, Kyowa Kirin, Shionogi, Boehringer Ingelheim,Kyorin, Nippon Kayaku. K. Nosaki: Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai Pharma, Lilly, MSD, Pﬁzer, Taiho Pharmaceutical, Jansen, Ono, Takeda, Novartis, Merck; Financial Interests, Personal, Advisory Board: Daiichi Sankyo, AbbVie; Financial Interests, Institutional,Local PI: Takeda, AstraZeneca, MSD, AbbVie, Chugai Pharma, Daiichi Sankyo/UCB Japan, Anheart Therapeutics. H. H. Izumi: Financial Interests, Institutional, Local PI: Amgen Inc, Eisai, AbbVie; Financial Interests, Personal and Institutional, Local PI, Invited Speaker: Ono Pharmaceutical Company,AstraZeneca; Financial Interests, Personal, Other, Invited Speaker: Chugai Pharmaceutical Co., Merck Biopharma Co., Takeda Pharmaceutical Co.; Financial Interests, Personal, Other, Advisory board:Amgen. T. Sakai: Financial Interests, Institutional, Research Grant: Amgen, Daiichi-Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai, Novartis, MSD, Thermo Fisher Scientiﬁc,Merck. S. Umemura: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical. S. Matsumoto: Financial Interests, Personal, Invited Speaker: Merck Biopharma, Eli Lilly, AstraZeneca,Chugai, Nvartis, Guardant Health, Amgen, Takeda; Financial Interests, Institutional, Local PI: Merck Biopharma, Janssen Pharmaceutical K.K., MSD. M. Tsuboi: Financial Interests, Personal, Invited Speaker, Lecture: Johnson & Johnson Japan; Financial Interests, Personal, Advisory Board, Lectures,Advisory boards: AstraZeneca KK, Chugai Pharmaceutical Co.,Ltd, MSD; Financial Interests, Personal,Invited Speaker, Lectures: Eli Lilly Japan, Bristol Myers Squibb KK, Taiho Pharma, Medtronic Japan,ONO Pharmaceutical Co.,Ltd; Financial Interests, Personal, Advisory Board, Advisory boards:Novartis; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo company limited; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim Japan, MSD, AstraZeneca KK, Ono Pharmaceutical CO.,LTD, Bristol Myers Squibb KK, Novartis, MiRXES; Financial Interests, Personal,Steering Committee Member: MSD, AstraZeneca, Novartis; Financial Interests, Institutional, Steering Committee Member: Eli Lilly Japan. K. K. Goto: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd., Amgen K.K., Takeda Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Amgen Inc., Amoy Diagnosties Co.,Ltd., AstraZeneca K.K., Bayer HealthCare Pharmaceuticals Inc., Boehringer Ingelheim Japan, Inc., Bristol Myers Squibb K.K., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Guardant Health Inc., Merck Biopharma Co., Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Thermo Fisher Scientiﬁc K.K., Taiho Pharmaceutical Co., Ltd., Syneos Health Clinical K.K., Life Technologies Japan Ltd.; Financial Interests, Personal, Advisory Board: Janssen Pharmaceutical K.K., Medpace Japan K.K., Haihe Biopharma Co., Ltd.; Financial Interests, Personal and Institutional, Funding: Amgen Inc., Amgen K.K., AstraZeneca K.K., Boehringer Ingelheim Japan,Inc., Bristol Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co.,Ltd., Eli Lilly Japan K.K., Haihe Biopharma Co., Ltd., Ignyta,Inc., Janssen Pharmaceutical K.K., Kissei Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Loxo Oncology, Inc., Medical ＆ Biological Laboratories Co., Ltd., Merck Biopharma Co., Ltd., Merus N.V., MSD K.K., Ono Pharmaceutical Co., Ltd.,Pﬁzer Japan Inc., Sysmex Corporation., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co.,Ltd., Turning Point Therapeutics,Inc., Amgen Astellas BioPharma K.K., Bayer Yakuhin, Ltd., Blueprint Medicines Corporation., Life Technologies Japan Ltd., NEC Corporation., Novartis Pharma K.K., Craif Inc., Pﬁzer R&D Japan G.K., Turning Point Therapeutics,Inc.; Non-Financial Interests, Member:American Society of Clinical Oncology, The Japan Lung Cancer Society, Japanese Society of Medical Oncology, The Japanese Cancer Association. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2959

237TiP GUIDE.MRD: A Consortium guiding multi-modal therapies against minimal residual disease (MRD) by liquid biopsy to assess implementation of circulating tumor DNA (ctDNA) in clinical practice to improve patient outcomes

K. Pantel1, C. Lindbjerg Andersen2, E. Schuuring3, N. Malats4, E. Heitzer5, L. Vat6,E. Kiernan7, E. Chin8, J.C. Barrett9, J.R. Kapp10, M. Thomas11, M. Gerling12,

|Table: 236TiP LC-SCRUM-Advantage/MRD |Table: 236TiP LC-SCRUM-Advantage/MRD |Table: 236TiP LC-SCRUM-Advantage/MRD |Table: 236TiP LC-SCRUM-Advantage/MRD |Table: 236TiP LC-SCRUM-Advantage/MRD |Table: 236TiP LC-SCRUM-Advantage/MRD |Table: 236TiP LC-SCRUM-Advantage/MRD | |---|---|---|---|---|---|---|

|A1 |NSCLC |I-III |Surgery |〇 |- |9800 |

|A2 ||||〇 |〇 |200 |

|A3 ||III |Chemoradiotherapy |- |〇 |100 |

|A4 ||III/IV |Chemotherapy |- |〇 |150 |

|B1 |SCLC |LD |Chemoradiotherapy |- |〇 |30 |

|B2 ||ED |Chemotherapy |- |〇 |200 |

M. Reck13, M. Löhr14, P. Hofman15, J.T.J.N. Hiltermann16, C. Alix-Panabières17,D.J. Smit18, M. Bolisetty19, M. Karasarides20

1Institute of Tumour Biology, UKE Universitätsklinikum Hamburg-Eppendorf KMTZ,Hamburg, Germany; 2Dept. of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; 3Pathology Dept., UMCG - University Medical Center Groningen,Groningen, Netherlands; 4Genetic and Molecular Epidemiology, CNIO - Centro Nacional de Investigaciones Oncologicas, Madrid, Spain; 5Diagnostik & Forschungsinstitut für Humangenetik, Medical University of Graz, Graz, Austria; 6From Testing to Targeted Treatment, The Synergist, Brussels, Belgium; 7Emerging Clinical Applications, Illumina, Inc., San Diego, CA, USA; 8Global Lab Operations, Horizon Discovery Ltd, Waterbeach, UK; 9Translational Science in Oncology, AstraZeneca,Waltham, MA, USA; 10Global Development, Amgen (Europe) GmbH, Risch-Rotkreuz,Switzerland; 11CGP Portfolio Strategy, F. Hoffmann-La Roche AG, Basel, Switzerland;12Tema Cancer Department, Karolinska University Hospital and Karolinska Institute -Huddinge, Stockholm, Sweden; 13Thoracic Oncology Dept., Krankenhaus Grosshansdorf, Grosshansdorf, Germany; 14Gastroenterology & Hepatology, Karolinska Institutet, Stockholm, Sweden; 15Alpes Maritimes, CHU Nice - Hopital Pasteur, Nice,France; 16Pulmonary Medicine, Aa11, UMCG - University Medical Center Groningen,Groningen, Netherlands; 17Laboratoire Cellules Circulantes Rares Humaines, Institut Universitaire de Recherche Clinique, Paris, France; 18Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 19Biomarkers, Bristol Myers Squibb, Lawrenceville, NJ, USA; 20Early Assets & Biomarkers, Bristol Myers Squibb, Plainsboro, NJ, USA

Background: An integrated precision oncology approach that can guide the selection of personalized therapy is paramount to achieving improved outcomes in patients while maintaining responsible healthcare economics. Actionable precision oncology requires in vitro diagnostic tests that are sufﬁciently sensitive, accurate, reproducible,and reliable in the real-world setting with minimal risk of patient overtreatment or undertreatment. Liquid biopsies and speciﬁcally ctDNA based diagnostics provide a unique opportunity to optimize clinical decisions and thereby improve individual patient care. Such techniques could be particularly valuable in the adjuvant setting where multi-modal therapy (MMT) has curative potential. Multiple studies provide evidence that serial ctDNA monitoring can predict or detect recurrence earlier than conventional surveillance. However, as highlighted in the most recent ESMO ctDNA recommendations, the detection limit of current diagnostics to accurately report ctDNA fragments in peripheral blood remains a challenge. Importantly, it is currently unclear how to incorporate ctDNA as MRD biomarker or as a decision tool for treatment selection to improve cancer outcomes. GUIDE.MRD, a patient-centered precision oncology public-private partnership under the Innovative Health Initiative umbrella, is designed to improve the utility and clinical implementation of ctDNA as MRD biomarker and to evaluate the potential of novel decision tools to match patients to MMTs.

Trial design: Partners from academic, medical technology, pharmaceutical and patient advocacy sectors will join to (a) benchmark available ctDNA assays for sensitivity,speciﬁcity, and predictive value using reference material that closely mimic patient samples in the adjuvant setting, (b) to clinically validate the top performing ctDNA assay characteristics in patients with NSCLC, CRC and PDAC and develop patientcentric clinical implementation roadmaps, and (c) determine the utility of ctDNA assays as a prospective decision tool of clinical response and choice of MMT including novel combinations.

Legal entity responsible for the study: Universitaetsklinikum Hamburg-Eppendorf.

Funding: Innovative Health Initiative.

Disclosure: K. Pantel: Financial Interests, Personal, Invited Speaker, Research Presentation and Discussion: Abcam, Agena, Ipsen Pharma, Medac; Financial Interests, Personal, Advisory Board: Hello Healthcare, Sanoﬁ; Financial Interests, Personal, Advisory Board, Research Presentation and Discussion: Menarini; Financial Interests, Personal, Advisory Board, Expert Input Forum: MSD; Financial Interests, Institutional, Other: Angle plc; Financial Interests, Institutional, Other, Clinical study:Boehringer Ingelheim; Financial Interests, Institutional, Other, UKE - European Liquid Biopsy Society(ELBS): ELBS; Financial Interests, Institutional, Other, EFPIA Partners of EU/IMI Cancer-ID consortium:UKE - European Liquid Biopsy Society (ELBS). C. Lindbjerg Andersen: Non-Financial Interests, Institutional, Funding: Natera, C2i Genomics. E. Schuuring: Financial Interests, Institutional, Research Grant: Abbott, Biocartis, AstraZeneca, Invitae/Archer, Bayer, Bio-Rad, Roche, Agena Bioscience, CC Diagnostics, MSD/MERCK, Boehringer Ingelheim; Financial Interests, Institutional, Advisory Board:MSD/Merck, AstraZeneca, Roche, Novartis, Bayer, BMS, Lilly, Amgen, Illumina, Agena Bioscience, CC Diagnostics, Janssen Cilag (Johnson&Johnson), Astellas Pharma; Financial Interests, Institutional,Invited Speaker: Bio-Rad, Seracare, Roche, Biocartis, Lilly, Agena Bioscience, Illumina; Financial Interests, Institutional, Other, Only travel expenses: BioRad, Biocartis, Ageno Sciences; Non-Financial Interests, Personal, Member of Board of Directors: Dutch Society of Pathology, European Society of Pathology, European Liquid Biopsy Society; Financial Interests, Personal and Institutional, Advisory Role: Advisory committee for assessment of molecular diagnostics (cieBOD; secretary/member),National guideline advisory committee member. N. N. Malats: Non-Financial Interests, Personal, Other,Partner GUIDE-MRD: Spanish National Cancer Research Centre (CNIO). E. Heitzer: Financial Interests,Personal, Advisory Board: Roche; Financial Interests, Institutional, Research Grant: Roche, Illumina,PreAnalytiX. E. Kiernan: Financial Interests, Personal, Full or part-time Employment: Illumina Inc. E.

Chin: Financial Interests, Institutional, Full or part-time Employment: Revvity; Financial Interests,Institutional, Stocks/Shares: Revvity. J.C. Barrett: Financial Interests, Institutional, Full or part-time Employment: AstraZenenca. J.R. Kapp: Financial Interests, Personal, Full or part-time Employment:Amgen Inc.; Financial Interests, Personal, Stocks/Shares: Amgen Inc. M. Thomas: Financial Interests,Institutional, Full or part-time Employment: F. Hoffmann La Roche; Financial Interests, Institutional,

Member: F. Hoffmann La Roche; Financial Interests, Institutional, Stocks/Shares: F. Hoffmann La Roche. M. Gerling: Financial Interests, Institutional, Local PI: IHI-EU project GUIDE.MRD. M. Reck:Financial Interests, Personal and Institutional, Invited Speaker: Amgen, AstraZeneca, BMS, Boehringer Ingelheim, GSK, Lilly, Mirati, MSD, Merck, Novartis, Regeneron, Sanoﬁ, Roche; Financial Interests, Personal and Institutional, Speaker’s Bureau: Amgen, AstraZeneca, BMS, Boehringer Ingelheim, GSK, Lilly, Mirati, MSD, Merck, Novartis, Regeneron, Sanoﬁ, Roche; Financial Interests,Personal and Institutional, Advisory Board: Amgen, AstraZeneca, BMS, Biontech, Boehringer Ingelheim, Daiichi Sankyo, Gilead, GSK, MSD, Mirati, Pﬁzer, Regeneron, Sanoﬁ, Roche; Financial Interests,Personal and Institutional, Other, DMSB: Daiichi Sankyo, Sanoﬁ. P. Hofman: Financial Interests,Personal, Invited Speaker: AstraZeneca, BMS, Qiagen, AbbVie, Novartis, Janssen; Financial Interests,

Personal, Advisory Board: AstraZeneca, BMS, Qiagen, AbbVie, Novartis, Janssen. J.T.J.N. Hiltermann:Financial Interests, Personal and Institutional, Other: Roche, BMS, MSD, Pﬁzer, CieBOM, GSK,Novartis, Merck Serono, Amgen; Financial Interests, Personal and Institutional, Advisory Role:AstraZeneca, Bristol Myers Squibb, Merck Sharp Dohme, Roche; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca, Hoffmann-La Roche. C. Alix-Panabières: Financial Interests, Personal, Other: Menarini, CTC technologies. M. Bolisetty: Financial Interests, Personal,Stocks/Shares: Bristol Myers Squibb. M. Karasarides: Financial Interests, Institutional, Full or parttime Employment: Bristol Myers Squibb. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2960

BREAST CANCER, EARLY STAGE

238MO

Long-term residential and workplace exposure to air

pollution and breast cancer risk: A case-control study nested in the French E3N cohort from 1990 to 2011

B. Fervers1, M. Duboeuf1, A. Amadou1, T. Coudon1, L. Grassot1, E. Faure2, G. Severi2,F. Mancini2, P. Salizzoni3, J. Gulliver4, D. Praud1

1Cancer and Environment Department, Centre Léon Bérard, Lyon, France; 2Exposome,Hérédité, Cancer et Santé INSERM 1018, Gustave Roussy, Villejuif, France; 3Mécanique des Fluides, Ecole Centrale, Ecully, France; 4Centre for Environmental Health and Sustainability, University of Leicester, Leicester, UK

Background: Air pollution, classiﬁed as carcinogenic to humans, is a major public health concern. Studies on breast cancer are scarce and remain inconsistent. We studied the association between breast cancer risk and long-term exposure to particulate matters (PM2.5, PM10) and nitrogen dioxide (NO2) estimated at the womens’residential and workplace addresses.

Methods: We conducted a case-control study of 2419 cases and 2984 individually matched controls nested in the French prospective E3N cohort, over the period 1990-2011. 2011. Controls were matched to cases on department of residence, age (±1 year);Controls were matched to cases on department of residence, age (1 year);date date (±3 months), and menopausal status at blood collection. Annual mean PM2.s,(3 months), and menopausal status at blood collection. Annual mean PM2.5,PM10 and NO2 concentration levels were estimated using a Land Use Regression (LUR)model (resolution 50m x 50m) and were assigned to women based on their geocoded residential and workplace addresses. The mean exposure was calculated for each woman from their inclusion into the E3N cohort to their index date (date of diagnosis of cases). Odds ratios (OR) and 95% conﬁdence intervals (CI) were estimated using multivariate logistic regression models, for a 10 mg/m3increase in PM2.5, PM10 and NO2. Adjustment variables were selected from the literature, using a directed acyclic graph.

Results: The results showed a statistically signiﬁcant linear increase in breast cancer risk related to mean exposure to PM2.5 (adjusted OR 1.28; CI 1.00e1.63, for an increment of 10 mg/m3). A numerically increased risk was observed for PM10(adjusted OR1.09; CI 0.92e1.30) and NO2 (adjusted OR 1.05; CI 0.97e1.13) for an increment of 10 mg/m3. No effect modiﬁcation by menopausal status was observed (p interaction 0.99, 0.90, and 0.86 respectively for PM2.5PM10 and NO2). Analyses by hormone receptor status showed a positive but not signiﬁcant association for PM2.5 for oestrogen receptor positive (ER+) breast cancer cases (adjusted OR 1.32; CI 0.97e

1.79).

Conclusions: To our knowledge, this study is the ﬁrst to investigate breast cancer risk associated with long term air pollution exposure at both, the subjects’ residence and workplace, estimated using a very ﬁne spatial resolution LUR model. Future studies should consider exposure during commuting.

Legal entity responsible for the study: INSERM.

Funding: ARC Foundation for Cancer Research (CANCAIR201601245), ANSES, French League against Cancer, Fondation de France.

https://doi.org/10.1016/j.annonc.2023.09.436

239MO Impact of body mass index and its change on survival

outcomes in patients with early breast cancer: A pooled analysis of individual-level data from BCIRG-001 and BCIRG005 trials

H. Chen1, X. Qian2, Y. Tao3, D. Wang4, Y. Wang1, Y. Yu1, H. Yao1

1Breast Tumor Centre, Department of Medical Oncology, Phase I Clinical Trial Centre,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou,China; 2Department of Oncology, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, Zhengzhou, China;3Department of Oncology, The Afﬁliated Hospital of Xuzhou Medical University, Xuzhou, China; 4Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China

Background: The relationships between body mass index (BMI) and survival outcomes are complex, and have not been thoroughly investigated in breast cancer patients who received adjuvant chemotherapy.

Methods: We collected data on 2394 patients from two randomized, phase III clinical trials that investigated adjuvant chemotherapy in breast cancer identiﬁed in Project Data Sphere. The objective was to examine the effect of baseline BMI, BMI after adjuvant chemotherapy, and BMI change from baseline to post-adjuvant

chemotherapy on disease-free survival (DFS) and overall survival (OS). Restricted cubic splines, adjusting for confounding factors, were used to examine potential nonlinear associations between continuous BMI value and survival. Stratiﬁed analyses involved chemotherapy regimens used.

Results: On multivariate analysis, severe obesity (BMI40.0 kg/m2) at baseline Results: On multivariate analysis, severe obesity (BMl≥40.0 kg/m2) at baseline waswasindependently associated with worse DFS (HR¼1.48, 95%CI 1.02-2.16, P¼0.04) andOS (HR¼1.79, 95%CI 1.17-2.74, P¼0.007) compared with underweight/normal weight(BMI24.9 kg/m2). A BMI loss >10% was also an independent prognostic factor (BMI≤24.9 kg/m2). A BMl loss >10% was also an independent prognostic factor forforadverse OS (HR¼2.14, 95%CI 1.17-3.93, P¼0.014). When stratiﬁed by chemotherapyregimens, the multivariate analysis revealed that severe obesity adversely affected DFS (HR¼2.38, 95%CI 1.26-4.34, P¼0.007) and OS (HR¼2.90, 95%CI 1.46-5.76,P¼0.002) in the docetaxel-based group, but not in the non-docetaxel-based group.Restricted cubic splines revealed a “J-shaped” association of baseline BMI with risk of recurrence (P for non-linearity¼0.111) or all-cause death (P for non-linearity¼0.008),and this relationship was more pronounced in the docetaxel-based group (DFS: P for non-linearity¼0.011; OS: P for non-linearity <0.001).

Conclusions: In early breast cancer patients treated with adjuvant chemotherapy,baseline severe obesity was lined to worse DFS and OS, while a BMI loss over 10%from baseline to post-adjuvant chemotherapy also negatively affected OS. Moreover,the prognostic role of BMI might differ between docetaxel-based and non-docetaxelbased groups.

Background: Clinical proﬁling studies have shed light on molecular features and mechanisms that modulate response or resistance to immunotherapy but their predictive value remains largely unclear. We (Bareche et al., Annals of Oncology 2022 )and others (Litchﬁeld et al., Cell 2021 ) have recently curated a compendium of public datasets of DNA, RNA and clinical proﬁles of patients treated with immunotherapy.

Methods: Leveraging our compendium of immunotherapy clinical datasets, we developed, PredictIO, an open-source meta-analysis pipeline to assess the predictive value of molecular predictors. We ﬁrst used PredictIO to compute the association between immunotherapy response and established biomarkers, such as tumor

mutation burden (TNB) or CD8 gene expression, and a collection of 91 molecular signatures curated from the literature. Second, we used PredictIO for de novo RNA signature discovery pipeline to build a new predictor of immunotherapy response.

Results: Using molecular and clinical proﬁles of w3600 patients across 12 tumor types, our meta-analysis pipeline revealed thatTMB andw50% of the gene signatures were signiﬁcantly predictive of immunotherapy response across tumor types,although their predictive value were strongly dependent on speciﬁc tumour types.We next developed a de novo gene expression signature from our pan-cancer analysis and demonstrated its superior predictive value over other biomarkers. To identify novel targets, we computed the T-cell dysfunction score for each gene within PredictIO and their ability to predict dual PD-1/CTLA-4 blockade in mice. Two genes,F2RL1 and RBFOX2, were concurrently associated with worse ICB clinical outcomes, Tcell dysfunction in ICB-naive patients and resistance to dual PD-1/CTLA-4 blockade in preclinical models.

Conclusions: Our study highlights the potential of large-scale meta-analyses in identifying novel biomarkers and potential therapeutic targets for cancer immunotherapy. These initial results, while promising, suffer from severe limitations in terms of data availability for speciﬁc cancer types and the lack of frameworks to develop and validate multi-omics predictors of immunotherapy response in a collaborative and scalable way.

Funding: University Health Network.

Disclosure: B. Haibe-Kains: Financial Interests, Personal, Advisory Board: BreakThorugh Cancer,IONIQ Sciences, CQDM; Financial Interests, Personal, Speaker, Consultant, Advisor: Code Ocean.

https://doi.org/10.1016/j.annonc.2023.09.2951

229P Leucine zipper 4 (LUZP4) IgG as a novel biomarker for testicular germ cell tumors

M.B. Hammami, et al.

Internal Medicine, Jacobi Medical Center/ NYC Health & Hospitals/Jacobi, Bronx, NY,USA

Late withdrawal

230P

Fibroblast growth factor receptor (FGFR) co-alteration (coalt) landscape and its impact on erdaﬁtinib (erda) response in the phase II open-label, single-arm RAGNAR trial

Y. Loriot1, S. Pant2, O. Witt3, D.A. Reardon4, T. Doi5, S. Qin6, J. Tabernero7, G. Iyer8,C. Massard9, D. Arnold10, I. Lugowska11, O. Carranza12, M. Gutierrez13, H. Winter14,H. Sweiti15, S. Thomas15, M. Gormley15, J. Zhang15, S. Triantos15, M.H.H. Schuler16

1Cancer Medicine Department, Gustave Roussy, DITEP, Université Paris-Saclay, Villejuif,Cedex, France; 2Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3Department of Pediatric Oncology, Hopp Children’s Cancer Center (KiTZ), Heidelberg University Hospital,German Cancer Research Center and National Center for Tumor Diseases (NCT),Heidelberg, Germany; 4Medical Oncology, Center for Neuro-Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; 5Experimental Therapeutics Dept., National Cancer Center Hospital East, Kashiwa, Chiba, Japan;6Department Medical Oncology, Jinling Hospital, Nanjing University of Chinese Medicine, Nanjing, China; 7Medical Oncology Dept., Vall d’Hebron Hospital Campus and Institute of Oncology (VHIO), IOB-Quiron, Barcelona, Spain; 8Department of Medicine,Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York,NY, USA; 9DITEP Department, Université Paris-Saclay, Le Kremlin Bicêtre e France INSERM U1030, Molecular Radiotherapy, Gustave Roussy, Université Paris-Saclay,Villejuif, France; 10Department of Oncology, AK Altona, Asklepios Tumourzentrum Hamburg, Hamburg, Germany; 11Department of Soft Tissue/Bone Sarcoma and Melanoma, Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie e Panstwowy Instytut Badawczy, Warsaw, Poland; 12Department of Clinical Oncology, Hospital Privado de Comunidad de Mar del Plata, Mar Del Plata, Argentina; 13Medical Oncology Department, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA; 14Oncology Department, Bristol Haematology and Oncology Centre, Bristol, UK; 15Research & Development, Janssen Research &Development, Spring House, PA, USA; 16Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen,Germany

Background: FGFRalts are present in 1%-20% of all cancers. Erda is an oral selective pan-FGFR inhibitor approved to treat locally advanced or metastatic (adv/met) urothelial carcinoma in adults with susceptible FGFR3/2alt who have progressed during or or after ≥1 line of platinum-based chemotherapy. Interim results of RAGNAR showedafter 1 line of platinum-based chemotherapy. Interim results of RAGNAR showedtumor agnostic efﬁcacy in patients (pts) with adv/met solid tumors with predeﬁned FGFRalt after failure of standard therapies (Loriot et al, ASCO 2022 ). Here, we evaluated the FGFR co-alt landscape and its impact on response to erda treatment(tx) in RAGNAR.

Methods: Archival tumors from pts with adv/met solid tumors were prospectively screened for FGFR1-4alts using FoundationOne (FM) or, for those pts enrolled based on local results, retrospectively tested using FM. 217 pts received erda until progression or intolerable toxicity. The impact of co-alts on erda tx was evaluated with respect to objective response rate (ORR) (primary end point) using Fisher exact test,Kaplan-Meier analysis for duration of response (DOR), and Wilcoxon rank-sum test for maximum tumor shrinkage (MTS).

Results: Of 217 pts, 175 (81%) had tumors with pathogenic co-alts, most prevalent in TP53 (27%), PIK3CA (18%), and CDK2NA (15%). Co-alts were histology dependent.

TP53 was altered in 75% of esophageal, 75% of ovarian, and 71% of colorectal; TERT mutations were seen in 55% of high-grade gliomas. ORR did not show an association between the presence or burden of co-alts (p¼0.51). Of the 12 most prevalent co-altsand pathways, none were signiﬁcantly associated with response vs non-response.

Within each histology, individual co-alts were not associated with response. Among responders, TP53 alt was associated with shorter DOR (HR¼0.29 [95% CI, 0.15-0.58];p¼0.002). Further, RTK-RAS pathway co-alts were associated with less MTS(p¼0.034).

Conclusions: High prevalence of FGFR co-alts reﬂects the complex genomic landscape of tx-refractory adv/met solid tumors. Despite most pts having histology-speciﬁc coalts, erda showed clinical activity in these pts, supporting FGFRalts as oncogenic drivers in these tumors.

Clinical trial identiﬁcation: NCT04083976.

Legal entity responsible for the study: Janssen Research & Development.

Funding: Janssen Research & Development.

Disclosure: Y. Loriot: Financial Interests, Institutional, Speaker, Consultant, Advisor, Consultancy Fees: Loxo/Lilly, Pﬁzer/EMD Serono, Roche, and Taiho Pharmaceutical, MSD Oncology, Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Immunomedics, Janssen; Financial Interests, Personal,Other, Travel Reimbursement: Astellas, AstraZeneca, Janssen Oncology, MSD Oncology, and Roche;Financial Interests, Institutional, Research Funding: Astellas Pharma, AstraZeneca, Basilea, Bristol Myers Squibb, Exelixis, Gilead Sciences, Incyte, Janssen Oncology, Merck KGaA, MSD Oncology,Nektar, Pﬁzer, Roche, Sanoﬁ, and Taiho Pharmaceutical. S. Pant: Financial Interests, Personal,Speaker, Consultant, Advisor, Consultancy Fees: Zyemworks, Ipsen, Novartis, Janssen; Financial Interests, Institutional, Research Funding: Mirati Terapeutics, Lilly, Xencor, Novarits, Rgenix, Bristol Myers Squibb, Astellas Pharma, Purple Biotech, 4D Pharma, Boehringer Ingelheim, NGM Biopharmaceuticals, Janssen, Arcus Bissceinces, Elicio Therapeutics. O. O. Witt: Financial Interests, Personal, Speaker, Consultant, Advisor, Consultancy Fees: Bayer US, LCC, Bristol Myers Squibb, Day One Therapeutics, Novartis, and Roche; Financial Interests, Institutional, Research Funding: AstraZeneca,Bayer US, LLC, Blueprint Medicines, Day One Therapeutics, GSK, Janssen, Lilly, Loxo, Novartis, and Roche. D.A. Reardon: Financial Interests, Personal, Speaker, Consultant, Advisor, Consultancy Fees:Advantagene, Agenus, Agios, AnHeart Therapeutics, Bayer, Bristol Myers Squibb, Delmar Pharmaceuticals, Ellipses Pharma, EMD Serono, Genenta Science, Imvax, Kintara Therapeutics, Kiyatec,Medicenna, Merck, Merck KGaA, Novocure, Oncorus, Regeneron, Taiho Ph; Financial Interests,Personal, Other, Honoraria: Advantagene, Agenus, AnHeart Therapeutics, Bayer, Bristol Myers Squibb, Deciphera, DelMar Pharmaceuticals, Ellipses Pharma, EMD Serono, Genenta Science, Imvax,

Inovio Pharmaceuticals, Kintara Therapeutics, Kiyatec, Medicenna, Merck, Merck KGaA, Neuvogen, ;Financial Interests, Institutional, Research Funding: Acerta Pharma, Agenus, Celldex, EMD Serono,Enterome, Incyte, and Omniox. T. Doi: Financial Interests, Personal, Speaker, Consultant, Advisor,Consultancy Fees: AbbVie, Amgen, Boehringer Ingelheim, Chugai Pharma, Daiichi Sankyo, Janssen,Kaken Pharmaceutical, Kyowa Kirin, MSD, Otsuka, PRA Health Science, Rakuten Medical, Shionogi,Sumitomo Dainippon Pharma, Taiho Pharmaceutical, and Takeda; Financial Interests, Personal,Other, honoraria: AstraZeneca, Bristol Myers Squibb Japan, Chugai Pharma, Daiichi Sankyo, Ono Pharmaceutical, Rakuten Medical Japan, and Taiho Pharmaceutical; Financial Interests, Institutional,Research Funding: AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharma, Daiichi Sankyo, Eisai, IQVIA, Janssen, MSD, Ono Pharmaceutical, Novartis, Pﬁzer, PRA Health Sciences,Sumitomo Dainippon Pharma, and Taiho Pharmaceutical. J. Tabernero: Financial Interests, Personal,Speaker, Consultant, Advisor, Consultancy Fees: Array BioPharma, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiff Oncology, Chugai Pharma, Daiichi Sankyo, F. Hoffman LaRoche, Genentech, HalioDx, Ikena Oncology, Inspirna, IQVIA, Lilly, Menarini, Merck Serono, Merus, Mirati Therapeutics,MSD, NeoPhore, ; Financial Interests, Personal, Other: Imedex/HMP, Medscape, MJH Life Sciences,Peerview, Physicians’ Education Resource; and stock and other ownership interests from Oniria Therapeutics. G. G. Iyer: Financial Interests, Personal, Speaker, Consultant, Advisor, Consultancy Fees:Basilea, Bayer, Flare Therapeutics, Janssen, Loxo/Lilly, and Mirati Therapeutics; Financial Interests,Personal, Speaker’s Bureau: Gilead Sciences and Lynx Group; Financial Interests, Institutional,Research Funding: Bayer, Debiopharm Group, Janssen, Mirati Therapeutics, Novartis, and Seagen. C.

Massard: Financial Interests, Personal, Speaker, Consultant, Advisor, Consultancy Fees: Amgen,Astellas Pharma, AstraZeneca, Bayer, BeiGene, Blueprint Medicines, Bristol Myers Squibb, Celgene,Debiopharm Group, Faron Pharmaceuticals, Genentech/Roche, Innate Pharma, Ipsen, Janssen, Lilly,MSD, Novartis, Orion, Pﬁzer, PharmaMar, Sanoﬁ, and T. D. Arnold: Financial Interests, Personal,Speaker, Consultant, Advisor, Consultancy Fees: CE Oncology, Amgen, Art Tempi Media, AstraZeneca,Bayer, Boston Scientiﬁc, Bristol Myers Squibb, Personal Aptitude Health, Clinical Care Options (CCO),CRA International, Eli Lilly, Hexal, Imedex, Ipsen, IQVIA, Ketchum, MedAhead, Merck Serono, Merck,Sh; Financial Interests, Personal, Leadership Role: OncoLytics . I. Lugowska: Financial Interests,Personal, Speaker, Consultant, Advisor, Consultancy Fees: Boehringer Ingelheim; honoraria from Agenus, Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Celon, Cullinan Oncology, Jacobio,Janssen, Loxo, Macrogenics, Menarini, MSD, Pﬁzer, Rhizen, Roche, Sanoﬁ, and Takeda; institutional research funding from Ag; Financial Interests, Personal, Other, Travel Expenses: Bristol Myers Squibb.

M. Gutierrez: Financial Interests, Personal, Speaker, Consultant, Advisor, Consultancy Fees: Celularity and Guardant. H. Sweiti, S. Thomas, M. Gormley, J. Zhang, S. Triantos: Financial Interests, Personal,Other, Employment: Janssen; Financial Interests, Personal, Stocks/Shares: Janssen. M.H.H. Schuler:Financial Interests, Personal, Speaker, Consultant, Advisor, Consultancy Fees: Amgen, AstraZeneca,Boehringer Ingelheim, Bristol Myers Squibb, GSK, Janssen Oncology, Merck Serono, Novartis, Roche,Sanoﬁ, and Takeda; Financial Interests, Personal, Other, honoraria: Amgen, Boehringer Ingelheim,Bristol Myers Squibb, Janssen-Cilag, and Novartis; Financial Interests, Institutional, Research Funding: AstraZeneca and Bristol Myers Squibb; Financial Interests, Personal, Other, institutional patents,royalties, or other intellectual property for a highly sensitive method for mutation detection: PCR. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2953

231P Time to deterioration of quality of life as a surrogate of OS:A trial-level surrogacy analysis

A. Shahnam1, U. Nindra2, J. Desai1, R. Hui3, A.M. Hopkins4, M. Sorich5

1Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia;2Medical Oncology Department, Liverpool Cancer Therapy Centre, Liverpool, NSW,Australia; 3The Centre of Cancer Medicine, University Hong Kong, Hong Kong, China;4Clinical Pharmacology Department, Flinders Medical Centre, Adelaide, SA, Australia;5College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia

Background: Overall survival (OS) is the optimal marker of efﬁcacy for evaluation of treatments in randomized clinical trials (RCTs) but can take a considerable amount of time to mature. Evaluation of changes in tumor size through objective response rate(ORR) and progression free survival (PFS) has served as an early surrogate of OS however they are imperfect. Time to deterioration (TTD) in quality of life (QoL)measures could act as an early alternative patient centered surrogate of OS.

Methods: We utilised published phase 3 RCTs in solid malignancies that reported OS,PFS, ORR, and time to deterioration (TTD) evaluations of overall QoL or physical function (PF) published between 1stof January 2010 and 30thof June 2022. Weighted regression analysis was utilised to assess the relationship between PFS, ORR ratio, TTD QoL and TTD PF with OS. The coefﬁcient of determination (R2) was used to quantify surrogacy.

Results: After identifying 9109 publications, 138 studies with 86199 patients were included for analysis. 47 RCT involved immunotherapy (IO) whilst 91 investigated nonIO agents. PFS (R2¼ 0.19) and ORR (R2¼ 0.05) were poor surrogates of OS. TTD QoLand TTD PF was available in 137 and 75 RCTs respectively. In the respected subset of studies, TTD QoL (TTD QoL R2¼ 0.18 vs. PFS R2¼ 0.19) and TTD PF (TTD PF R2¼ 0.10vs PFS R2¼ 0.09) performed similarly to PFS as surrogates of OS. However, for IOagents, TTD PF (R2¼ 0.38) had a higher surrogacy to OS compared to PFS (R2¼ 0.19).Furthermore, combining PFS and TTD PF enabled improved prediction of OS (R2¼0.57). Importantly, TTD PF and PFS were not correlated with each other (R2¼ 0). TTDPF was not a surrogate endpoint of OS for non-IO trials.

Conclusions: Our trial level analysis identiﬁed TTD in PF as a potential marker of early OS in trials that utilized IO agents. It could potentially be used in conjunction with PFS to improve surrogacy in speciﬁc tumor types. Our results are based on published results and should be validated using patient-level data.

https://doi.org/10.1016/j.annonc.2023.09.2954

S273

232P

S274

Identiﬁcation of ‘secondary’ germline cancer predisposition variants from somatic tumour testing: Should we evolve towards universal screening?

A. Gallego Martinez1, T. Imizcoz2, L. Sánchez-Lorenzo1, M. Mora2, D. Domínguez2,A. Gurpide3, J. Espinos Jimenez4, J.M. Aramendia3, A. Chopitea Ortega3,

M. Santisteban Eslava5, M. Ponz-Sarvise6, J.L. González3, A. Landa Magdalena3,M.F. Sanmamed3, G. Alkorta-Aranburu2, J. Rodriguez Rodriguez3, T. Herráiz Bayod7,A. Gonzalez Martin6, A. Patiño-García8

Methods: We prospectively collected pre-treatment blood from patients with NSCLC treated with ﬁrst-line pembrolizumab in combination with chemotherapy. DNA was extracted from white blood cells and used for high resolution HLA-I/II typing. Genomic HLA-I/II homozygosity was correlated with clinical beneﬁt. We used Sidney et al to classify genomic HLA-A and -B into supertypes.

Results: Of 65 patients recruited, 53 complied with the inclusion criteria. Of those 76%(40/53) have PD-L1 expression of <50% of their cancer cells. Our analysis did notﬁnd any association between HLA-I/-II homozygosity and clinical outcome among patients with NSCLC treated with pembrolizumab in combination with chemotherapy.

However, the absence of HLA-A01 was associated with favourable PFS (HR¼2.09, 95%CI 1.03-4.27, P¼0.22) and improved OS (HR¼2.58, 95%CI 0.96-6.89, P¼0.038). thepresence of HLA-B27 was associated with improved PFS (HR¼0.24, 95%CI 0.12,P¼0.004) but not OS.

Conclusions: The absence of association between genomic HLA-I/-II homozygosity and clinical outcome among patients with advanced NSCLC treated with pembrolizumab in combination with chemotherapy might reﬂect a diminished role for HLA molecules among patients with low or no PD-L1. HLA-A01 and HLA-B27 might have a role in predicting clinical outcome among this cohort of patients. Further studies are needed to explore biomarkers for this group of patients.

Funding: Higher degree by research award scheme provided by Centre for Precision Health at ECU.

Disclosure: M. Millward: Financial Interests, Personal, Advisory Board: BeiGene Australia Pty Ltd,Bristol Myers Squibb Australia Pty Ltd, AstraZeneca Australia Pty Ltd, The Limbic, Eli Lilly Australia Pty Ltd, IQVIA Australia Pty Ltd, Amgen Australia Pty Ltd, Merck Pte Ltd, Pﬁzer Australia Pty Ltd,Guardant Health, Roche Products Pty Ltd; Financial Interests, Personal, Full or part-time Employment, Employee: University of Western Australia; Financial Interests, Personal, Other, Consultant:Linear Clinical Research; Financial Interests, Institutional, Local PI, Trial payments to Institution:Bristol Myers Squibb, Genentech/Roche, BeiGene, Eli Lilly, Albion Laboratories, Akeso Biopharma,AbbVie, Five Prime Therapeutics, Dizal Pharma, Maxinovel, Amgen, Atridia, INXMED, Alpine Immune Sciences, Turning Point Therapeutics, IMPACT Therapeutics, Kinnate Biopharma, Rely Therapeutics,GenFleet Therapeutics, Vivace Therapeutics, Eucure Biopahrma, InventisBio, Cullinan Oncology, Tyra Biosciences, Axelia Oncology; Non-Financial Interests, Other, Scientiﬁc Advisory Committee member:Thoracic Oncology Group Australasia. E.S. Gray: Financial Interests, Personal, Invited Speaker, Invited to present at an MSD event in Melbourne, Australia: MSD Discovery Research Symposium, 28-29th October 2019, Melbourne, Victoria. “Liquid Biopsy for Predicting and Monitoring Response to Immune Checkpoint Blockade in Metastatic Melanoma Patients”: MSD; Financial Interests, Personal,Invited Speaker, Invited to present on a industry sponsored session at ESMO 2022European Society of Medical Oncology, 9-13th September 2022, Paris, France. “Circulating tumour DNA in patients with advanced ovarian cancer receiving neoadjuvant chemo-immunotherapy”: Thermo Fisher Scientiﬁc; Financial Interests, Institutional, Research Grant, Grant recipient for the following project:TCR repertoire in combination with HLA and TMB as predictor of response to immune checkpoint blockade in melanoma and lung cancer. Thermo Fisher Scientiﬁc Oncomine Clinical Research Grant. 2021. $200,000: Thermo Fisher Scientiﬁc. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2947

225P Utility of next-generation sequencing (NGS) in patients with advanced cancer in a low-middle income country

M. Lombana Quinonez1, J.C. Avila Valencia2, M. Garcia2, M.A. Ortiz2,A.M. Torres Paredes3

1Oncology Department, Clinica de Occidente, Cali, Colombia; 2Statitics, Clinica de Occidente, Cali, Colombia; 3Clinical Research, NALT SAS, Cali, Colombia

Background: NGS use improve outcomes in cancer patients. However, approved drugs in differents countries is a concern. The impact in intermediate-low income populations is less studied. We report the results about the utility of NGS at a comprehensive cancer center in Cali, Colombia. Country with less approved drugs by the national regulator (INVIMA) compared to populations such as in Europe (EMA) or United States (FDA).

Methods: Retrospective study of patients with advanced cancer who underwent NGS either by tissue or liquid biopsy, between March 2019 and March 2023 at The Comprehensive Cancer Center Clinica de Occidente in Cali-Colombia. Relevant sociodemographic, clinical, and molecular variables were included. We performed descriptive, Kaplan Meier and cox regression analysis. The study was approved by the institutional ethics committee. The information was analyzed with Stata 16.

Results: 156 patients were identiﬁed. Median age was 66 years (20-89), 51% men. 18 different tumors types were included, with lung (39.1%), prostate (22.4%), breast(7.0%), colorectal (6.3), ovarian (5.1%), gastroesophageal (5.0%), between the principals. Actionable alterations (ESCAT I-V) were found in 49.6% of the patients, most were evidence I in 81% of them. 90% had FDA approval, 84% EMA, and 59% national approval by INVIMA. After the NGS result, clinical decision was modiﬁed in 46.4% of cases and match therapy was used in 57.5% of them. In those patients, there was better clinical beneﬁt with OR 6 (95% CI 1.31-29.39, P¼0.0059) and objectiveresponse OR 12 (95% CI 1.88-88.38, P¼0.0012) There was signiﬁcant improvement ofPFS HR 0.27 (95% CI 0.13-0.56, P¼0.000) and OS HR 0.34 (95% CI 0.15-0.73, P¼0.002)Conclusions: Genomic proﬁling through NGS had a signiﬁcant impact on decisionmaking and patient prognosis, despite the fact that only 59% of the indicated matched drugs had national approval for their use.

Funding: Roche.

Disclosure: M. Lombana Quinonez: Financial Interests, Institutional, Invited Speaker: Roche. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2948

226P LongiBloodImmunoM: A multi-step analysis pipeline for longitudinal blood-based immunomonitoring for

immunotherapy clinical trial

J. Ye1, X. Lim1, K.S. Ng1, N.A. Kaya2, M.C. Lau3, M. Jia4, C.C.L. Cheung5, H.C. Toh6,S.P. Choo6, S.Y. Lee6, J.J.X. Lee6, J. Liu7, T.K.H. Lim8, W. Zhai9, D.W.M. Tai6,

J.P.S. Yeong10

1Institute of Molecular and Cell Biology, A*STAR - Agency for Science, Technology and Research, Singapore; 2Genome Institute of Singapore, A*STAR - Agency for Science,Technology and Research, Singapore; 3Bioinformatics Institute, A*STAR - Agency for Science, Technology and Research, Singapore; 4Institute of Molecular and Cell Biology,Singapore; 5Department of Anatomical Pathology, Singapore General Hospital,Singapore; 6Medical Oncology Department, NCCS - National Cancer Centre Singapore,Singapore; 7Centre for Quantitative Medicine and the Signature Programme in Health Services and Systems Research, Duke-NUS Medical School, Singapore; 8Department of Anatomical Pathology, SGH - Singapore General Hospital, Singapore; 9Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; 10Institute of Molecular and Cell Biology, Agency for Science,Technology and Research, Singapore

Background: Yttrium-90 (Y90)-resin microspheres radioembolization followed by nivolumab (Nivo) has shown encouraging response rate in advanced hepatocellular carcinoma (HCC), but only a subset of patients beneﬁt from it. Predictive biomarkers help to identify patients for the treatment.

Methods: Longitudinal plasma and peripheral blood mononuclear cells (PBMCs)collection from HCC patients who received sequential Y90-RE followed by nivolumab(CA209-678; NCT03033446) allowed assessment of dynamics changes. Predictor selection procedure includes individual timepoint comparison, average analysis, trajectory description, responsiveness prediction, and combined modalities validation.

65-plex Human ProcartaPlex Luminex panel was employed to examine the concentration of cytokines and chemokines in 187 plasma samples collected at eight timepoints (responder [R]¼11, non-responder [NR]¼22). Immunomonitoring of PBMCs(NR¼12, R¼5) was assessed with a 39-plex Cytek panel followed by dimensionreduction analysis. CXCL9 was reported impacting the immune treatment response,thus we focused on CXCL9+ CD8 cluster. Mixed models were ﬁtted for responsiveness represented by Luminex analytes and CD8 phenotypes. Logistic regression and Cox model were ﬁtted for the association between analytes and treatment response and 3-year overall survival (OS). Biomarkers showed signiﬁcant association (P<0.05) and AUC > 0.7 were selected as the potential predictors.

S271

Results: All Luminex biomarkers showed difference between the R and NR groups 14 days after Y90 treatment (P<0.05). The higher increment of IL-18, IL-12p70, and CCL24 after Y90 treatment related to better treatment response and 3-year OS.

CXCL9+ and CXCR3+ CD8 clusters differed between R and NR on the 21stand 35thday after Y90-RE, respectively. IL-18 and IL-12p70 were signiﬁcantly associated with CXCL9+ and CXCR3+ CD8 clusters in the Rs, but not NRs.

Conclusions: IL-18, IL-12p70, and CCL24 were potential predictors for treatment response as well as 3-year OS for HCC patients treated by Y90-Nivo.

https://doi.org/10.1016/j.annonc.2023.09.2949

227P

Biomarkers for novel NK checkpoint inhibitor anti LLT1 antibody, ZM008: Patient transcriptome analysis

M.S. Madhusudhan1, I. Garcia Ribas2, M. Ghosh3, A. Tiwari3, A. Dubey3,S. Bhattacharjee3, Y. Manjunath3, S. Kashipathi3, S. Krishna3, T. Mandal3,S. Gnanasegaran3, G. Rodrigues1

1Biology Bioinformatics and Structure, Indian Institute of Science Education and Research (IISER), Pune, India; 2Medical, IGR Consultant, Las Rozas, Spain; 3R&D,Zumutor Biologics, Bangalore, India

Background: C-type lectin superfamily protein LLT1 interacts with CD161 on NK cells and facilitates tumor immune escape. Disruption of LLT1-CD161 with anti LLT1 antibody, ZM008 activates immune cells and kills cancer cells. This study aims to identify new biomarkers to classify speciﬁc patient population in ZM008 clinical studies.

Methods: TCGA transcriptome data was used to understand expression of LLT1 in 33 cancers. Correlation analysis was performed to compare LLT1 expression with immune gene signatures. Genomic cancer markers (TMB, MATH, MMR and MSI) status were determined using “Maftools” and “MSI sensor”. Univariate Cox proportional hazard regression analysis (SURVIVAL) was used to measure patient survival.

Results: High expression of LLT1 was found in 11 different cancers. CIBERSORT analysis revealed signiﬁcant immune cell inﬁltration (activated NK or CD8+ T) in TME.

However, LLT1 expression in multiple cancers is negatively correlated with proin-ﬂammatory gene signatures (IL-2, IL-6, EOMES, and LAMP1 etc.), positively correlated with immune exhaustion markers PD1, LAG3, TIM3, TIGIT, ICOS and immune suppressive signals (high Treg cells and CD33+ MDSC; p <0.05). These data suggest immune suppressive “Cold tumor” phenotype associated with LLT1 expressing cancers. Further, immune check point predictors analysis in LLT1 positive tumors suggests positive correlation with high TMB score in COAD, UCEC and KICH; MSI score is elevated in PRAD and COAD; MMR genes expression is negatively correlated in COAD,KICH, BRCA, HNSC, KIRC, LUAD and PRAD; lastly, MATH score is correlated for GBM patients only (p <0.05). Subsequently, signiﬁcant hazard ratios of 1.115, 2.114 and

1.067 were observed only for COAD, KICH and KIRC, respectively (p < 0.05).

Conclusions: The transcriptome data analysis revealed LLT1 expression is associated with immune repressive TME in multiple cancers, suggesting therapeutic signiﬁcance of ZM008. Multiple anti-inﬂammatory gene signatures could be useful in stratifying patients for ZM008 treatment. In addition, TMB & MSI scores and MMR gene expression could be monitored as potential biomarkers in phase I clinical trials with ZM008.

Legal entity responsible for the study: Zumutor Biologics.

Funding: Zumutor Biologics.

Disclosure: I. Garcia Ribas: Other, Personal, Advisory role, Independent senior medical advisor:Zumutor. All authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2950

228P Biomarker discovery via meta-analysis of immunotherapy clinical trials in cancer

B. Haibe-Kains

Princess Margaret Cancer Centre, UHN - University Health Network - Princess Margaret Cancer Center, Toronto, ON, Canada

1Department of Medical Oncology and Genetic Counseling Unit, Cancer Center Clinica Universidad de Navarra (CCUN), Madrid And Pamplona, Spain; 2CIMA LAB Diagnostics, Universidad de Navarra, Pamplona, Spain; 3Department of Medical Oncology, Cancer Center Clinica Universidad de Navarra (CCUN), Madrid And Pamplona, Spain; 4Department of Medical Oncology, Cancer Center Clinica Universidad de Navarra (CCUN), Madrid And Pamplona, Madrid, Spain; 5Department of Medical Oncology, Cancer Center Clinica Universidad de Navarra (CCUN) and Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; 6Department of Medical Oncology and Program in Solid Tumors Cima-Universidad de Navarra, Cancer Center Clinica Universidad de Navarra (CCUN), Madrid And Pamplona, Spain; 7Genetic Counseling Unit, Cancer Center Clinica Universidad de Navarra (CCUN), Madrid And Pamplona, Spain; 8Genomic Medicine Unit, Cancer Center Clinica Universidad de Navarra (CCUN), Madrid And Pamplona, Spain

Background: In recent years, the use of Next Generation Sequencing based gene panels for the management of solid tumours has become almost routine testing in many Cancer Genomics Laboratories. In most cases, the purpose of the analysis is to identify biomarkers with potential predictive value. However, the mutations identiﬁed in the tissue may also have a hereditary origin. The objective of this study was to analyse the pathogenic germline variants identiﬁed as a somatic secondary ﬁnding in genes that have not been established to confer an increased risk for this speciﬁc tumour (‘off-tumour’).

Methods: A retrospective analysis was carried out on 330 patients in whom a tumour genomic analysis (somatic testing) had been performed in our institution between February 2022 and 2023. The genomic analysis tool was OncomineTMComprehensive Assay in all cases (500 gene panel). Germline-focused analysis was performed to variants with a variant allele frequency >30% (or >20% if small insertions/deletions)in genes consistent with hereditary predisposition to cancer.

Results: In the solid biopsies from 330 patients studied, 58 pathogenic variants of potential germline origin were identiﬁed in 54 patients (16.3%). In 23 of these patients (42.5%) the pathogenic variant was an ‘off-tumour’ ﬁnding. The median age at diagnosis of these 23 patients was 56 years-old, 21 patients (91.3%) had a metastatic or recurrent tumour and 11 (47.8%) did not meet any criteria of inherited predisposition to cancer. The results of the germline study are available in 10 of these 23 patients and the germline pathogenic variant was conﬁrmed in 7 cases (70%): 4 BRCA1, 1 ATM, 1 MUTYH and 1 PMS2. The most frequent related tumour was lung cancer, in 3 cases.

Conclusions: In our series of 330 cases tested for tumour genomics, 23 patients harboured an "off-tumour" pathogenic variant with potential germline origin, that was conﬁrmed in 7 out of 10 patients. Detected germline mutations included high penetrance cancer predisposing genes as BRCA1. This detection rate reﬂects the clinical utility, for patients and their families, of using the somatic genomic analysis as a source of information about a potential hereditary cancer predisposition syndrome.

|Table: 233P |Table: 233P ||| |---|---|---|---|

|Pts with PV/LPV (n[31) |||n (%) |

||Avoid radiotherapy||1(3.2%)|

||PARP inhibitors ||1 (3.2%) |

||Platinum-based |chemotherapy |2 (6.4%) |

||None (due t ||(22.6%)|

Disclosure: M.F. Sanmamed: Financial Interests, Personal, Advisory Board: Numab, Pieris, MSD;Financial Interests, Personal, Speaker’s Bureau: MSD, Replimune; Financial Interests, Personal,Research Grant: Roche, BMS, AZ. A. Gonzalez Martin: Financial Interests, Personal, Advisory Board:Amgen, AstraZeneca, Clovis, GSK, Genmab, Alkermes, Sutro, Roche, Sotio, PharmaMar, Oncoinvent,Novartis, Mersana, MSD, Macrogenics, Eisai, Inmunogen, Regeneron, HederaDx, Illumina; Financial Interests, Personal, Invited Speaker: GSK, AstraZeneca, Clovis, Roche, Novocure, MSD, Takeda, Zaylab; Financial Interests, Institutional, Coordinating PI, PI of ANITA trial: GSK, Roche; Financial Interests, Personal, Steering Committee Member, Member of ENGOT ov43-SC: MSD; Financial Interests, Institutional, Coordinating PI, ENGOT PI of EPIK-O trial: Novartis; Financial Interests,Institutional, Coordinating PI, ENGOT PI of AVB-500 phase III trial: ARAVIVE. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2955

233P Germline genetic testing before formal counseling: Impact in cancer management in a Spanish university hospital

M. Bringas Beranek1, I. Echavarria Diaz-Guardamino1, C. Polo1, C. Flores Sanchez2,A.J. Munoz Martin3, L. Ortega Morán1, B. Herrero Lopez1, P.A. Calvo Ferrandiz1,Y. Jerez Gilarranz1, G. Torres Perez-Solero1, S. Lopez-Tarruella Cobo4,

S. Gamez Casado1, S. Perez Ramirez1, A. Veiga Fernández5, J.A. Pajares6, M. Sanz7,J. Suarez8, M. Del Monte-Millan9, M. Martin Jimenez4, I. Marquez-Rodas1

1Medical Oncology Service, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; 2Medical Oncology Service, Hospital General Universitario Gregorio Marañón, Hospital General Universitario Gregorio Marañón, Madrid, Spain; 3Medical Oncology Service, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Hospital General Universitario Gregorio Marañón, Madrid, Spain; 4Medical Oncology Service, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, CIBERONC,Geicam, Universidad Complutense, Hospital General Universitario Gregorio Marañón,Madrid, Spain; 5Gynecology and Obstetrics Department, Hospital General Universitario Gregorio Marañón, Hospital General Universitario Gregorio Maranon,Madrid, Spain; 6Gastroenterology Service, Hospital General Universitario Gregorio Marañón. Gregorio Marañon, Hospital General Universitario Gregorio Maranon,Madrid, Spain; 7General Surgery Service, Hospital General Universitario Gregorio Marañón. Gregorio Marañon, Hospital General Universitario Gregorio Maranon,Madrid, Spain; 8Genomics Unit, Hospital General Universitario Gregorio Marañón,Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; 9Medical Oncology Service, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, CIBERONC, Hospital General Universitario Gregorio Marañón, Madrid, Spain

Background: Performing rapid genetic testing before consultation in a Hereditary Cancer Unit (HCU) is becoming increasingly common due to its importance in the decision-making of cancer management. There are few studies analyzing this new genetic counseling approach.

Methods:We conducted a retrospective descriptive study in a cohort of patients (pts)who underwent germinal genetic testing during their treatment plan at Hospital Gregorio Marañon since April 2019 to November 2022. Tests were directly ordered by their oncologists with a brief pre-test counseling prior to the formal evaluation in the HCU. Primary objective was to analyze if having these results available prior to formal genetic counseling could impact in the management of the patient’s cancer.

Results: 225 pts (32.9% men, 67.1% women) underwent genetic test. Cancer diagnoses were: pancreatic (49.3%), breast (40.4%), ovarian (5.8%), colorectal (2.6%),gastric (2.6%), prostate (1.3%), cholangiocarcinoma (1.3%), renal (1.3%) and endometrial 0.9%. A speciﬁc-syndrome genetic panel was performed in 55.1%, multigenetic in 44% and single gene in 0.9%. We found pathogenic/likely pathogenic variants (PV/LPV) in 31 pts (13.8%) and variants of unknown signiﬁcance (VUS) in 53(23.5%). 22.6% of the pts with PV/LPV (n¼7) didn’t meet the Spanish Society forMedical Oncology (SEOM) criteria for hereditary cancer. 40% of the pts (n¼90) Medical Oncology (SEOM) criteria for hereditary cancer. 40% of the pts (n=90) didn'tdidntreceive post-test counseling in the HCU: 81.1% due to negative result and non-signiﬁcant familial background, 10% due to patient’s death, 4.4% did not attend the appointment (rest unknown). According to retrospective chart review in 32.3% with PV/LPV (n¼10; 4.4% of the total) a change in cancer management was decided(Table).

Volume 34 - Issue S2

Avoid radiotherapy

1 (3.2%)

o death)

(22.6%)

*One patient could have more than one change

Conclusions: Genetic testing performance can modify the therapeutic plan of pts with cancer, especially for those with PV/LPV. Rapidity in obtaining the results is essential.

The balance between this rapidity and a proper post-test genetic counseling needs to be warranted.

Legal entity responsible for the study: Hospital General Universitario Gregorio Marañon.

Funding: Fondo de Investigación Sanitaria (FIS): PI18/01775.

Disclosure: M. Bringas Beranek: Financial Interests, Personal, Invited Speaker: Amgen; Other,Training: Pﬁzer, Lilly. I. Echavarria Diaz-Guardamino: Financial Interests, Personal, Advisory Board:Lilly, AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Pﬁzer, Novartis, Roche; Financial Interests, Personal, Writing Engagement: Pierre Fabre. A.J. Munoz Martin: Financial Interests, Personal, Speaker’s Bureau: Rovi, Stada, Menarini, Amgen, Merck; Financial Interests, Institutional,Funding: Rovi, Celgene, Leo Pharma; Financial Interests, Personal, Other: AstraZeneca, Roche. L.

Ortega Morán: Financial Interests, Personal, Speaker’s Bureau: Rovi, Leo Pharma, Menarini, Servier.

B. Herrero Lopez: Financial Interests, Personal, Other: Roche, Novartis, PharmaMar, Eisai, Teva,Kyowa Kirin, AstraZeneca, GSK. Y. Jerez Gilarranz: Financial Interests, Personal, Speaker’s Bureau:Daichii Sankyo, Pﬁzer, Novartis, Gilead, Lilly. S. Lopez-Tarruella Cobo: Financial Interests, Personal,Advisory Board: AstraZeneca, Daiichi Sankyo, Pﬁzer, Novartis, Lilly, Gilead, GSK, Roche, Pierre Fabre,Seagen, Menarini_Stemline, Gebro Pharma; Non-Financial Interests, Member of Board of Directors:Geicam, SEOM. A. Veiga Fernández: Financial Interests, Personal, Other, Book chapter: Amazing

- 2023

Books. M. Martin Jimenez: Financial Interests, Personal, Advisory Board: AstraZeneca, Lilly, Roche/Genentech, Daiichi Sankyo, Menarini-Stemline; Financial Interests, Personal, Invited Speaker: Pﬁzer,AstraZeneca, Lilly, Novartis, Roche/Genentech; Financial Interests, Institutional, Research Grant:Novartis, Roche, Puma; Non-Financial Interests, Member of Board of Directors: TRIO; Non-Financial Interests, Leadership Role: Geicam; Non-Financial Interests, Member: ASCO; Non-Financial Interests,Advisory Board: SEOM. I. Marquez-Rodas: Financial Interests, Personal, Advisory Board: BMS, MSD,Novartis, Pierre Fabre, Roche, GSK, AstraZeneca, Celgene, Regeneron, Sanoﬁ, Merck Serono, Highligth Therapeutics, Bioline Rx, Sun Pharma, Immunocore; Financial Interests, Personal and Institutional, Coordinating PI, GEM1802 clinical trial: Pierre Fabre; Financial Interests, Institutional,Coordinating PI, GEM1801 clinical study: Novartis, BMS, Roche, Pierre Fabre, Incyte, MSD; Financial Interests, Institutional, Coordinating PI, National coordinator of Spotlight 203 clinical trial: Highlight Therapeutics; Non-Financial Interests, Member of Board of Directors: Spanish Melanoma Group. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2956

234P

Plasma cell free DNA hydroxymethylation proﬁling reveals anti-PD1 treatment response and resistance biology in nonsmall cell lung cancer

F. Feng, et al.

Radiation Oncology, UCSF Medical Center at Mission Bay, San Francisco, CA, USA

235TiP Hamlet.rt Trans: Prospective single-centre translational study evaluating liquid biomarkers of radiation response

M. Denholm1, H.W. Martin2, A. Roshan3, S. Miller4, G. Harden4, C. Towns4,

S. Kadyan4, P. Mennea5, D. Muñoz-Espín1, N. Rosenfeld2, G.C. Barnett6, R. Rintoul3,C.E. Coles7, H. Yang6, R. Jena8

1Oncology, Early Cancer Institute, Cambridge University, Cambridge, UK; 2Oncology,CRUK Cambridge Institute, Cambridge, UK; 3Oncology, CRUK - Cancer Research UK Cambridge Institute - University of Cambridge, Cambridge, UK; 4Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK;5Rosenfeld Lab, CRUK - Cancer Research UK Cambridge Institute - University of Cambridge, Cambridge, UK; 6Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; 7Oncology Department, University of Cambridge -Clinical Oncology - R block (R4), Cambridge, UK; 8Oncology, Addenbrooke’s Hospital,Cambridge, UK

Background: Hamlet.rt (Heuristics, Algorithms and Machine Learning: Evaluation &Testing in Radiation Therapy) is a multi-centre study exploring the role of machine learning in predicting response and toxicity in patients receiving radical radiotherapy for non-small cell lung cancer (NSCLC), Head and Neck Cancer (H&N Cancer) and Prostate cancer. Hamlet.rt Trans is a translational sub-study that leverages the infrastructure of Cancer Research UK RadNet Cambridge to evaluate multiple liquid biomarkers of radiation response. This study aims to investigate biomarkers of treatment response in patients with lung and head and neck cancers and markers of treatment toxicity in patients with prostate cancer.

https://doi.org/10.1016/j.annonc.2023.09.437

240MO Prognostic and predictive impact of estrogen/progesterone receptor (ER/PR), and Ki-67 expression: An exploratory

analysis from the monarchE trial in patients with high-risk,HR+, HER2-, early breast cancer (EBC)

M.P. Goetz1, N. Turner2, H. Sasano3, C. Arteaga4, S. Chandarlapaty5, S. Loi6,J.S. Reis-Filho5, H. Kreipe7, N. Harbeck8, P. Fasching9, C.S. Rubenstein10,S. Wijayawardana10, M. Muñoz10, L.M. Litchﬁeld10, S.R.D. Johnston2

1Department of Oncology, Mayo Clinic, Rochester, NY, USA; 2Department of MedicineBreast Unit, Royal Marsden NHS Foundation Trust & Institute of Cancer Research,London, UK; 3Department of Pathology, Tohoku University Hospital, Sendai, Japan;4Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; 5Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 6Division of Research and Clinical Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; 7Institute of Pathology, Hannover Medical School, Hannover, Germany; 8Breast Center,Department of Gynecology and Obstetrics, Comprehensive Cancer Center Munich,Ludwig Maximilians University Hospital, Munich, Germany; 9Department of Gynecology and Obstetrics, Universitätsklinikum Erlangen, Erlangen, Germany; 10Oncology,Eli Lilly and Company, Indianapolis, IN, USA

Background: The monarchE trial demonstrated that the addition of abemaciclib to endocrine therapy (ET) signiﬁcantly improved invasive disease-free survival (IDFS) and distant relapse-free survival in node-positive, high-risk EBC patients (pts) with beneﬁt deepening beyond the 2-year (yr) treatment (tx) period. Ki-67 20% was deepening beyond the 2-year (yr) treatment (tx) period. Ki-67 ≥20% was prognosticprognosticof breast cancer outcomes but not predictive of abemaciclib beneﬁt. Here, we evaluate expression of ER, PR and Ki-67 to determine their prognostic and predictive impact, including analyses as continuous variables.

Methods: ER/PR and Ki-67 expression was determined by immunohistochemistry(IHC). The graphical Subpopulation (subp) Tx Effect Pattern Plot (STEPP) analysis was conducted for each biomarker to robustly assess the tx effect ensuring a balance between subp sample size and enough number of overlapping subp. Cox proportional hazards model was used to estimate hazard ratios (HR) and 95% conﬁdence intervals(CI) (CI) for ER/PR status subtypes (positive ≥1%).for ER/PR status subtypes (positive 1%).

Results: Each IHC cohort varied slightly in number of pts and the precise IDFS HR point estimate (abemacilib+ET vs ET), but STEPP analysis revealed consistent abemaciclib tx beneﬁt regardless of ER, PR or Ki-67 expression (Table, A). The IDFS beneﬁt of abemaciclib was also consistent in ER+/PR+ and ER+/PR- tumors (Table, B). The 3-yr IDFS rates of the control arm showed that pts with PR- tumors had a higher risk of recurrence. Pts with ER- tumors followed a similar trend, but the effect could not be robustly estimated due to small numbers..

Conclusions: Consistent IDFS beneﬁt of adjuvant abemaciclib was observed regardless of the level of ER, PR or Ki-67 expression, as well as in ER+/PR+ and ER+/PR- tumors.

Similar to Ki-67 20%, PR- status was prognostic of worse outcomes with ET Similar to Ki-67 ≥20%, PR-status was prognostic of worse outcomes with ET alone.alone.

|Table: 240MO Summary of STEPP and IDFS analysis |||||| |---|---|---|---|---|---|

|A. Summary statistics for the deviation of the STEPP |Subp, HRs from the overall Tx effect Overall IDFS HR |Subp, HRs from the overall Tx effect Overall IDFS HR |Subp, HRs from the overall Tx effect Overall IDFS HR |Subp, HRs from the overall Tx effect Overall IDFS HR |Median of the STEPP HRs (IQR) |

|ER (n¼4520) ||0.74 |||0.75 (0.69 e 0.87) |

|PR (n¼4012) ||0.78 |||0.71 (0.64 e 0.78) |

|Ki-67 (n¼4425) ||0.65 |||0.65 (0.55 e 0.76) |

|B. IDFS in ER/PR Subtypes ||||||

|Abemaciclib+ET ||ET |||HR (95% CI) Interaction p-valu |

|n events 3-yr |rate |n |events |3-yr rate ||

|ER+/PR+ 2405 275 89.9% ||2437 |392 |85.9% |0.698 (0.599, 0.815) 0.2531 |

|ER+/PR- 298 50 |83.2% |295 |86 |73.0% |0.560 (0.395, 0.794) |

|ER-/PR+ 16 5 NE* ||17 |8 |NE* |NE* NE* |

|IQR, Interquartile range. *Not estimated (NE) due to low |numbers |numbers |numbers |numbers ||

Clinical trial identiﬁcation: NCT03155997.

Editorial acknowledgement: Monique Mendonca, employee of Eli Lilly and Company,

provided medical writing support and editorial assistance.

Legal entity responsible for the study: Eli Lilly and Company.

Funding: Eli Lilly and Company.

Disclosure: :M.P. Goetz: Financial Interests, Institutional, Advisory Board: ARC Therapeutics, Biotheranostics, Blueprint Medicines, Rna Diagnostics, Sanoﬁ Genzyme; Financial Interests, Institutional, Other, Consulting: AstraZeneca, Seattle Genetics; Financial Interests, Institutional, Other,

General Consulting: Lilly; Financial Interests, Personal, Invited Speaker, CME Activity: Research to

Practice, Clinical Education Alliance, Medscape, MJH Life Sciences; Financial Interests, Personal,

Invited Speaker, CME Panel Discussant: Total Health Conferencing; Financial Interests, Personal,

Other, Moderator for CME Activity: Curio Science; Financial Interests, Institutional, Local PI: Lilly,

Pﬁzer, LOXO, ATOSSA Therapeutics, AstraZeneca, Sermonix. N. Turner: Financial Interests, Personal,

Advisory Board: AstraZeneca, Lilly, Novartis, Pﬁzer, Roche/Genentech, GSK, Zentalis pharmaceuticals,

Repare therapeutics, GSK, Relay therapeutics, Gilead, Inivata, Guardant, Exact Sciences; Financial

Interests, Institutional, Funding: AstraZeneca, Pﬁzer, Roche/Genentech, Merck Sharpe and Dohme,

Invitae, Inivata, Personalis, Natera; Financial Interests, Institutional, Other, provision of materials:

BioRad; Financial Interests, Institutional, Other, Provision of assays: Guardant Health. H. Sasano:

Financial Interests, Personal, Full or part-time Employment: Tohoku University . C. Arteaga: Financial

Interests, Personal, Speaker, Consultant, Advisor: Novartis, Eli Lilly, Merck, AstraZeneca, Daiichi

Sankyo, TAIHO Oncology, PUMA Biotechnology, Immunomedics, OrigiMed, Sanoﬁ; Financial Interests, Personal, Research Funding: Pﬁzer, Pﬁzer, Takeda. S. Chandarlapaty: Financial Interests,

Personal, Advisory Board, Consultant: Novartis, Boxer Capital, Totus Medicines, Nuvalent, Inivata,

Neogenomics; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests,international guidelines lowered the cutoffs for ER to ≥1% in 2010, the ≥10%Personal and Institutional, Advisory Board, Consultant: AstraZeneca; Financial Interests, Personal,Research Grant: AstraZeneca; Financial Interests, Personal, Ofﬁcer: Odyssey Biosciences; Financial

Interests, Personal, Stocks/Shares: Odyssey Biosciences. S. Loi: Financial Interests, Institutional,

Advisory Board, Consultant: Aduro Biotech, Novartis, GSK, Roche Genentech, AstraZeneca, Silverback

Therapeutics, G1 Therapeutics, Pﬁzer, Seattle Genetics; Financial Interests, Institutional, Advisory

Board, COnsultant: PUMA Biotechnologies, BMS; Financial Interests, Institutional, Advisory Board,

consultant: Gilead Therapeutics, Daiichi Sankyo, Merck, Amunix, Tallac Therapeutics, Eli Lilly;

Financial Interests, Institutional, Funding, Research: Novartis, BMS, Merck, PUMA Biotechnology, Eli

Lilly, Roche - Genentech, Nektar Therapeutics, AstraZeneca, Seattle Genetics; Non-Financial Interests, Advisory Role, Consultant (Non remunerated): Seattle Genetics, Novartis, Bristol Myers

Squibb, Merck, AstraZeneca, Roche Genentech; Non-Financial Interests, Advisory Role, consultant

(not compensated): Pﬁzer, Eli Lilly, Gilead Therapeutics. J.S. Reis-Filho: Financial Interests, Personal,

Other, Consultant: Goldman Sachs, Eli Lilly, Saga Diagnostics; Financial Interests, Personal, Other,

Member of the Scientiﬁc Advisory Board and Consultant: Repare Therapeutics, Paige.AI; Financial

Interests, Personal, Advisory Board: Personalis, Roche Tissue Diagnostics; Financial Interests, Personal, Advisory Board, Member of the Scientiﬁc Advisory Board: Bain Capital; Financial Interests,

Personal, Advisory Board, Ad hoc member of the Pathology Scientiﬁc Advisory Board: Daiichi Sankyo,

Merck; Financial Interests, Personal, Advisory Board, Ad hoc member of the Oncology Scientiﬁc

Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board, Member of the SAB:

MultiplexDX; Financial Interests, Personal, Member of Board of Directors: Odyssey Bio, Grupo

Oncoclinicas; Financial Interests, Personal, Stocks/Shares: Repare Therapeutics; Financial Interests,

Personal, Other, Stock options: Paige.AI. H. Kreipe: Financial Interests, Personal, Other, Payment or

honoraria for lectures: Roche Pharma, Novartis, Genomic Health, AstraZeneca, Eli Lilly, Pﬁzer, Daiichi

Sankyo; Financial Interests, Personal, Advisory Board: Roche Pharma, Genomic Health, AstraZeneca.

N. Harbeck: Financial Interests, Personal, Speaker’s Bureau, Fees for Non-CME Services Received

Directly from Commercial Interest or their Agents: Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly,

Exact Sciences, MSD, Novartis, Pﬁzer, Pierre Fabre, Seagen; Financial Interests, Personal, Advisory

Board, Consulting Fees: AstraZeneca, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Pﬁzer, Pierre Fabre,

Roche, Sandoz, Seagen; Financial Interests, Personal, Sponsor/Funding, Fees for Non-CME Services

Received Directly from Commercial Interest or their Agents: Roche; Financial Interests, Personal,

Research Funding, Contracted Research: Roche; Financial Interests, Personal, Writing Engagement,

Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of

Health Interactions: Roche; Financial Interests, Personal, Stocks or ownership: WSG. P. Fasching:

Financial Interests, Personal, Advisory Board: Roche, Novartis, Pﬁzer, Daiichi Sankyo, Eisai, Merck,

Sharp & Dohme, AstraZeneca, Hexal, Lilly, Pierre Fabre, Seagen, Agendia, Sanoﬁ Aventis; Financial

Interests, Personal, Invited Speaker: Novartis, Daiichi Sankyo, Eisai, Merck, Sharp & Dohme, AstraZeneca, Lilly, Seagen, Gilead; Financial Interests, Personal, Other, Medical Writing Support: Roche;

Financial Interests, Institutional, Local PI: BionTech, Cepheid; Non-Financial Interests, Member:

ASCO, Arbeitsgemeinschaft für Gynäkologische Onkologie e.V., Translational Research in Oncology,

Deutsche Gesellschaft für Senologie e.v. C.S. Rubenstein: Financial Interests, Institutional, Full or

part-time Employment: Loxo at Lilly. S.Wijayawardana: Financial Interests, Personal, Full or part-time

Employment: Eli Lilly and Company; Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company. M. Muñoz: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company;

Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company. L.M. Litchﬁeld: Financial Interests,

Personal, Full or part-time Employment: Eli Lilly and Company; Financial Interests, Personal, Stocks/

Shares: Eli Lilly and Company. S.R.D. Johnston: Financial Interests, Personal, Advisory Board,

Consulting Fees: AstraZeneca, Eli Lilly and Company, Pﬁzer, Biotechnology, Novartis, Sanoﬁ Genzyme,

Puma Biotechnology; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Pﬁzer, Eisai,Roche/Genentech.

https://doi.org/10.1016/j.annonc.2023.09.438

241MO Patient characteristics and real-world outcomes in HER2 negative/ ER zero and ER low patients treated as triplenegative breast cancer in Sweden 2008-2020

I. Fredriksson1, B. Acs2, J. Hartman2, D. Sönmez3, H. Lindman4

1Department of Molecular Medicine and Surgery, Karolinska Institutet & Karolinska University Hospital, Comprehensive Cancer Center, Stockholm, Sweden; 2Department of Oncology-Pathology & Department of Clinical Pathology and Cancer Diagnostics,Karolinska Institutet & Karolinska University Hospital, Comprehensive Cancer Center,Stockholm, Sweden; 3Oncology Department, MSD - Merck Sharp & Dohme (Sweden)AB, Stockholm, Sweden; 4Oncology, University Hospital Uppsala/Akademiska Sjukhuset, Uppsala, Sweden

Background: Estrogen receptor-low (ER-low) Her2-negative breast cancer has similar pathological and molecular characteristics as triple-negative breast cancer (TNBC),and it is questionable whether it should be considered a separate entity. When the international guidelines lowered the cutoffs for ER to 1% in 2010, the 10%threshold was kept in Sweden. ER-low breast cancer (ER 1-9%) has thus in Sweden been treated as TNBC, which is interesting now that the international community recognize limited data for beneﬁt of endocrine therapy in the ER-low group The beneﬁt of endocrine therapy in these tumors is under debate and discussion. We aimed to describe real-world patient and tumor characteristics, treatment patterns and overall survival in a Swedish population-based cohort of patients with HER2 negative/ ER zero and ER low breast cancer treated as TNBC.

Methods: TNBC cases diagnosed in Sweden 2008-2020 were included in a populationbased cohort study. Patient, tumour and treatment characteristics were analysed by ER status (ER-negative 0% vs ER-low 1-9%), and associations between subgroups compared using c2test. Endpoints were overall survival (OS) and distant disease-free survival (DDFS). Kaplan-Meier curves were used to describe time-to-event endpoints and Cox proportional hazards models to estimate adjusted hazard ratios.

Results: Of the 5657 tumors, 90.1% were ER-negative and 9.9% ER-low. In the unadjusted analysis of OS, ER-low disease was associated with a borderline signiﬁcantly better OS than ER-negative disease (n¼3893, HR 0.83 (0.70-1.001), p¼0.051), but thiswas restricted to patients not given chemotherapy (n¼1764, HR 0.65 (0.50-0.88),p¼0.002). ER-status 0% vs 1-9% did not affect OS in the multivariable analysis (HR1.09, 95% CI 0.89-1.34). DDFS did not differ by ER-status 0% vs 1-9% (n¼1299, HR0.97 for ER-negative vs ER-low (0.62-1.53)). After preoperative treatment, the importance of pCR for OS did not signiﬁcantly differ between ER-negative or ER-low disease.

Conclusions: ER-low breast cancer has characteristics and prognosis similar to ERnegative breast cancer when treated as TNBC. The use of 10% as threshold for negative breast cancer when treated as TNBC. The use of ≥10% as threshold for ERERpositivity is supported by this study.

Legal entity responsible for the study: Karolinska Institutet.

Funding: MSD.

Disclosure: I. Fredriksson: Other, Institutional, Coordinating PI: MSD. J. Hartman: Financial Interests, Personal, Full or part-time Employment: Stratipath. D. Sönmez: Financial Interests, Personal,Full or part-time Employment: MSD. H. Lindman: Other, Institutional, Invited Speaker: MSD. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.439

242MO

Association of tumor-inﬁltrating lymphocytes (TILs) with recurrence score (RS) in patients with hormone receptorpositive (HR+)/HER2-negative (HER2-) early breast cancer(BC): A translational analysis of four prospective multicentric studies

F. Miglietta1, M.V. Dieci2, T. Giarratano3, V. Torri4, M. Giuliano5, F. Zustovich6,M. Mion7, C. Tondini8, E. Bria9, M. Franchi10, L. Merlini11, R. Giannatiempo12,D. Russo13, V. Fotia8, P. Poletti8, E. Rota Caremoli8, G. Arpino14, G. De Salvo15,A. Zambelli16, V. Guarneri17

1Oncologia 2; Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche, IOV - Istituto Oncologico Veneto IRCCS; Unipd, Padua, Italy; 2DiSCOG,University of Padua, Padua, Italy; 3Oncology 2, IOV - Istituto Oncologico Veneto IRCCS,Padua, Italy; 4Oncology, Istituto di Ricerche Farmacologiche Mario Negri - IRCCS,Milan, Italy; 5Oncology, AOU “Federico II”, Naples, Italy; 6Oncology, Ospedale di Belluno, Belluno, Italy; 7UOC Oncologia, Camposampiero-Cittadella, AULSS6, Camposampiero, Italy; 8Medical Oncology Department, ASST Papa Giovanni XXIII, Bergamo,Italy; 9Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS Rome, Italy, Medical Oncology, Università; Cattolica del Sacro Cuore,Rome, Italy; 10Oncology, FROM Fondazione per la Ricerca Ospedale Maggiore, Bergamo, Italy; 11Oncology, UOSD Montecchio Maggiore, Vicenza, Italy; 12UOD di Anatomia Patologica, Ospedale Evangelico Betania, Naples, Italy; 13Unit of Pathology,Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples,Italy; 14Oncology, Università degli Studi di Napoli Federico II - Dipartimento di Farmacia, Naples, Italy; 15Unità di Ricerca Clinica, IOV - Istituto Oncologico Veneto IRCCS, Padua, Italy; 16Humanitas Cancer Center, Humanitas University, Milan, Italy;17Department of Surgery, Oncology and Gastroenterology Dept., University of Padua,Padua, Italy

Background: Oncotype DX represents one of the genomic assays associated with the highest quality of evidence driving a strong recommendation for its use to guide decisions on adjuvant therapy for HR+/HER2- early BC patients. The clinical value of TILs in HR+/HER2- BC may be unearthed by focusing on patients whose tumors exhibit features of higher biological aggressiveness. Here we deepen and describe the correlation between RS and TILs, proposing an immuno-genomic model for HR+/HER2-BC.

Methods: We enrolled T1-T3, N0-N1 BC patients with available RS and TILs in the context of four multicenter, prospective studies primarily aimed at assessing the impact of the Oncotype DX test on adjuvant treatment decisions in a clinical practice scenario. RS was categorized into: 0-10 (low risk), 11-25 (intermediate risk)and 26-100 (high risk); TILs were categorized into: low (0-10%), intermediate (11-59%)and high (60-100%).

Results: 811 patients were included. RS distribution was (n¼810): low risk 22.0%,intermediate risk 61.2%, high risk 16.8%. TIL distribution was (n¼455): low TILs 84.6%,intermediate TILs 13.6% and high TILs 1.8%. A signiﬁcant, weak positive, linear correlation was found between continuous TILs and RS (Pearson coefﬁcient¼0.223,p<0.001). When considering RS and TILs categories, tumors with intermediate/high TIL levels signiﬁcantly enriched the high RS subgroup (p¼0.006). This was conﬁrmedboth both within Luminal A (Ki67<20% and PgR ≥20%) and Luminal B cohorts (ki67≥20%within Luminal A (Ki67<20% and PgR 20%) and Luminal B cohorts (ki6720%and/or PgR <20%). Among high-RS patients, 16.7% of Luminal A and 26.7% of Luminal B tumors had intermediate/high TILs.

Conclusions: We observed that RS and TILs capture only slightly overlapping information on the biology of HR+/HER2- tumor microenvironment. We demonstrated the feasibility of combining RS and TILs into a composite immuno-genomic model, which may identify patients simultaneously showing features of high biological/clinical risk and enhanced immunogenicity and may serve the purpose of guiding and focalizing patient selection in the further development of immunotherapy strategies for Luminal-like disease.

Funding: Fondazione AIRC under 5 per mille 2019 - ID. 22759 program to VG and IG20583 to EB; Institutional funds from UniPD (FM, MVD, VG).

Disclosure: F. Miglietta: Financial Interests, Personal, Speaker, Consultant, Advisor, outside the submitted work: Roche, Novartis, Gilead, Pﬁzer, Seagen. M.V. Dieci: Financial Interests, Personal,Invited Speaker: Eli Lilly, Exact sciences, Gilead, Seagen, Daiichi Sankyo, Novartis; Financial Interests,Personal, Advisory Board: Novartis, Eli Lilly, Seagen, Exact Science, Daiichi Sankyo, Gilead; Financial Interests, Personal, Other, Consultancy: Pﬁzer; Financial Interests, Personal, Other, Consultancy on educational project: Roche. T. Giarratano: Financial Interests, Personal, Speaker, Consultant, Advisor,outside the submitted work: Roche. E. Bria: Financial Interests, Personal, Advisory Board: AZ, Roche,BMS, MSD, Eli-Lilly, Amgen, Pﬁzer, Novartis; Financial Interests, Personal, Invited Speaker: AZ, Roche,BMS, MSD, Eli-Lilly, Pﬁzer, Novartis; Financial Interests, Institutional, Research Grant: AZ, Roche. A.

Zambelli: Financial Interests, Personal, Advisory Board, outside the submitted work: Pﬁzer, Roche,Novartis, Lilly, Daiichi Sankyo, Seagen, AstraZeneca, MSD, ExactSciences. V. Guarneri: Financial Interests, Personal, Invited Speaker: Eli Lilly, Novartis, Amgen, GSK; Financial Interests, Personal,Advisory Board: Eli Lilly, Novartis, MSD, Gilead, Eli Lilly, Sanoﬁ, Merck Serono, Exact Sciences, Eisai,Olema Oncology; Financial Interests, Institutional, Local PI: Eli Lilly, Roche, BMS, Novartis, AstraZeneca, MSD, Synton Biopharmaceuticals, Merck, GSK, Daiichi Sankyo, Nerviano; Non-Financial Interests, Member: ASCO. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.440

243MO Omission of breast surgery after neoadjuvant systemic

therapy for invasive cancer: Three-year preplanned primaryendpoint on a phase II multicentre prospective trial

H.M. Kuerer1, G. Rauch2, S. Krishnamurthy3, E. Diego4, W. Yang2, Y. Shen5, H. Lin6,A. Lucci7, T. Moseley2, D.L. Ramirez8, J.A. Mouabbi8, J. Boughey9, S. Shaitelman10,R.White11, K. Hunt1, M. Mitchell10, M. Teshome1, H. Johnson1, B. Smith10, V. Valero8

1Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center,Houston, TX, USA; 2Breast Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 4Breast Surgery, University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA; 5Biostatistics, MD Anderson Cancer Center, Houston, TX, USA; 6Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 7Breast Surgery Dept., The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 8Breast Medical Oncology, The University of Texas MD Anderson Cancer Cente, Houston, TX, USA; 9Division of Breast and Melanoma Surgical Oncology, Mayo Clinic, Rochester, NY, USA; 10Breast Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 11Surgery, Levine Cancer Institute-Concord - Carolinas HealthCare System, Concord, MA, USA

Background: Neoadjuvant systemic therapy (NST) for triple-negative breast cancer(TNBC) and HER2+ breast cancer (HER2+BC) yields a pathol-ogic complete response(pCR) in approximately 60% of patients. A pCR to NST predicts an excellent prognosis and can be accurately determined by percutaneous image-guided vacuum-assisted core biopsy (VACB). Radiotherapy alone, without breast surgery after NST among patients who had a VACBedetermined pCR was evaluated in the feasibility phase(Johnson et al. JACS 2023 ), 2-year pre-planned primary outcome (Kuerer et al Lancet Onc 2022 ), the 32.4 mo patient reported outcomes (Johnson et al SSO 2023 ) and now at the preplanned 3-year primary endpoint.

Methods: This multicentre phase ll clinical trial enrolled women aged ≥40 years withThis multicentre phase II clinical trial enrolled women aged 40 years withunicentric cT1-2N0-1M0 TNBC or HER2+BC and a residual breast lesion <2 cm on imaging after NST. One biopsy was obtained by 9G image-guided VACB containing a minimum of 12 cores from the tumour bed. If no invasive/in situ disease was identiﬁed, breast surgery was omitted, and patients underwent whole-breast radiotherapy/boost. Primary outcome was ipsilateral breast tumour recurrence (IBTR) rate and secondary outcomes included evaluation of baseline and longitudinal obtained circulating tumor cells (CTCs) in a total of 33 blood samples and patient-reported outcomes.

impact of the Oncotype DX test on adjuvant treatment decisions in a clinicalResults: During 2017-2021 50 total patients were enrolled and underwent VACB following NST. The mean age was 60$4 years (SD 7$8); 21 patients had TNBC and 29 had HER2+BC. Mean imaging ﬁnal tumour size after NST was 0$90 cm (SD 0$81), and 17 patients (34%) had a complete radiologic response. VACB identiﬁed a pCR in 31 patients (62%). Among these 31 patients, median follow-up was 38.4 months (IQR:

22.4-49$5) the 3-year IBTR rate was 0% (primary endpoint) and 3-year DFS and OS rates were 100%. Two patients were CTC-positive at baseline, 2 were positive at 6-months, and 1 at 12-months. No patients had CTCs detected at more than one timepoint.

Conclusions: Eliminating breast surgery in highly selected patients with an imageguided VACBedetermined pCR following NST shows promising 3-year results and additional time and clinical trials evaluating this approach are indicated.

Clinical trial identiﬁcation: NCT02945579; 20-1-2017 release date.

Legal entity responsible for the study: The University of Texas MD Anderson Cancer Center.

Funding: US National Cancer Institute (National Institutes of Health).

Disclosure: H.M. Kuerer: Financial Interests, Personal, Writing Engagements, Editor: NEJM Group;Financial Interests, Personal, Advisory Board: Merck Inc; Financial Interests, Personal, Invited Speaker: Physician Education Resources Inc; Financial Interests, Personal, Royalties, Textbook Editor:McGraw-Hill Professional, Inc; Financial Interests, Personal, Royalties: Elsevier Publishing, Inc;Financial Interests, Personal, Royalties, Editor: Up-To-Date, Inc; Other, Institutional, Invited Speaker,Breast Committee Leadership: NRG Oncology. G. Rauch: Financial Interests, Institutional, Research Grant: GE Healthcare, Inc. S. Krishnamurthy: Financial Interests, Personal, Advisory Board: AstraZeneca Inc; Financial Interests, Personal, Royalties: Elsevier Publishing, Inc. W. Yang: Financial Interests, Personal, Royalties: Elsevier Publishing, Inc. J.A. Mouabbi: Financial Interests, Personal,Advisory Board: GE Healthcare, Inc, Cardinal Health, Inc. J. Boughey: Financial Interests, Institutional,Research Grant: SymBioSis, Inc. S. Shaitelman: Financial Interests, Institutional, Research Grant:Alpha Tau, Exact Sciences, TAE Life Sciences, Artios Pharmaceuticals. K. Hunt: Financial Interests,Personal, Advisory Board: ArmadaHealth, AstraZeneca; Financial Interests, Institutional, Research Grant: Cairn Surgical, Eli Lilly and Company, Lumicell. M. Mitchell: Financial Interests, Institutional,Research Grant: Artidis. B. Smith: Financial Interests, Institutional, Research Grant: Artidis, Varian Medical Systems; Financial Interests, Personal, Stocks/Shares: Oncora Medical. V. Valero: Financial Interests, Personal, Invited Speaker: Roche. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.441

244MO

Volume 3

A phase II trial targeting disseminated dormant tumor cells with hydroxychloroquine, everolimus or the combination to prevent recurrent breast cancer (“CLEVER”)

A. DeMichele1, A.S. Clark1, L. Bayne1, K. Rohn1, I. Nivar1, P. Wileyto2, L. Berry3,S. DeLuca1, J. Savage4, I. Makhlin1, T.C. Pan5, J. Graves5, G. Belka5, J. Wang5,N. Shih6, D. Berry3, A. Nayak6, M. Feldman7, L. Chodosh5

1Department of Hematology-Oncology, University of Pennsylvania, Philadelphia, PA,USA; 2Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA, USA; 3Clinical Trials, Berry Consultants, Austin, TX,USA; 4Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA;5Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA;6Department of Pathology, University of Pennsylvania, Philadelphia, PA, USA;7Department of Pathology, Indiana University, Indianapolis, IN, USA

Background: Breast cancer (BC) recurrence may follow a dormant phase in which quiescent cells reside in niches such as bone marrow (BM). Dormant BM disseminated tumor cells (DTCs) are independently associated with BC recurrence/death. We investigated whether targeting dormancy through autophagy inhibition (hydroxychloroquine (HCQ), and/or mTOR signaling (everolimus (EVE) in DTC+ BC survivors was feasible, reduced DTCs and/or prevented recurrence.

Methods: The CLEVER trial (NCT03032406) is a randomized, phase II trial in patients(pts) diagnosed within 5 years, with positive nodes, triple-negative disease, high-risk Oncotype/Mammaprint, and/or residual disease post-neoadjuvant therapy who completed all treatment except endocrine therapy. DTCs were detected in BM aspirate (BMA) by IHC with pan-CK antibody AE1/AE3. DTC+ pts were randomized to six 28-day cycles (C) of HCQ (600 mg BID), EVE (10 mg daily) or both (+/- 3-month (m0)observation period). If DTC+ persisted after C6, pts received another 6C HCQ+EVE.

DTC assessment was done after C3, C6, C12 (if applicable) and 6-mo after end of treatment. .Adverse events (AE) were assessed by CTCAEv4. Primary endpoint was feasibility, deﬁned as >75% completion of C6C without G3/G4 AE. Secondary endpoints were safety, DTC response rate (RR) and 3-year RFS. DTC RR was analyzed with Bayesian Poisson regression models.

Results: 184/197 eligible pts had baseline BMA, 55 (30%) were DTC+, 53 were randomized: HCQ (n¼15), EVE (n¼15), and HCQ+EVE (n¼23). 13 patients had repeatafter 3-mo observation. Feasibility endpoint was met. There were no G4/5 toxicities.

At a median follow up of 42 mo (range 7-60), 1 pt recurred in lung (after 2 cycles EVE),1 pt developed new contralateral breast cancer. The posterior probabilities that HCQ,EVE, and HCQ+EVE reduced DTCs by at least 80% after C3 vs observation alone are

99.1%, 98.2%, and 99.9%, respectively.

Conclusions: The CLEVER trial provides proof-of-principle that therapeutic targeting of dormant BC is feasible and active in eliminating DTCs by targeting dormancy-speciﬁc mechanisms. Follow up for recurrence and survival is ongoing.

Clinical trial identiﬁcation: NCT03032406.

Legal entity responsible for the study: University of Pennsylvania.

Funding: National Cancer Institute R01CA208273, Novartis (Drug Only).

Disclosure: A. DeMichele: Financial Interests, Institutional, Research Funding: NOVARTIS, Neogenomics, Pﬁzer, Genentech, Calithera. I. Makhlin: Financial Interests, Personal, Advisory Board:AstraZeneca, Bayer, Gilead. L. Chodosh: Financial Interests, Personal, Expert Testimony: Teva Pharmaceuticals, Eisai, Sanoﬁ, Lilly, Whittaker, Clark and Daniels, Imerys, Colgate, Sterigenics. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.442

|Table: 245P |Table: 245P || |---|---|---|

|QL1209 (n[257) |QL1209 (n[257) |P (n[259) |

|Overall, n (%) |||

|No ofpts |255* |259 |

|tpCR by INV |108 (42.4) |120 (46.3) |

|bpCR by IRC |128/256 (50.0) |134 (51.7) |

|bpCR by INV |124 (48.6) |133 (51.4) |

|ORR by INV, n (%) |211/257 (82.1) |212/259 (81.9)|

4 - Issue S2 - 2023

245P

*IRC didn

Neoadjuvant QL1209 (a pertuzumab biosimilar) compared with pertuzumab plus trastuzumab and docetaxel in early or locally advanced, HER2-positive, ER(-)/PR(-) breast cancer: A multicenter, randomized, double-blind, equivalence, phase III study

Z. Shao1, J. Zhang2, J. Qian3, X. Ma4, Z. Niu5, J. Ou6, Q. Mo7, J. Sun8, X. Li9,

Q. Wang10, Y. Yao11, G. Yu12, H. Li13, D. Chen14, H. Zhang15, C. Geng16, G. Qiao17,M. Zhao18, B. Zhang19, X. Kang18

1Breast Surgery Department, Fudan University Shanghai Cancer Center, Shanghai,China; 2Breast Oncology Department 3, Tianjin Medical University Cancer Institute &Hospital, Tianjin, China; 3Surgical Oncology Department, The First Afﬁliated Hospital of Bengbu Medical College, Bengbu, China; 4General Surgery Department, Center of Creast and Thyroid, The First Afﬁliated Hospital of USTC/ Anhui Provincial Hospital,Hefei, China; 5Breast Disease Department, Yuncheng Central Hospital, Yuncheng,China; 6Breast Surgery Department, Cancer Hospital Afﬁliated to Xinjiang Medical University, Xinjiang, China; 7Breast Surgery Department, Guangxi Medical University Canter Hospital, Nanning, China; 8Breast Medicine Department, Anyang Tumour Hospital, Anyang, China; 9Breast Surgery Department, Shanxi Cancer Hospital,Taiyuan, China; 10Breast Surgery Department 1., Qingdao Central Hospital Afﬁliated to Qingdao University, Qingdao, China; 11Breast Surgery Department, The Afﬁliated Hospital of Nanjing University Medical School, Nanjing, China; 12Medicine-Oncology Department, Weifang People’s Hospital, Weifang, Kuiwen District, China; 13Breast Surgery Department, Afﬁliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China; 14Breast Surgery Department 2., Yunnan Cancer Hospital, Kunming, Yunnan, China; 15Breast Surgery Department, Nanyang Central Hospital, Nanyang, China; 16Breast Center, The Fourth Hospital of Hebei Medical University Hebei Tumor Hospital, Shijiazhuang, China; 17Breast Surgery Department,Yantai Yuhunagding Hospital, Yantai, Shangdong, China; 18Department of Medicine,Qilu Pharmaceutical Co., Ltd., Jinan, China; 19Statistics and Statistical Programming,Qilu Pharmaceutical Co., Ltd., Jinan, China

Background: Dual HER2-blockade with trastuzumab (T) and pertuzumab (P) plus docetaxel as neoadjuvant therapy showed an improved pathological complete response (pCR) rate and was approved by the FDA and EMA for early HER2-positive breast cancer. QL1209 is a biosimilar of the originator P (Perjeta, Roche). Here we present the results of the phase 3 study comparing the efﬁcacy, safety, immunogenicity of QL1209 with P in the neoadjuvant setting for early HER2-positive breast cancer.

Methods: Eligible patients (pts) had HER2-positive, early (T2-3, N0-1, M0) or locally advanced (T2e3, N2e3,M0 or T4, any N, M0), ER(-) and PR(-) breast cancer with primary tumor larger than 2cm in diameter, and had not received any previous anticancer therapy. Pts were randomly assigned (1:1, stratiﬁed by disease stage) to receive neoadjuvant treatment of QL1209 or P (loading dose 840 mg at cycle 1,followed by 420 mg from cycles 2 to 4) plus T and docetaxel once every 3 weeks for 4 cycles. The primary endpoint was tpCR by IRC. Secondary endpoints included tpCR by investigator (INV), bpCR by IRC, bpCR by INV, ORR, safety, immunogenicity etc.

Results: 517 pts were enrolled (52 sites in China) and 516 pts (QL1209/P: n¼257/259)received neoadjuvant treatment, of whom 482 (93.2%) underwent surgery (QL1209:238; P: 244). tpCR (by IRC) was observed in 109 (42.7%) pts with QL1209 and 117(45.2%) pts with P; ratio of tpCR (QL1209:P) 0.946 (90% CI: 0.8-1.11), p¼0.014. In-cidences of TEAEs and Gr3 TEAEs: (QL1209 vs P) (94.6% vs 96.1%; Gr3, 31.9% cidences of TEAEs and Gr≥3 TEAEs: (QL1209 vs P) (94.6% vs 96.1%; Gr≥3, 31.9% vsvs34.7%). TRAEs: 77.4% vs 78%. Incidences of ADA and Nab were similar between 2 groups (2.3% vs 3.1%; 0.8% vs 0.8%).

212/259 (81.9)

’t receive the complete specimens for 2 patients

Conclusions: QL1209 demonstrated equivalence to P in efﬁcacy and showed comparable safety proﬁle and immunogenicity in patients with early or locally advanced HER2-positive breast cancer.

Clinical trial identiﬁcation: NCT04629846.

Legal entity responsible for the study: Qilu Pharmaceutical Co., Ltd.

Funding: Qilu Pharmaceutical Co., Ltd.

Disclosure: M. Zhao, B. Zhang, X. Kang: Other, Personal, Full or part-time Employment: Qilu Pharmaceutical Co., Ltd. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.443

S281

246P

Phase II study of anlotinib combined with taxanes and lobaplatin in the neoadjuvant treatment of triple-negative breast cancer: Efﬁcacy, safety and biomarker analysis from the neoALTAL trial

X. Qi1, Y. Liang2, J. Liu2, Q. Shi2, K. Zhu3, J. Jiang2, Y. Zhang2

1Breast Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China; 2Department of Breast and Thyroid Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing,China; 3Department of Oncology, Chia Tai Tianqing Pharmaceutical Group Co., Ltd. L.,Lianyungang, China

Background: Anlotinib, a novel multi-target tyrosine kinase inhibitor, has been proven effective in HER2-negative metastatic breast cancer, but its efﬁcacy in early-stage TNBC is unknown. This phase 2 study aims to evaluate the efﬁcacy and safety of adding anlotinib to neoadjuvant chemotherapy (NCT) in patients (pts) with TNBC.

Methods: Pts with clinical stage II/III TNBC were treated with 5 cycles of anlotinib(12mg, d1-14, q3w) plus 6 cycles of taxanes (docetaxel 75 mg/m2or nab-paclitaxel 125 mg/m2, d1 and d8, q3w) and lobaplatin (30 mg/m2, d1, q3w), followed by surgery. The primary endpoint was total pathological complete response (tpCR; ypT0/is ypN0) and the secondary endpoints include breast pCR (bpCR), axillary pCR (apCR),survival, and safety. Exploratory endpoints were efﬁcacy biomarkers based on FUSCC classiﬁcation (IHC-based) and NGS (425 gene panel).

Results: From Jan 2021 to Aug 2022, 48 pts were assessed and 45 were enrolled. All pts received at least one dose of study treatment and underwent surgery. The median age was 50 years (range, 26-65), 71% were nodal involved, and 20% had stage III. In the ITT population, 26 out of 45 pts achieved tpCR (57.8%; 95% CI, 42.2%e72.3%),and 39 achieved RCB 0-I (86.7%; 95% CI, 73.2%-94.9%). The bpCR and apCR rates were

64.4% (29/45) and 71.9% (23/32), respectively. No recurrence or metastasis occurred during the short-term follow-up. Based on the FUSCC IHC-based subtypes, the tpCR rates were 68.8% (11/16) for IM subtype, 58.3% (7/12) for BLIS subtype, and 33.3%(4/12) for LAR subtype, respectively. Next-generation sequencing revealed that the tpCR were 69.2% (9/13) and 53.6% (15/28) in MYC-ampliﬁed and wild-type pts,respectively, and 75.0% (9/12) and 51.7% (15/29) in BRCA1/2-mutated and wild-type pts, respectively. In the safety population (N¼45), Grade 3 or 4 TEAEs occurred in 29pts (64%), and the most common events were neutropenia (38%), leukopenia (27%),thrombocytopenia (25%), anemia (13%), and hypertension (13%), respectively. No treatment-related deaths occurred.

Conclusions: The addition of anlotinib to NCT showed manageable toxicity and promising antitumor activity for pts with early-stage TNBC.

Clinical trial identiﬁcation: ChiCTR2100043027.

Funding: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. L.

https://doi.org/10.1016/j.annonc.2023.09.444

247P KN026 in combination with docetaxel as neoadjuvant

treatment for HER2+ early or locally advanced breast cancer(BC): A single-arm, multicenter, phase II study

L. Ma1, B. Yang1, M. Zhang2, K. Wang3, Y. Chen4, Z. Fan5, J. Zhang6, B. Xia6, J. Wu1

1Department of Breast Surgery, Fudan University Cancer Institute, Shanghai, China;2Surgical Oncology, The First Afﬁliated Hospital of Bengbu Medical College, Bengbu,China; 3Department of Breast Oncology, Guangdong Provincial People’s Hospital,Guangzhou, China; 4Breast Surgery, The Second Afﬁliated Hospital Zhejiang University School of Medicine, HangZhou, China; 5Breast Surgery, The First Hospital of Jilin University, Changchun, China; 6Clinical Medicine, Jiangsu Alphamab Oncology Co.,Ltd., Suzhou, China

Background: Trastuzumab (H) plus Pertuzumab (P) combined with cytotoxic agents has been the SOC for Her2+BC across perioperative to late stage. Even with high efﬁcacy, optimized treatment strategy still needs to be explored. KN026 is a bispeciﬁc monoclonal antibody that targets domain II and IV of HER2. KN026 showed comparable or better efﬁcacy with H+P in preclinical study. The superior efﬁcacy had also been validated in a series of clinical trials in late line Her2+ solid tumors as well as theﬁrst-line Her2+ breast cancer and gastric cancer. Here we report the results of KN026 plus docetaxel as neoadjuvant treatment in HER2+ BC pts.

Methods: Treatment naive pts with HER2+ early or LABC were enrolled to receive 4 cycles of KN026 (30mg/kg, ivgtt d1, q3w) and docetaxel (75 mg/m2, ivgtt d1, q3w) as neoadjuvant treatment. The primary endpoint was tpCR rate. Secondary endpoints were bpCR, ORR, safety, etc. This study is registered in ClinicalTrials.gov, number NCT04881929.

Results: From August 9th, 2021, to July 29th, 2022, a total of 30 pts were enrolled from 5 sites. 16 pts (53.3%) were stage II, and 14 pts (46.7%) were stage III; 26 (86.7%)pts with biopsy-conﬁrmed lymph node metastases; 15 (50.0%) pts were hormone receptor positive. As of Nov 21st, 2022, the study completed the primary outcome. 28 pts completed the surgery followed by pathological evaluation, and 2 pts

discontinued from the study earlier due to AEs. In FAS, tpCR rate was 56.7% (17/30,95% CI: 37.43%-74.53%), bpCR rate was 60% (18/30, 95% CI:40.60%-77.34%), ORR was 90.0% (27/30, 95% CI: 73.47%-97.89%). The incidence of TEAEs and CTCAE Grade 3 (≥5%) Grade ≥3 TEAEs were neutrophil count decreased (50%, 15/30), white blood≥3 TEAEs were 100% (30/30) and 53.3% (16/30), respectively. The most commonTEAEs were 100% (30/30) and 53.3% (16/30), respectively. The most common(5%）Grade 3 TEAEs were neutrophil count decreased (50%, 15/30), white bloodcell count decreased (40.0%, 12/30), and lymphocyte count decreased (10%, 3/30). 7(23.3%）pts required docetaxel dose reduction due to AEs. KN026 and docetaxel related SAEs occurred in only one patient. No Grade 5 TEAEs occurred.

Conclusions: KN026 plus docetaxel as neoadjuvant treatment has shown promising clinical beneﬁt and acceptable safety for pts with HER2+ early or LABC. Further validation in a large-scale randomized controlled trial is warranted.

Legal entity responsible for the study: Jiangsu Alphamab Biopharmaceuticals Co. Ltd.

Funding: Jiangsu Alphamab Biopharmaceuticals Co. Ltd.

https://doi.org/10.1016/j.annonc.2023.09.445

248P Targeting triple-negative breast cancer metabolism with neoadjuvant chemotherapy plus fasting-mimicking diet plus/minus metformin: The BREAKFAST trial

F. Ligorio1, G. Fucà1, A. Vingiani2, F. Iannelli3, R. Lobefaro1, C. Ferraris4, A. Belﬁore5,G. Scaperrotta6, C. Depretto6, A. Martinetti1, P. Corsetto7, G.V. Bianchi1, G. Capri1,S. Folli4, S. Minucci8, M. Foiani9, M. Pagani10, G. Pruneri2, F.G.M. De Braud1,

C. Vernieri1

1Medical Oncology and Hematology Department, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy; 2Department of Advanced Diagnostics, Molecular Tumor Board & Department of Oncology and Hemato-Oncology, University of Milan, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 3Bioinformatics, IFOM ETSthe AIRC Institute of Molecular Oncology, Milan, Italy; 4Breast Unit, Istituto Nazionale dei Tumori di Milano - Fondazione IRCCS, Milan, Italy; 5Department of Advanced Diagnostics, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy; 6Department of Radiology, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy;7Department of Pharmacological and Biomolecular Sciences, UNIMI - Università degli Studi di Milano Statale, Milan, Italy; 8Department of Experimental Oncology, European Institute of Oncology, Milan, Italy; 9Genome Integrity Research Lab, IFOM-IEO Campus, Milan, Italy; 10Molecular Oncology and Immunology, IFOM-IEO Campus,Milan, Italy

Background: Cyclic fasting or fasting-mimicking diets (FMDs) enhanced the antitumor activity of chemotherapy (CT) in TNBC mouse models, while the combination of fasting and metformin resulted in impressive antitumor activity in several preclinical tumor models. The BREAKFAST study was designed to investigate if cyclic FMD, plus/minus metformin, improves the antitumor activity of neoadjuvant CT in patients (pts)with localized TNBC.

Methods: BREAKFAST is a randomized, non-comparative, phase II trial originally designed to enrol 90 stage I-III (cT>1cm) TNBC pts candidate to receive neoadjuvant doxorubicin-cyclophosphamide q3w for 4 cycles, followed by weekly paclitaxel for 12 cycles. Pts were randomized 1:1 to receive: CT + triweekly 5-day FMD cycles (arm A),or CT + FMD + daily metformin (1700 mg) (arm B). The primary study objective was to investigate if one or both experimental treatments were able to increase pCR rates when compared to anthracycline-taxane CT alone according to historical data.

Results: We enrolled 30 pts between June 2020 and February 2022, when the study was prematurely interrupted after the introduction of chemo-immunotherapy (CT-IO)as a standard neoadjuvant therapy for early stage TNBC. Of these pts, 13 were randomized to arm A and 17 to arm B; 73.3% of enrolled pts completed the maximum of 8 FMD cycles, with an average number of 6.9 completed FMD cycles. The observed pCR rate was 56.6%, i.e., signiﬁcantly higher than pCR rates previously reported with CT alone in phase II/III trials (26-39%), and with no signiﬁcant differences among treatment arms (OR 1.67, 95% CI 0.39-7.43; p¼0.49). RNA-seq analysis in tumorspecimens revealed higher pCR probability in pts undergoing precocious enhancement of tumor inﬁltration by activated T and NK cells, as well as precocious downmodulation of glycolysis and oxidative mitochondrial metabolism pathways.

Conclusions: Preoperative CT plus cyclic FMD (plus/minus metformin) results in excellent pCR rates in early TNBC pts. Based on these ﬁndings, we recently initiated a phase II, randomized, multicentric trial, namely BREAKFAST-2, to investigate if adding cyclic FMD to neoadjuvant CT-IO increases pCR rates in stage II-III TNBC pts.

Clinical trial identiﬁcation: NCT04248998.

Legal entity responsible for the study: Fondazione IRCCS Istituto Nazionale dei Tumori.

Funding: Fondazione IRCSS Istituto Nazionale dei Tumori; AIRC.

Disclosure: F. Ligorio: Financial Interests, Personal, Other, Travel/accomodation: Eli Lilly, Istituto Gentili; Financial Interests, Personal, Invited Speaker: Novartis. R. Lobefaro: Financial Interests,Personal, Advisory Board: Daiichi Sankyo, AstraZeneca; Financial Interests, Personal, Speaker,Consultant, Advisor: Pﬁzer; Financial Interests, Personal, Other, Travel/accomodation: Eli Lilly. G.V.

Bianchi: Financial Interests, Personal, Advisory Board: Novartis, Eli Lilly, Daiichi Sankyo, AstraZeneca,Roche, MSD, Seagen. G. Pruneri: Financial Interests, Personal, Advisory Role: Roche, Bayer; Financial Interests, Personal, Advisory Board: AstraZeneca. F.G.M. De Braud: Financial Interests, Personal,Advisory Board: Roche, EMD Serono, NMS Nerviano Medica Science, Sanoﬁ, MSD, Novartis, Incyte,

BMS, Menarini, AstraZeneca, Pierre Fabre, Mattioli 1885 , MCCann Health, Taiho, IQVIA; Financial Interests, Personal, Speaker’s Bureau: BMS, Healthcare Research & Parmacoepidemiology, Merck Group, MSD, Pﬁzer, Servier, Sanoﬁ, Roche, AMGEN, Incyte, Dephaforum, Seagen, Nadirex, Ambrosetti, Itanet; Financial Interests, Personal and Institutional, Sponsor/Funding: Novartis, F.HoffmannLaRoche Ltd, BMS, Ignyta Operating INC, Merck Sharp & Dohme Spa, Kymab, Pﬁzer, Tesaro, MSD,MedImmune LCC, Exelixis Inc., LOXO Oncology Incorporated, Daiichi Sankyo, Basilea Pharmaceutica International AG, Janssen-Cilag Internationa NV, Merck KGAA. C. Vernieri: Financial Interests, Personal, Advisory Board: Novartis, Pﬁzer, Lilly, Daiichi Sankyo, Novartis, Lilly, Istituto Gentili; Financial Interests, Institutional, Research Grant: Roche. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.446

250P

The impact of inter-cycle treatment delays on progressionfree survival in early stage breast cancer

L. Steventon1, E. Kipps2, K. Man3, M.D. Forster4, I. Wong5, S. Shah1, R. Miller4,S. Nicum4, O. Almossawi6, P. Chambers1

1Cancer Services, UCLH - University College London Hospitals NHS Foundation Trust,London, UK; 2Breast, Royal Marsden Hospital NHS Foundation Trust, London, UK;3RDPP, UCL - University College London, London, UK; 4Medical Oncology Department,UCLH - University College London Hospitals NHS Foundation Trust, London, UK;5Department of Pharmacology and Pharmacy, UCL - University College London, London, UK; 6Population, Policy & Practice Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK

Background: Up to 30% of systemic anti-cancer therapy (SACT) treatments are reported to be delayed within cycle, due to drug toxicity, hospital capacity issues and patient choice; however, the impact on survival is unknown. This study aimed to determine the association of delays on PFS.

Methods: This population-based observational study included stage II-III breast cancer patients in England for whom guidelines recommend SACT, and who received six cycles of treatment from 01/01/2014-31/12/2015 in adjuvant and neo-adjuvant settings. Data were collected by the National Health Service as part of routine care.

Cox proportional hazards model was applied to evaluate risk of progression with respect to treatment delays, adjusting for age, stage, histology, Charlson comorbidity index, ethnicity, socioeconomic group, BMI, region of England, hospital type and surgical status. Overall survival at 5 years was assessed. Delays were deﬁned as treatment >7 days after expected date. Progression was deﬁned as time from completion of 1stline to start of 2ndline SACT.

Results: 8680 patients were included. 2211 (25.5%) experienced at least one delay of 7 days or more during a six-cycle drug regimen. PFS probability was signiﬁcantly lower at 1, 2 and 5 years in delayed patients; 97% (CI 96.6-97.4) vs 95.8% (CI 94.9-96.6),

93.9% (CI 93.3-94.5) vs 91.6% (CI 90.5-92.8) and 86.6% (CI 85.8-87.5) vs 81.5% (CI

79.9-83.2) respectively at each timepoint in patients treated to schedule vs delayed.

Cox proportional hazards analysis showed a positive association of delays >7 days with disease progression or death (HR 1.36, CI 1.19e1.55) compared to those treated to schedule. Covariates associated with reduced PFS were triple-negative histology(HR 1.63, CI 1.29-2.06) and BMI>40 (HR 1.55, CI 1.16-2.08). Non-signiﬁcant associations were seen between treatment at local vs academic hospital (HR 1.15, CI 0.98-1.35), Asian (HR 0.73, CI 0.53-1.01) and Chinese (HR 0.54, CI 0.13-2.19) ethnicity compared to White ethnicity.

|Table: 251P |Table: 251P |Table: 251P |Table: 251P |Table: 251P | |---|---|---|---|---|

||Normal |Overweight |Obese |Severely obese |

|D vs. non- D |70% vs. 62% |67% vs. 66% |66% vs. 62% |64% vs. 67% |

||HR 0.73 |HR 0.83 |HR 0.84 |HR 1.12 |

||95% CI |95% CI |95% CI |95% CI |

||0.59-0.89 |0.66-1.05 |0.61-1.16 |0.70-1.78 |

||p[0.003 |p¼0.124 |p¼0.285 |p¼0.646 |

|P vs.non-P |79% vs. 77% |77% vs. 74 |78% vs. 72% |71% vs. 65% |

||HR 0.94 |HR 0.89 |HR 0.72 |HR 0.70 |

||0.75-1.17 |0.71-1.13 |0.52-0.98 |0.45-1.09 |

||p0.554 |p=0.347|p=0.039||

Conclusions: Treatment delays were signiﬁcantly associated with reduced PFS and occur frequently in early-stage breast cancer patients in England. Hospitals must avoid centre-led treatment delays where possible to maximise treatment efﬁcacy in this patient cohort.

Legal entity responsible for the study: University College London Hospital NHS Foundation Trust.

Funding: National Institute for Health and Care Research.

Disclosure: L. Steventon: Financial Interests, Institutional, Research Grant, Award ID: NIHR201481:UK National Institute for Health and Care Research. E. Kipps: Financial Interests, Personal, Advisory Board: Pfzier, Novartis, Roche, AstraZeneca. K. Man: Financial Interests, Personal, Research Grant: UK National Institute for Health and Care Research, Hong Kong Research Grant Council, CW Maplethorpe Fellowship, European Commission Framework Horizon 2020 , Innovation and Technology Commission of the Government of the Hong Kong Special Administrative Region; Financial Interests,Personal, Funding: IQVIA Ltd . M.D. Forster: Financial Interests, Personal, Advisory Board: Bayer,EQRx, Janssen, MSD, Roche, Takeda, Transgene; Financial Interests, Personal, Research Grant: Merck,MSD. I. Wong: Financial Interests, Personal, Research Grant, Award ID: NIHR201481: UK National Institute for Health and Care Research. R. Miller: Financial Interests, Personal, Advisory Board: GSK,AZD, Merck, Shionogi, Ellipses; Financial Interests, Personal, Invited Speaker: GSK, AZD, Clovis Oncology. S. Nicum: Financial Interests, Personal, Advisory Board: GSK, AstraZeneca; Financial Interests, Personal, Invited Speaker: GSK, AstraZeneca, Clovis; Financial Interests, Personal, Other,scientiﬁc committee: GSK; Financial Interests, Personal, Stocks/Shares: GSK; Financial Interests,Institutional, Funding: AstraZeneca. P. Chambers: Financial Interests, Personal, Research Grant,Award ID: NIHR201481: UK National Institute for Health and Care Research. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.447

251P Body mass index as a predictive factor for efﬁcacy of taxanebased chemotherapy in early breast cancer patients

J.A. García-Sáenz1, G. Spera2, M.A. Pollán3, B. Bermejo4, M. Ruiz Borrego5, A. Chan6,M. Martin Jimenez7, A.L. Guerrero Zotano8, L. Calvo-Martinez9,

A. Rodríguez-Lescure10, A. Arcusa Lanza11, L.I. Chap12, J.P. Crown13,

V. Bee-Munteanu14, M. Casas15, O. Polonio16, D. Slamon17

1Oncology Department, Hospital Clínico San Carlos. GEICAM Spanish Breast Cancer Group, Madrid, Spain; 2Medical, TRIO - Translational Research in Oncology, Montevideo, Uruguay; 3National Center for Epidemiology, Instituto de Salud Carlos III(ISCIII), Madrid, Spain; 4Medical Oncology Dept., Hospital Clinico Universitario de Valencia. GEICAM Spanish Breast Cancer Group, Valencia, Valencia, Spain; 5Medical Oncology, Hospital Universitario Virgen del Rocio. GEICAM Spanish Breast Cancer Group, Seville, Spain; 6Medical Oncology, Curtin Medical School, Faculty of Health Sciences, Bentley, QLD, Australia; 7Servicio de Oncologia Médica Department, Hospital General Universitario Gregorio Marañon, IiSGM. CIBERONC. GEICAM Spanish Breast Cancer Group, Madrid, Spain; 8Medical Oncology Dept., IVO - Fundación Instituto Valenciano de Oncología. GEICAM Spanish Breast Cancer Group, Valencia, Spain;9Medical Oncology, CHUAC - Complejo Hospitalario Universitario A Coruña. GEICAM Spanish Breast Cancer Group, A Coruña, Spain; 10Medical Oncology Department,Hospital General Universitario de Elche. GEICAM Spanish Breast Cancer Group, Elche,Spain; 11Medical Oncology Department, Hospital Terrassa - Consorci Sanitari de Terrassa, Terrassa, Barcelona, Spain; 12Oncology, Beverly Hills Cancer Center, Beverly Hills, CA, USA; 13Department of Medical Oncology, St Vincent’s University Hospital,Dublin, Ireland; 14Project Management, TRIO - Translational Research In Oncology,Paris, France; 15Statistics Department, GEICAM - Spanish Breast Cancer Research Group, San Sebastian De Los Reyes, Spain; 16Scientiﬁc, GEICAM-Spanish Breast Cancer Research Group, San Sebastian De Los Reyes, Madrid, Spain; 17Hematology/Oncology,UCLA - David Geffen School of Medicine, Los Angeles, CA, USA

Background: Adjuvant anthracyclines and taxanes reduce risk of recurrence and death in Early Breast Cancer (EBC) patients (pts) but the toxicity proﬁle is a major concern.

Several studies have shown conﬂicting results correlating Body Mass Index (BMI) and outcomes in these pts. There are limited data on the efﬁcacy of adjuvant taxanes among BMI categories. The prognostic effect of BMI on disease recurrence between adjuvant Paclitaxel (P)-based Chemotherapy (CT) vs. Docetaxel (D)-based CT has not ever been reported.

Methods: Pt-level pooled analysis of 13,486 EBC pts treated with adjuvant anthracyclines +/- taxanes from 7 GEICAM & TRIO adjuvant randomized controlled trials(RCTs) carried out from 1996 to 2008. Pts were classiﬁed in 4 BMI (kg/m2) categories:normal (< 25.0), overweight (25.0 to 29.9), obese (30.0 to 34.9), and severely obese( (≥35.0), to evaluate BMl as a predictive factor for efficacy and toxicity of adjuvant35.0), to evaluate BMI as a predictive factor for efﬁcacy and toxicity of adjuvanttaxane-based CT. Hazard Ratios (HR) were calculated using a Cox proportional hazard model stratifying by RCT.

Results: Pts distribution based on BMI was: 44% normal, 33% overweight, 16% obese,and 8% severely obese. 79% were treated with taxane-based CT (83% with D and 17%with P). 10y iDFS was 71%, 70%, 68% and 64% in normal, overweight, obese, and severely obese pts who received CT, respectively, being statistically signiﬁcant in obese (HR 1.15; 95% CI 1.05-1.26; p¼0.002) and severely obese (HR 1.29; 95% CI1.15-1.45; p<0.001). 10y iDFS by type of CT are describe in the table. Relevant toxicity was 5%, 5.5%, 5.9% and 9.3% in normal, overweight, obese, and severely obese pts who received D.

p¼0.347p[0.039p¼0.113

Conclusions: Prognosis is worse in heavier vs. leaner EBC pts receiving adjuvant taxane-based CT. Leaner pts receiving D (compared to non-D) achieved a better outcome, while pts who beneﬁted most from P were the obese subgroup (compared to non-P).

Legal entity responsible for the study: GEICAM Spanish Breast Cancer Research Group.

Disclosure: J.A. García-Sáenz: Financial Interests, Personal, Advisory Role: Seagen, Astrazenecea,Daiichi Sankyo, Novartis, Gilead and Menarini; Financial Interests, Personal, Speaker, Consultant,Advisor: Celgene, Eli Lilly, EISAI, MSD, Exact Sciences, Tecnofarma, Nolver; Financial Interests,Institutional, Funding: AstraZeneca; Financial Interests, Personal, Other, Travel support: Novartis,AstraZeneca and Pﬁzer. M.A. Pollán: Financial Interests, Personal, Advisory Board, Participation in the elaboration of a divulgative summary on predictive medicine: Ascendo; Financial Interests, Personal,Invited Speaker, Speaker in a scientiﬁc event: Roche. M. Ruiz Borrego: Financial Interests, Personal,Speaker, Consultant, Advisor: Roche, AstraZeneca, Daiichi Sankyo, Pierre FABRE, Pﬁzer, Novartis,

S283

Gilead; Financial Interests, Personal, Advisory Role: Daiichi Sankyo, Gilead and Pierre Fabre. M.

Martin Jimenez: Financial Interests, Personal, Advisory Board: AstraZeneca, Lilly, Roche/Genentech,Daiichi Sankyo, Menarini-Stemline; Financial Interests, Personal, Invited Speaker: Pﬁzer, AstraZeneca,Lilly, Novartis, Roche/Genentech; Financial Interests, Institutional, Research Grant: Novartis, Roche,Puma; Non-Financial Interests, Member of Board of Directors: TRIO; Non-Financial Interests, Leadership Role: GEICAM; Non-Financial Interests, Member: ASCO; Non-Financial Interests, Advisory Board: SEOM. A.L. Guerrero Zotano: Financial Interests, Personal, Advisory Role: Pﬁzer, AstraZeneca,Pierre Fabre, Novartis, Exact Science, Stemline; Financial Interests, Institutional, Funding: Pﬁzer;Financial Interests, Personal, Speaker, Consultant, Advisor: Roche, MSD, Novartis, Pﬁzer, AstraZeneca,Daiichi Sankyo, Pierre Fabre, Exact Science. A. Rodríguez-Lescure: Financial Interests, Personal,Speaker, Consultant, Advisor: Pﬁzer, Novartis, AstraZeneca, Daiichi Sankyo and Seagen ; Financial Interests, Personal, Advisory Role: Pﬁzer, Novartis, Roche, AstraZeneca, Daiichi Sankyo, Pierre Fabre and Seagen. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.448

252P

S284

Adjuvant chemotherapy in T1a/bN0 breast cancer patients with high oncotype DX recurrence scores (RS>25)

D. Katz1, I. Feldhamer2, A. Hammerman3, H. Goldvaser1, D. Goldstein4

1Oncology Department, Shaare Zedek Medical Center, Jerusalem, Israel; 2Division of Planning and Strategy, Clalit Health Services, Tel Aviv, Israel; 3Medison Pharma Israel,Petah Tikva, Israel; 4Oncology Department, Rabin Medical Center, Petah Tikva, Israel

Background: RS>25 is prognostic for distant recurrence and predictive for adjuvant chemotherapy (aChem) beneﬁt in ER+HER2-negative early breast cancer (BC), independent of tumor size. For patients with tumors >0.5 cm and candidates for aChem,current NCCN guidelines recommend strongly considering OncotypeDX testing and aChem treatment for RS>25. Herein, we sought to evaluate the beneﬁt of aChem in T1a/bN0 early BC patients with high RS>25 tested.We used the Clalit Health Services(CHS) dataset, the largest HMO in Israel, with more than 4.5 million insurers.

Methods:We identiﬁed all CHS patients tested between Feb-2006 and Dec-2019 with T1a/bN0 early breast cancer and a RS>25. Demographic, clinicopathological, and treatment data were extracted from the CHS centralized registry. A propensity score matching method based on nearest neighbor with replacements was used to balance differences. Kaplan-Meier analysis with log-rank test was used to test differences in clinicopathological characteristics. Freedom from recurrence of BC locally and at a distant site and freedom from second primary cancer and death also known as invasive disease-free survival (iDFS) between the treatment groups.

Results: 159 patients were identiﬁed of which 76 patients (47.7%) received aChem.

Before applying the propensity- score matching aChem was more common among younger patients >50-years-old (25%) compared with patients 70-years-old younger patients >50-years-old (25%) compared with patients ≤70-years-old (7.9)%,(7.9)%,healthier patients with Charlson comorbidity score 0-1 (70%) compared with 30.2%for score 2, among Oncotype RS >30 72.5%. aChem was more often omitted for score ≥2, among Oncotype RS >30 72.5%. aChem was more often omitted inininvasive lobular carcinoma (75%) and grade 1 tumors (72.7%). Propensity score matching balanced discrepancies among both treatment groups and Kaplan-Meier analysis demonstrated no iDFS improvement with aChem in T1a/bN0 early BC patients with high Oncotype DX recurrence scores (RS>25).

Conclusions: Utility of aChem in T1a-bN0 tumors and RS>25 is dependent on clinocopathologic variables beyond RS. After balancing between these variables no iDFS beneﬁt for aChem was observed.

https://doi.org/10.1016/j.annonc.2023.09.449

253P Is 6-weekly administration of pembrolizumab in

combination with chemotherapy for early triple-negative breast cancer safe? A real-world early comparison of q6w versus q3w administration of pembrolizumab in two large cancer centres in the UK

V. Angelis1, E. Scott1, C. Gousis2, P.E. Hall1, K.M. Hawkesford1, R. Nijjar1, M. Nathan2,P. Schmid3, M. Phillips1

1Medical Oncology, St. Bartholomew’s Hospital - Barts Health NHS Trust, London, UK;2Medical Oncology, Guys and St Thomas NHS Trust, London, UK; 3Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London,London, UK

Background: The KEYNOTE 522 regimen is now established as the gold standard for patients with at least T2N0 or N+ early triple-negative breast cancer. In KEYNOTE 522,Pembrolizumab was administered every 3 weeks at 200mg. Following approval of 6-weekly administration by the FDA and EMA, hospitals could choose to implement q6w (400mg) or q3w (200mg) administration of Pembrolizumab. On implementation of q6w Pembrolizumab at St Bartholomew’s Hospital (SBH), we observed a higherthan-expected rate of grade 3-4 hepatotoxicity. This led to this real-world retrospective study, comparing our rates of toxicity with those seen at Guys Cancer Centre using the q3w regime.

Methods: We identiﬁed 21 eligible patients treated at SBH, who received at least one of cycle of q6w Pembrolizumab and 17 patients who received it q3w at GSTT from November 2022 e March 2023. Epidemiological and clinical data were collected retrospectively.

Results: In KEYNOTE 522, grade 3-5 transaminitis was seen in 5.5% of patients receiving Pembrolizumab. Of the 21 patients receiving q6w Pembrolizumab at SBH,there was a higher frequency of grade 3 transaminitis (Table). All 4 patients (19%)with G3 transaminitis required hospitalisation for IV steroids, with 2 developing grade 4 hyperbilirubinaemia requiring additional immunosuppression. A liver biopsy was carried out with 1 of 2 patients demonstrating vanishing bile duct syndrome. Pembrolizumab was discontinued in all 4 patients and 1 patient had to discontinue chemotherapy. In comparison, patients who received q3w Pembrolizumab at GSTT experienced no grade 3 toxicities.

|Table: 253P ||| |---|---|---|

|Pembrolizumab frequency |Q6w |Q3w |

|Patient number |21 |17 |

|Mean age |49 |50 |

|T2 |17 (80%) |10 (59%) |

|N+ |10 (48%) |11 (65%) |

|HBcAb positive requiring prophylaxis |0 |1 |

|Transaminitis |||

|G1 |0 |3 (18%) |

|G2 |3 (14%) |2 (12%) |

|G3 . |4 (19%) |0 |

Conclusions: Although this study is limited by short follow-up and small number of patients it suggests that administration of q6w Pembrolizumab may be associated with a higher risk of grade 3 immune related hepatotoxicity. Further studies are required to conﬁrm these ﬁndings.

Disclosure: V. Angelis: Financial Interests, Personal, Invited Speaker: Pﬁzer, AstraZeneca, Novartis.

C. Gousis: Financial Interests, Personal, Invited Speaker: Pﬁzer, Kinks Pharmaceuticals; Financial Interests, Personal, Stocks/Shares: Personal Mind Medicine; Non-Financial Interests, Personal, Training:AstraZeneca. P.E. Hall: Financial Interests, Personal, Invited Speaker: Eisai, Pﬁzer, MSD, Gilead,Seagen; Financial Interests, Personal, Advisory Board: Novartis. M. Nathan: Financial Interests,Personal, Invited Speaker: AstraZeneca, Lilly, Pﬁzer, MSD. P. Schmid: Financial Interests, Personal,Advisory Board: AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Pﬁzer, Puma, Roche,Gilead, Eisai, MSD, Seagen, Amgen, Celgene, Lilly; Financial Interests, Institutional, Research Grant:Astellas, AstraZeneca, Genentech, Novartis, Oncogenex, Roche, Medivation. M. Phillips: Financial Interests, Personal, Invited Speaker: MSD, Pﬁzer, Eisai, Gilead; Non-Financial Interests, Personal,Invited Speaker: Seagen. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.450

254P

|Table: 255P |Table: 255P |Table: 255P | |---|---|---|

||CPS+EG HER2-low (n [288) |CPS+EG HER2-zero (n [320 |

|Score |5-year DFS rate (%) (95% CI) |5-year DFS rate (%) (95% CI) |

|0 |100 (100-100) |100 (100-100) |

|1 |92.9 (82.14-97.28) |86.11 (74.1-92.81) |

|2 |71.95 (60.8-80.43) |86.8 (77.89-92.3) |

|3 |69.78 (58.09-78.8) |72.5 (61.18-81.01) |

|4 |48.03 (29.17-64.63) |55.48 (40.12-68.39) |

Effects of delaying adjuvant chemotherapy initiation on clinical outcomes in early triple-negative breast cancer patients

M.E. Hatzipanagiotou1, M. Pigerl1, M. Gerken2, S. Räpple1, V. Zeltner1,

M. Hetterich1, P. Ugocsai1, E.C. Inwald1, M. Klinkhammer-Schalke3, O. Ortmann1,S. Seitz1

1Department of Gynecology and Obstetrics, University Medical Centre Regensburg,Regensburg, Germany; 2Regional Centre Regensburg, Bavarian Health and Food Safety Authority, Bavarian Cancer Registry, Regensburg, Germany; 3Tumor Center Regensburg - Centre for Quality Management and Health Services Research, University of Regensburg, Regensburg, Germany

Background: TNBC is known for its aggressive nature, with early recurrence and limited treatment options beyond chemotherapy and recently immunotherapy. The optimal time to initiation of adjuvant chemotherapy (TTAC) for triple-negative breast cancer (TNBC) patients remains unclear. We aim to clarify, whether TTAC has an impact on survival in patients with early TNBC.

Methods: Data from a large population-based regional cancer registry covering over

2.2 million people was used for evaluation, including women with diagnoses of TNBC between 2010 and 2018. Data collected included demographics, pathology, treatment, recurrence, and survival. TTAC was deﬁned as days from primary surgery to ﬁrst dose of adjuvant chemotherapy. Kaplan-Meier and Cox regression methods were used to evaluate impact of TTAC on overall survival (OS).

Results: We identiﬁed 37 382 patients with malignant neoplasms of the mammary gland. The ﬁnal study cohort included 732 patients with early TNBC, of whom 43.6%were treated with neoadjuvant chemotherapy and 40.3% with adjuvant chemotherapy. 245 patients with TNBC treated with adjuvant chemotherapy had a valid TTAC. Treatment given within 22-28 days led to the best outcome with a mean OS of

10.2 years, while later treatment (29-35, 36-42 days, or >6 weeks) had signiﬁcant reduced survival rates of 8.3, 7.8, and 6.9 years. Patients who received therapy within 22-28 days had signiﬁcantly better survival than those who received therapy between 29-35 days (p¼0.043) or after more than 43 days (p¼0.033).

Conclusions: The results in this large population-based study indicate that timing of adjuvant systemic therapy can inﬂuence OS in TNBC patients, with reduced OS if adjuvant chemotherapy is applied later than 42 days after surgery. To optimize patients’ outcomes, we recommend avoiding a delay of more than 6 weeks when administering adjuvant chemotherapy for early TNBC patients.

https://doi.org/10.1016/j.annonc.2023.09.451

255P Prognostic stratiﬁcation capacity of the CPS+EG scoring system in HER2-low and HER2-zero early breast cancer treated with neoadjuvant chemotherapy

N. Roussot1, G. Constantin2, I. Desmoulins1, C. Kaderbhai1, A. Hennequin1,D. Mayeur1, S.M. Ilie1, L. Arnould3, A. Bertaut2, J-C. Eymard4, C. Jouannaud4,A.M. Savoye5, G. Yazbek5, D. Allouache6, C. Delcambre6, I. Hrab6, C. Levy6,C. Segura Djezzer6, M. Deblock7, S. Ladoire1

1Medical Oncology, Centre Georges-François Leclerc, Dijon, France; 2Biostatistics,Centre Georges-François Leclerc (Dijon), Dijon, France; 3Pathology, Centre GeorgesFrançois Leclerc, Dijon, France; 4Medical Oncology, Institut Jean Godinot, Reims,France; 5Medical Oncology, CHU de Reims - Hôpital Robert Debré, Reims, France;6Medical Oncology, Centre Francois Baclesse, Caen, France; 7Medical Oncology,Institut de Cancérologie de Lorraine - Alexis Vautrin, Vandoeuvre-lès-Nancy, France

|Table: 256P Risk of recurrence and death in HR+, HER2- early breast cancer1 |Table: 256P Risk of recurrence and death in HR+, HER2- early breast cancer1 |Table: 256P Risk of recurrence and death in HR+, HER2- early breast cancer1 |Table: 256P Risk of recurrence and death in HR+, HER2- early breast cancer1 | |---|---|---|---|

|N0, or LN1-3 without risk |Ref. |Ref. |Ref. |

|feature ||||

|LN≥4, or LN1-3 with≥1risk|2.38(1.82,3.12) ** |3.20(2.31,4.43) ** |3.81(2.34,6.21) ** |

|LN≥4|3.44(2.55,4.65) ** |4.86(3.40,6.94) ** |6.47(3.84,10.92) * |

|LN1-3 with ≥1 risk feature|1.50(1.05,2.14) * |1.82(1.19,2.80) ** |1.68(0.85,3.30) |

Background: CPS+EG scoring system properly deﬁned prognosis subgroups of early breast cancer (eBC) patients (pts) treated with neoadjuvant chemotherapy (NACT)with a higher CPS+EG associated with worse outcomes. It remains unknown if CPS+EG similarly stratify prognostic in HER2-low and HER2-zero eBC patients after NACT.

Methods: This pluricenter french retrospective study included eBC pts treated with NACT from 2 cohorts, a monocenter local database at CGFL, Dijon and a pluricenter clinical trial PRIMUNEO (NCT01513408). Molecular features were determined on core biopsies. Threshold for HR positivity was 10%. HER2-low/zero status was deﬁned biopsies.Threshold for HR positivity was ≥10%. HER2-low/zero status was defined bybyimmunohistochemistry (IHC) HER2 staining. CPS+EG score was calculated for all pts with available data.

Results: 608 patients with HER2-negative eBC that have received NACT were included. Median age at diagnosis was 51.0 y-o. Nearly all pts (98.2%) received >3 NACT cycles. In the overall population, 288 pts (47.4%) were HER2-low. More pts were HR+ than TNBC with 367 (60.3%) and 241 pts (39.7%), respectively. The majority of pts harboring HR+ disease were HER2-low (61.0%) contrary to TNBC eBC pts(26.5%). In the HER2-low and HER2-zero population, CPS+EG was able to well categorized pts within prognosis subgroups (log-rank p <0.0001).

38.1 (8.92-68.02)

30.77 (9.5-55.43)

In HR+/HER2-negative pts, CPS+EG still properly separated pts within prognosis subgroups between HER2-low and HER2-zero pts (log-rank p ¼0.0012 and p <0.0001,respectively). In TNBC population, CPS+EG appears to be less accurate. Within HR+and TNBC molecular subtypes, there was no difference in 5-year DFS between HER2-low and HER2-zero pts harboring a similar CPS+EG score.

Conclusions: In this study, we show that the CPS+EG scoring system retains its interest for the prognostic stratiﬁcation of pts treated with NACT for HER2-low and HER2-zero eBC. While it seems especially true for HR+ disease, CPS+EG appears to be less effective for TNBC in isolating different outcomes.

https://doi.org/10.1016/j.annonc.2023.09.452

256P Evolution and risk stratiﬁcation of adjuvant treatment strategies for early breast cancer: A Chinese perspective based on a national cancer database

Y. Fan1, D. Ji1, M. Jiang1, Y. Tan1, Y. Yang2, T. Li2, X. Ma2, B. Xu1

1Department of Medical Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College - National Cancer Center, Cancer Hospital, Beijing, China; 2Lilly China Drug Development & Medical Affairs Center, Eli Lilly and Company, Shanghai, China

Background: HR+, HER2- early breast cancer (EBC) patients (pts) with high-risk clinicopathologic features (CPF) are at increased risk of early recurrence. This is the ﬁrst study aimed at investigating the evolving adjuvant therapy landscape.

Methods: The study cohort, based on the medical records from 50 major hospitals across China linked with China Vital Registration (death information), included pts with HR+, HER2- stage I-III EBC who received surgery and adjuvant endocrine therapy(AET) from Jan 1, 2013, to Mar 31, 2021. CPF were used to identify a ‘high-risk group’(HiR) (including 4 positive axillary lymph nodes (LN), or LN1-3 with 1 of (HiR) (including ≥4 positive axillary lymph nodes (LN), or LN1-3 with ≥ 1 of thethefollowing high-risk CPF: Grade 3, tumor size 5 cm or Ki-67 20%) and following high-risk CPF: Grade 3, tumor size ≥5 cm or Ki-67 ≥20%) and 'low-risk‘low-riskgroup’ (LoR) (do not meet above criteria). Survival analysis was performed on invasive disease-free survival (iDFS), distant relapse-free survival (DRFS), and overall survival(OS) with cutoff date of Sep 30, 2021.

Results: Of the 4088 eligible pts (median age: 50 years), 1310 were identiﬁed in HiR(46.6% had LN 4 and 53.4% had LN1-3 with high-risk CPF), and 2778 in LoR (46.6% had LN≥ 4 and 53.4% had LN1-3 with high-risk CPF), and 2778 in LoR (90.8%(90.8%N0 pts). Pts in HiR were more likely to receive adjuvant chemotherapy (74.9% vs

63.7%) and radiotherapy (72.1% vs 45.6%) than LoR. From 2013 to 2021, the use of aromatase inhibitors and ovarian function suppression in AET gradually increased while the use of selective estrogen receptor modulators (tamoxifen/toremifene)decreased. The 5-year iDFS was 75.3% in HiR and 89.9% in LoR, respectively. Pts in HiR had a higher risk of recurrence or death than pts in LoR (Hazard Ratio: 2.38, 95% CI:

1.82-3.12). Similar results were observed for DRFS and OS (Table).

*P < 0.05; **P<0.01

CI: Conﬁdence interval; HR: hazards ratio; LN: positive axillary lymph nodes.

1 HR and 95%CI were estimated from Cox proportional hazards regression models with adjustments for age, menopausal status, neoadjuvant therapy,adjuvant chemotherapy and radiotherapy..

S285

Conclusions: Nearly 25% EBC pts with high-risk CPF experienced recurrence or death within 5 years of initiating AET. Novel treatments are needed to prevent recurrence and death in these pts.

Disclosure: Y. Yang, T. Li, X. Ma: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company; Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company. B. Xu: Financial Interests, Personal, Advisory Board: Novartis, AstraZeneca; Financial Interests, Personal, Invited Speaker: Pﬁzer, Roche; Financial Interests, Institutional, Research Grant: Henrui. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.453

257P

The characteristics of HER2-positive microinvasive breast cancer and the necessity of chemotherapy and anti-HER2 therapy in these patients: A real-world study

B. Lan1, D. Lv1, C. Guo2, Z. Feng2, Y. Fan1, F. Ma1, B. Xu1

1Department of Medical Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College - National Cancer Center, Cancer Hospital, Beijing, China;2Department of Pathology, Chinese Academy of Medical Sciences and Peking Union Medical College - National Cancer Center, Cancer Hospital, Beijing, China

Background: The prognosis of microinvasive breast cancer (MIBC) is between ductal carcinoma in situ and T1aN0 stage tumors. We conducted this real-world study to explore the prognosis of human epidermal factor receptor 2 (HER2)-positive MIBC, as well as to ﬁnd out whether chemotherapy and anti-HER2 therapy could improve outcome in this population.

Methods: Patients who received radical surgery and were diagnosed with lymph node-negative HER2-positive MIBC at the National Cancer Center in China from January 2010 to December 2019 were consecutively enrolled. The invasive components were conﬁrmed HER2-positive by pathologists from our center. The exclusion criteria included: 1) distant metastasis before surgery; 2) HER2 status of the invasive components was unknown. Clinicopathologic characteristics and follow-up outcome data were collected.

Results: A total of 121 patients were included. The median age was 51 years old, and the median follow-up time was 68.3 months. Twenty-four patients (19.8%) received adjuvant chemotherapy (CT), of which 7 patients received CT combined with trastuzumab. Among these 24 patients, 17 patients were aged 50, and 20 tuzumab. Among these 24 patients, 17 patients were aged ≤ 50, and 20 patientspatientswere estrogen receptor (ER) negative. In total, 5 patients experienced recurrence (2 in situ breast recurrence, 3 distant metastasis), all within 3 years after surgery. The 3-year disease free survival (DFS) rate and 5-year DFS rate were all 95.9%. Univariate analysis showed that patients aged 50 might have worse outcomes than those analysis showed that patients aged≤ 50 might have worse outcomes than those agedaged> 50 (5-year DFS rate 92.5% versus 98.5%, p¼0.098). Using propensity scorematching, patients who received CT with or without trastuzumab were matched with those who did not receive CT in a 1:2 ratio based on age and ER status. Patients who received CT with or without trastuzumab showed a trend of increase in 5-year DFS rate compared to those who did not receive CT (100% vs 89.6%, p¼0.106).

Conclusions: HER2-positive MIBC had a relatively good prognosis. For patients with risk factors of relapse, CT and trastuzumab might decrease recurrence, so adjuvant CT and anti-HER2 therapy could be considered in this population.

https://doi.org/10.1016/j.annonc.2023.09.454

258P Cost-effectiveness of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab for high-risk early-stage triple-negative breast cancer in Colombia

R. Brugés Maya1, J.C. Urrego2, C. Marrugo2, V. Wurcel3, A. Khandelwal4, J. Singh4,M. Huang5, A. Haiderali6

1Clinical Oncology, Centro Javeriano de Oncología Hospital San Ignacio, Bogota,

Colombia; 2Market Access, MSD Colombia, Bogota, Colombia; 3CABA, MSD Argentina,

Munro, Argentina; 4Economic Modeling and Adaptations, CHEORS - Complete Health

Economics Outcomes and Research Solutions, North Wales, PA, USA; 5Economic andResults: The mean age of breast cancer diagnosis was 51±9 years with a median Data Sciences, Merck & Co., Inc., Rahway, NJ, USA; 6Center for Observation and RealWorld Evidence, Merck & Co., Inc., Rahway, NJ, USA

Background: In Colombia, 15,509 new cases of breast cancer (BC) were diagnosed in

2020. Furthermore, BC was the leading cause of cancer deaths. Triple-negative breast

cancer (TNBC) is an aggressive subtype that represents 15-20% of BC. The KEYNOTE522 (KN522) trial showed that neoadjuvant pembrolizumab + chemotherapy followed

by adjuvant pembrolizumab signiﬁcantly improved pathological complete response

and event-free survival when compared to neoadjuvant placebo + chemotherapy

followed by adjuvant placebo in patients with high-risk early stage TNBC (eTNBC). This

study evaluated the cost-effectiveness of neoadjuvant pembrolizumab + chemotherapy [paclitaxel + carboplatin followed by anthracycline + cyclophosphamide] plus adjuvant pembrolizumab versus neoadjuvant chemotherapy in high-risk eTNBC, from a third payer perspective in Colombia.

Methods: A Markov cohort model was developed with four mutually exclusive health states: event-free, locoregional recurrence, distant metastasis, and death, to simulate patients’ lifetime disease course based on the efﬁcacy and safety data from KN522.

Outcomes and costs were discounted at 3% annually. Time on treatment was estimated using observed Kaplan-Meier curves from KN522. Utility inputs were derived from EuroQoL-ﬁve-dimension questionnaire in KN522. Costs for initial and subsequent therapies, disease and adverse events management, and terminal care were estimated using drug and healthcare public lists prices of Colombia.

Results: Over a 51-year time horizon, patients receiving pembrolizumab + chemotherapy accrued an additional 2.39 life-years (LYs) and 2.19 quality-adjusted life-years(QALYs) compared to neoadjuvant chemotherapy. The resulting incremental costeffectiveness ratios (ICER) were COP 65,159,259/LY and COP 71,172,546/QALY, which were lower than the willingness-to-pay threshold of COP 85,093,272 in Colombia(based on 3-GDP per capita).

Conclusions: Neoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab is a cost-effective treatment versus neoadjuvant chemotherapy for high-risk eTNBC in Colombia, constituting a novel and key therapy option for those patients.

Legal entity responsible for the study: MSD Colombia.

Funding: MSD Colombia.

Disclosure: R. Brugés Maya: Financial Interests, Personal, Advisory Board, Advisory board neoadyuvant therapy in breast cancer triple negative: MSD; Non-Financial Interests, Advisory Role,Advisory in triple-negative breast cancer: MSD; Non-Financial Interests, Leadership Role, President of Asociacion Colombiana de Hematologia y Oncologia: ACHO. J.C. Urrego: Financial Interests, Personal,Full or part-time Employment, MSD Employee HTA - Market Access: MSD Colombia. C. Marrugo:Financial Interests, Personal, Full or part-time Employment, Market Access Manager: MSD Colombia.

V. Wurcel: Financial Interests, Personal, Full or part-time Employment: MSD; Financial Interests,Personal, Stocks/Shares: MSD. M. Huang: Other, Full time employee: Merck & CO., Inc. A. Haiderali:Financial Interests, Institutional, Full or part-time Employment: Merck & Co., Inc. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.455

259P Adjuvant doxorubicin-cyclophosphamide in early-stage breast cancer provides long-term cardiac safety

T. Susiriwatananont1, N. Poovorawan1, C. Teerapakpinyo2, S. Shuangshoti3,L. Jarutasnangkul4, M. Tumkosit4, P. Chattranukulchai5, N. Theerasuwipakorn5,S. Manasnayakorn6, C. Vinayanuwattikun1, Y. Vorasettakarnkij7, V. Sriuranpong1

1Division of Medical Oncology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and The King Chulalongkorn Memorial Hospital, Bangkok,Thailand; 2Chula GenePro Center, Research Affairs, Faculty of Medicine, Chulalongkorn University and The King Chulalongkorn Memorial Hospital, Bangkok, Thailand;3Department of Pathology, Faculty of Medicine, Chulalongkorn University and The King Chulalongkorn Memorial Hospital, Bangkok, Thailand; 4Department of Radiology,Faculty of Medicine, Chulalongkorn University and The King Chulalongkorn Memorial Hospital, Bangkok, Thailand; 5Division of Cardiovascular Medicine, Department of Medicine, Faculty of Medicine, Chulalongkorn University and The King Chulalongkorn Memorial Hospital, Bangkok, Thailand; 6Department of Surgery, Faculty of Medicine,Chulalongkorn University and The King Chulalongkorn Memorial Hospital, Bangkok,Thailand; 7Division of Hospital and Ambulatory Medicine, Department of Medicine,Faculty of Medicine, Chulalongkorn University and The King Chulalongkorn Memorial Hospital, Bangkok, Thailand

Background: Anthracyclines have been crucial chemotherapy for breast cancer treatment. However, its use has been limited by cardiotoxicity. We investigated the long-term outcomes and potential biomarkers associated with cardiac toxicities in breast cancer survivors who received anthracycline.

Methods: We prospectively collected data from 212 early-stage breast cancer patients who received adjuvant doxorubicin-cyclophosphamide (AC) at KCMH from 2007 to

2012. Echocardiography was performed pre-AC and within 3 months post-AC in 177 patients. Cardiac MRI (CMR) was conducted in asymptomatic patients (n¼49) betweenJuly and December 2022 to assess long-term cardiac outcomes. We analyzed plasma microRNA expression using the Nanostring platform at pre-AC and before 2ndcycle of AC AC of 18 patients who had decline of LVEF >10% (n= 9) and ≤10% LVEF (n =9).of 18 patients who had decline of LVEF >10% (n¼ 9) and 10% LVEF (n ¼9).

Results: The mean age of breast cancer diagnosis was 519 years with a medianfollow-up of 11 years [6-12]. The mean cumulative doxorubicin was 223.319.8 follow-up of 11 years [6-12].The mean cumulative doxorubicin was 223.3±19.8 mg/mg/m2. At end-AC evaluation, 43 patients (24.3%) and 15 patients (8.5%) had decreased LVEF by 10-20% and >20% respectively. 32 patients (18%) received subsequent antiHER2 therapy. 8 patients (3.7%) had arrhythmia (n¼6) and cardiomyopathy (n¼2) inlong-term follow-up. The miR-16-5p, miR-25-3p, miR-873-5p, miR-19b-3p, and miR30d-5p were the top 5 microRNAs that overexpressed in end-AC LVEF decline >10%with the fold change of 1.77-2.99. There was no difference in long-term CMR ﬁndings,including LVEF, LVEDVI, LVESVI, LV mass index, RVEF, T1 mapping, and strain in asymptomatic patients with end-AC LVEF decline >10% vs. 10%. Abnormal asymptomatic patients with end-AC LVEF decline >10% vs. ≤10%. Abnormal scarsscars

were found in 8 patients who had end-AC LVEF decline >10% (n¼7) vs. 10% (n¼1).All were located at the RV insertion site or mid-wall.

Table: 259P

LVEF at pre-AC, end-AC, and long-term CMR

LVEF

olume 34 - Issue S2

End-AC LVEF decline >10%(n ¼ 16)

End-AC decline 10% (n ¼ 30)

Pre-AC echocardiogram 75.2% +/- 7.2% 68.4% +/- 5.2% <0.01 End-AC echocardiogram 62.7% +/- 6.5% 68.1% +/- 5.3% <0.01 Long-term CMR

60.3% +/- 4.9% 60.6% +/- 5.3% 0.87

Conclusions: Our study demonstrated acceptable long-term cardiac outcomes in early-stage breast cancer patients who received 4 cycles of AC. Potential plasmamicro-RNAs were identiﬁed and will be further studied in more patients.

Funding: The Ethnic Research Initiatives, GSK Oncology International and Matching fund, Faculty of Medicine, Chulalongkorn University.

Disclosure: T. Susiriwatananont: Financial Interests, Personal, Invited Speaker: Roche, Amgen,Novartis. N. Poovorawan: Financial Interests, Personal, Invited Speaker: MSD, Astellas; Financial Interests, Institutional, Invited Speaker: Ipsen. S. Shuangshoti: Financial Interests, Personal and Institutional, Speaker, Consultant, Advisor: Novartis, Roche; Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Biocartis, MiRXES, Takeda. V. Sriuranpong: Financial Interests, Personal and Institutional, Speaker, Consultant, Advisor: Roche, AstraZeneca, Novartis, MSD, Pﬁzer,Amgen. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.456

260P Oncology efﬁcacy of gonadotropin-releasing hormone agonist in hormone receptor-positive very young breast cancer patients treated with neoadjuvant chemotherapy

H.J. Choi

Breast Surgery, Samsung Changwon Hospital - Sungkyunkwan University School of Medicine, Changwon, Republic of Korea

Background: Breast cancer in young women has been shown to have an aggressive behavior and poor prognosis. This study aimed to evaluate the outcomes of hormonereceptor (HR)-positive young breast cancer patients treated with neoadjuvant chemotherapy (NAC) and the oncologic efﬁcacy of gonadotropin-releasing hormone(GnRH) agonist.

Methods: This was a retrospective study on a prospectively collected cohort. We included 1123 patients who, between January 2006 and June 2018, were diagnosed with invasive breast cancer and treated with NAC followed by curative surgery at 000.

Among patients with HR-positive and human epidermal grow factor 2 (HER2)-negative breast cancer, we analyzed the characteristics and oncology outcomes between the patients equal to or younger than 35 years and the patients older than 35 years.

Results: Among 288 patients with NAC and strong HR-positive/HER2-negative breast cancer, 72 patients were equal to or younger than 35 years of age, and 213 patients were older than 35 years of age. The median follow-up is 74.0 months. There was no statistically signiﬁcant difference in disease free survival (DFS, p ¼ 0.261) and overallsurvival (OS, p ¼ 0.625) between the patients equal to or younger than 35 years andthe patients older than 35 years. The two groups differed in that the GnRH agonist was used more frequently in the group of patients equal to or younger than 35 years than in the other group (52.4% vs. 11.2%, p<0.001). Interestingly, for the DFS according to the GnRH agonist in the group of patients equal to or younger than 35 years, patients treated with the GnRH agonist had better DFS (p ¼ 0.016).

Conclusions: GnRH agonists might improve the DFS rate of HR-positive/HER2-negative breast cancer in the equal to or younger than 35 years group of patients with NAC.

Disclosure: The author has declared no conﬂict of interest.

https://doi.org/10.1016/j.annonc.2023.09.457

261P Dysregulation of immune checkpoint proteins in

newly- diagnosed early breast cancer patients undergoing neoadjuvant chemotherapy: A comparison between TNBC and non-TNBC patients

B.L. Rapoport1, H. Steel1, C-A. Benn2, S. Nayler3, T. Smit4, L. Heyman4, L. Kwoﬁe1,A. Theron1, N. Hlatswayo1, P. Meyer1, R. Anderson1

1Department of Health, University of Pretoria, Pretoria, South Africa; 2Surgery, Breast Care Centre of Excellence, Johannesburg, South Africa; 3Pathology, Gritzman &Thatcher, Randburg, South Africa; 4Research, The Medical Oncology Centre of Rosebank, Johannesburg, South Africa

Background: Breast cancer is associated with up-regulation or down-regulation of proteins in the immune system, to evade anti-tumor immune responses. Soluble forms of immune checkpoint molecules (sICMs) can be measured in human plasma.

The study aimed to measure the systemic levels of a series ICMs at diagnosis, postneo-adjuvant chemotherapy (NAC) and post-surgery in newly- diagnosed BC patients(pts) and compare the biological behaviour of these sICMs between TNBC and nonTNBC patients.

Methods: Soluble ICMs were measured using multiplex bead array technology in plasma from 72 BC pts and 45 healthy controls. Data were prospectively obtained and levels were compared between pre-treatment, post-NAC, and post-surgery using nonparametric tests (Mann-Whitney & Kruskal-Wallis).

Results: Following NAC, the plasma levels of six soluble co-stimulatory checkpoints(CD28, CD40, ICOS, CD27, CD80, GITR), all involved in the activation of CD8+ cytotoxic T cells, were signiﬁcantly increased (p < 0.04-p < 0.00001). Four of the soluble coinhibitory checkpoints (LAG-3, PDL1, TIM-3 and HVEM) increased signiﬁcantly postNAC. PD-1 remained unchanged, while BTLA and CTLA-4 decreased signiﬁcantly (p <

0.03 and p < 0.00001, respectively). Normalization of sICM seemingly indicates a reversal of systemic immune dysregulation following the administration of NAC in early BC. In contrast, recovery of immune homeostasis may explain the increased levels of several negative checkpoint proteins, albeit with the exceptions of CTLA-4 and PD-1.

Conclusions: This study demonstrates low levels of co-stimulatory and co-inhibitory sICMs in newly-diagnosed, non-metastatic BC pts. Following treatment with NAC, the sICMs levels increase substantially, except CTLA-4. In the case of co-stimulatory sICMs,these novel ﬁndings are indicative of an immune-restorative mechanism. The pattern of co-inhibitory sICMs (elevated levels of PD-L1, LAG-3, TIM-3 and HVEM), might be indicative of immune-therapeutic resistance, underscoring the augmentative immune-therapeutic promise of targeting these molecules, either individually or in combination, to improve the outcome of pts with early BC.

Funding: Cancer Association of South Africa.

Clinical trial identiﬁcation: NCT03879577.

Legal entity responsible for the study: Funmi Olopade, University of Chicago, Chicago, IL, USA.

Funding: University of Chicago.

https://doi.org/10.1016/j.annonc.2023.09.459

263P

Efﬁcacy and safety of neoadjuvant chemotherapy

combination with pembrolizumab in triple-negative breast cancer: Real-world data

L.W. Rached1, M.P. Spotti1, C. Baldini2, A. Laparra3, C.A. Dutertre Remote4,M. Sakkal5, A. Perret6, A.A. Viansone1, J.Z. Zeghondy6, E. Rassy7, C. Bousrih1,P. Abdayem8, R.M. Khoury Abboud9, H.K. El Masri6, T. Grinda6,

S. Moragon Terencio1, B. Verret6, S. Champiat2, B. Pistilli10, J.T.M.L. Ribeiro11

1Oncology Department, Institut Gustave Roussy, Villejuif, France; 2Drug Development Department, (DITEP), Institut Gustave Roussy, Villejuif, France; 3DIOPP, Institut Gustave Roussy, Villejuif, France; 4Clinical Research, Gustave Roussy - Cancer Campus,Villejuif, France; 5Gustave Roussy - Cancer Campus, Villejuif, France; 6Medical Oncology, Institut Gustave Roussy, Villejuif, France; 7Adult Medicine Department,Institut Gustave Roussy, Villejuif, France; 8Cancer Medicine Department, Gustave Roussy - Cancer Campus, Villejuif, France; 9Hematology/Oncology Dept., Institut Gustave Roussy, Villejuif, France; 10Breast Cancer Group, Institut Gustave Roussy,Villejuif, France; 11Breast Unit, Gustave Roussy - Cancer Campus, Villejuif, France

Background: Neoadjuvant chemotherapy (NAC) with the addition of Pembrolizumab(anti-PD1) is the current standard of care for early-stage II-III triple-negative breast cancer (TNBC). Although immunotherapy improves efﬁcacy, toxicity rates remain a paramount parameter to consider since many of the events are long-lasting for this subset of patients (pts) treated with a curative intent.

Methods: We conducted a retrospective analysis of the medical records of 95 pts with early-stage TNBC treated with NAC and Pembrolizumab, between April 2022 and April 2023 in our institution. At the time of this submission, the toxicity analysis is available for 74 pts and efﬁcacy for 64 pts. A complete analysis of 95 pts will be presented at ESMO. Treatment-related toxicities are reported according to the common terminology criteria for adverse events (CTCAE) v5.0.

Results: The cohort currently comprises 74 female patients, with a median age of 50 years [20-74]; 52% were premenopausal, and 20% harboured a deleterious BRCA germline mutation. Efﬁcacy analysis (n¼64): Pathologic complete response (pCR) ratewas 56 % (n¼36). The rate of pCR in pts with BRCA1/2 germline mutations was 80%(n¼12). Toxicity analysis (n¼74): We reported 376 toxicity events, of which 27% weregrade 3-4. Most events were attributed to chemotherapy (55%). The immune-related adverse events (irAE) rate was 26%. A total of 35% of pts discontinued treatment due to toxicity, most commonly: liver toxicity, recurrent severe haematological and severe skin toxicities; while 50% of pts required dose reductions. The most common grade 3-4 AEs were neutropenia in 49% of pts and hepatic toxicity in 30% of cases. Immunemediated thyroid dysfunction occurred in 25.7%, adrenal insufﬁciency was witnessed in 5%(4) of pts and hypophysitis in 4%(3). Immune-mediated myocarditis was witnessed in 1 elderly patient.

Conclusions: In this real-life cohort of early-stage TNBC patients treatment with a chemo-immunotherapy combination in the neoadjuvant setting was effective. However, we witnessed an important rate of treatment discontinuation due to toxicity.

The impact on the quality of life of these patients should be carefully evaluated,especially in regard to permanent toxicities.

Disclosure: C. Baldini: Financial Interests, Personal, Advisory Role: Bicycle therapeutics, Rising Tide Fundation, ITEOS; Financial Interests, Institutional, Principal Investigator: Abbvie, Adaptimmune,

Adlai Nortye USA Inc, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca Ab, Aveo, Basilea Pharmaceutica International Ltd,Bayer Healthcare Ag, Bbb Technologies Bv, Beige; Financial Interests, Institutional, Research Grant:AstraZeneca, BMS, Boehringer Ingelheim, GSK, INCA, Janssen Cilag, Merck, Novartis, Pﬁzer, Roche,Sanoﬁ; Non-Financial Interests, Institutional, Product Samples: AstraZeneca, Bayer, BMS, Boringher Ingelheim, GSK, MedImmune, Merck, NH TherAGuiX, Pﬁzer, Roche. S. Champiat: Financial Interests,Personal, Invited Speaker: Amgen, Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Genmab,Janssen, Merck, Merck Serono, Novartis and Roche; Financial Interests, Personal, Other, Principal Investigator of Clinical Trials: AbbVie, Amgen, Boehringer Ingelheim, Cytovation, Eisai, Imcheck Therapeutics, Molecular Partners Ag, Merck, Ose Pharma, Pierre Fabre, Sanoﬁ Aventis, Sotio A.S,Transgene; Financial Interests, Personal, Advisory Board: Alderaan Biotechnology, Amgen, AstraZeneca, Avacta, Celanese, Domain Therapeutics, Ellipses Pharma, Genmab, Immunicom, Inc., Nanobiotix, Nextcure, Oncovita, Pierre Fabre, Seagen, Tatum Bioscience, Tollys SAS, UltraHuman8;Financial Interests, Personal, Other, Travel and congress: Amgen, AstraZeneca, Bristol Myers Squibb,Merck, Ose Pharma, Roche, Sotio; Financial Interests, Institutional, Other, As part of the Drug Development Department (DITEP) ¼Principal/sub-Investigator of Clinical Trials: Adaptimmune, AdlaiNortye USA Inc, Aduro Biotech, Agios Pharmaceuticals, Amgen, Adaptimmune, AdlaiAstex Pharmaceuticals, AstraZeneca Ab, Aveo, Basilea Pharmaceutica International Ltd, Bayer Healthcare Ag,Bbb Technologies Bv, Beigene, BicycleTx Ltd, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Casi Pharmaceuticals, Inc, Celgene Corporation, Cellcentric, Chugai Pharmaceutical Co, Cullinan-Apollo, Curevac, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, Exelixis, Faron Pharmaceuticals Ltd, Forma Tharapeutics, Gamamabs, Genentech,GSK, H3 Biomedicine, Hoffmann La Roche Ag, Imcheck Therapeutics, Incyte Corporation, Imcheck Therapeutics, Incyte Corporation, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier,Iteos Belgium SA, Janssen Cilag, Janssen Research Foundation, Janssen R&D LLC, Kura Oncology,Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, MedImmune, Menarini Ricerche, Merck Sharp& Dohme Chibret, Merrimack Pharmaceuticals, Merus, Molecular Partners Ag, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Oncopeptides, Orion Pharma,Genomics, Ose Pharma, Pﬁzer, PharmaMar, Pierre Fabre Medicament, Relay Therapeutics, Inc,Roche, Sanoﬁ Aventis, Seattle Genetics, Sotio A. S, Syros Pharmaceuticals, Taiho Pharma, Tesaro,Transgene S.A, Turning Point Therapeutics, Xencor; Financial Interests, Institutional, Research Grant,As part of the Drug Development Department (DITEP) ¼Research Grants: AstraZeneca, BMS,Boehringer Ingelheim, GSK, INCA, Janssen Cilag, Merck, Pﬁzer, Roche, Sanoﬁ; Non-Financial Interests,Institutional, Product Samples, As part of the Drug Development Department (DITEP)¼Non-ﬁnancialsupport (drug supplied): AstraZeneca, BMS, Boehringer Ingelheim, GSK, MedImmune, Merck, NH TherAGuiX, Pﬁzer, Roche. B. Pistilli: Financial Interests, Institutional, Advisory Board: AstraZeneca,Seagen, Lilly, Daiichi Sankyo, MSD; Financial Interests, Institutional, Invited Speaker: Gilead, Novartis;Financial Interests, Personal, Advisory Board: Pierre Fabre, Daiichi Sankyo; Financial Interests, Personal, Other, travel support: AstraZeneca, Pierre Fabre, MSD, Daiichi Sankyo; Financial Interests,Institutional, Steering Committee Member: AstraZeneca, Novartis; Financial Interests, Institutional,Research Grant: AstraZeneca; Financial Interests, Institutional, Local PI: AstraZeneca, Gilead, Seagen,MSD, Novartis; Financial Interests, Institutional, Funding: Daiichi Sankyo; Non-Financial Interests,Project Lead: UNICANCER. J.T.M.L. Ribeiro: Financial Interests, Personal, Advisory Board: Gilead Sciences, Inc.; Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests,Personal, Invited Speaker: eESO. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.460

264P Tumor-inﬁltrating lymphocytes (TILs) for prediction of

response to platinum-based neoadjuvant chemotherapy(NACT) in triple-negative breast cancer (TNBC): Final analysis

S. Abdullaeva1, T.Y. Semiglazova1, A. Artemyeva2, A. Kudaibergenova2,V. Semiglazov3, P. Krivorotko4, V. Semiglazov4

1Department of Innovative Methods of Therapeutic Oncology and Rehabilitation, N.N.

Petrov National Medical Research Center of Oncology, St. Petersburg, Russian Federation; 2Anatomic Pathology Department, N.N. Petrov National Medical Research Center of Oncology, St. Petersburg, Russian Federation; 3Oncology Department, First Saint Petersburg State Medical University named after I.I. acad. I.P. Pavlova, St.

Petersburg, Russian Federation; 4Breast Cancer Department, N.N. Petrov National Medical Research Center of Oncology, St. Petersburg, Russian Federation

Background: According to several previous trials, event-free survival (EFS) in patients with TNBC is improved when carboplatin is added to NACT. Stromal TILs represent an important predictive and prognostic biomarker in patients with breast cancer. We are now reporting the analysis of EFS in patients with TNBC who received NACT now reporting the analysis of EFS in patients with TNBC who received NACT ±car-car-boplatin regarding TILs status.

Methods: The clinical data were obtained from 132 patients diagnosed with TNBC(ER&PgR<10%) and treated with either anthracycline-taxane NACT (n¼68) or car-boplatin-based chemotherapy (n¼64) from 2017 to 2022 at N.N. Petrov NationalMedicine Research Center of Oncology. TILs were evaluated in FFPE tumor tissue samples stained with H&E at baseline biopsies according to guidelines from the International TILs Working Group. EFS was estimated by the Kaplan-Meier method and compared between groups by log-rank test. Multivariate analysis for EFS was performed using Cox’s proportional hazards regression model, covariates included TILs level (<40 vs. 40), NACT, nodal status, BRCA status and level(<40 vs. ≥40),NACT, nodal status,BRCA status and pCR.pCR.

Results: High TILs were associated with signiﬁcantly higher 5-year EFS (94.3% vs

56.1% HR¼0.119, 95%CI 0.02-0.88, r¼0.037). Patients with pCR had a signiﬁcantlybetter 5-year EFS (74.5% vs 53.2%, HR¼0.231, 95%CI 0.09-0.58, r¼0.002). 5-year EFSrates were similar for both platinum-based and standard NACT groups (68.6% and

61.9%, respectively HR¼0.537, 95%CI 0.24-1.19, p¼0.124).5-year EFS for platinum-based NACT was 100% vs 84.6% in the standard NACT group(HR¼1.374, 95%CI 0.66-2.88, r¼0.40) in patients with high TILs, compared withpatients with low TILs levels EFS was lower 61.3% vs. 56.9%, respectively (HR¼1.602,95%CI 0.71-3.61, r¼0.256). In univariate analysis, the nodal status, pCR, and TILs levelwere signiﬁcant predictors of EFS. In multivariate analysis, only pCR (p¼0.006) andTILs level (p¼0.048) are two independent predictors of EFS.

Conclusions: EFS is numerically lower in the low TILs tumors which justiﬁes the escalation of the NACT regimen. Treatment de-escalation may be considered in patients with high TILs level. Further research in larger datasets is needed to validate these hypothesis generating ﬁndings.

https://doi.org/10.1016/j.annonc.2023.09.461

265P

Effect of HER2-low-positive status on neoadjuvant chemotherapy and survival outcome of breast cancer:A 10-year dual-center retrospective study

Y. Li, H. Zhang

Breast Surgery, The First Afﬁliated Hospital of Xi’an Jiaotong University, Xi’an, China

Background: Various novel HER2-targeted antibody-conjugated drugs (ADCs) have shown satisfactory antitumor activity in HER2-low-positive breast cancer (BC). The effect of HER2 status on neoadjuvant chemotherapy (NAC) and survival outcome is controversial. It is urgent to clarify whether HER2-low-positive tumors have unique biological behavior and should be considered a new molecular subtype. In our study, a 10-year dual-center retrospective research was conducted to analyze the effect of HER2-low-positive status on NAC and survival outcome of BC.

Methods: We screened eligible BC patients and collected relevant information at the First Hospital of Jilin University and the the First Afﬁliated Hospital of Xi’an Jiaotong University from January 2010 to December 2020. The primary outcome indicator was pathologic complete response(pCR). The secondary outcome indicators were overall survival (OS) and disease-free survival (DFS).

Results: A total of 1027 patients were included in our study cohort, and 66.0% (678/1027) had HER2-low-positive tumors. Compared to HER2-zero, HER2-low-positive patients tended to have more lymph node metastasis, a larger proportion of hormone receptor (HR)-positive tumors, and a lower proliferation rate (Ki-67). The pCR rate of HER2-low-positive was lower than that of HER2-zero patients (19.3% vs 21.6%),especially in the HR-positive subgroup (12.00% vs 20.29%). However, multivariate logistic regression analysis showed that HER2 status was not an independent factor for predicting pCR. HER2-low-positive patients had a higher OS rate in the HR-positive subgroup. The Cox regression model analysis suggested that HER2-low-positive status did not affect the survival outcomes, regardless of DFS (p¼0.308) or OS (p¼0.066).

Conclusions: HER2-low-positive tumors have unique clinical and pathological characteristics, with a lower pCR rate in the HR-positive subgroup and better survival in the HR-negative subgroup compared to HER2-zero tumors. However, HER2-low-positive status is not an independent predictor of pCR or survival outcome. The authors have equally contributed to the study.

Funding: This study was funded by the Innovation Capability Support Project of Shaanxi Province (No. 2023KJXX-032).

https://doi.org/10.1016/j.annonc.2023.09.462

266P Discontinuation rate and serious adverse events of chemoimmunotherapy as neoadjuvant treatment for triple-negative breast cancer: A systematic review and meta-analysis

F.M. Schipilliti1, A. Rizzo2, F. Di Costanzo3, S. Acquafredda4, G. Arpino5, F. Puglisi6,L. Del Mastro7, F. Montemurro8, M. De Laurentiis9, M. Giuliano10

1Oncology Department, Sant’ Andrea University Hospital, Rome, Italy; 2Oncology Department, Istituto Tumori Bari Giovanni Paolo II - IRCCS, Bari, Italy; 3Oncologia Medica, Azienda Ospedaliera Universitaria Federico II, Naples, Italy; 4Dipartimento di Oncologia, Policlinico di Bari - Ospedale Giovanni XXIII, Bari, Italy; 5Oncology Department, Università degli Studi di Napoli Federico II - Dipartimento di Farmacia,Naples, Italy; 6Medical Oncology Department, ASU Friuli Centrale - Ospedale S. Maria della Misericordia, Udine, Pordenone, Italy; 7Internal Medicine Dept., IRCCS Ospedale Policlinico San Martino, Genoa, Italy; 8Investigative Clinical Oncology Dept., IRCCS -Istituto di Candiolo - FPO, Candiolo, (TO), Italy; 9Dept. Breast and Thoracic Oncology,Istituto Nazionale Tumori IRCCS - Fondazione G. Pascale, Naples, Italy; 10Oncology Department, AOU “Federico II”, Naples, Italy

Background: Combination of chemotherapy plus immune checkpoint inhibitors (ICIs)has recently shown efﬁcacy in triple-negative breast cancer (TNBC), and thus, has been introduced in clinical practice in both the advanced and early disease stage.

However, few data are available regarding the extent and the potential consequences of discontinuation rate and serious adverse events of these treatments, especially in the neoadjuvant setting. Herein, we performed a comprehensive systematic review and meta-analysis to assess discontinuation rate and serious adverse events of

chemoimmunotherapy compared to chemotherapy alone in phase II and III neoadjuvant clinical trials in TNBC.

Methods: Following the Preferred Reporting Items for Systematic Reviews and Metaanalyses (PRISMA) guidelines, EMBASE, Cochrane Library, and PubMed/ Medline were searched for articles published from June 2008 to March 2023. The outcomes of interest were discontinuation rate, serious adverse events, and grade 3-4 adverse events.

Results: Overall, 4 studies were included in the analysis. The pooled Odds Ratios (ORs)for discontinuation rate and serious adverse events were 1.26 (95% CI, 0.78-2.06) and

1.79 (95% CI, 1.4-2.28), respectively, in patients receiving chemoimmunotherapy versus chemotherapy alone as neoadjuvant treatment for TNBC. A higher risk of grade 3-4 adverse events was reported in the chemoimmunotherapy group (OR 1.30; 95%CI, 1.07-1.59). The analysis was associated with substantial heterogeneity and the risk of discontinuation rate was strongly conditioned by the KEYNOTE-522 trial.

Conclusions: Our ﬁndings support the design of clinical trials which could be speciﬁcally focused on safety and treatment adherence, as well as the potential impact on outcome and quality of life in TNBC patients receiving neoadjuvant treatment.

Careful monitoring of tolerability remains a crucial need in this clinical setting.

Legal entity responsible for the study: M. Giuliano.

https://doi.org/10.1016/j.annonc.2023.09.463

267P Pathological complete response after neoadjuvant

chemotherapy plus pertuzumab and trastuzumab for HER2+early breast cancer: Real-world data from NeoPowER study

F. Canino1, M. Barbolini2, U.F.F. De Giorgi3, L. Gianni4, A. Maestri5, L. Moscetti2,C. Omarini2, C. Zamagni6, R. Cuoghi Costantini7, F. Tamburrano1, G. Antonelli1,F. Baglio1, L. Belluzzi1, G. Martinelli1, S. Natalizio1, O. Ponzoni1, M. Dominici1,F. Piacentini1

1Division of Medical Oncology, Department of Medical and Surgical Sciences for Children and Adults - University Hospital of Modena, Azienda Ospedaliero - Universitaria Policlinico di Modena, Modena, Italy; 2Division of Medical Oncology,Department of Oncology and Ematology - University Hospital of Modena, Azienda Ospedaliero - Universitaria Policlinico di Modena, Modena, Italy; 3Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; 4Oncology and Haematology Department, Ospedale Infermi,Rimini, Italy; 5Department of Medical Oncology, Ospedale Bellaria Carlo Alberto Pizzardi, Bologna, Italy; 6Oncology&Haematology Dept., AOU Policlinico S. Orsola-Malpighi, F.Addarii, Bologna, Italy; 7Unit of Clinical Statistics, Azienda Ospedaliero -Universitaria Policlinico di Modena, Modena, Italy

Background: The addition of pertuzumab (P) to trastuzumab (H) and standard chemotherapy (CT) as neoadjuvant treatment (NaT) for patients (pts) with HER2 positive (HER2+) breast cancer (BC), has shown to increase the pathological complete response (pCR) rate, without main safety concerns. The aim of multicentric NeoPowER trial is to evaluate safety and efﬁcacy of P+H+CT in a real world population.

Methods: We retrospectively reviewed the electronic medical records of stage II-III,HER2+ BC pts treated with preoperative CT+HP. The pts who received P+H+CT in HER2+ BC pts treated with preoperative CT+H±P. The pts who received P+H+CT in 55Emilia Romagna oncology centers (Modena, Bologna Bellaria, Bologna S.Orsola, Meldola, Rimini) between 2017-2022, were compared with a historical group who received H+CT (control) at Modena Cancer Center between 2007-2021. Clinicopathological variables were collected. Univariate and multivariate analysis were performed to assess the impact of covariates on pCR. Results were expressed as odds ratios (OR).

Results: 259 pts were included in the analysis, 125 (48%) received P+H+CT. Median age was 52 years, 63% were node-positive and 62% had hormone receptors positive(HR+). Features were balanced in the two groups, 62% of pts in the P+H+CT cohort had had a Ki67 ≥ 30%, vs 43% in the control. All pts received preoperative taxane-baseda Ki67 30%, vs 43% in the control. All pts received preoperative taxane-basedCT: 82% and 45% of pts also received anthracyclines, in the control and P+H+CT respectively. P+H+CT pts achieved higher pCR rate than the control: 46% vs 40%(p¼0.462). At univariate analysis, HR negative (OR¼3.79 p<0.001), Ki67 (p=0.462). At univariate analysis, HR negative (OR=3.79 p<0.001), Ki67 ≥ 30%30%(OR¼1.29 p¼0.04) and the use of preoperative anthracyclines (OR¼1.72 p¼0.04),were statistically related to pCR. Only ER expression (OR: 0.97 p¼0.004) conﬁrmed itsstatistical relation to pCR at multivariate analysis.

Conclusions: NeoPowER study conﬁrms the efﬁcacy of neoadjuvant chemotherapy combined with dual HER2 directed therapy: a higher pCR rate is achievable in case of HR negative and ki6730% in pts receiving neoadjuvant P+H+CT, when compared HR negative and ki67≥30% in pts receiving neoadjuvant P+H+CT, when compared totoH+CT.

Disclosure: M. Barbolini: Financial Interests, Personal, Other: Lilly, Novartis, Gentili. U.F.F. De Giorgi: Financial Interests, Personal, Advisory Board: Pﬁzer, BMS, MSD, PharmaMar, Astellas, Bayer,Ipsen, Novartis, EISAI, Janssen; Financial Interests, Personal, Invited Speaker: Roche, BMS, Clovis Oncology, AstraZeneca; Financial Interests, Institutional, Research Grant: AstraZeneca, Sanoﬁ, Roche.

L. Gianni: Financial Interests, Personal, Advisory Board, Advisory board in Trastuzumab Deruxtecan in her2 low breast cancer: AstraZeneca; Financial Interests, Personal, Advisory Board, Advisory board in

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tucatinib: Seagen; Financial Interests, Personal, Invited Speaker: Novartis, Pﬁzer; Non-Financial Interests, Other, Olympia Stearing Commitee: IBCSG; Other, Travel, Accommodations, Expenses: IPSEN,Novartis, Roche, Daiichi Sankyo/AstraZeneca. L. Moscetti: Financial Interests, Personal, Advisory Board: Lilly, Pﬁzer, Eisai; Financial Interests, Personal, Other, Honoraria: Roche; Financial Interests,Personal, Other, Honoraria: Daiichi Sankyo, Gilead, Pﬁzer; Financial Interests, Personal, Other,Honoraria: Novartis. C. Omarini: Financial Interests, Personal, Other: Lilly, Gentili, Novartis, Daiichi Sankyo, Seagen. F. Piacentini: Financial Interests, Personal, Other: Lilly, Gilead, Gentili, Daiichi Sankyo, Novartis. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.464

268P

Evaluating the efﬁcacy of adjuvant capecitabine in triplenegative breast cancer patients with residual disease:A real-world evidence study

M.J. Kim1, H.J. Kim1, S. Park2, Y.H. Park3

1Digital Health, Samsung Advanced Institute for Health Science & Technology(SAIHST), Sungkyunkwan University, Seoul, Republic of Korea; 2Health Sciences and Technology, Samsung Medical Center (SMC) - Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 3Hematology-Oncology Dept, Samsung Medical Center (SMC) - Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

Background: In early breast cancer, residual disease after neoadjuvant chemotherapy is considered an important prognostic factor, especially for triple-negative breast cancer (TNBC) and HER2-positive patients. The CREATE-X study demonstrated a survival beneﬁt of adjuvant capecitabine (adjC) for these patient groups, particularly in TNBC. Researchers have been trying to ﬁnd the appropriate population for adjC as Real-World Evidence (RWE). However, RWE in the Asian population was lacking, and previous RWE studies were limited in number. In addition, these studies did not include patients who received neoadjuvant immunotherapy treatment, while the Keynote-522 trial demonstrated the beneﬁt of immunotherapy in early TNBC.

Therefore, we evaluated the advantages of adjC in non-pCR TNBC patient group by using RWD.

Methods:We conducted a retrospective analysis of 1,033 TNBC patients who received neoadjuvant treatment at Samsung Medical Center between 2018 and 2023, using deidentiﬁed, anonymous data from the institutional Clinical Data Warehouse. Among these patients, we identiﬁed 403 patients who received at least one cycle of adjC,while 36 received no adjuvant treatment. Residual Cancer Burden (RCB) classiﬁcation were available for 399 patients. The primary outcome of the study was Disease-Free Survival (DFS). We conducted a survival analysis using Kaplan-Meier method.

Results: The median DFS has not yet been reached. The disease risk of the adjC group tended to be lower than that of the no adjuvant treatment group, but the difference was not statistically signiﬁcant (Hazard ratio(HR), 0.52; p-value¼0.083). At 36 months,86% of patients in the adjC group were disease-free or alive, compared to 76% of patients in the no adjuvant treatment group. Compared to the RCB-I group (n¼114,28.4%), the HR for the RCB-II group (n¼233, 58.5%) was 1.40, and the for the RCB-IIIgroup (n¼52, 13.1%), it was 5.88 (p<0.0001). The DFS at 36 months was 90%, 89%,and 67% for the RCB-I, II, and III groups, respectively.

Conclusions: In this study, adjC demonstrated a potential survival beneﬁt for non-pCR TNBC patients. Subgroup analysis based on RCB classiﬁcation indicated a higher risk associated with higher RCB class.

Funding: This study was supported by Future Medicine 2030 Project of the Samsung Medical Center [SMO1230451].

Disclosure: M.J. Kim: Financial Interests, Personal, Full or part-time Employment: Roche Korea. Y.H.

Park: Financial Interests, Personal, Advisory Board: AstraZeneca, Pﬁzer, Roche, Novartis, MSD, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca, Pﬁzer, Roche, Novartis, MSD;Financial Interests, Institutional, Other, Research Grant: AstraZeneca, Pﬁzer, Roche, MSD; NonFinancial Interests, Principal Investigator: AstraZeneca, Pﬁzer, Novartis, MSD, Lilly, Roche, Daiichi Sankyo. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.465

269P Achieving treatment goals in elderly breast cancer patients with neoadjuvant chemotherapy: A remarkable insight

E. Caliskan Yildirim1, H.S. Semiz1, O.U. Unal2, E. Atag1, A. Karaoglu1

1Medical Oncology, Dokuz Eylul University - Faculty of Medicine, Izmir, Turkey;2Medical Oncology, Tepecik Education and Research Hospital, Izmir, Turkey

Background: Neoadjuvant chemotherapy (NAC) is widely used for locally advanced breast cancer, including HER2-positive and triple-negative subtypes. However, the impact of age on treatment response remains uncertain. This study aims to investigate treatment outcomes in elderly breast cancer patients receiving neoadjuvant chemotherapy.

Methods: A retrospective analysis was conducted on breast cancer patients who underwent neoadjuvant treatment at two tertiary centers between 2010 and 2021.

https://doi.org/10.1016/j.annonc.2023.09.458

262P Pragmatic clinical trial assessing response to neoadjuvant taxotere and trastuzumab in Nigerian women with HER2-positive breast cancer (ARETTA): First report from the Nigerian breast cancer study group

A.I. Ntekim1, A. Sanni2, A.O. Popoola3, A.C. Sowunmi4, O. Olasehinde5,A. Ibraheem6, A. Folasire1, A. Adeniji-Sofoluwe7, T. Olajide8, F. Omodele9,A. Komolafe10, A. Omisore11, M. Ajani12, A. Daramola13, F. Abdulkareem13,O. Balogun14, T. Karrison15, C. Olopade16, J. Obafunwa2, O. Olopade16

1Radiation and Clinical Oncology, College of Medicine, University of Ibadan, Ibadan,Nigeria; 2Pathology, Lagos State University Teaching Hospital, Ikeja, Nigeria; 3Radiation and Clinical Oncology, Lagos State University Teaching Hospital, Ikeja, Lagos State, Nigeria; 4Radiotherapy, LUTH - Lagos University Teaching Hospital, Lagos,Nigeria; 5Surgery, Obafemi Awolowo University Teaching Hospital, Ile Ife, Nigeria;6Oncology, University of Illinois Cancer Center, Chicago, IL, USA; 7Radiology, College of Medicine, University of Ibadan, Ibadan, Nigeria; 8Surgery, LUTH - Lagos University Teaching Hospital, Lagos, Nigeria; 9Surgery, Lagos State University Teaching Hospital,Ikeja, Nigeria; 10Pathology, Obafemi Awolowo University Teaching Hospital, Ile Ife,Nigeria; 11Radiology, Obafemi Awolowo University Teaching Hospital, Ile Ife, Nigeria;12Pathology, College of Medicine, University of Ibadan, Ibadan, Nigeria; 13Pathology,CMUL - College of Medicine, University of Lagos, Lagos, Nigeria; 14Radiation Oncology, New York-Presbyterian Hospital/ Weill Cornell Medical Center, New York, NY,USA; 15Biostatistics, The University of Chicago, Chicago, IL, USA; 16Medicine, The University of Chicago, Chicago, IL, USA

Background: There is unacceptably low level of oncology clinical trials in Nigeria, the country with the highest burden of breast cancer in Africa. This has been attributed to poor research infrastructure and trained personnel. This study was designed to assess the feasibility of establishing a robust platform for multi-institutional biomarker driven oncology clinical trials to improve quality of cancer care in Nigeria.

Methods: One-stage phase II single arm design in women with HER2-positive breast cancer with clinical stages IIA to IIIC ( AJCC 2009 ). All patients received 4 cycles of docetaxel + Herceptin SC. Breast ultrasound (USS) was done at diagnosis and after

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every 2 cycles of neoadjuvant phase. Those with complete clinical response by USS after 4 cycles had surgery. Those with partial response or stable disease (operable)switched to FEC for additional 3 cycles before surgery. All responders received 18 cycles of Herceptin SC. Adjuvant treatment included hormonal therapy as indicated.

Radiation therapy was administered as per institutional practice.

Results: Study was initiated in April 2020 at onset of the pandemic and completed accrual in August 2022. Forty-seven of 53 enrolled patients (pts) were evaluable; 4 pts withdrew consent and 2 refused surgery. The median age was 50yrs (range 25-71 yrs.); Fifty-ﬁve percent were premenopausal. Majority were clinical stage III (60%),58% ER- and 60% PR-. Twenty-ﬁve of 47 (53.2%) evaluable pts had pathological complete response (pCR) [including 6 pts (12.8%) after 4 cycles of docetaxel + Herceptin SC]. Treatment was well tolerated with Grade 3 toxicities of myelosuppression 6 (12.8%), diarrhea 1 (2.1%) and hepatic toxicity 2 (4.2%). The maximum reductions in LVEF were 20% and 26% in 2 pts respectively but without cardiac symptoms.

Conclusions: The study met its primary endpoint with pCR rate of 53% and manageable toxicity. To our knowledge, this is the ﬁrst investigator initiated multiinstitutional biomarker driven oncology clinical trial ever conducted in sub-Sahara Africa, paving the way for future pragmatic patient-centric biomarker informed clinical trials in populations of African Ancestry.

Methods: Post-menopausal women with stage IeIII operable ER+, HER2- untreated EBC 1 cm were enrolled to imlunestrant 200, 400 (RP2D), or 800 mg once daily forapproximately two weeks up to the surgery date. Pre- and on-treatment tumor samples were compared for changes in PD biomarkers. Primary endpoint was change in ER expression by IHC. Secondary endpoints were change in progesterone receptor(PR) expression and Ki-67, safety, and tolerability.

Hamilton: Financial Interests, Institutional, Other,Consulting/Advisory Role: Genentech/Roche, Novartis, Lilly, Pﬁzer, Mersana, iTeos, Janssen, Loxo,Relay Therapeutics, Olema Pharmaceuticals, Orum Therapeutics, Stemline Therapeutics, AstraZeneca, Daiichi Sankyo, SeaGen, Ellipses Pharma, Greenwich LifeSciences, Tubulis, Verascity Science,Theratechnologies; Financial Interests, Institutional, Research Grant: Oncomed, Genentech/Roche,Zymeworks, Rgenix, Arqule, Clovis, Millennium, Acerta Pharma, Sermonix Pharmaceuticals, Black Diamond, Karyopharm, Curis, Syndax, Novartis, Boehringer Ingelheim, Immunomedics, FujiFilm,Taiho, Deciphera, Molecular Templates, Onconova Therapeutics, Dana Farber Cancer Inst, Hutchinson MediPharma, MedImmune, SeaGen, Compugen, TapImmune, Lilly, Pﬁzer, H3 Biomedicine,Merus, Regeneron, Arvinas, StemCentRx, Verastem, eFFECTOR Therapeutics, CytomX, InventisBio,Lycera, Mersana, Radius Health, Abbvie, Nucana, Leap Therapeutics, Zenith Epigenetics, Harpoon,Orinove, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, PharmaMar, Olema, Immunogen, Plexxicon, Amgen, Akesobio Australia, Shattuck Labs, ADC Therapeutics, Aravive, Atlas MedX, Ellipses Pharma, Incyte, Jacobio, Mabspace Biosciences, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Repertoire Immune Medicine,Treadwell Therapeutics, Accutar Biotechnology, Artios, BeiGene, Bliss BioPharmaceuticals, Cascadian Therapeutics, Context Therapeutics, Cullinan, Dantari, Duality Biologics, Elucida Oncology, Inﬁnity Pharmaceuticals, K-Group Beta, Kind Pharmaceuticals, Loxo Oncology, Oncothyreon, Orum Therapeutics, Prelude Therapeutics, Profound Bio, Relay Therapeutics, Tolmar, Torque Therapeutics R.

Ismail-Khan, C. Karacsonyi, S.T. Estrem, U. Ozbek : Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company; Financial Interests, Personal, Stocks or ownership: Eli Lilly and Company. E.M. Ciruelos: Financial Interests, Personal, Other, Speakers Bureau. Educational activities:Roche; Financial Interests, Personal, Invited Speaker, Symposia and Educational activities: Roche;Financial Interests, Personal, Advisory Board, Non-permanent advisor: Roche, Lilly, Novartis, Pﬁzer,

400 mg

800 mg

Total

27 (36)

26 (35)

75 (100)

-82 (-91, -60)

-70 (-78, -59)

-81 (-87, -72)

26 (36)

72 (100)

-76 (-90, -38)

-82 (-92, -60)

-81 (-89, -66)

22 (37)

17 (29)

59 (100)

-71 (-80, -57)

-78 (-84, -70)

-73 (-78, -67)

Fatigue e 13 Hot ﬂush e 7

Diarrhea e 18 Nausea e 11 Fatigue e 7 Hot ﬂush e 7

Fatigue e 9 Diarrhea e 8 Hot ﬂush e 7 Nausea e 7

tric mean percent change.

Daiichi Sankyo, MSD; Financial Interests, Personal, Invited Speaker, Symposia and Education: Lilly;Financial Interests, Personal, Invited Speaker, Educational activities: Pﬁzer; Financial Interests, Personal, Advisory Board, Non-permanent advisor, Travel accommodation: AstraZeneca; Financial Interests, Personal, Other, Advisory Board: Gilead; Financial Interests, Personal, Other, Advisory Board,Invited speaker: Seagen; Financial Interests, Institutional, Funding, PI for Patricia 2 trial (sponsor:SOLTI Group): Pﬁzer; Financial Interests, Institutional, Funding, PI for Prometeo 2 trial (sponsor:SOLTI Group): Pﬁzer; Financial Interests, Institutional, Funding, PI for TATEN trial (sponsor: SOLTI Group): MSD; Financial Interests, Institutional, Funding, PI for ATREZZO trial (sponsor: SOLTI Group):Roche; Non-Financial Interests, Member of Board of Directors, Non-proﬁt organization dedicated to breast cancer research: SOLTI Cooperative Group; Non-Financial Interests, Advisory Role, Scientiﬁc Evaluator at ISCIII (Spanish Government Academic Research Platform): Instituto de Salud Carlos III.

https://doi.org/10.1016/j.annonc.2023.09.470

274P

Impact of dose reductions on efﬁcacy of adjuvant

abemaciclib for patients with high-risk early breast cancer(EBC): Analyses from the monarchE study

J. O’Shaughnessy1, I. Cicin2, L. Testa3, S.M. Tolaney4, J. Huober5, V. Guarneri6,S.R.D. Johnston7, M. Martin Jimenez8, P. Rastogi9, N. Harbeck10, H.S. Rugo11,R.J. Wei12, V. Andre13, A. Shahir13, M.P. Goetz14

1Medical Oncology, Texas Oncology - Baylor Sammons Cancer Center, Dallas, TX, USA;2Medical Oncology Department, Trakya University Rektorlugu, Edirne, Turkey;3Oncology, ICESP - Instituto do Cancer do Estado de Sao Paulo, Sao Paulo, Brazil;4Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA; 5Oncology,Cantonal Hospital St. Gallen, St. Gallen, Switzerland; 6Department of Surgery,Oncology and Gastroenterology, University of Padova Medical School, Padua, Italy;Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy; 7Breast Unit, The Royal Marsden Hospital (Chelsea) - NHS Foundation Trust, London, UK;8Medical Oncology Service, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, CIBERONC, Geicam, Universidad Complutense, Madrid, Spain, Hospital General Universitario Gregorio Marañón,Madrid, Spain; 9Oncology, NSABP Foundation, Pittsburgh, PA, USA; 10Breast Center,Ludwig Maximilians University - Grosshadern, Munich, Germany; 11Breast Department, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA;12Oncology, Eli Lilly and Company - Global Headquarters, Indianapolis, IN, USA;13Oncology, Eli Lilly and Company, Indianapolis, IN, USA; 14Department of Oncology,Mayo Clinic, Rochester, NY, USA

Background: Abemaciclib is approved as adjuvant therapy for HR+, HER2-, high risk EBC based on clinically signiﬁcant improvements in invasive disease-free survival(IDFS) and distant relapse-free survival (DRFS), which were maintained and deepened after the 2-year treatment period was completed. In monarchE, 44% of patients required dose reductions of abemaciclib to proactively manage adverse events. In abemaciclib MBC trials, similar rates of dose reductions did not compromise PFS (Rugo, 2021 ). Here we present the exploratory analyses to investigate the impact of dose reductions on efﬁcacy in monarchE.

Methods: In monarchE, up to 2 abemaciclib dose reductions were permitted prior to discontinuation. Pts treated with abemaciclib were classiﬁed into 3 equal-sized subgroups according to their abemaciclib relative dose intensity (RDI), and IDFS rates were estimated within each subgroup. A time-dependent Cox proportional hazard(PH) model ( Therneau, 2000 ) was also implemented to assess the impact of dose levels over time on IDFS.

Conclusions: Consistent with observations in the metastatic setting, the efﬁcacy of adjuvant abemaciclib in monarchE was not compromised by dose reductions.

Therefore, dose reductions should be considered as a safe and effective way to manage toxicity and retain patients on treatment, in order to maintain beneﬁt from adjuvant abemaciclib in combination with endocrine therapy.

Editorial acknowledgement: Trish Huynh, employee of Eli Lilly and Company, provided medical writing support.

Disclosure: J. O’Shaughnessy: Financial Interests, Other, Consulting, payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events: AbbVie,Agendia, Amgen, Aptitude, AstraZeneca, Athenex, Bayer, Bristol Myers Squibb, Carrick Therapeutics ,Celgene, Daiichi Sankyo, Eisai, Genzyme, Gilead, Heron, Immunomedics, Lilly, Seagen, Syndax;Financial Interests, Other, Consulting, payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events fees: G1 therapeutics, Genentech, Grail, Halozyme, Ipsen, Merck, Myriad, Nektar, Novartis, Ontada, Pﬁzer, Pharmacyclics, Pierre Fabre, Puma,Prime Oncology, Roche, Samsung BIoepis, Sandoz, Sanoﬁ, Taiho, Takeda, Theralink, Synthon. I. Cicin:Other, Principal investigator for Jounce Therapeutic: Jounce Therapeutic. L. Testa: Financial Interests,Local PI, All support for the present manuscript (e.g., funding, provision of study materials, medical

writing, article processing charges, etc.) No time limit for this item. Lilly As the trial sponsor, Lilly funded the study and payed for all processing charges: Eli Lilly and Company; Financial Interests,Institutional, Research Funding, 2 Grants or contracts from any entity (if not indicated in item #1 above). Novartis Grant for clinical research at other institution: Novartis; Financial Interests, Advisory Board: MSD, Eli Lilly and Company, AstraZeneca, Novartis, Daiichi Sanko; Financial Interests, Other,Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: MSD, Eli Lilly an Company, Pﬁzer, Daiichi Sankyo, Novartis, AstraZeneca; Financial Interests, Other, Support for attending meetings and/or travel: Pﬁzer, AstraZeneca, Gilead; Financial Interests, Other, Leadership or ﬁduciary role in other board, society, committee or advocacy group,paid or unpaid: AstraZeneca. S.M. Tolaney: Financial Interests, Personal, Advisory Board, Ad board participant/consultant: 4D Pharma, ARC Therapeutics, Daiichi Sankyo, Eisai, Genentech/Roche,Gilead, Novartis, Sanoﬁ, SeaGen; Financial Interests, Personal, Other, Consulting: Aadi BioPharma;Financial Interests, Personal, Advisory Board, Ad board participation: Artios, Incyte Corp, BeyondSprings; Financial Interests, Personal, Advisory Board, Ad Board Participant/Consultant: AstraZeneca,Eli Lilly; Financial Interests, Personal, Advisory Board, Advisory Board participation: Bayer, Inﬁnity Therapeutics, Myovant, OncXerna, Umoja Biopharma, Zentalis, Zetagen; Financial Interests, Personal, Other, Consultant: Blueprint Medicines; Financial Interests, Personal, Advisory Board, Ad board participant: Bristol Myers Squibb, Ellipses Pharma, Mersana Therapeutics; Financial Interests,Personal, Other, Steering Committee Member/Consultant: CytomX; Financial Interests, Personal,Advisory Board, Advisory Board participation/consulting: Menarini/Stemline; Financial Interests,Personal, Advisory Board, Ad Board participant/consultant: Merck; Financial Interests, Personal,Advisory Board, Ad board participant/Consultant: Pﬁzer; Financial Interests, Personal, Advisory Board, Advisory board participation: Reveal Genomics; Financial Interests, Personal, Advisory Board,Advisory Board Participation: Zymeworks; Financial Interests, Institutional, Funding: AstraZeneca, Eli Lilly, Pﬁzer, Sanoﬁ, SeaGen, Odonate, Cyclacel, Exelixis, Gilead, Bristol Myers Squibb, Eisai, Merck,Novartis, Nektar, Genentech/Roche; Financial Interests, Personal and Institutional, Steering Committee Member: CytomX. J. Huober: Financial Interests, Institutional, Other, Grants or contracts from any entity: Celgene, Novartis, Hexal, Eli Lilly and Company; Financial Interests, Personal, Other,Consulting fees: Eli Lilly and Company, Novartis, Roche, Pﬁzer, Novartis , Celgene, Daiichi, Gilead;Financial Interests, Personal, Other, Payment or honoraria for lectures presentations speaker’s bureau manuscript writing or educational events: Eli Lilly and Company, Novartis, Roche, Pﬁzer,AstraZeneca, MSD, Celgene , Eisai, AbbVie, Seagen, Gilead; Financial Interests, Personal, Other,Support for attending meetings and travel: Roche, Pﬁzer, Novartis, Celgene, Daiichi , Gilead . V.

Guarneri: Financial Interests, Personal, Invited Speaker: Eli Lilly, Novartis, Amgen, GSK; Financial Interests, Personal, Advisory Board: Eli Lilly, Novartis, MSD, Gilead, Eli Lilly, Sanoﬁ, Merck Serono,Exact Sciences, Eisai, Olema Oncology; Financial Interests, Institutional, Local PI: Eli Lilly, Roche, BMS,Novartis, AstraZeneca, MSD, Synton Biopharmaceuticals, Merck, GSK, Daiichi Sankyo, Nerviano; NonFinancial Interests, Member: ASCO. S.R.D. Johnston: Financial Interests, Personal and Institutional,Advisory Role, Research funding to institue for clinical trials: Eli Lilly and Company, AstraZeneca,Pﬁzer, Novartis; Financial Interests, Personal and Institutional, Advisory Role, Research funding to institute for laboratory studies: Biotechnology, Puma Biotechnology ; Financial Interests, Personal,Advisory Role: Sanoﬁ Genzyme; Financial Interests, Personal, Speaker’s Bureau: Eisai; Financial Interests, Personal and Institutional, Speaker’s Bureau, Research funding to institute for clinical trials:Roche/Genentech. M. Martin Jimenez: Financial Interests, Personal, Advisory Board: AstraZeneca,Lilly, Roche/Genentech, Daiichi Sankyo, Menarini-Stemline; Financial Interests, Personal, Invited Speaker: Pﬁzer, AstraZeneca, Lilly, Novartis, Roche/Genentech; Financial Interests, Institutional,Research Grant: Novartis, Roche, Puma; Non-Financial Interests, Member of Board of Directors:TRIO; Non-Financial Interests, Leadership Role: GEICAM; Non-Financial Interests, Member: ASCO;Non-Financial Interests, Advisory Board: SEOM. N. N. Harbeck: Financial Interests, Other, Consulting fees: Gilead, Sandoz, Seagen; Financial Interests, Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Amgen, AstraZeneca, Daiichi Sankyo, Gilead, Lilly, MSD, Novartis, Pierre Fabre, Pﬁzer, Roche, Seagen; Financial Interests, Other,Participation on a Data Safety Monitoring Board or Advisory Board: Roche; Other, Leadership orﬁduciary role in other board, society, committee or advocacy group, paid or unpaid: West German Study Group, ESMO. H.S. Rugo: Financial Interests, Personal, Other, Consultancy/advisory support:PUMA, NAPO, Mylan, Daiichi Sankyo, Eisai; Financial Interests, Institutional, Local PI: Novartis, Lilly,Pﬁzer, Daiichi, AstraZeneca, Gilead Sciences, Inc., GSK, Sermonix Pharmaceuticals Ins., Pionyr Immunotherapeutics, Taiho Oncology, Inc., Veru Inc; Financial Interests, Institutional, Coordinating PI:OBI Pharma, Astellas Pharma Inc., F. Hoffmann-La Roche AG/Genentech, Inc., Merck; Financial Interests, Personal, Other, Travel support to academic meetings: Merck, AstraZeneca, Gilead; NonFinancial Interests, Advisory Role, I advise a number of companies without compensation: various.

R.J. Wei: Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company; Financial Interests,Personal, Full or part-time Employment: Eli Lilly and Company. V. Andre: Financial Interests, Personal,Full or part-time Employment: Eli Lilly and Company; Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company. A. Shahir: Financial Interests, Personal, Stocks or ownership: Eli Lilly and Company; Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company. M.P. Goetz:Financial Interests, Institutional, Advisory Board: ARC Therapeutics, Biotheranostics, Blueprint Medicines, Rna Diagnostics, Sanoﬁ Genzyme; Financial Interests, Institutional, Other, Consulting:AstraZeneca, Seattle Genetics; Financial Interests, Institutional, Other, General Consulting: Lilly;Financial Interests, Personal, Invited Speaker, CME Activity: Research to Practice, Clinical Education Alliance, Medscape, MJH Life Sciences; Financial Interests, Personal, Invited Speaker, CME Panel Discussant: Total Health Conferencing; Financial Interests, Personal, Other, Moderator for CME Activity: Curio Science; Financial Interests, Institutional, Local PI: Lilly, Pﬁzer, LOXO, ATOSSA Therapeutics, AstraZeneca, Sermonix. All other authors have declared no conﬂicts of interest.

Results: Among the 2791 pts treated with abemaciclib, 832 (30%) had one and 389(14%) had two dose reductions. Patients 65 years old, or those with 4 pre-existingco-morbidities were more likely to have dose reductions. Across the 3 RDI groups(66% vs 66%-93% vs 93%), 4-year IDFS rates were generally consistent (87.1% vs86.4% vs 83.7% from the lowest RDI group to the highest). According to the timedependent model, the effect of abemaciclib is similar when staying at the full 150mg dose compared to being dose reduced to either 100mg or 50mg (HR ¼ 0.905; 95% CI¼ 0.727, 1.125).

Patients were divided into two groups based on age: 65 years and <65 Patients were divided into two groups based on age: ≥65 years and <65 years.years.Pathologic response and surgical outcomes were compared between the groups.

Results: A A total of 535 patients were included in the study, with 12% aged ≥65 years.total of 535 patients were included in the study, with 12% aged 65 years.There were no statistically signiﬁcant differences in the clinicopathological characteristics between older and younger patients. The overall rate of receiving anthracycline-based chemotherapy (CT) in the entire population was 97.6%, with ddAC used more in the younger patients (71.7% vs 38.5%, p<0.001). Breast-conserving surgery and sentinel lymph node dissection were comparable between the groups. In older patients, the rate of breast downstaging was 73.5% and the rate of axillary downstaging was 70.6%, with no statistically signiﬁcant difference compared to younger patients. A comparison of the groups in terms of pathological complete response revealed rates of 26.6% in younger patients and 33.3% in older patients (p>0.05). The rate of grade 3-4 toxicity was statistically higher in elderly patients (71% vs. 46.4%,p<0.01). No treatment-related deaths were observed. The median follow-up period was 50 months. Recurrence occurred in only 84 (17%) patients, with a recurrence rate of 10.4% in elderly patients compared to 17% in the other group (p¼0.17).

Conclusions: The study suggests that elderly patients achieve similar outcomes to younger patients, indicating that age alone should not be a basis for undertreatment.

Further research focusing on personalized approaches for the geriatric population is needed.

https://doi.org/10.1016/j.annonc.2023.09.466

270P Inﬂuence of neoadjuvant chemotherapy-induced short-term amenorrhea on pathologic response and treatment outcome in ER+HER2- breast cancer

S.E. Lee1, Y. Kook2, B. Seung Ho2, S. Moon1, J. Kim1, M.J. Kim1, S.J. Bae2, J. Jeong2,S.B. Lee3, S.G. Ahn2

1Department of General Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea; 2Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea;3Department of Surgery, Asan Medical Center - University of Ulsan, Seoul, Republic of Korea

Background: Premenopausal women experience temporary ovarian function suppression (OFS) during the period of chemotherapy. In ER+ breast cancer, chemotherapy-induced temporary OFS may offer anti-estrogenic effect in addition to direct cytotoxic anti-tumor effect. It is unclear whether anti-estrogenic effect by temporary OFS during neo-adjuvant chemotherapy (NAC) enhance anti-tumor effect. Based on pathologic complete response (pCR) and complete cell-cycle arrest (CCCA), we compared pathologic response and outcomes between younger and older patients with ER+HER2- breast cancer treated with NAC.

Methods: Between 2007 January and 2021 June, we retrospectively identiﬁed 1,178 patients with ER+HER2- breast cancer who underwent NAC in the Gangnam Severance Hospital and the Asan Medical Center. We compared the pCR rate according to age under 45 and over 55 and investigated durations of NAC, clinical stage, and Ki-67.

Pathologic complete response was deﬁned as no invasive residual disease in both breast and axillae. In addition, we collected available Ki67 expression in surgical specimen after NAC. We deﬁned low Ki67 with a cutoff of 2.7%. The recurrence-free survival was evaluated in patients with post-NAC Ki67.

Results: In all 1,178 patients, the pCR rate was 1.9% (22/1,178). The rate was 1.4% (8/552) 552) in younger patients (age ≤45), whereas it was 3.6% (9/250) in older patientsin younger patients (age 45), whereas it was 3.6% (9/250) in older patients(age 55) (p¼ 0.063, Chi-square test). In 524 patients who received NAC consisting (age ≥55) (p= 0.063, Chi-square test). In 524 patients who received NAC consisting ofofanthracyclines and taxanes with a duration of NAC longer than 6 months, the pCR rate did not differ between the younger patients and the older (2.1%, 5/243 vs. 2.8%, 3/106; p¼ 0.703). In patients with post-NAC Ki67, the CCCA rates were 66.2% (307/464)in the younger and 39.8% (86/216) in the older, respectively (p<0.001). Survival analyses showed that, compared to patients with CCCA, those without CCCA experienced a signiﬁcant decrease in RFS in both younger and older women.

Conclusions: While short-term OFS resulting from NAC led to a higher rate of CCCA in premenopausal women, younger women had notably poorer survival outcomes compared to older women. Among premenopausal women, achieving CCCA was associated with a slight improvement in treatment outcomes.

Legal entity responsible for the study: Gangnam Severance Hospital.

https://doi.org/10.1016/j.annonc.2023.09.467

271P

First clinical demonstration of the predictive value of tissue nanomechanical signature in breast cancer patients in

neoadjuvant therapy setting

S. Nizzero1, T. Appenzeller2, L. Briner3, R.A. Burian4, A. Jizawi5, S. Schädelin6,C. Raez7, S. Muenst-Soystal8, T. Vlajnic8, E. Obermann9, S. Dellas10, S. Forte11,Z. Marusic12, P.D. Ndiaye2, P. Oertle13, G. Zaugg14, M. Loparic15, M. Plodinec

Z.Marusic12,P.D.Ndiaye2,P. Oertle13,G.Zaugg14,M.Loparic15,M. Plodinecis15

1Mathematics in Medicine, Houston Methodist Research Institute, Houston, USA;2Clinical Science, ARTIDIS AG, Basel, Switzerland; 3Breast Center, University of Basel -Medizinische Fakultät, Basel, Switzerland; 4Breast Center, University Hospital Basel,Basel, Switzerland; 5Research and Innovation, ARTIDIS AG, Basel, Switzerland; 6Clinical Trials Unit, University Hospital Basel, Basel, Switzerland; 7University Hospital Basel,Basel, Switzerland; 8Institute of Pathology, University Hospital Basel, Basel,Switzerland; 9Pathology, Luzerner Kantonsspital, Sursee, Switzerland; 10Breast Imaging and Diagnostics, University Hospital Basel, Basel, Switzerland; 11Radiology, Roentgeninstitut Baden, Baden, Switzerland; 12Pathology, KBC - University Hospital Centre Zagreb, Zagreb, Croatia; 13Medical Device Development, ARTIDIS AG, Basel,Switzerland; 14Data Science, ARTIDIS AG, Basel, Switzerland; 15ARTIDIS AG, Basel,Switzerland

Background: Structural remodeling of cells and extracellular matrix (ECM) during cancer initiation and progression are accompanied by substantial biomechanical alterations, which can be measured by Atomic Force Microscopy (AFM). Increasing(pre)- and clinical evidence demonstrate the importance of cancer biomechanics in mediating therapy response. Incorporating AFM measurements of clinical biopsies within standard of care is thus a promising avenue to leverage tissue mechanics as prognostic and predictive biomarker for solid cancers.

Methods: We conducted a single center, blinded, prospective study to measure a multiparameter nanomechanical signature (NS) of response to neoadjuvant therapy(NAT) in breast cancer (BC). Between 2016 and 2019, 588 fresh, baseline, clinical breast biopsy samples from 545 patients were measured using the AFM based Automated and Reliable Tissue Diagnostics (ARTIDIS) investigational device e ART-1,within routine clinical setting in the Breast Clinic, University Hospital Basel. 35 patients received NAT: combination chemotherapy (CHT) (n¼30) and endocrine NAT(n¼5). Study endpoints were radiological complete response (rCR) prior and patho-logical complete response (pCR) after surgery. NS data has been analyzed in an automated manner using proprietary ARTIDISNet software platform. 10 y follow up is ongoing.

Results: The ARTIDIS NS of response to NAT in BC showed 100% negative predictive value (NPV) and 89% positive predictive value (PPV) with 93% of accuracy for patients receiving CHT, independent of molecular subtype or treatment regimen. Sensitivity was 100% and speciﬁcity was 85% (AUC¼0.91). When 5 patients with endocrine NATwere included, performance was decreased, meaning: NPV¼92%, PPV¼91, Sensitivity¼ 95 and Speciﬁcity ¼ 85 (AUC¼0.83).

Conclusions: NS can be prospectively used in clinical settings to predict response to NAT in BC. Mechanistically, these results highlight the importance of cell and TME mechanics in modulating therapy response. Furthermore, these results are being validated in a multicenter prospective study (ANGEL) currently enrolling 2706 patients with the aim to support implementation of the ARTIDIS NS into routine clinical practice.

Legal entity responsible for the study: ARTIDIS AG.

Funding: ARTIDIS AG.

Disclosure: S. Nizzero: Financial Interests, Personal, Other, Travel cost: ARTIDIS AG; Financial Interests, Personal, Advisory Role: ARTIDIS AG. T. Appenzeller, P. Oertle:: Other, Personal and Institutional, Leadership Role: ARTIDIS AG. L. Briner: Non-Financial Interests, Institutional, Research Funding: ARTIDIS AG. R.A. Burian: Non-Financial Interests, Institutional, Principal Investigator:ARTIDIS AG. A. Jizawi: Financial Interests, Institutional, Leadership Role: ARTIDIS AG. S. Schädelin:Financial Interests, Institutional, Financially compensated role: ARTIDIS AG. C. Raez: Financial Interests, Institutional, Other: ARTIDIS AG. S. Muenst-Soystal, T. Vlajnic, E. Obermann: Other, Institutional, Non ﬁnancial beneﬁts: ARTIDIS AG. S. Dellas, S. Forte: Other, Institutional, Non remunerated activity: ARTIDIS AG. Z. Marusic: Financial Interests, Personal and Institutional, Financially compensated role: ARTIDIS AG. P.D. Ndiaye, G. Zaugg: Other, Personal and Institutional, Afﬁliate:ARTIDIS AG. M. Loparic, M. Plodinec: Other, Personal and Institutional, Ofﬁcer: ARTIDIS AG.

https://doi.org/10.1016/j.annonc.2023.09.468

272P Primary prevention of bone fractures in patients (pts) with hormone receptor (HR)+ early breast cancer (EBC) during adjuvant hormonal therapy (HT): The predict & prevent project (P&P)

S. Gori1, R. Berardi2, A. Zaniboni3, T. Prochilo3, C. Bighin4, F. Puglisi5, A. Del Conte6,A. Fabi7, F. Riccardi8, M. Airoldi9, A. Chirco10, S. Cinieri11, L. Orlando11, A. Orlandi12,M. Verzè13, M. Valerio1, F. Nicolis13

1Medical Oncology, IRCCS Ospedale Sacro Cuore Don Calabria, Negrar Di Valpolicella,Verona, Italy; 2Clinical Oncology, Dept. of Internal Medicine, AOU - Ospedali Riuniti Umberto I - G.M. Lancisi - G. Salesi, Torrette Di Ancona, Italy; 3Department of Clinical Oncology, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy; 4Oncologia Medica 2, Ospedale Policlinico San Martino - IRCCS, Genoa, Italy; 5Department of Medical Oncology, Centro di Riferimento Oncologico (CRO), IRCCS, Aviano, Pordenone,Italy; 6SOC Oncologia Medica e dei Tumori Immunocorrelati, Centro di Riferimento Oncologico (CRO), IRCCS, Aviano, Italy; 7Precision Medicine Unit in Senology, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy; 8Oncology Department, AORN Cardarelli, Naples, Italy; 9Oncology Department, AOU Città della Salute e della Scienza, Turin, Italy; 10Oncology Department, ASST Papa Giovanni XXIII, Bergamo, Italy;11Medical Oncology Department, Ospedale A. Perrino, Brindisi, Italy; 12Medical Oncology, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy; 13Medical Direction, IRCCS Ospedale Sacro Cuore Don Calabria, Negrar Di Valpolicella, Italy

Background: High rate of clinical fractures was reported during adjuvant HT trials (9-14% in BIG 1-98, ATAC, IES). Since 2015, in Italy, bisphosphonates and denosumab are reimbursed for prevention of bone fractures in EBC HR+ postmenopausal pts receiving HT, regardless of T-score values (Note 79 of AIFA-Agenzia Italiana del Farmaco). In 2019, these drugs were administered only in 25% of potentially beneﬁciary pts. The P&P is a nationwide Bone Health (BH) management project designed to improve adherence to recommendations regarding fracture risk assessment and risk prevention measures in pts receiving HT for HR+ EBC.

Methods: The BH management model P&P was developed in 10 Italian cancer centres and includes: 1- training of multidisciplinary team and presentation of a BH management model by the oncologist (with referral to the Bone Specialist if osteoporosis);2- implementation of this model in every centre; 3- evaluation, after 12 months, of rate of EBC HR+ pts in postmenopausal status (natural, surgical, secondary to chemotherapy or hormonal blockage) assessed for BH within 30 days from the start of adjuvant HT; 4- evaluation, after 12 months, of rate of EBC HR+ pts receiving therapy within 90 days from the start of adjuvant HT, according to the criteria for reimbursement by AIFA.

Results: At 12 months after implementation of P&P, data are available from 6 centres(IRCCS Negrar, Ancona Hospital, IRCCS San Martino Genova, Poliambulanza Brescia,Cardarelli Napoli, Papa Giovanni XXIII Bergamo) in 1,551 postmenopausal EBC HR+pts. The ﬁrst analysis reports that 83% of EBC HR+ patients who started adjuvant HT were assessed for BH within 30 days compared to 43% in the 2019 national survey and 68% of pts started bisphosphonates/denosumab compared to 25% in the 2019 national survey.

Conclusions: Implementation of the P&P model has been shown to increase the rate of postmenopausal EBC HR+ pts on adjuvant HT assessed for BH and treated with bisphosphonate/denosumab to reduce the risk of bone fractures. A new project is ongoing to assess the rate of fractures in Italian pts after the approval of Note 79 by AIFA.

Legal entity responsible for the study: S. Gori.

Funding: Amgen.

Disclosure: C. Bighin: Financial Interests, Personal, Research Grant: Novartis, Roche, Lilly, Eisai,Gilead, Italfarmaco. F. Puglisi: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca,Daiichi Sankyo, Celgene, Eisai, Eli Lilly, Exact Sciences, Gilead, Ipsen, Menarini, MSD, Novartis, Pierre Fabre, Roche, Pﬁzer, Seagen, Takeda, Viatris; Financial Interests, Personal, Research Grant: AstraZeneca, Eisai, Roche. A. Fabi: Financial Interests, Personal, Advisory Board: Roche, Pﬁzer, Novartis,Lilly, Seagen, Gilead, Exact Science, Dompè Biotech. All other authors have declared no conﬂicts of activity: ARTIDIS AG. Z. Marusic: Financial Interests, Personal and Institutional, Financiallyinterest.

https://doi.org/10.1016/j.annonc.2023.09.469

S291

273P

Table:Endpo ER (N[

n (%)GMPC

PR (N[

Ki-67 a(N [

All-gra advers

Grade Discon

N ¼ num

A preoperative window-of-opportunity (WOO) study of imlunestrant in ER+, HER2- early breast cancer (EBC): Final analysis from EMBER-2

P. Neven1, N. Stahl2, M.J. Vidal Losada3, M. Martin Jimenez4, P.A. Kaufman5,N. Harbeck6, K. Hunt7, S.A. Carter8, F.C. Bidard9, P. Fasching10, P.G. Aftimos11,D. Wheatley12, E.P. Hamilton13, R. Aft14, S. Kulkarni15, R. Ismail-Khan16,

C. Karacsonyi16, S.T. Estrem16, U. Ozbek17, E.M. Ciruelos18

1Dept. Gynaecological Oncology/Multidisciplinary Breast Center, University Hospitals Leuven - Campus Gasthuisberg, Leuven, Belgium; 2Oncology Department, HELIOS Kliniken Schwerin, Schwerin, Germany; 3Breast Cancer, Hospital Clinic of Barcelona,Barcelona, Spain; 4Servicio de Oncologia Médica Department, Hospital General Universitario Gregorio Marañon, Madrid, Spain; 5Medicine, University of Vermont -Larner College of Medicine, Burlington, VT, USA; 6Breast Center, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Munich, Ludwig Maximilians University Hospital, Munich, Germany; 7Breast Surgical Oncology, MD Anderson Cancer Center, Houston, TX, USA; 8Department of Surgical Oncology, Baylor College of Medicine Lester and Sue Smith Breast Center, Houston, TX, USA; 9Medical Oncology Department, Institut Curie, Paris, France; 10Department of Obstetrics and Gynecology,Erlangen University Hospital, Erlangen, Germany; 11Clinical Trials Conduct Unit,Institute Jules Bordet, Anderlecht, Belgium; 12Oncology Department, Royal Cornwall Hospital, Truro, Cornwall, UK; 13Medical Oncology, Sarah Cannon Research Institute at Tennessee Oncology, Nashville, TN, USA; 14Department of Surgery, Washington University School of Medicine in St. Louis - Siteman Cancer Center, St. Louis, MO, USA;15Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 16Medical Oncology, Loxo@Lilly, Lilly Corporate Center, Indianapolis, IN,USA; 17Statistics - Oncology, Eli Lilly and Company, New York, IN, USA; 18Medical Oncology Dept, Hospital Universitario 12 de Octubre, Madrid, Spain

Background: Imlunestrant is an investigational, next-generation, oral SERD designed to deliver continuous ER target inhibition, including in ESR1-mutant BC. Imlunestrant monotherapy demonstrated favourable safety, pharmacokinetics, and preliminary efﬁcacy in patients (pts) with heavily pre-treated ER+ advanced BC ( Jhaveri ASCO 2022 ). We present ﬁnal pharmacodynamic (PD) biomarker data from the preoperative EMBER-2 WOO study (NCT04647487), including the expanded data at the 200 mg dose level, evaluating imlunestrant in ER+, HER2- EBC.

Results: Seventy-ﬁve pts were evaluable for ER expression (200 mg: n ¼ 22; 400 mg: n¼ 27; 800 mg: n ¼ 26). Baseline characteristics were similar across cohorts, with amedian age of 64 years, 69% invasive ductal carcinoma, 30% invasive lobular carcinoma, 1% other, 55% stage I, 40% stage II and 5% stage III. Among evaluable pts,relative reduction in PD biomarkers after a median of 16 days of treatment are presented in the table. There was no signiﬁcant difference in PD biomarker modulation between imlunestrant doses or tumor histology. Imlunestrant was well tolerated..

Conclusions: Imlunestrant demonstrated evidence of consistent and robust target engagement across all evaluated doses and was well tolerated in an EBC population,supporting adjuvant development in the EMBER-4 study.

Clinical trial identiﬁcation: NCT04647487.

Editorial acknowledgement: John Hurley, Eli Lilly and Company, provided editorial assistance in the writing of this abstract.

273P Reduction in PD biomarkers from baseline and safety

int

200 mg

75)

22 (29)

- % (90% CI)

-89 (-96, -72)

72)

20 (28)

-85 (-97, -37)

mong pts with baseline Ki-67 >5%59)

20 (34)

-70 (-80, -56)

de treatment related

e events (TRAEs) ‡5% - %

Nausea e 11 Diarrhea e 7 Dizziness e 7 Fatigue e 7 Hot ﬂush e 7

‡3 TRAEs - %

tinuations due to AEs

ber of biomarker evaluable pts; n ¼ number of pts in category; GMPC ¼ geome

Disclosure: P. Neven: Financial Interests, Institutional, Speaker, Consultant, Advisor: AstraZeneca;Eli Lilly and Company; Hoffman/La Roche; Novartis; Pﬁzer; Pierre Fabre; Radius Health; Roche; Teva.;Financial Interests, Institutional, Other, Travel and accommodation expenses: Eli Lilly and Company;Pﬁzer; Roche . M.J. Vidal Losada: Financial Interests, Personal, Advisory Board: Novartis/Pﬁzer,Roche, Pﬁzer, AstraZeneca/Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Novartis/Pﬁzer, Roche/Genentech, AstraZeneca/Daiichi Sankyo, Gilead Sciences; Financial Interests, Personal,Other, Travel, Accommodations, expenses: Pﬁzer; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Gilead Sciences. M. Martin Jimenez: Financial Interests, Personal, Advisory Board: AstraZeneca, Lilly, Roche/Genentech, Daiichi Sankyo, Menarinio-Stemline; Financial Interests,Personal, Invited Speaker: Pﬁzer, AstraZeneca, Lilly, Novartis, Roche/Genentech; Financial Interests,Institutional, Research Grant: Novartis, Roche, Puma; Non-Financial Interests, Member of Board of Directors: TRIO; Non-Financial Interests, Leadership Role: GEICAM; Non-Financial Interests, Member:ASCO; Non-Financial Interests, Advisory Board: SEOM. P. P.A. Kaufman: Financial Interests, Personal,Speaker, Consultant, Advisor: AstraZeneca; Eisai; Eli Lilly and Company; H3 BioMedicine; Pﬁzer;Polyphor; Roche/Genetech; Sanoﬁ; Seagen; Financial Interests, Personal, Stocks or ownership:Amgen ; Financial Interests, Institutional, Research Funding: AstraZeneca; Eisai; Macrogenics; Sanoﬁ;Seagen; Financial Interests, Personal, Other, Contracted Research: Eli Lilly and Company; Macrogenics; Polyphor; Sanoﬁ ; Financial Interests, Personal, Other, Travel and accommodation expenses:Eli Lilly and Company; Polyphor; Seagen. N. Harbeck: Financial Interests, Personal, Speaker,Consultant, Advisor: Amgen; AstraZeneca; Daiichi Sankyo; Eli Lilly and Company; Exact Sciences;MSD; Novartis; Pﬁzer; Pierre Fabre; Roche; Sandoz; Seagen; Financial Interests, Institutional,Research Funding: Roche; Financial Interests, Personal, Stocks or ownership: WSG. K. Hunt: Financial Interests, Personal, Speaker, Consultant, Advisor: Armada Health; AstraZeneca; Merck ; Financial Interests, Institutional, Research Funding: Cairn Surgical; Eli Lilly and Company; Lumicell. S.A. Carter:Financial Interests, Personal, Other, Honoraria: Mena Hereditary Conference; Perimeter. F. F.C. Bidard:Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca, Pﬁzer, Seagen, Rain Oncology; Financial Interests, Personal, Advisory Board:Pﬁzer, Lilly, Novartis, AstraZeneca, Sanoﬁ, Rain Oncology, GE Healthcare, SAGA Diagnostics, Caris,Daiichi Sankyo, Gilead, Inatherys; Financial Interests, Institutional, Invited Speaker: Pﬁzer, Sanoﬁ;Financial Interests, Institutional, Research Grant: Pﬁzer; Financial Interests, Institutional, Funding:Prolynx, Saga Diagnostics, Seagen, Merck KGaA; Financial Interests, Personal and Institutional,Steering Committee Member: AstraZeneca, Lilly. P. Fasching: Financial Interests, Personal, Advisory Board: Roche, Novartis, Pﬁzer, Daiichi Sankyo, Eisai, Merck, Sharp & Dohme, AstraZeneca, Hexal, Lilly,Pierre Fabre, Seagen, Agendia, Sanoﬁ Aventis; Financial Interests, Personal, Invited Speaker:Novartis, Daiichi Sankyo, Eisai, Merck, Sharp & Dohme, AstraZeneca, Lilly, Seagen, Gilead; Financial Interests, Personal, Other, Medical Writing Support: Roche; Financial Interests, Institutional, Local PI:BionTech, Cepheid; Non-Financial Interests, Member: ASCO, Arbeitsgemeinschaft für Gynäkologische Onkologie e.V., Translational Research in Oncology, Deutsche Gesellschaft für Senologie e.v.. P.G.

Aftimos: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Macrogenics, Roche,Novartis, Amcure, Servier, G1 Therapeutics, Radius, Deloitte, Menarini, Gilead, Novartis, Eisai, Lilly;Financial Interests, Personal, Invited Speaker: Synthon, Amgen; Financial Interests, Institutional,Research Grant: Roche. D. Wheatley: Financial Interests, Personal, Speaker, Consultant, Advisor:AstraZeneca; Gilead; Novartis; Roche. E.P.lovis, Millennium, Acerta Pharma, Sermonix Pharmaceuticals, Black Diamond, Karyopharm, Curis, Syndax, Novartis, Boehringer Ingelheim, Immunomedics, FujiFilm,Taiho, Deciphera, Molecular Templates, Onconova Therapeutics, Dana Farber Cancer Inst, Hutchinson MediPharma, MedImmune, SeaGen, Compugen, TapImmune, Lilly, Pﬁzer, H3 Biomedicine,Merus, Regeneron, Arvinas, StemCentRx, Verastem, eFFECTOR Therapeutics, CytomX, InventisBio,Lycera, Mersana, Radius Health, Abbvie, Nucana, Leap Therapeutics, Zenith Epigenetics, Harpoon,Orinove, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, PharmaMar, Olema, Immunogen, Plexxicon, Amgen, Akesobio Australia, Shattuck Labs, ADC Therapeutics, Aravive, Atlas MedX, Ellipses Pharma, Incyte, Jacobio, Mabspace Biosciences, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Repertoire Immune Medicine,Treadwell Therapeutics, Accutar Biotechnology, Artios, BeiGene, Bliss BioPharmaceuticals, Cascadian Therapeutics, Context Therapeutics, Cullinan, Dantari, Duality Biologics, Elucida Oncology, Inﬁnity Pharmaceuticals, K-Group Beta, Kind Pharmaceuticals, Loxo Oncology, Oncothyreon, Orum Therapeutics, Prelude Therapeutics, Profound Bio, Relay Therapeutics, Tolmar, Torque Therapeutics R.

1Department of Breast and Thoracic Oncology, National Cancer Institute Pascale Foundation, Naples, Italy; 2Department of Gynecology, UZ Leuven, Leuven, Belgium;3Department of Obstetrics and Gynecology, University General Hospital of Catalonia,Barcelona, Spain; 4Department of Oncology, La Louvière Private Hospital, Lille, France;5Department of Oncology, Hospital of Jaen, Jaen, Spain; 6Real World Evidence and Data, Pierre Fabre, Boulogne-Billancourt, France; 7Medical Affairs, Pierre Fabre,Boulogne-Billancourt, France; 8Department of Oncology, University Hospital Centre Zagreb, Zagreb, Croatia

An Early Access Program (EAP) was initiated in Europe in 2017 and provided access to individual patients for extended adjuvant neratinib based upon the ExteNET protocol while neratinib was awaiting product approval and availability in multiple countries.

Since ExteNET, the treatment landscape of HER2+ eBC has evolved and there is a need to document the clinical proﬁle, the tolerability, and the effectiveness of patients treated with neratinib in a real-world setting.

Methods: This is a multicenter, retrospective, observational, longitudinal study in Croatia, France, Belgium, Spain and Italy. Eligible patients will be selected among those having received at least one dose of neratinib in the EAP, between 01/08/17 and 31/12/20. The aim of the study is to describe the characteristics of patients receiving neratinib and its use in the real world. Demography and clinical proﬁles of patients are presented.

Results: As of 30/01/23, 108 patients were included in the Full Analysis Set. Median age at neratinib initiation was 48.0 years and 37.4% of patients were premenopausal.

29.6% of patients had cT1 and 46.3% had cT2. Two-thirds of patients were N+ and three-quarters had stage II + III tumours. Overall, 85.2% of patients had HR+ eBC.

41.7% of patients had upfront surgery followed by adjuvant therapy while 58.3%received neoadjuvant therapy ﬁrst; of them 19.0% achieved a pathological complete response. In the neoadjuvant setting, most patients received trastuzumab + pertuzumab (58.7%) and trastuzumab (31.7%), whereas in the adjuvant setting, anti-HER2 treatment mainly consisted of trastuzumab (79.6%).

Conclusions: Patients treated in this EAP reﬂected the proﬁle of patients who were expected to receive extended adjuvant neratinib during the observational period,which included the use of more recent (neo)adjuvant treatments.

Clinical trial identiﬁcation: NCT05599334.

Legal entity responsible for the study: Pierre Fabre.

Funding: Pierre Fabre.

Disclosure: M. De Laurentiis: Financial Interests, Personal, Speaker, Consultant, Advisor: Roche,Novartis, Seagen, Eli Lilly, Takeda, Daiichi Sankyo, Tomalab, Gilead, Genetic, Menarini, Sophos;Financial Interests, Personal, Sponsor/Funding: Roche, AstraZeneca; Financial Interests, Personal,Advisory Board: Novartis; Financial Interests, Institutional, Advisory Board: Seagen, Roche, Ipsen,Pﬁzer, AstraZeneca, Sanoﬁ, Pierre Fabre, Daiichi Sankyo, GSK. X. González Farre: Financial Interests,Personal, Speaker, Consultant, Advisor: AstraZeneca, Pierre Fabre, Novartis, Roche; Financial Interests, Personal, Sponsor/Funding: AstraZeneca, Roche, Lilly. O. Romano: Financial Interests, Personal, Speaker, Consultant, Advisor: Roche, Amgen, Pﬁzer. A. Cano Jimenez: Financial Interests,Personal, Speaker, Consultant, Advisor: Pierre Fabre, Pﬁzer. F. Beghdad, O. Dialla, M. Zivanov:Financial Interests, Personal, Full or part-time Employment: Pierre Fabre. T. Silovski: Financial Interests, Personal, Speaker, Consultant, Advisor: Novartis, Pﬁzer, Eli Lilly, Roche, Amgen, Sandoz,Abbott, AstraZeneca; Financial Interests, Personal, Sponsor/Funding: Pﬁzer, Novartis, Roche; Financial Interests, Institutional, Product Samples: Novartis, Pﬁzer, Puma Biotechnology Inc. All other authors have declared no conﬂicts of interest.

Results: After 5 years of observation, 96.7% (95% CI 94.5-98.9) of patients with low uPA/PAI-1 were without any RFI event compared to 87.2% (95% CI 84.1-90.3) with high uPA/PAI-1 (aHR 2.6, 95% CI 1.293-5.227, p¼0.001). Also considering OS, a sig-niﬁcant difference was detected; with low uPA/PAI-1, 93.9% (95% CI 91.0-96.8) were alive after 5 years (aHR 2.38, 95% CI 1.359-4.156) compared to 82.9% (95% CI 79.1-86.4) with high uPA/PAI-1. With regard to the intermediate risk group (n¼378), evenwithout chemotherapy, less than 1% of patients with low uPA/PAI-1 (n¼120) had anRFI event. While patients with high uPA/PAI-1 had a signiﬁcantly higher risk of disease-related events over the entire observation time (aHR 4.27, 95% CI 1.132-16.124).

If patients were treated with adjuvant chemotherapy (n¼181), uPA/PAI-1 had nofurther prognostic signiﬁcance. Patients with high uPA/PAI-1 beneﬁted signiﬁcantly from adjuvant chemotherapy compared to patients without chemotherapy (aHR 0.21,95% CI 0.076-0.600).

Conclusions: These real-world cohort data conﬁrm that uPA/PAI-1 can routinely be used as an independent prognostic factor for decisions about adjuvant chemotherapy and underline the assumption that uPA/PAI-1 might be predictive for the effect of adjuvant chemotherapy.

Clinical trial identiﬁcation: NCT01592825 (release date: 16.12.09).

Legal entity responsible for the study: M. Vetter and E. Kantelhardt.

Funding: Wilhelm Roux Program of the Medical Faculty, Martin -Luther-University Halle-Wittenberg (grant number: FKZ 25/36) German Federal Ministry of Education and Research (grant number: Med FKZ 031A429).

Disclosure: C. Thomssen: Financial Interests, Personal, Speaker, Consultant, Advisor: Amgen,AstraZeneca, Aurikamed, Daiichi Sankyo, Forum Sanitas, Gilead, Jörg Eickeler, Hexal, Lilly, Medupdate, MSD, Nanostring, Novartis, Onkowissen, Pﬁzer, Roche, Seagen, Vifor; Non-Financial Interests,Personal, Member: AGO Breast Committee, ASCO, DGGG (Germ Soc OB/GYN), DGS (Germ Soc Senology), DKG (Germ Cancer Soc), EORTC PathoBiomarker Group; Non-Financial Interests, Personal,Member of Board of Directors: AGO-B Breast Study Group; Non-Financial Interests, Personal, Ofﬁcer:BIG; Non-Financial Interests, Personal, Invited Speaker: ESO; Non-Financial Interests, Personal,Steering Committee Member: ESMO. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.481

S297

285P

Treatment patterns and clinical outcomes of germline BRCA mutation (gBRCAm)-associated breast cancer (BC): A

matched, case-control study

S. Morganti1, S.E. Kim2, Q. Jin2, J. Cha3, J.E. Zeigler4, A.B. Newman5, J. Vincuilla6,T. Parker6, R. Buehler4, E.A. Mittendorf6, T.A. King6, B. Bychkovsky1, G. Curigliano7,A.H. Partridge1, N.U. Lin1, J.E. Garber4, N. Tayob2, S.M. Tolaney1, F. Lynce1

1Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA;2Department of Data Science, Dana Farber Cancer Institute, Boston, MA, USA;3Department of Medicine, Harvard Medical School, Boston, MA, USA; 4Center for Cancer Genetics and Prevention, Dana Farber Cancer Institute, Boston, MA, USA;5Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA;6Department of Surgery, Brigham and Women’s Hospital, Boston, MA, USA; 7Early Drug Development for Innovative Therapies Division, IEO - Istituto Europeo di Oncologia, Milan, Italy

Methods: Consecutive patients (pts) who underwent surgery for BC at Dana-Farber Brigham Cancer Center between 1/2016 and 8/2021 and had known gBRCA status were included. gBRCAm cases were matched 1:3 with non-gBRCAm controls by age groups, stage, hormone receptor (HR) status and year of diagnosis. HER2-negative BC were excluded. Clinicopathologic features, treatments, and outcomes of gBRCAm carriers and non-gBRCAm controls were compared.

Results:We identiﬁed 189 gBRCAm (107 BRCA1, 82 BRCA2) carriers and 567 matched non-gBRCAm controls. Median age was 43 years (yrs) in carriers and 46 yrs in controls. Most pts had stage I (41.7%) or II (44.7%) BC; 55% of BC were HR+ (38 in gBRCA1m, 66 in gBRCA2m; 312 in non-gBRCAm). Compared to controls, gBRCAm carriers had higher tumor grade (p<0.001), higher recurrence score in HR+ (median 25 vs 19, p<0.001), were more likely to receive chemotherapy (CT) (81 vs 67.4%,p<0.001), including platinum-based regimens (17.6 vs 9.2%, p¼0.007). 11 gBRCAmcarriers and 3 controls received PARPi. At a median follow up of 42.3 months, invasive disease-free survival (iDFS) and relapse-free survival (RFS) did not differ between gBRCAm and controls after adjusting for age, grade, and CT administration (Table). In triple-negative BC (TNBC), risk of relapse was lower for gBRCAm vs controls(p¼0.025).

Table: 285P

Tolaney: Financial Interests, Personal,Advisory Board, Ad board participant/consultant: 4D Pharma, ARC Therapeutics, Daiichi Sankyo,Eisai, Genentech/Roche, Gilead, Novartis, Sanoﬁ, SeaGen; Financial Interests, Personal, Other,Consulting: Aadi BioPharma; Financial Interests, Personal, Advisory Board, Ad board participation:Artios, Incyte Corp, BeyondSprings; Financial Interests, Personal, Advisory Board, Ad Board Participant/Consultant: AstraZeneca, Eli Lilly; Financial Interests, Personal, Advisory Board, Advisory Board participation: Bayer, Inﬁnity Therapeutics, Myovant, OncXerna, Umoja Biopharma, Zentalis, Zetagen;Financial Interests, Personal, Other, Consultant: Blueprint Medicines; Financial Interests, Personal,Advisory Board, Ad board participant: Bristol Myers Squibb, Ellipses Pharma, Mersana Therapeutics;Financial Interests, Personal, Other, Steering Committee Member/Consultant: CytomX; Financial Interests, Personal, Advisory Board, Advisory Board participation/consulting: Menarini/Stemline;Financial Interests, Personal, Advisory Board, Ad Board participant/consultant: Merck; Financial Interests, Personal, Advisory Board, Ad board participant/Consultant: Pﬁzer; Financial Interests, Personal, Advisory Board, Advisory board participation: Reveal Genomics; Financial Interests, Personal,Advisory Board, Advisory Board Participation: Zymeworks; Financial Interests, Institutional, Funding:AstraZeneca, Eli Lilly, Pﬁzer, Sanoﬁ, SeaGen, Odonate, Cyclacel, Exelixis, Gilead, Bristol Myers Squibb,Eisai, Merck, Novartis, Nektar, Genentech/Roche; Financial Interests, Personal and Institutional,Steering Committee Member: CytomX. F. Lynce: Financial Interests, Personal, Advisory Board: Pﬁzer,AstraZeneca; Financial Interests, Personal, Invited Speaker: ION; Other, Institutional, Principal Investigator: AstraZeneca, CytomX, Cyclacel, Genentech, Eisai, Incyte. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.482

286P Prognostic role of HER2 expression in patients with ER-positive/HER2-negative breast cancer: Results from a population-based cancer registry study

A. Musolino1, O. Serra2, B. Pellegrino1, C. Tommasi1, D. Zanoni2, F. Faccini3,M. Michiara2, P. Sgargi2, G. Carrozzi4, S. Ferretti5, V. Grossi6, A. Ravaioli6,F. Zamagni6, F. Falcini6

1Department of Medicine and Surgery, University of Parma; Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC), Parma, Italy; 2Medical Oncology and Breast Unit,Emilia-Romagna Cancer Registry, Parma Unit; University Hospital of Parma, Parma,Italy; 3Public Health Department, AUSL Piacenza, Emilia-Romagna Cancer Registry,Piacenza Unit, Piacenza, Italy; 4Public Health Department, Local Health Authority,Emilia-Romagna Cancer Registry, Modena Unit, Modena, Italy; 5Department of Translational Medicine, Local Health Authority, Emilia-Romagna Cancer Registry,Ferrara Unit, Ferrara; University of Ferrara, Ferrara, Italy; 6Clinical and Experimental Epidemiology and Cancer Registry, Emilia-Romagna Cancer Registry, Romagna Unit,IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola,Italy

Background: Estrogen Receptor (ER)-positive (+)/Human Epidermal Growth Factor Receptor 2 (HER2)-negative (-) breast cancers (BCs) express variable protein levels of HER2, which can inﬂuence prognosis.

Methods: This cohort study was conducted using data on all consecutive patients(pts) diagnosed with BC between 2005 and 2017, which were systematically and prospectively collected by the Emilia-Romagna Cancer Registry (Provinces of Piacenza,Parma, Modena, and Ferrara), Italy. The study included 13527 pts with ER+/HER2- BC.

Tumors were classiﬁed by HER2 IHC score (0 [n¼7155], 1+ [n¼5186], or 2+ withnegative FISH [n¼1186]). Comparisons of clinicopathologic characteristics and diseaseoutcome were performed.

Background: PAM50 gene expression subtypes represent a cornerstone in molecular classiﬁcation of breast cancer and are included in risk prediction models to guide therapy. We aimed to illustrate the impact of included genes and biological processes on subtyping while considering a tumor’s underlying clinical subgroup deﬁned by ER,PR and HER2 status.

Methods: We used a population-representative and clinically annotated primary breast tumor cohort of 6233 samples proﬁled by RNA sequencing and applied a perturbation strategy of excluding co-expressed genes (gene sets) from the PAM50 centroids followed by nearest centroid classiﬁcation.

Results: We demonstrate how PAM50 nearest centroid classiﬁcation depends on biological processes present across, but also within, ER/PR/HER2 subgroups and PAM50 subtypes themselves. Our analysis highlights several key aspects of PAM50 classiﬁcation. Firstly, we observed a tight connection between a tumor’s nearest and second nearest PAM50 centroid. Additionally, we show that second-best subtype is associated with overall survival in ER-positive, HER2-negative, and node-negative disease. We also note that ERBB2 has little impact on PAM50 classiﬁcation in HER2-positive disease regardless of ER-status, that the Basal subtype is highly stable in

288P Survival according to clinical & pathological features

5-year

DFS (%)

Median

DFS (95% CI)

85.5

89.7

128.2 (88.4-167.9)

ausal status enopausal

89.2

menopausal

85.7

128.2 (95.3-161.1)

83.9

70.2

tatus ative

83.4

121.8 (93.6-150.1)

90.8

e Lymph node

92.3

156.1 (124.3-187.9)

63.2

e 1

e 2A

91.4

e 2B

121.8 (69.3-174.4)

e 3

73.8

128.2 (70.3-186.1)

(-)

91.5

(+)

75.4

108.8 (40.3-177.2)

contrast to the Normal subtype, and that the LumB subtype classiﬁcation is mainly reliant on expression of proliferation-related genes and low expression of keratinassociated genes.

Funding: Swedish Cancer Society, Swedish Research Council, Fru Berta Kamprads research foundation.

https://doi.org/10.1016/j.annonc.2023.09.484

288P

p-va

0.316

0.599

0.02

0.00

Prognostic factors in nonmetastatic HER2 ‘low’ & HER2‘negative’ breast cancer: Single institute experience

A. Türkel1, M. Dogan1, E. Sertesen1, C. Karacin1, S.Ç. Irkkan2, O. Ates1

1Medical Oncology, Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Ankara, Turkey; 2Pathology, Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Ankara, Turkey

Background: Human epidermal growth factor-2 (HER2) low breast cancer is a novel entity that differs from HER2-negative ones. We evaluated prognostic factors in HER2 low & compared with HER2-negative breast cancer retrospectively.

Methods: Estrogen receptor (ER) +/ progesterone receptor (PR) +, HER2 low and HER2-negative patients without distant metastasis were included.

Results: 444 (HL n:209, HN n:235) patients were evaluated. Median follow-up was 47 months. Most (59%) were postmenopausal. 121 (27.3%) had immunohistochemistry(IHC) score 1, 88 (19.8%) had IHC score 2 (SISH -). Mean age was 54.5 vs 53.3 years.

Stage 2 (35.8%) & grade 2 (49.3%) were most common. Median ER/PR/ki67 were 95/60/25% for HER2 low & HER2 negative. 375 patients had chemotherapy, most (86%)had adjuvant chemotherapy. 40 (9%) had relapse & most (n: 31, 77.5%) had distant relapse. HER2-negative patients tended to have higher relapse rate (11.5% vs 6.2%,p:0.053). 5 year-disease free survival (DFS) was shorter for patients with HER2 negative (83.4% vs 90.8%), positive lymph nodes 10 (63.2% vs 92.3%), ECE + (75.4%vs 91.5%), ki6720% (70.2% vs 83.9%) (p: 0.021, p:0.008, p:0.004, p:0.026) (Table).Stage was inversely correlated with DFS (p: 0.001). HER2 status [HR: 0.43 (95% Cl:

0.20 e0.94), p¼0.035] & ki67 [OR: 2.99 (95% Cl: 1.21e7.36), p¼0.017] were signif-icant prognostic factors in multivariate analysis. Overall survival (OS) data was immature..

Conclusions: HER2 low breast cancer patients, especially with ki67 <20% had better DFS, Most patients had IHC score 1.

lue

5-year OS (%)

Median OS (95% CI)

0.579

95.2

97.6

0.523

96.1

96.2

0.441

96.6

97.1

0.214

96.7

0.946

97.2

97.4

0.463

97.9

95.6

0.714

S299

Legal entity responsible for the study: Clinical of Medical Oncology.

https://doi.org/10.1016/j.annonc.2023.09.485

289P

Table:Respo

sRANK Ki-67 %CLEAV TILS %TILS %TILS %TILS %TILS w

https://doi.org/10.1016/j.annonc.2023.09.471

S293

275P

Clinical and molecular impact of neoadjuvant chemotherapy(NACT) or endocrine therapy (NET) on hormone receptor positive (HR+)/HER2-negative (-) breast cancer (BC)

F. Schettini1, F. Brasó-Maristany1, T. Pascual2, P. Galván3, B. Conte4, L. Ghiglione5,C. Falato6, O. Martínez-Sáez7, N. Chic8, A.B. Rodriguez2, E. Sanfeliu Torres9,

B. Gonzalez-Farre9, M.J. Vidal Losada10, B. Adamo11, I. Cebrecos12, E. Mension12,G. Oses13, M. Mollá13, M. Munoz7, A. Prat2

1Oncology Department, IDIBAPS - Fundació de Recerca Clinic Barcelona - Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain; 2Medical Oncology Department, Hospital Clinic y Provincial de Barcelona, Barcelona, Spain; 3Translational Genomics and Targeted Therapies in Solid Tumors Lab, IDIBAPS - Fundació de Recerca Clinic Barcelona - Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona,Spain; 4Medical Oncology Dept., IDIBAPS - Institut D’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; 5Dept., Clinical Oncology, Hospital Clinic y Provincial de Barcelona, Barcelona, Spain; 6Translational Genomics and Targeted Therapies, IDIBAPS - August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain;7Medical Oncology Dept., Hospital Clinic of Barcelona, Barcelona, Spain; 8Dept.

Medical Oncology, Hospital Clinic y Provincial de Barcelona, Barcelona, Spain; 9Pathology, Hospital Clinic of Barcelona, Barcelona, Spain; 10Breast Cancer, Hospital Clinic of Barcelona, Barcelona, Spain; 11Breast Cancer Dept., Hospital Clinic y Provincial de Barcelona, Barcelona, Spain; 12Clinic Institute of Gynecology, Hospital Clinic y Provincial de Barcelona, Barcelona, Spain; 13Radiation Oncology Department, Hospital Clinic y Provincial de Barcelona, Barcelona, Spain

Background: Clinicopathological and molecular features of HR+/HER2- BC associated with response and survival following NACT or NET have been poorly characterized.

Methods: A total of 186 patients with early-stage HR+/HER2- BC treated with NACT(52.2%) and NET (47.8%) at the Hospital Clinic of Barcelona between 2014-2018 were evaluated. Associations with pathologic complete response (pCR), event-free survival(EFS) and overall survival (OS) were assessed with logistic and Cox regressions, where appropriate. Intrinsic subtypes (IS), risk of relapse (ROR) and selected genes’expression before and after neoadjuvant treatment (NAT) were assessed with a research-based PAM50. SAM analyses were carried out. Signiﬁcance was set at p0.05 and false discovery rate (FDR)5%.

Results: The pCR rates following NACT and NET were 18.6% and 3.4%, respectively.

NACT (adjusted odds ratio [aOR]: 6.26, p¼0.044) and non-Luminal IS (aOR: 8.89,p¼0.021) were independently associated to pCR. Both NAT strategies reduced PgRand Ki67 levels signiﬁcantly (p<0.001 all). After NAT, a signiﬁcant (p<0.001) larger proportion of tumor samples were Luminal A/Normal-like (95.1% vs 55.3% at baseline) and ROR-low (78.8% vs. 22.9% at baseline). Both treatments induced the upregulation of selected immune genes and Basal-like-related genes/signature and downregulation of Luminal, proliferation and HER2-related genes/signatures(FDR<5% all). At a median follow-up of 64.0 months, 5-year EFS and OS were 90.4%and 95.0% with no signiﬁcant difference based on NAT strategy (71.9% NET patients did not receive posterior CT). After adjusting for NAT cohort and signiﬁcant factors at univariate analyses, including IS switch, only reduction of the proliferation signature remained signiﬁcantly associated with better EFS (p¼0.011) and OS (p¼0.014).Similar results were observed with reduction of ROR for EFS (p¼0.034), but not OS.

Conclusions: This study suggests that molecular downstaging induced by NACT or NET follows similar biological patterns and is associated with favorable survival outcomes,supporting molecular-driven neo-/adjuvant strategies, as tested in the ongoing RIBOLARIS phase II trial (NCT05296746).

Funding: European Society for Medical Oncology (ESMO) through an ESMO Fellowship - Translational to Dr. Schettini.

Disclosure: F. Schettini: Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, Gilead,Novartis; Financial Interests, Personal, Other, Travel expenses: Daiichi Sankyo, Gilead, Novartis. T.

Pascual: Financial Interests, Personal, Invited Speaker: Pﬁzer/ AstraZeneca / Veracyte / Novartis;Financial Interests, Personal, Advisory Board: Roche/Genentech. M.J. Vidal Losada: Financial Interests, Personal, Advisory Board: Novartis/Pﬁzer, Roche, Pﬁzer, AstraZeneca/Daiichi Sankyo;Financial Interests, Personal, Invited Speaker: Novartis/Pﬁzer, Roche/Genentech, AstraZeneca/Daiichi Sankyo, Gilead Sciences; Financial Interests, Personal, Other, Travel, Accommodations, expenses:Pﬁzer; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Gilead Sciences. M.

Munoz: Financial Interests, Personal, Advisory Board: Roche, Novartis, Pierre Fabre, Seagen, AstraZeneca; Financial Interests, Personal, Other, International conference travel grants: Roche, Pﬁzer,Lilly, Gilead. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pﬁzer, Oncolytics Biotech, Guardant Health, Peptomyc;Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests,Institutional, Other, Contracted research: Boehringer Ingelheim, Medica Scientia inno. Research;Financial Interests, Personal, Advisory Board: AstraZeneca, 1TRIALSP, S.L.; Financial Interests, Personal, Member of Board of Directors, Leadership role: Reveal Genomics, SL.; Financial Interests,Personal, Stocks/Shares: Reveal Genomics, Oncolytics Biotech; Financial Interests, Personal, Royalties: Reveal Genomics, International Oncology Bureau, S.L.,; Financial Interests, Institutional, Local PI: Roche, AstraZeneca; Financial Interests, Personal and Institutional, Steering Committee Member:Daiichi Sankyo; Financial Interests, Institutional, Coordinating PI: Novartis; Non-Financial Interests,Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation, Actitud Frente al Cáncer Foundation; Non-Financial Interests, Personal, Other, Asociación Española de Investigación sobre el Cáncer: ASEICA. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.472

276P Development and external validation of an artiﬁcial

intelligence (AI)-based machine learning model (ML) for predicting pathological complete response (pCR) in

hormone-receptor (HoR)-positive/HER2-negative early

breast cancer (EBC) undergoing neoadjuvant chemotherapy(NCT)

L. Mastrantoni1, G. Garuﬁ1, E. Di Monte2, G. Arcuri1, V. Frescura1, N. Maliziola3,A. Rotondi3, G. Giordano4, L. Carbognin5, A. Fabi6, I. Paris7, G. Franceschini8,A. Orlandi9, A. Palazzo10, F. Puglisi11, M.V. Dieci12, M. Milella13, G. Scambia14,G. Tortora15, E. Bria16

1Medical Oncology Department, Università Cattolica del Sacro Cuore, Rome, Italy;2Clinical Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome,Italy; 3Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS,Rome, Italy; 4Geriatrics, Università Cattolica del Sacro Cuore, Rome, Italy; 5Division of Gynecologic Oncology, Department of Woman and Child Health, Fondazi, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; 6Precision Medicine Unit in Senology, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy; 7Gynecologic Oncology Department, Università Cattolica del Sacro Cuore, Rome, Italy; 8Senology,Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; 9UOC di Oncologia Medica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome,Italy; 10Scienze Gastroenterologiche, Endocrino Metaboliche e Nefrourologiche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; 11Medical Oncology Department, ASU Friuli Centrale - Ospedale S. Maria della Misericordia,Udine, Pordenone, Italy; 12DiSCOG, University of Padua, Padua, Italy; 13Medical Oncology 1, University of Verona - Faculty of Medicine, Verona, Italy; 14Women,Children and Public Health Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; 15Universita Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; 16Translational Medicine and Surgery Department, Fondazione Policlinico Universitario Agostino Gemelli IRCCS,Rome, Italy

Background: In HoR-positive/HER2-negative EBC pCR rates are low and ML algorithms could help to predict pCR using clinical and pathological characteristics.

Methods: Patients with EBC receiving NCT followed by surgery were included in the training/validation cohorts (TC/VC). pCR was deﬁned as absence of residual invasive cancer on pathologic breast specimen and lymph nodes (ypT0/is ypN0). Eight ML models (c5.0, k-nearest neighbour, random forest [RF], neural network, support vector machine [linear/radial], boosted trees and boosted logistic regression) were trained and tuned. A stratiﬁed ten-fold cross-validation was used and models’ performance was evaluated using the area under the receiver operation characteristics curve (AUC), sensitivity and speciﬁcity.

Results: 572 patients were included in the TC and 87 achieved pCR (15%, 95% CI 12-18%). Ten variables (menopausal status, age, histology, grade, clinical T/N, ER/PgR,Ki67 and HER2 [zero/low]) were included according to multivariate analysis and clinical relevance. The RF algorithm had the best performance: AUC 0.77, 95% CI 0.71-0.83; sensitivity 0.86 (95% CI 0.82-0.88) and speciﬁcity 0.56 (95% CI 0.46-0.66). Variables with the highest importance were Ki67, ER/PgR status, age and nodal status.

293 patients were included in the VC and 24 achieved pCR (8%, 95% CI 6-12%). The RF algorithm had an AUC of 0.71 (95% CI 0.61-0.81), sensitivity of 0.29 (95% CI 0.13-0.51)and speciﬁcity of 0.90 (95% CI 0.86-0.94). With a median follow-up of 53.3 and 57.7 months for DFS and OS, patients whose pCR was predicted by the model had longer DFS (HR 0.51, 95% CI 0.31-0.83, p¼0.003) and OS (HR 0.48, 95% CI 0.29-0.79,p¼0.001). A one percentage increase in the probability of predicted pCR wassigniﬁcantly associated with longer DFS (HR 0.992; 95% CI 0.986-0.999, p¼0.02) andOS (HR 0.992, 95% CI 0.985-0.998, p¼0.01).

Conclusions: The ML algorithm has the potential to predict pCR in HoR-positive/HER2-negative patients undergoing NCT, thus supporting clinicians to individualize treatment for EBC.

https://doi.org/10.1016/j.annonc.2023.09.473

277P

Fat body mass independently predicts incident vertebral fractures in breast cancer patients given adjuvant aromatase inhibitor therapy and denosumab

G. Schivardi1, R. Pedersini1, D. Cosentini1, P. di Mauro1, M. Zamparini1, L. Rinaudo2,N. Di Meo3, A. Delbarba4, C. Cappelli4, M. Laganà1, A. Alberti1, M. Baronchelli5,G. Guerci1, L. Laini1, E.L. Simoncini1, D. Farina3, G. Mazziotti6, A. Berruti1

1Medical Oncology Department, ASST Spedali Civili di Brescia, University of Brescia,Brescia, Italy; 2Technologic, Turin, Italy; 3Radiology Unit, ASST Spedali Civili di Brescia,Brescia, Italy; 4Endocrinology, ASST Spedali Civili di Brescia, Brescia, Italy; 5Medical Oncology Department, University of Parma, Parma, Italy; 6Endocrinology, Diabetology and Medical Andrology Unit, Metabolic Bone Diseases and Osteoporosis Section,IRCCS Humanitas Research Hospital Rozzano, Humanitas University, Pieve Emanuele,Italy

Background: Women with early breast cancer (EBC) receiving adjuvant aromatase inhibitors (AIs) are frequently given denosumab (Den) with the aim to both reducing fracture risk and preventing disease recurrence. However, a proportion of these patients still experience fragility fractures despite Den, and risk factors in women treated with upfront AIs and Den have never been explored.

Methods: Dual-X-ray absorptiometry (DXA) at baseline conditions and after 18 months was performed in 237 consecutive patients undergoing adjuvant therapy with AIs and Den (60 mg subcutaneously every 6 months), recruited at the Breast Unit of the ASST-Spedali Civili of Brescia. The following baseline parameters were evaluated to predict the risk of vertebral fracture (VF) as assessed by a morphometric approach on DXA images: age, body mass index (BMI), history of previous fractures, family history of fractures, smoking, alcohol consumption, FRAX score, DXA-derived bone mineral density (BMD), trabecular bone score (TBS), percentage fat body mass (%FBM), lean body mass (LBM), appendicular mass index (ALMI).

Results: Seventeen out of 237 (7%) reported incident VFs after 18 months of AIs therapy. At the univariate analysis, incident VFs were signiﬁcantly associated with high FRAX score (Odd Ratio [OR]: 3.786, 95% Conﬁdence interval [CI]: 1.039-13.790),previous VFs (OR: 3.217, 95% CI: 1.185-8.736), high %FBM (OR 5.174, 95% CI: 1.418-18.873, p¼0.013), high android fat (OR 9.580, 95% CI: 1.174-78.209, p¼0.035) andlow ALMI/FBM ratio (OR 0.252, 95% CI: 0.078-0.818, p¼0.022). Only high %FBM wasindependently associated to incident VFs at multivariate analysis.

Conclusions: FBM is an independent risk factor for VFs in EBC patients treated with adjuvant AIs and Den. A supervised physical activity aiming at avoiding obesity and potentiating LBM could synergize with Den in preventing AI-induced bone fragility.

Disclosure: R. Pedersini: Financial Interests, Personal and Institutional, Invited Speaker: Novartis,Amgen, Gilead, Sankyo, Roche, Seagen; Financial Interests, Personal and Institutional, Advisory Board: Eli Lilly, Daiichi, Eisai. G. Mazziotti: Financial Interests, Personal and Institutional, Advisory Board: Novartis, Ipsen, Eli Lilly; Financial Interests, Personal and Institutional, Invited Speaker:Amgen, Abiogen. A. Berruti: Financial Interests, Personal, Advisory Board: Amgen, Astellas, Janssen,IPSEN; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Invited Speaker, Public speaking in international webinar: HRA; Financial Interests, Institutional, Funding:Astellas, Janssen; Non-Financial Interests, Institutional, Product Samples: Sanoﬁ, Novartis. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.474

278P Association between tamoxifen and endoxifen plasma levels and clotting proteins in patients with primary breast cancer

D. van Dorst1, S.M. Buijs1, M.J.H.A. Kruip2, R.F.P. van den Akker3, K.L. Cheung3,R. Porrazzo1, E. Oomen-de Hoop1, A. Jager1, S.L. Koolen1, J. Versmissen4,

J.A.H. Danser4, H.H. Versteeg3, M.H.A. Bos3, R.H. Mathijssen1

1Medical Oncology Department, Erasmus MC Cancer Institute, Rotterdam,Netherlands; 2Department of Hematology, Erasmus MC - Erasmus University Rotterdam, Rotterdam, Netherlands; 3Einthoven Laboratory for Vascular and Regenerative Medicine, LUMC-Leiden University Medical Center, Leiden, Netherlands; 4Department of Internal Medicine, Erasmus MC - Erasmus University Rotterdam, Rotterdam,Netherlands

Background: Tamoxifen is effective for the adjuvant treatment of primary breast cancer, but increases the risk for venous thromboembolism. Tamoxifen decreases anticoagulant proteins, including antithrombin (AT), protein C (PC) and tissue factor pathway inhibitor, and increases thrombin generation (TG). However, the relation between levels of both tamoxifen and its active metabolite endoxifen and coagulation is unknown. To gain insight in the prothrombotic effects of tamoxifen and to guide safe dose-escalation, which may be performed in case of sub-therapeutic endoxifen levels, we studied the association between tamoxifen and endoxifen levels and various clotting proteins.

Methods: Tamoxifen and endoxifen levels were measured in 148 patients from the prospective TOTAM study (NL6918) after 3 months (m) and 6m of tamoxifen treatment. Plasma levels of the anticoagulants AT and PC, the procoagulant tissue factor(TF), and TG parameters were determined at both timepoints if samples were available (n¼65-138 per analysis). Levels of clotting proteins and TG parameters were

compared between: 1) quartiles of tamoxifen and endoxifen levels with ANOVA or Kruskall-Wallis with Dunnett’s test, and 2) 3m and 6m of treatment in patients without dose adjustments with paired sample t-tests or Wilcoxon signed rank tests.

Results: After 3m of tamoxifen, levels of AT, PC, TF and TG parameters were not associated with tamoxifen nor endoxifen levels. At 6m, median TF levels were lower in patients in the 3rd (45 [range: 101] pg/mL), and 4th (50 [90] pg/mL) endoxifen quartiles compared to the 1st (lowest) quartile (70 [143] pg/mL) (adjusted P of 0.024 and 0.012, respectively), but no differences in anticoagulants or TG were observed.

An increase in both median TF levels (3m: 46 [94], 6m: 54 [143] pg/mL, P<0.001) and TG parameters was observed at the 6m treatment period, while the AT and PC levels remained stable.

Conclusions: Our results indicate that higher tamoxifen and endoxifen levels are not associated with increased coagulation system activation, suggesting that both tamoxifen dose-escalation and high endoxifen levels do not have an additional prothrombotic effect. The time-dependent effect of tamoxifen on coagulation warrants further study.

Clinical trial identiﬁcation: NL6918.

Disclosure: M.J.H.A. Kruip: Financial Interests, Institutional, Research Grant, Unrestricted research grant, payment to institute, unrelated to this research: Sobi; Financial Interests, Institutional,Speaker, Consultant, Advisor, Speakers fee, payment to institute, unrelated to this research: Sobi,Roche, BMS. R.H. Mathijssen: Financial Interests, Institutional, Research Grant, Investigator-initiated research: Astellas, Bayer, Cristal Therapeutics, Pﬁzer, Roche, Sanoﬁ, Servier, Boehringer-Ingelheim,Novartis; Financial Interests, Institutional, Coordinating PI: Pamgene. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.475

279P Early changes in bone turnover biomarkers during AI

therapy are related to loss bone mineral density, data of the B-ABLE cohort

T. Martos Cardenas1, N. Garcia-Giralt2, I. Petit3,

M. Castro-Henriques Pinto-Machado1, M. Martinez García1,

X. Monzonis Hernandez4, J. Albanell Mestres1, X. Nogués Solan3, S. Servitja Tormo1

1Medical Oncology Deparment, Hospital del Mar - Parc de Salut Mar, Barcelona,Spain; 2Internal Medicine, IMIM - Institut Hospital del Mar d’Investigacions Mediques,Barcelona, Spain; 3Internal Medicine, Hospital del Mar - Parc de Salut Mar, Barcelona,Spain; 4Bioinformatics, IMIM - Institut Hospital del Mar d’Investigacions Mediques,Barcelona, Spain

Background: Aromatase inhibitors (AI) are the preferred hormonal therapy in postmenopausal women with early breast cancer (eBC). Bone turnover markers (BTM)provide dynamic information about the accelerated bone remodeling in patients taken AI. Here we described early changes in BTM during the ﬁrst year of AI therapy in patients included at B-ABLE cohort.

Methods: B-ABLE cohort includes 1071 postmenopausal women with eBC, candidates to receive AI. PTH, Vit D and BTMs including carboxy-terminal crosslinked telopeptide of type 1 collagen (CTX), amino-terminal crosslinked telopeptide of type 1 collagen(NTX), procollagen type 1 N-terminal propeptide (P1NP), bone-speciﬁc alkaline phosphatase (BAP) and osteocalcin (OC), were evaluated previous AI therapy, at 3 months, and then annually. Bone mineral density (BMD) was assessed by DXA (at lumbar spine (LS) and femoral neck (FN)) baseline and annually. Here we report data of early changes in BMTs the ﬁrst year of AI and its relation with BMD at 12 months in 768 women receiving AI as single agent or switching from tamoxifen, no treated with antiresorptive agents.

Results: The median age was 60 years, BMI was 29.15 and 18% are current smokers.

30% were switching from tamoxifen and 54.3% received Chemotherapy. 62% have osteopenia, 0.5% osteoporosis, and 4% of patients had fragility fractures at baseline.

Baseline BTM were CTX 0.44ng/ml, NTX 45.09ng/ml, P1NP 60.14ng/ml, OC 6.05ng/ml, BAP 13.44mcg/l. In patients with osteopenia, BTM were higher compared with patients with normal DXA (p< 0.005) at baseline and at 3 months. Early changes in FAO (p¼0.001) and CTX (p¼0.001) were correlated with higher risk of LS and FN BMDloss (Table).

Table: 279P Association of BMD loss at 12 months with bone remodelling markers at 3 months of AI treatment

Changes in BTMs at 3-mo LS 12-mo OR (95% CI) FN 12-mo OR (95% CI)

CTX

3.13 (1.94-5.04)

2.45 (1.56-3.83)

NTX

1.81 (0.93-3.60)

1.13 (0.58-2.12)

P1NP

1.90 (0.86-4.22)

1.16 (0.60-2-24)

1.21 (0.77-1.92)

1.06 (0.68-1.66)

BAP

2.086 (1.43-2.49) 2.01 (1.43-2.81)

Conclusions: Early dynamic changes in CTX and BAP are related to bone loss at 12 month in LS and FN.

S295

Legal entity responsible for the study: IMIM.

https://doi.org/10.1016/j.annonc.2023.09.476

280P

Adjuvant aromatase inhibitors in patients with PIK3CA mutation early breast cancer

K. Reinhardt1, M. Vetter2, S. Kaufhold1, E. Kantelhardt2, C. Thomssen2

1Department of Gynaecology, Martin Luther Universität Halle-Wittenberg, Halle(Saale), Germany; 2Department of Gynaecology, UKH - Universitätsklinikum Halle(Saale), Halle (Saale), Germany

Background: Phosphatidylinositide-3-kinase (PI3K) regulates proliferation and apoptosis and; somatic PIK3CA-mutations may activate these processes. In a prospective cohort study of early breast cancer (eBC) patients, in case of somatic PIK3CAmutation we observed resistance to aromatase inhibitor (AI) therapy (Reinhardt K et al., Breast Cancer Res Treat 2022;196:483e493). This study is aimed at validating these ﬁndings in a second cohort.

Methods: We studied a unicentre cohort of 262 patients with steroid hormone receptor-positive, HER2-negative eBC, who were planed to be treated with endocrine therapy only: aromatase inhibitor (AI, n¼183) or Tamoxifen (TAM, n¼69), AI and TAM(n¼9), Fulvestrant (n¼1) and tested the three most common somatic PIK3CA genemutations (H1047R, E545K, E542K) by qPCR. The primary endpoint was recurrencefree survival (RFS), secondary endpoint overall survival (OS). Median follow up was 62 months.

Results: The PIK3CA-mutation rate was 42% (110 of 262). Overall, there was no difference considering RFS between patients with AI (n¼183) and TAM (n¼69) therapy(5 yrs-RFS 91.7% in both groups). Patients of the AI group harbouring a somatic PIK3CA mutation (n¼75) had non-signiﬁcantly more RFS related events compared topatients with PIK3CA wildtype (n¼108): 5 yrs-RFS 89.5% (95% CI 82.1-97.0) versus93.2% (95%CI 87.9 - 98.5), respectively (HR¼1.2, 95%CI 0.461-2.961; n.s.). After 5 yrs,91.2% (95% CI 84.5 e 97.9) of the patients with PIK3CA mutation were alive and

94.4% (95% CI 89.7 e 99.1) of patients without PIK3CA mutation, respectively(HR¼1.3, 95% CI 0.453-3.447; n.s.). In the group of patients who were treated withTAM only (n¼69), no interaction was observed between PIK3CA mutation and RFS orOS, respectively.

Conclusions: Although we observed a trend that AIs are less effective in patients with PIK3CA mutated tumours, formal validation is still lacking. Further data including prospective studies are required.

Disclosure: C. Thomssen: Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca,Aurikamed, Daiichi Sankyo, Gilead, Jörg Eickeler, Hexal, Lilly, Medupdate, MSD, Nanostring, Novartis,Onkowiisen, Pﬁzer, Roche, Seagen, Vifor; Financial Interests, Personal, Financially compensated role:Forum Sanitas; Non-Financial Interests, Personal, Member: AGO Breast committee, ASCO, DGGG,DGS, DKG, EORTC; Non-Financial Interests, Personal, Member of Board of Directors: AGO-B Breast Study Group; Non-Financial Interests, Personal, Ofﬁcer: BIG; Non-Financial Interests, Personal,Invited Speaker: ESO; Non-Financial Interests, Personal, Steering Committee Member: ESMO. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.477

281P Cyclin-dependent kinase 4/6 inhibitors combined with endocrine therapy for hormonal receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer: A meta-analysis of randomized clinical trials

V.F.C. Alves1, F.C.A. Moraes2, G.D.C. Gomes3, G.D.O. Almeida4, S. Carnevalli5,J.N. Priantti6, T.M. Madeira7, M. Silveira Vilbert8, C. Stecca9

1University of Sao Paulo Medical School, São Paulo, Brazil; 2Medicine, Federal University of Pará, Belem, Brazil; 3Medicine, Pontiﬁcal Catholic University of Minas Gerais, Belo Horizonte, Brazil; 4Medicine, Federal University of Triângulo Mineiro,Uberaba, Brazil; 5Medicine, Federal University of Santa Catarina, Florianópolis, Brazil;6Internal Medicine Department, Federal University of Amazonas, Manaus, Brazil;7Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil; 8Department of Clinical Oncology, UHN - University Health Network - Princess Margaret Cancer Center,Toronto, ON, Canada; 9Medicine, Center of Oncology of Parana, Curitiba, Brazil

Background: The use of cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors combined with endocrine therapy (ET) has recently emerged in the early stages breast cancer(eBC) treatment landscape. The present analysis aims to clarify the efﬁcacy and safety of this treatment for hormonal receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER-) patients in the early stages of breast cancer (eBC).

Methods: PubMed, Scopus, Web of Science, Cochrane, and the Central Register of Clinical Trials were systematically searched for studies using CDK4/6 inhibitors with ET in patients with HR+/HER- early breast cancer (I-IIIA stage). For the meta-analysis,

statistical analysis was performed using RStudio v 4.4.2. Heterogeneity was examined with Cochran Q test and I2 statistics and p-values inferior to 0.10 and I>25% were considered signiﬁcant for heterogeneity. The p-value< 0.05 was considered statistically signiﬁcant.

Results: This study included 9345 patients from six randomized clinical trials. Ductal(87%) and lobular (10%) were the most common, and 53% of women were postmenopausal. Lymph node status data revealed that 9% had N0 status, 72% had N1 status, and 19% had N2 status. In a pooled analysis, the invasive disease freesurvival (iDFS) was 82% (95% CI, 0.64-1.06), and the overall survival rates were consistent across the studies, with 12-month rates at 1.00 (95% CI 0.99-1.01), 24-month rates at 1.00 (95% CI 0.99-1.01), 36-month rates at 1.01 (95% CI 0.93-1.10),and 48-month rates at 1.04 (95% CI 0.91-1.19). The most common treatment-related adverse events (AE) included neutropenia (78.1%), leukopenia (51.6%), fatigue(37.6%), diarrhea (31.4%), anemia (30.5%), and arthralgia (29.3%). Any grade 3 adverse events were observed in 2.44 (95% CI 0.84-7.08) and grade 4 in 1.39 (95% CI

0.15-12.68).

Conclusions: This meta-analysis reinforces the antitumor activity of the combination of CDK4/6is with ET in patients with eBC, regardless of iDFS rate. Despite high rates of serious adverse events related to treatment, most were manageable.

https://doi.org/10.1016/j.annonc.2023.09.478

282P Analysis of Prosigna in hormone receptor-positive earlystage breast cancer cohort after 8 years of experience at a single institution

D. Morchón Araujo1, A. Olivares Hernandez1, L. Figuero Pérez1, J. Claros Ampuero2,M. García Muñoz3, J. Roldán-Ruiz1, M.D.C. Garijo Martínez1, E. Terán Brage1,

Á. López Gutiérrez1, M. Sancho de Salas4, A. Gómez Muñoz4, R. Seijas Tamayo5,R. Lozano Mejorada1, R.A. Marcos Sánchez1, E. Fonseca Sánchez1,

C.A. Rodríguez Sánchez1

1Medical Oncology, University Hospital of Salamanca, Salamanca, Spain; 2Medical Oncologist, Hospital Universitario Severo Ochoa, Madrid, Spain; 3Medical Oncology,University Hospital of Burgos, Burgos, Spain; 4Pathology, University Hospital of Salamanca, Salamanca, Spain; 5Oncology Department, Hospital of Avila, Avila, Spain

Background:Molecular signatures are recommended in HR+, HER2- early-stage breast cancer (EBC) to guide decisions for adjuvant treatment. Prosigna is a standardized test based on the PAM50 gene signature with provides information on risk of recurrence and permits intrinsic subtype classiﬁcation of tumor. The study aimed to evaluate the clinical impact of adopting Prosigna assay after 8y.

Methods: A retrospective study of patients (pts) with ER+, HER2- EBC was carried out between 2015 and 2023 in a single center. Gene expression analysis of tumors was performed with PAM50/Prosigna (NanoString Technologies, Seattle, WA, USA).

Results: 232 pts were included. All were node-negative. The median age was 55y (32-80) and 152 (65.5%) were postmenopausal. Risk of Recurrence (ROR) risk groups were as follows: low ROR: 97 (42%); intermediate ROR: 76 (33%); high ROR: 59 (25%).

Intrinsic Subtype Reclassiﬁcation: According to immunohistochemistry (IHC), 102 tumors (44%) were initially classiﬁed as luminal A and 130 (56%) as luminal B. After PAM50, 144 tumors (62%) were classiﬁed as luminal A, 86 (37%) as luminal B and 2(0.01%) as HER2-E. The discordance rate for luminal B by IHC is noteworthy. 67 (52%)were reclassiﬁed as luminal A after PAM50. Impact on decision making: Prosigna led to a treatment decision change in 64 pts (28%). Chemotherapy (CT) was added in 36(27%) of the 132 pts (57%) initially assigned to hormonal therapy (HT). Of 100 pts(43%) initially assigned to HT-CT, 28 pts (28%) ﬁnally received HT alone. Follow-up:With a median follow-up of 48 months and a maximum follow-up of 90 months, no recurrence of the disease has been reported.

Background: Neratinib is an oral pan-HER TKI approved in 2018 in Europe in adult patients with HR+ HER2+ early breast cancer (eBC) who completed adjuvant trastuzumab-based therapy. The approval is based on the phase III ExteNET trial that demonstrated clinically meaningful beneﬁt for neratinib vs. placebo in this population, including signiﬁcantly improved 5-year iDFS (D5.1%, HR 0.58, 95% CI 0.41-0.82).

https://doi.org/10.1016/j.annonc.2023.09.480

284P Prognostic and predictive impact of uPA/PAI-1 in early breast cancer

V. Wieder1, J. Engel1, M. Bauer2, S. Kaufhold1, V. Hanf3, C. Uleer4, T. Lantzsch5,S. Peschel6, J. John7, M. Pöhler8, E. Weigert9, K-F. Bürrig10, J. Buchmann11,E. Kantelhardt1, C. Thomssen1, M. Vetter1

1Department of Gynaecology, Martin Luther University Halle-Wittenberg, Halle(Saale), Germany; 2Institute of Pathology, Martin Luther University Halle-Wittenberg,Halle (Saale), Germany; 3Department of Obstetrics and Gynaecology, Klinikum Fuerth,Fuerth, Germany; 4Department of Gynaecology, Gynäkologisch-Onkologische Praxis,Hildesheim, Germany; 5Department of Gynecology, KH St. Elisabeth und St. Barbara Halle, Halle (Saale), Germany; 6Department of Gynaecology, St. Bernward Krankenhaus GmbH, Hildesheim, Germany; 7Department of Gynaecology, Helios Hospital Hildesheim, Hildesheim, Germany; 8Department of Gynaecology and Obstretrics,Hospital Wolfenbüttel, Wolfenbüttel, Germany; 9Institute of Pathology, Gemeinschaftspraxis Amberg, Amberg, Germany; 10Institute of Pathology, Institute of Pathology Hildesheim, Hildesheim, Hildesheim, Germany; 11Institute of Pathology,Hospital Martha-Maria Halle-Doelau, Halle (Saale), Germany

Background: The prognostic marker uPA/PAI-1 is recommended by international guidelines for treatment decisions in node-negative breast cancer (BC). This study is aimed at validating the prognostic impact of uPA/PAI-1 by using a daily routine cohort and to consider the predictive impact with regard to chemotherapy in HR+ /HER2-breast cancer.

Methods: In a multicentre cohort study (PiA-study, Prognostic assessment in routine Application n¼1,270, NCT 01592825), the concentrations of uPA and PAI-1 in freshtumour tissue (n¼813) were prospectively determined by ELISA (FEMTELLE, Bio-Medica Diagnostics GmbH). The ﬁrst objective was the association of uPA/PAI-1 with recurrence-free Interval (5 yrs RFI) and overall survival (5 yrs OS). As the second objective, we evaluated the impact of uPA/PAI-1 as a predictive factor for adjuvant chemotherapy in the intermediate risk group, which was deﬁned as HR+, HER2-, G2,35 yrs., 0-3 positive lymph nodes. Median follow-up was 60.3 months (1-129).

Background: Up to 10% of early BC occur in gBRCAm carriers. Whether gBRCAmrelated and sporadic BC have different outcomes is controversial.

N (%) Events 3-yr IDFS

Adjusted

hazard

ratio [95% CI]

All 746 (100) 95 gBRCAm ¼ 88.4%[83.3, 93.9]Non-gBRCAm ¼ 88.9%[86.2, 91.7]

0.82 [0.46,1.44] 0.49

HR+ BC 411 (55) 47 gBRCAm ¼ 88.4%[83.3, 93.9]Non-gBRCAm ¼ 88.9%[86.2, 91.7]

1.44 [0.55, 3.81] 0.46

TNBC 335 (45) 48 gBRCAm ¼ 91.8%[85.6, 98.5]Non-gBRCAm ¼ 84.3%[79.7, 89.3]

0.53 [0.22, 1.31] 0.17

N (%) Events 3-yr RFS

All 748 (100) 83 gBRCA ¼ 92.2%[87.8, 96.9]Non-gBRCA ¼ 89.4%[86.8, 92.2]

0.57 [0.30, 1.08] 0.085

HR+ BC 412 (55) 40 gBRCA ¼ 90.6%[84.1, 97.6]Non-gBRCA ¼ 93.6%[90.7, 96.5]

1.14 [0.41, 3.21] 0.80

TNBC 336 (45) 43 gBRCA ¼ 94.4%[89.1, 100.0]Non-gBRCA ¼ 84.3%[79.7, 89.3]

0.25 [0.07, 0.84] 0.025

Conclusions: Pts with BRCA-associated BC have higher-risk pathologic features and are more often treated with CT compared to matched non-gBRCAm BC. After adjusting for treatment and clinicopathologic variables, short-term outcomes did not differ in gBRCAm carriers vs controls overall. However, in TNBC pts, risk of relapse was signiﬁcantly lower among carriers than controls. Our results provide risk estimates for gBRCAm carriers that could inform the design of future clinical trials.

Disclosure: E.A. Mittendorf: Financial Interests, Personal, Advisory Board: Merck, BioNTech;Financial Interests, Institutional, Research Grant, I have a grant from SU2C funded by Roche/

Genentech that supports the conduct of a clinical trial: Roche/Genentech; Financial Interests,Institutional, Coordinating PI, Gillead provides clinical trial support to my institution for a study that I am the PI on: Gillead; Financial Interests, Personal, Steering Committee Member: Roche/Genentech,BMS; Non-Financial Interests, Member of Board of Directors: American Society of Clinical Oncology;Non-Financial Interests, Advisory Role, I serve in an advisory role as a Komen Scholar: Komen for the Cure. T.A. King: Financial Interests, Personal, Advisory Board: Exact Sciences; Financial Interests,Personal, Invited Speaker: Exact Sciences. G. Curigliano: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Daiichi Sankyo, Novartis, Pﬁzer; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Daiichi Sankyo, Lilly, Pﬁzer, Veracyte, BMS, Merck, Exact Sciences, Celcuity; Financial Interests, Personal, Writing Engagement: Pﬁzer; Financial Interests, Personal, Other,Advisory Board: Ellipsis; Financial Interests, Institutional, Research Grant, Investigator Initiated Trial:Merck; Financial Interests, Institutional, Funding, Phase I studies: BMS, Novartis, AstraZeneca, Daiichi Sankyo, Roche, Blueprint Medicine, Kymab, Astellas, Sanoﬁ, Philogen; Financial Interests, Institutional, Coordinating PI, Phase I clinical basket trial: Relay Therapeutics; Non-Financial Interests,Member of Board of Directors, No compensation for this role. This a public national company for cancer prevention: Lega Italiana Lotta ai Tumori; Non-Financial Interests, Ofﬁcer, Italian National Health Council as Advisor for Ministry of Health: Consiglio Superiore di Sanità; Non-Financial Interests, Advisory Role, Member of the Scientiﬁc Council. Patient advocacy association: Europa Donna; Non-Financial Interests, Advisory Role, Cancer Research Foundation: Fondazione Beretta;Non-Financial Interests, Ofﬁcer, Member of the Advisory Council: EUSOMA; Non-Financial Interests,Ofﬁcer, ESMO Clinical Practice Guidelines Chair: ESMO. A.H. Partridge: Financial Interests, Personal,Royalties, Royalties received for authorship of Breast Cancer Survivorship section: UpToDate; NonFinancial Interests, Leadership Role, co-Chair of Breast Committee: Alliance for Clinical Trials, National Cancer Institute; Non-Financial Interests, Other, Board of Directors, Member 2022-2026:ASCO. N. N.U. Lin: Financial Interests, Personal, Advisory Board, Ad board participation: Seattle Genetics, Daiichi Sankyo, Prelude Therapeutics; Financial Interests, Personal, Advisory Board, Ad board/Steering Committee participation; consultant: AstraZeneca; Financial Interests, Personal, Other,Consultant: Denali Therapeutics, Blueprint Medicines, Janssen, Afﬁnia Therapeutics; Financial Interests, Personal, Advisory Board, Ad board/Steering committee participation: Olema Pharmaceuticals; Financial Interests, Personal, Advisory Board, Advisory Board: Atera Inc.; Financial Interests,Personal, Royalties, Royalties for book chapter(s): Up to Date; Financial Interests, Institutional,Funding, Trial funding to institute (and steering committee): Olema Pharmaceuticals, AstraZeneca,Seattle Genetics; Financial Interests, Institutional, Funding, Trial funding to institute: Zion Pharmaceuticals; Financial Interests, Institutional, Funding, trial funding to institute: Pﬁzer, Genentech. J.E.

Garber: Financial Interests, Personal, Advisory Board: The James P. Wilmot Foundation , Inc., Helix;Non-Financial Interests, Personal, Advisory Board: Earli Inc.; Financial Interests, Institutional, Funding: Invitae Genetics, Myriad Genetics, Ambry Genetics. S.M.terests, Personal, Other, Consultant: Blueprint Medicines; Financial Interests, Personal,Advisory Board, Ad board participant: Bristol Myers Squibb, Ellipses Pharma, Mersana Therapeutics;Financial Interests, Personal, Other, Steering Committee Member/Consultant: CytomX; Financial Interests, Personal, Advisory Board, Advisory Board participation/consulting: Menarini/Stemline;Financial Interests, Personal, Advisory Board, Ad Board participant/consultant: Merck; Financial Interests, Personal, Advisory Board, Ad board participant/Consultant: Pﬁzer; Financial Interests, Personal, Advisory Board, Advisory board participation: Reveal Genomics; Financial Interests, Personal,Advisory Board, Advisory Board Participation: Zymeworks; Financial Interests, Institutional, Funding:AstraZeneca, Eli Lilly, Pﬁzer, Sanoﬁ, SeaGen, Odonate, Cyclacel, Exelixis, Gilead, Bristol Myers Squibb,Eisai, Merck, Novartis, Nektar, Genentech/Roche; Financial Interests, Personal and Institutional,Steering Committee Member: CytomX. Results: BCs with late-stage diagnosis, high histological grade, or high proliferative rate were more likely to be HER2 1+ or 2+/FISH- in comparison with earlier stage, lowgrade, or low-proliferative tumors (lower bounds of 95% conﬁdence intervals [CIs] for odds ratios [ORs] > 1). BCs with high expression of ER ( 80% [n¼12383]) were moreenriched with HER2 1+ (OR 1.39; 95%CI, 1.2-1.6) or 2+/FISH- tumors (OR 1.26; 95%CI,

1.0-1.6) than ER-low/moderate (1-79% [n¼1144]) ones. The 5-year overall survival(OS) for HER2 1+ BCs was lower than that for HER2 0 or 2+/FISH- tumors (P¼ 0.0018).This ﬁnding was conﬁrmed also after stratiﬁcation by ER status (low/moderate and high expression; P ¼ 0.07 and 0.007, respectively).

Conclusions: The worse prognostic impact of HER2 expression in pts with ER-positive/HER2-negative BCs seems to be restricted to HER2 1+ tumors. The better outcome observed in pts with HER2 2+/FISH- BCs may be related to the known FISH-negative(HER2-non-ampliﬁed) status of this subgroup. These ﬁndings may help identify optimal patient inclusion criteria for clinical trials with novel anti-HER2 therapies in ER-positive/HER2-negative disease.

Legal entity responsible for the study: A. Musolino on behalf of the Emilia-Romagna Cancer Registry.

Funding: Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC).

Disclosure: A. Musolino: Financial Interests, Personal, Advisory Board: Roche, Novartis, Gilead,AstraZeneca; Financial Interests, Institutional, Coordinating PI: Roche; Financial Interests, Institutional, Research Grant: Lilly; Financial Interests, Institutional, Funding: Seagen; Non-Financial Interests, Principal Investigator: Roche, Lilly, Gilead, Novartis. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.483

287P

Table:

Age<55 55 Menop Prem Post Ki67<20 20 HER2 s Neg Low Posivit<10 10 Stage Stag Stag Stag Stag ECE ECE ECE

Perturbation and stability of PAM50 subtyping in population-based primary invasive breast cancer

J. Staaf1, S. Veerla1, L. Hohmann1, D.F. Nacer1, J. Vallon-Christersson2

1Laboratory Medicine, Lund University, Lund, Sweden; 2Division of Oncology Department of Clinical Sciences, Lund University, Lund, Sweden

Conclusions: Improved consciousness of the commonly used PAM50 subtyping scheme will aid in our understanding and interpretation of breast tumors that have seemingly conﬂicting PAM50 classiﬁcation when compared to clinical biomarkers. Our study adds further support in challenging the common misconception that PAM50 subtypes are distinct classes by illustrating that PAM50 subtypes in tumors represent a continuum that may have clinical implications.

Conclusions: The use of gene expression platforms such as Prosigna directly impacts treatment decision making, allowing the selection the best adjuvant treatment adapted to the de risk of recurrence, without having registered any relapse so far in our HR+, HER2- EBC and node-negative patients. In addition, it seems that the intrinsic subtype determined by Prosigna assay cannot be replaced by IHC parameters.

Disclosure: R. Lozano Mejorada: Financial Interests, Personal, Invited Speaker: Janssen, Astellas,Roche, Bayer, Ipsen, AstraZeneca; Financial Interests, Personal, Advisory Board: Janssen, Merck/Pﬁzer, Orion Pharma, Advanced Accelerator Applications (Novartis); Financial Interests, Personal,Other, Travel / accommodation: MSD, Sanoﬁ; Financial Interests, Personal, Other, Travel / accommodation: BMS; Non-Financial Interests, Member: Sociedad Española de Oncología Médica. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.479

283P

Patient proﬁles treated with extended adjuvant neratinib in the early access registry study: NEAR study

M. De Laurentiis1, G. Hoste2, X. González Farre3, O. Romano4, A. Cano Jimenez5,F. Beghdad6, O. Dialla6, M. Zivanov7, T. Silovski8

https://doi.org/10.1016/j.annonc.2023.09.489

294P Prognostic signiﬁcance and evolution of HER2 zero, HER2 low and HER2 positive in breast cancer after neoadjuvant treatment

T. Wei1, D. Wang2, Y. Peng1

1Department of VIP Medical, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; 2Department of Breast Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Background: With the development of anti-HER2 targeted antibody-drug conjugates,HER2 low has attracted a lot of attention in breast cancer (BC). It’s signiﬁcant to study the pathological response of HER2 zero, HER2 low and HER2 positive BC after neoadjuvant treatment and the HER2 status evolution.

S301

Methods: A retrospective study was conducted at National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. Data from patients who were diagnosed with BC between 2015 and 2021 at our center and who had received neoadjuvant treatment were collected. The pathological complete response (pCR) rate of HER2 zero, HER2 low, and HER2 positive was analyzed. And the analysis of HER2 status evolution were carried out.

Results: 1173 patients with BC who had received neoadjuvant treatment were collected. 11.85% of the patients (n¼193) achieved pCR, and 88.15% of the patients(n¼1034) were non-pCR. Among 526 patients with available baseline biopsy reportsand matched pathological reports after neoadjuvant treatment, HER2 low BC was related to the lowest rate of pCR, followed by HER2 zero and HER2 positive BC(13.79% vs. 20.00% vs. 40.20%, respectively, p¼0.000). Of the 526 patients, 381 werehormone-receptor-positive BC, and 145 were triple-negative breast cancer (TNBC) on baseline biopsy. In 381 patients with hormone-receptor-positive BC, HER2 low BC was also related to the lowest rate of pCR, followed by HER2 zero and HER2 positive BC as well (9.14% vs. 12.28% vs. 36.22%, respectively, p¼0.000). A similar trend was alsoobserved in TNBC without a statistically signiﬁcant difference. On the converting of HER2 zero, HER2 low and HER2 positive before and after neoadjuvant treatment,HER2 zero has the highest discordance rate and 58.21% of HER2 zero on baseline biopsy converted into the other two types after neoadjuvant treatment. The conversion rates of HER2 low and HER2 positive on baseline biopsy were 28.10% and

14.43%, respectively.

Conclusions: Compared with HER2 zero and HER2 positive, HER2 low has the lowest pCR rate after neoadjuvant treatment. Besides, HER2 zero had the highest incidence of conversion to other HER2 statuses after neoadjuvant treatment.

Legal entity responsible for the study: National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.

https://doi.org/10.1016/j.annonc.2023.09.490

295P

ESR1, PGR, ERBB2, MKI67 single gene analysis in neoadjuvant-treated early breast cancer patients

R. Spiller1, T. Bracht1, S. Kaufhold1, M. Bauer2, T. Lantzsch3, V. Hanf4, C. Uleer5,S. Peschel6, J. John7, M. Pöhler8, J. Buchmann9, E. Weigert10, K-F. Bürrig11,E. Kantelhardt12, C. Thomssen13, M. Vetter13

1Gynaecology, UKH - Universitätsklinikum Halle (Saale), Halle (Saale), Germany;2Institute of Pathology, Martin Luther University Halle-Wittenberg, Halle (Saale),Germany; 3Department of Gynecology, KH St. Elisabeth und St. Barbara Halle, Halle(Saale), Germany; 4Department of Obstetrics and Gynaecology, Klinikum Fuerth,Fuerth, Germany; 5Department of Gynaecology, Gynäkologisch-Onkologische Praxis,Hildesheim, Hildesheim, Germany; 6Department of Gynaecology, St. Bernward Krankenhaus GmbH, Hildesheim, Germany; 7Department of Gynaecology, Helios Klinikum Hildesheim, Hildesheim, Germany; 8Department of Gynaecology and Obstretrics,Hospital Wolfenbüttel, Wolfenbüttel, Germany; 9Institute of Pathology, Hospital Martha-Maria Halle-Doelau, Halle (Saale), Germany; 10Institute of Pathology,Gemeinschaftspraxis Amberg, Amberg, Germany; 11Institute of Pathology, Institute of Pathology Hildesheim, Hildesheim, Hildesheim, Germany; 12Department of Gynaecology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany;13Department of Gynaecology, UKH - Universitätsklinikum Halle (Saale), Halle (Saale),Germany

Background: Currently, early breast cancer (eBC) is classiﬁed by using clinical and histopathological factors that are often considered insufﬁcient for individualised therapy. This study is aimed at examining whether single gene mRNA expression of ESR1, PGR, ERBB2 and MKI67 can be used instead of histopathological analysis in high-risk eBC.

Methods: For this study, a sample of high-risk patients who were treated with neoadjuvant chemotherapy was selected from a prospective, multicentre cohort of 1,270 eBC patients (PiA, Prognostic Assessment in routine application, NCT 01592825). Histopathological data for ER, PgR, HER2 and Ki67 were taken from the routine results from pre-treatment core needle biopsies. Single gene mRNA expression analysis of ESR1, PGR, ERBB2 and MKI67 and intrinsic subtyping (PAM50) were generated by multiplex hybridisation method (nCounter, NanoString ) using formalin ﬁxed tumour material. Cut-off values were determined by ROC-analysis.

Results: A strong correlation for ESR1, PGR and ERBB2 with corresponding histopathological results (IHC/ISH) was demonstrated (Pearson’s r¼ 0.701, r¼0.716, andr¼ 0.669, respectively; all p<0.001). After dichotomisation positive predictive valuewas 98%, 92%, and 92%, resp. Overall percent agreement was 94.5%, 92.8% and

90.8%, resp. Cohen’s Kappa showed high inter-reliability (k¼0.888, k¼0.856,k¼0.766 resp, all p<0.001). Odds ratio also indicates an association of single genemRNA-expression with complementary histopathological and intrinsic subtypes(p<0.05). Single gene mRNA expression data of all four genes (including MKI67) was used to classify the tumours following the surrogate deﬁnitions by the St. Gallen International Expert Consensus and demonstrated concordance with histopathological groups and intrinsic subtypes.

Conclusions: Single gene mRNA expression analysis for ESR1, PGR, ERBB2 and MKI67 is feasible and, in our sample, the results show a strong correlation to the corresponding histopathological results. Single gene expression may be used as an alternative to standard histopathological analysis. In addition, also subtyping can be performed by using single gene data; however, the clinical reliability has still to be proven.

Clinical trial identiﬁcation: NCT01592825 (release date: 16.12.2009).

Funding: Wilhelm Roux Program of the Medical Faculty, Martin Luther University Halle-Wittenberg (grant number FKZ 25/36) German Federal Ministry of Education and Research (grant number: Med FKZ 031A429).

Disclosure: C. Thomssen: Financial Interests, Personal, Speaker, Consultant, Advisor: Amgen,AstraZeneca, Aurikamed, Daiichi Sankyo, Gilead, Jörg Eickeler, Hexal, Lilly, Medupdate, MSD,Nanostring, Onkowiisen, Pﬁzer, Roche, Seagen, Vifor; Financial Interests, Personal, Financially compensated role: Forum Sanitas; Non-Financial Interests, Personal, Member: AGO Breast Committee, ASCO, DGGG (Germ Soc OB/GYN), DGS (Germ Soc Senology), DKG (Germ Cancer Soc), EORTC PathoBiomarker Group; Non-Financial Interests, Personal, Member of Board of Directors: AGO -B Breast Study Group; Non-Financial Interests, Personal, Ofﬁcer, representing AGO-B: BIG; NonFinancial Interests, Personal, Invited Speaker: ESO; Non-Financial Interests, Personal, Steering Committee Member: ESMO. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.491

296P Identiﬁcation of metabolism-related therapeutic targets to improve response to neoadjuvant chemotherapy in early breast cancers

F. Derouane1, C. Van Marcke de Lummen1, J. Ambroise2, M. Berliere3,

M.R. Van Bockstal4, G. Jerusalem5, V. Bours6, C. Josse6, C. Corbet7, F.P. Duhoux1

1Oncology Department, Cliniques Universitaires Saint-Luc (UCLouvain Saint-Luc),Woluwe-Saint-Lambert, Belgium; 2IREC (CTMA), UCLouvain - Université Catholique de Louvain, Woluwe-Saint-Lambert, Belgium; 3Gynecology Department, Cliniques Universitaires Saint-Luc (UCLouvain Saint-Luc), Woluwe-Saint-Lambert, Belgium; 4Pathology Department, Cliniques Universitaires Saint-Luc (UCLouvain Saint-Luc),Woluwe-Saint-Lambert, Belgium; 5Medical Oncology Department, Centre Hospitalier Universitaire Sart Tilman, Liège, Belgium; 6Human Genetics, CHU de Liège - Sart Tilman Site, Liège, Belgium; 7Pole of Pharmacology and Therapeutics, UCLouvain -Université Catholique de Louvain, Woluwe-Saint-Lambert, Belgium

Background: Pathological complete response (pCR) after neoadjuvant chemotherapy(NAC) is known as a prognostic factor correlated with improved EFS and OS. Better prediction of pCR would allow better patient and treatment selection. We aim to reveal speciﬁc transcriptomic and metabolic signatures correlated with distinct responses to NAC based on patient diagnostic biopsies. We also compared metabolic proﬁles of in vitro models.

Methods: We performed bulk-RNA sequencing on 95 samples from diagnostic biopsies from all subtypes of early BC treated with NAC (NCT03314870 study). Early triple-negative BC cell lines (HCC38, HCC1143, HCC1937) and patient-derived tumor organoids were cultured for drug testing, RT-qPCR and metabolomics studies using Seahorse bioenergetic analyzer.

Results: Transcriptomic analyses showed a down-regulation of genes related to tumor cell metabolism such as genes involved in the glycolysis (e.g. STC2, FDR ¼ 0.05) innon-responding patients (n¼39). Gene set enrichment analysis (hallmark and KEGGpathway databases) showed a down-regulation of the glycolysis and the oxidative phosphorylation pathways in non-responding patients (adjusted p-value <0.05). In 2D cell cultures, the HCC1937 cell line showed resistance to paclitaxel and a higher glycolysis proﬁle than the HCC38 and HCC1143 cells. Exposure to epirubicin or paclitaxel decreased the glycolysis in HCC38 and HCC1937 cell lines, while a decrease in the oxidative phosphorylation was observed in all 3 cell lines. A triple-negative organoid model (BCO17), initiated from a treatment naive tumor, showed resistance to epirubicin and paclitaxel. In BCO17, exposure to epirubicin or paclitaxel did not change the glycolysis or oxidative phosphorylation proﬁle. Targeting glycolysis with 2-deoxy-2-glucose (2DG) in monotherapy showed 50% of cell mortality in a 2D and organoid models, while combination of 2DG with epirubicin and paclitaxel did not increase the cell mortality.

Conclusions: Glycolysis and oxidative phosphorylation are involved in non-response to NAC in early breast cancer. 2D and organoid models with distinct chemotherapy sensitivity showed different metabolic proﬁles that may be explored in drug development.

Clinical trial identiﬁcation: NCT03314870.

Legal entity responsible for the study: Cliniques Universitaires Saint-Luc.

Funding: WALINNOV.

https://doi.org/10.1016/j.annonc.2023.09.492

297P

Prognostic and predictive impact of NOTCH1 in early breast cancer

J. Engel1, V. Wieder1, M. Bauer2, S. Kaufhold1, V. Hanf3, C. Uleer4, T. Lantzsch5,S. Peschel6, J. John7, M. Pöhler8, E. Weigert9, K-F. Bürrig10, J. Buchmann11,E. Kantelhardt1, C. Thomssen1, M. Vetter1

Elisabeth und St. Barbara Halle, Halle (Saale), Germany; 6Department of Gynaecology,St. Bernward Krankenhaus GmbH, Hildesheim, Germany; 7Department of Gynaecology, Helios Hospital Hildesheim, Hildesheim, Germany; 8Department of Gynaecology and Obstretrics, Hospital Wolfenbüttel, Wolfenbüttel, Germany; 9Institute of Pathology, Gemeinschaftspraxis Amberg, Amberg, Germany; 10Institute of Pathology, Institute of Pathology Hildesheim, Hildesheim, Hildesheim, Germany; 11Institute of Pathology, Hospital Martha-Maria Halle-Doelau, Halle (Saale), Germany

Background: The notch signalling pathway is considered to be an interesting prognostic and predictive marker in breast cancer as it is involved in proliferation, invasiveness and chemotherapy resistance.

Methods: From a prospective, multicenter cohort (Prognostic Assessment in Routine Application (PiA), 2009-2011, NCT01592825) of 1,270 breast cancer patients with a median follow-up of 60 months, the relative mRNA expression of NOTCH1 was determined in 414 tumour samples by qPCR. The primary objective was the evaluation of NOTCH1 mRNA expression and its association with patients and tumour characteristics. The secondary objectives were the associations with recurrence-free interval (RFI), overall survival (OS), and the predictive value of NOTCH1 mRNA expression with regard to adjuvant chemotherapy.

Results: Within our study, high NOTCH1 expression was detected in one-third of the tumours. We observed a signiﬁcant prognostic impact of high NOTCH1 expression with regard to RFI (adjusted hazard ratio 2.1, 95% CI 1.077e4.118). Patients with high NOTCH1 expression and chemotherapy (n ¼ 86) had a worse clinical outcomecompared to those without chemotherapy with an adjusted 3.1 higher risk for disease-related events (RFI events, 95% CI 1.321e7.245, p ¼ 0.009).

Conclusions: In summary, in our cohort for NOTCH1 we showed a prognostic and,particularly, a signiﬁcant predictive impact. We observed that tumours with high NOTCH1 expression seem to be less sensitive to cytotoxic treatment. Therefore, we postulate, that downregulation of the Notch signalling pathway, e.g. with y-secretase inhibitors, may improve the efﬁcacy of breast cancer therapy by restoring chemosensitivity.

Legal entity responsible for the study: E. Kantelhardt, M.Vetter.

Funding: Wilhelm Roux Program of the Medical Faculty, Martin Luther University Halle-Wittenberg (grant number: FKZ 25/36); German Federal Ministry of Education and Research (grant number: Med FKZ 031A429).

Disclosure: C. Thomssen: Financial Interests, Personal, Speaker, Consultant, Advisor: Amgen,AstraZeneca, Aurikamed, Daiichi Sankyo, Gilead, Jörg Eickeler, Hexal, Lilly, Medupdate, MSD,Nanostring, Novartis, Onkowissen, Pﬁzer, Roche, Seagen, Vifor; Financial Interests, Personal, Financially compensated role: Forum Sanitas; Non-Financial Interests, Personal, Member: AGO Breast Committee, ASCO, DGGG (Germ Soc OB/GYN), DGS (Germ Soc Senology), DKG (Germ Cancer Soc),EORTC PathoBiomarker Group; Non-Financial Interests, Personal, Member of Board of Directors:AGO - B Breast Study Group ; Non-Financial Interests, Personal, Ofﬁcer: BIG; Non-Financial Interests,Personal, Invited Speaker: ESO; Non-Financial Interests, Personal, Steering Committee Member:ESMO. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.493

298P Association of luminal-androgen receptor (LAR) subtype with low HER2 in triple-negative breast cancer

L. Min Ji, B. Seung Ho, S.E. Lee, Y. Kook, S. Moon, J. Kim, M.J. Kim, S.J. Bae, J. Jeong,S.G. Ahn

Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea

Background: Low level of HER2+ breast cancer, a subset of HER-2 negative, accounts for about 50-60% of breast cancer. A recent publication highlighting the improved survival outcomes with trastuzumab deruxtecan in this group has raised the need to redeﬁne low HER2+ breast cancer in the context of molecular characterization. In triple-negative breast cancer (TNBC), we compared molecular TNBC subtype, PAM50 subtypes, and clinical-pathological characteristics between the low HER2 and zero HER2 groups.

Methods: A study population included two cohorts with early TNBC. The adjuvant cohort consisted of 199 TNBC patients who underwent upfront surgery, while the neoadjuvant cohort comprised 124 TNBC patients treated with neoadjuvant chemotherapy (NAC). Transcriptome analysis was conducted in the adjuvant cohort to determine the TNBC molecular subtype and PAM50 types. Tumor-inﬁltrating lymphocyte (TIL) levels, PD-L1, and Ki67 expression were evaluated in both cohorts,

along with recurrence-free survival (RFS) and event-free survival (EFS) investigations in each cohort.

Results: In 199 patients with transcriptome analysis, 66 (33.2%) had low HER2 disease, while 133 (66.8%) had zero HER2 tumors. The rates of luminal androgen receptor (LAR) and HER2-E subtypes were 13.1% (26/199) and 7.0% (14/199),respectively. Comparing the two groups, low HER2 tumors showed higher rates of LAR(22.7% vs. 8.5%, p¼0.006) and HER2-E (15.2% vs. 3.3%, p¼0.016), while othercharacteristics such as TIL, PD-L1, ROR-P score, and Ki67 did not differ between the two groups. In the neoadjuvant cohort, 31 (25.0%) had low HER2 disease while 93(75.0%) had zero HER2 tumors, and there were no signiﬁcant differences in TIL, PD-L1,and Ki67 expression between the two groups. Furthermore, low HER2 status did not signiﬁcantly affect RFS and EFS in either cohort.

Conclusions: Low HER2 status in TNBC is distinctly associated with enriched LAR and HER2-E subtypes. However, other characteristics such as TIL, PD-L1, and Ki67 expression, as well as survival outcomes, were found to be similar between the two groups.

https://doi.org/10.1016/j.annonc.2023.09.494

299P Single-cell transcriptomic analysis reveals speciﬁc luminal and T cell subpopulations associated with response to neoadjuvant therapy in early-stage breast cancer

X. Wang1, D. Gacquer1, S. Majjaj1, M. Rediti1, L. Craciun2, D. Larsimont2, F. Rothé1,C. Sotiriou1

1Breast Cancer Translational Research Laboratory J-C. Heuson, Institut Jules Bordet,Hôpital Universitaire de Bruxelles (H.U.B), Brussels, Belgium; 2Pathological Department, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B), Brussels,Belgium

Background: Neoadjuvant therapy (NAT) remains the standard of care for most earlystage breast cancer (BC) patients, especially in HER2+ and triple-negative (TNBC)subtypes. Patients who do not achieve pathological complete response (pCR) present an increased risk of disease recurrence. Here, we applied single cell RNA sequencing(SCS) to investigate tumor and immune landscape for the identiﬁcation of predictive biomarkers of response to NAT.

Methods: Twenty-one BC patients treated with NAT were included in the study. Pretreatment biopsies, matched residual disease and adjacent normal tissue samples were prospectively collected for all patients. After tissue dissociation, single cell RNA proﬁles were investigated using the Chromium Next GEM Single Cell 5’ kit (10X Genomics). After removing batch effect using Seurat integration, cell clusters were annotated based on the expression of speciﬁc marker genes. Epithelial luminal cells(KRT18+/KRT19+) were classiﬁed as malignant or non-malignant using copy number proﬁles computed by inferCNV. Wilcoxon rank sum test was used to compare cell proportions between pCR and non-pCR groups.

Results: pCR rates were 61.5% (8/13), 100% (4/4) and 25% (1/4) in TNBC, HER2+ and Luminal B patients respectively. A total of 21 TNBC, 6 HER2+ and 6 Luminal B samples were proﬁled with SCS. Malignant luminal epithelial cells were classiﬁed in luminal progenitor (LP) (KIT+/SLPI+/KRT5low), luminal mature (LM) (KIT-/SLPI-/KRT5-) and luminal cycling cells (LC) (MKI67+/TOP2A+). Patients achieving pCR had a higher fraction of LC cells at baseline, considering all BC subtypes (p<0.05). Enrichment of LP cells at baseline was observed in TNBC patients achieving pCR (p<0.05). T cells reclustering further identiﬁed four CD4+ subtypes. Of note, lower proportions of FOXP3+ regulatory T cells and RORC+/CCR6+ Th17 cells at baseline were associated with a better response to NAT both in TNBC and HER2+ patients (p<0.05).

Conclusions: Our study showed substantial heterogeneity at the single cell level with speciﬁc cell types being associated with response to neoadjuvant chemotherapy,towards an improved BC care.

Legal entity responsible for the study: Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B).

Funding: Fond de la Recherche Scientiﬁque (FNRS), Télévie, Association Jules Bordet,Breast Cancer Research Foundation (BCRF), Fondation contre le Cancer, Fondation de l’Université Libre de Bruxelles.

Disclosure: C. Sotiriou: Financial Interests, Institutional, Advisory Board: Astellas, Vertex, Seattle Genetics, Amgen, INC, Merck & Co; Financial Interests, Personal, Advisory Board: Cepheid, Puma;Financial Interests, Personal, Invited Speaker: Eisai, Prime oncology, Teva; Financial Interests, Institutional, Other, Travel: Roche; Financial Interests, Institutional, Other, Internal speaker: Genentech;Financial Interests, Personal, Other, Regional speaker: Pﬁzer; Financial Interests, Institutional, Invited Speaker: Exact Sciences. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.495

S303

300P

Correlation of PD-L1 protein and mRNA expression and their prognostic impact in triple-negative breast cancer

K. Schüler1, M. Bauer2, S. Kaufhold1, E. Kantelhardt3, C. Thomssen4, M. Vetter1

1Department of Gynaecology, UKH - Universitätsklinikum Halle (Saale), Halle (Saale),Germany; 2Institute of Pathology, Martin Luther University Halle-Wittenberg, Halle(Saale), Germany; 3Institute of Epidemiology, Biometry and Informatics, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany; 4Department of Gynaecology,Martin Luther University Halle-Wittenberg, Halle (Saale), Germany

Background: PD-L1 expression is determined by immunohistochemical (IHC) analyses.

PD-L1 positivity can differ depending on the used antibody. The aim of this study was to evaluate the correlation of IHC and mRNA PD-L1 expression and their associations to prognosis.

Methods: For this analysis, 85 TNBC samples from a prospective cohort of breast cancer patients (n¼1,270, PiA Prognostic Assessment in routine application, NCT01592825) were eligible. IHC was performed using CAL10 antibody (BioCare), 1%staining was considered PD-L1 positive for immune cell score (IC), tumour proportion score (TPS) and combined positive score (CPS). For analysis of mRNA expression,microarray analysis was performed (Affymetrix, HG U133 Plus 2.0, probesets #1:223824, #2: 227458, detecting different transcripts of the PD-L1 gene); maximum likelihood method was used for cut off determination. Correlations with IHC and TILs were tested using Spearmans rank correlation. Survival analysis included recurrence free interval (RFI) and overall survival (OS), considering only those patients who received chemotherapy (n¼76). Median follow up was 73 months (20-127).

Results: In IHC analysis, half of the samples were classiﬁed PD-L1 positive for IC and CPS (50.6% and 49.4%) and only 23.5% considering TPS. In probeset #1, 63.5% were determined PD-L1 positive, no correlation to the IHC scores, TILs and probeset #2 was shown. In probeset #2 only 34.1% showed a PD-L1 positivity and had a strong correlation to the IHC scores and to TILs (p<0.01). PD-L1 positivity had no impact on survival when determined by IHC scores or probeset #2. In contrast, patients with high PD-L1 expression in probeset #1 had a more favourable 7-years RFI probability(84.6% vs 64.3%). Low PD-L1 expression showed higher risk for recurrence in univariate (2.68, 95%CI 1.089-7.532) and multivariate analysis (3.43, 95%CI 1.294-9.080,adjusted to nodal status). Considering OS only a trend was shown (HR 1.445, 95%CI

0.570-3.662).

Conclusions: In our cohort, the PD-L1 mRNA analysis detected additional PD-L1 positive tumours compared to IHC analysis. For validation of the prognostic impact and to examine the predictive value considering therapy with immune checkpoint inhibitors, further studies are warranted.

Clinical trial identiﬁcation: NCT01592825 release date 16.12.2009.

Legal entity responsible for the study: M. Vetter, E. Kantelhardt.

Funding: Wilhelm Roux Program of the Medical Faculty Martin Luther University Halle-Wittenberg (grant number FKZ 25/36), German Federal Ministry of Education and Research (grant number Med FKZ 031A429).

Disclosure: C. Thomssen: Financial Interests, Personal, Speaker, Consultant, Advisor: Amgen,AstraZeneca, Aurikamed, Daiichi Sankyo, Gilead, Jörg Eickeler, Hexal, Lilly, Medupdate, MSD,Nanostring, Novartis, Onkowissen, Pﬁzer, Roche, Seagen, Vifor; Financial Interests, Personal, Financially compensated role: Forum Sanitas; Non-Financial Interests, Personal, Member: AGO Breast Committee, ASCO, DGGG (Germ Soc OB/GYN), DGS (Germ Soc Senology), DKG (Germ Cancer Soc),EORTC PathoBiomarker Group; Non-Financial Interests, Personal, Member of Board of Directors:AGO -B Breast Study Group; Non-Financial Interests, Personal, Ofﬁcer: BIG; Non-Financial Interests,Personal, Invited Speaker: ESO; Non-Financial Interests, Personal, Steering Committee Member:ESMO. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.496

301P Epigenetic modiﬁcations of IL-17 gene in patients with early breast cancer and healthy controls

L. Radmilovic Varga1, T. Maric2, A. Katusic Bojanac2, K. Horvatovic3, M. Popovic4,A. Kulic4, T. Silovski5, M. Sirotkovic-Skerlev6, M. Krizic4, K. Bulic7, H. Silovski8,N. Dedic Plavetic4

1Oncology Department, General Hospital Varazdin, Varazdin, Croatia; 2Department of Medical Biology, School of Medicine, University of Zagreb, Zagreb, Croatia; 3School of Medicine, University of Zagreb, Zagreb, Croatia; 4Department of Oncology, KBC -University Hospital Centre Zagreb, Zagreb, Croatia; 5Medical Oncology Department,KBC - University Hospital Centre Zagreb, Zagreb, Croatia; 6Department of Pathophysiology, School of Medicine, University of Zagreb, Zagreb, Croatia; 7Department of Surgery, KBC - University Hospital Centre Zagreb, Zagreb, Croatia

Background: During malignant transformation, the composition and expression of cell surface molecules are changing allowing recognition by the host immune system.

Interleukin 17 (IL-17) is an inﬂammatory mediator involved in all phases of the in-ﬂammatory process and tumour development and progression. The aim of this study was to determine the IL-17 gene methylation level and IL-17 serum concentration in patients with different surrogate subtypes of early breast cancer (eBC) and healthy controls (HCs).

Methods: Peripheral blood samples were obtained from a consecutive series of 130 female patients treated at the University Hospital Centre (UHC) Zagreb, Croatia, and

30 female HCs. The level of methylation of four CpG dinucleotide loci (CPG1, CPG2,CPG3, CPG4) in the promoter region of the IL-17 gene was measured by pyrosequencing with prior bisulﬁte conversion, while serum IL-17 concentrations were determined by enzyme-linked immunosorbent assay (ELISA). Blood samples, clinical and histopathological data were collected with prior UHC Zagreb 02/21 AG Institutional Review Board approval.

Results: According to the Mann-Whitney test, the HCs methylation level of the promotor region of the IL-17 gene differed signiﬁcantly from the BC patients (p ¼0.0011), together with the methylation level of four individual CpG loci, also (p values;CPG1 0.0067; CPG2 0.0018; CPG3 CPG 0.0029; CPG4 0.0032, respectively). There was a statistically signiﬁcant difference according to the Kruskal-Wallis test in CPG3 locus methylation among BC surrogate subtypes (p¼0.010), whereas no difference in themethylation of the other three loci was observed. Preoperative IL-17 serum concentration was signiﬁcantly higher in patients with HER-2 enriched and triple-negative eBC (Kruskal-Wallis test, p¼0.022).

Conclusions: This study conﬁrmed differences in epigenetic modiﬁcation of IL-17 gene in women with eBC compared to HCs. Differences in the IL-17 gene methylation and IL-17 serum concentration in patients with different subtypes of BC were observed.

Further research is planned to deﬁne the impact of IL-17 on eBC outcome in this cohort.

Funding: Research was funded by the grants from University of Zagreb for ﬁnancial support to research groups 2019 and 2020.

https://doi.org/10.1016/j.annonc.2023.09.497

302P Clinicopathological features and outcomes of pregnancy associated breast cancer: Case control study -single

institution experience

N. Kordy1, A. Haggag1, S. Seddik1, R. Eid2, E. Shash3

1Biostatics, Epidemiology and Science Computing, Shefaa El Orman Oncology Hospital(SOH), Luxor, Egypt; 2Biostatics, Epidemiology, National Cancer Institute - Cairo University, Cairo, Egypt; 3Medical Oncology Department, National Cancer Institute - Cairo University, Cairo, Egypt

Background: Globally, breast cancer ranks among the primary contributors to the incidence and mortality rates of cancer. Pregnancy-Associated Breast Cancer (PABC) is an infrequent occurrence among young patients (45 years), characterized by diag-nosis of breast cancer during pregnancy or within a year after delivery. In recent meta-analysis study, PABC patients showed higher mortality than control group. This retrospective case-control study aimed to assess the outcomes of PABC vs nonpregnancy-associated breast cancer (NPABC). The primary outcome measure was overall survival (OS), and secondary outcome measures included disease-free survival(DFS) and recurrence-free survival (RFS).

Methods: A retrospective case-control study was conducted at Shefa El Orman Hospital (SOH) from 2016 to 2021, on patients who met PABC criteria and were under follow-up for at least 3 years. Data collection was carried out using SOH Cancer Registry. 54 PABC patients cross matched with an equal number of control NPABC(45 years of age) with a 1:1 ratio. Statistical analysis was conducted through SPSSsoftware. The Chi-square c2 test was employed to conduct a comparative analysis of frequency distributions for categorical variables.

Results: Total of 54 PABC patients and equal number of control subjects. The median age of PABC cohort ¼ 33 (IQR: 23-42), which did not differ signiﬁcantly from NPABC(34, IQR: 22-42; p¼0.650). PABC demonstrated a higher likelihood of presenting withmetastasis at initial diagnosis compared to those NPABC (metastatic: 66.7% vs. 33.3%,p¼0.018). PABC patients exhibited a noteworthy contrast in advanced stages duringdiagnosis, particularly in stage III and IV, in comparison to NPABC patients (61.1% vs

40.7%, p¼0.021). Additionally, PABC patients showed an inferior median OS rate(48.9% vs 69.3%, p¼0.085) compared to NPABC.

Conclusions: In conclusion, a signiﬁcant difference exists between the OS and clinicopathological characteristics of PABC patients compared to NPABC. Furthermore,PABC patients exhibited an advanced stage of the disease upon presentation. Larger cohort studies are necessary to evaluate the treatment efﬁcacy and to acquire molecular indicators that may impact the disease outcomes.

Legal entity responsible for the study: Shefaa El Orman Oncology Hospital (SOH).

https://doi.org/10.1016/j.annonc.2023.09.498

303P

Differential prognostic role of PDGFRA alterations in breast cancer subtypes

P.J. Vlachostergios1, N. Spathas2, K. Thomopoulou3, E. Lymperopoulos4

1Medical Oncology,Weill Cornell Medicine, New York, USA & IASO Thessalias Hospital,Larissa, Greece; 24th Oncology Department, Metropolitan Hospital, Athens, Greece;3Department of Medical Oncology, Hygeia General Hospital, Athens, Greece; 4Obstetrics and Gynecology, IASO General Hospital, Cholargos/Holargos, Greece

Background: The platelet e derived growth factor (PDGF) signaling pathway and its main representative, PDGF receptor alpha is reportedly expressed in early breast cancer and has been associated with aggressive tumor features and worse outcomes.

The aim of this study was to examine the prognostic relevance of PDGFRA molecular alterations across different breast cancer subtypes.

Methods: Patients with a diagnosis of non-metastatic, invasive breast carcinoma from The Cancer Genome Atlas (TCGA), including estrogen receptor (ER)-positive (n¼594),ER-negative (n¼174), human epidermal growth factor receptor 2 (HER2)-positive(n¼120), and triple-negative (n¼82) cohorts were interrogated for presence of so-matic molecular alterations in PDGFRA gene. Kaplan Meier survival analysis was used to determine the associations between altered PDGFRA and disease-free survival(DFS).

Results: Sixty patients (10%) from the ER-positive cohort had altered PDGFRA,including 2 patients with gene ampliﬁcation, 3 with missense mutations, 1 with homologous deletion and 55 with elevated mRNA expression. These patients had a longer DFS compared to those with unaltered PDGFRA (not reached vs 168 months,log-rank p¼0.04). In the ER-negative cohort, 24 patients (14%) had tumors harboringPDGFRA alterations including 5 ampliﬁcations, 2 missense and 1 nonsense mutation,and high mRNA (n¼16). There was a trend towards a shorter DFS in these patients(p¼0.23). Within the HER2-positive cohort, 11 patients (9%) had somatic gene am-pliﬁcations (n¼1), missense mutation (n¼1), and elevated mRNA (n¼9). These pa-tients experienced a signiﬁcantly worse DFS (56 months vs not reached, p<0.001).

Among TNBC patients, 10 (12%) were characterized by PDGFRA ampliﬁcation (n¼2),missense (n¼2) and nonsense (n¼1) mutations, and high mRNA (n¼5). This groupalso featured a non-signiﬁcant trend towards worse DFS (p¼0.39).

Conclusions: PDGFRA molecular alterations in early breast cancer are mainly characterized by ampliﬁcation and increased transcript levels. Their prognostic utility is variable depending on the hormone receptor- and HER2-status. An intriguing association with favorable prognosis in ER-positive cohort was found that merits further investigation.

https://doi.org/10.1016/j.annonc.2023.09.499

304P Generalizability of 313-SNP PRS for breast cancer risk in non-European ancestries

H. Shang1, Y. Ding2, V. Venkateswaran2, K. Boulier3, B. Pasanuic2,N. Kathuria-Prakash4, P. Brown1

1Internal Medicine, Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA;2Computational Medicine, UCLA, Los Angeles, CA, USA; 3Computational Medicine,Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA; 4Hematology/Oncology,Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA

Background: Polygenic risk scores (PRS), which summarize the combined effect of multiple common risk variants, have been associated with elevated breast cancer risk in patients who lack any identiﬁable monogenic risk factors. One of the most wellvalidated PRSs in breast cancer to date is PRS313, which was developed from a Northern European biobank (n ¼ 33,673 cases and n ¼ 33,381 controls). However,subsequent work has demonstrated an attenuated effect of PRS313 in African females, raising generalizability concerns. In this work, we further investigate the generalizability of the PRS313 for American women of European (EA), African (AFR),Asian (EAA), and Latinx (HL) ancestry within one institution, leveraging a singular EHR system, genotyping platform, and quality control process.

Methods: Participants were females drawn from the UCLA ATLAS Biobank(N¼18,627) from 2018-2023. SNPs were genotyped on a genome-wide array andimputed to the TOPmed reference panel. Breast cancer cases and controls were identiﬁed using ICD9 and ICD10 coding. We previously identiﬁed 5 Genetically Inferred Ancestries (GIA) based on Principal Component Analysis (PCA) and k-means clustering including African Americans (AA), Hispanic Latino Americans (HLA), East Asian Americans (EAA), European Americans (EA). Breast cancer subtypes were identiﬁed based on prescription patterns.

Results: We found that the PRS313 achieved overlapping AUCs in females of Lantix(AUC, 0.68; 95% CI, 0.65-0.71) and European ancestry (AUC, 0.70; 95% CI, 0.69-0.71)with lower AUCs for the AFR and EAA populations (AFR: AUC, 0.61; 95% CI, 0.56-0.65;EAA: AUC, 0.64; 95% CI, 0.60-0.680).

Conclusions: In summary, we found that PRS313 was signiﬁcantly associated with breast cancer in American females of Hispanic and East Asian ancestry but with attenuated accuracy in women of African descent. Our results are consistent with prior studies on PRS313 and further highlight the need for ethnically diverse cohorts in developing and implementing polygenic risk scores.

https://doi.org/10.1016/j.annonc.2023.09.500

305P Prognostic implications of HER2 changes after neoadjuvant chemotherapy in patients with HER2-zero and HER2-low breast cancer

S. Kang1, S.H. Lee2, H.J. Lee3, H. Jeong4, J-H. Jeong2, J.E. Kim2, J-H. Ahn2, K.H. Jung2,H.H. Kim5, S. Lee6, J. Lee6, S-B. Kim2

1Hemato-Oncology, Chungnam National University Hospital, Daejeon, Republic of Korea; 2Department of Oncology, Asan Medical Center - University of Ulsan College of Medicine, Seoul, Republic of Korea; 3Pathology, Asan Medical Center - University of Ulsan College of Medicine, Seoul, Republic of Korea; 4Internal Medicine Department,Asan Medical Center - University of Ulsan College of Medicine, Seoul, Republic of Korea; 5Department of Radiology, Asan Medical Center - University of Ulsan, Seoul,Republic of Korea; 6Surgery, Asan Medical Center - University of Ulsan, Seoul, Republic of Korea

Results of the window-of-opportunity clinical trial DBIOMARK: Study of biomarkers of the antitumor activity of denosumab and its role as a modulator of the immune response in early breast cancer

A. Vethencourt1, E.M. Trinidad2, E. Dorca Duch3, A. Petit3, M.T. Soler-Monsó4,E. Purqueras3, M.E. Brizzi5, M. Matas Garcia6, G. Pérez-Chacón7, M. Jimenez7,M. Ciscar2, A. Stradella8, A. Iserte9, A. Gumà Martinez10, R. Ortega10, M.J. Gil11,S. Pernas Simon8, C. Falo8, E. Gonzalez-Suarez7

1Breast Cancer Unit, ICO - Institut Català d’Oncologia l’Hospitalet (Hospital Duran i Reynals), Barcelona, Spain; 2Transformation and Metastasis Laboratory, IDIBELL -Bellvitge Biomedical Research Institute, Hospitalet De Llobregat, Spain; 3Pathology,Hospital Universitari de Bellvitge, Hospitalet De Llobregat, Spain; 4Pathology, ICO -Institut Català d’Oncologia l’Hospitalet (Hospital Duran i Reynals), Hospitalet De Llobregat, Spain; 5Pathology, Hospital Universitario La Paz, Madrid, Spain; 6Medical Oncology, Hospital de Sant Joan de Déu - Althaia, Xarxa Assistencial Universitària de Manresa, Manresa, Spain; 7Molecular Oncology, CNIO - Centro Nacional de Investigaciones Oncologicas, Madrid, Spain; 8Breast Cancer Unit, ICO - Institut Català d’Oncologia l’Hospitalet (Hospital Duran i Reynals), L’Hospitalet De Llobregat, Spain;9Clinical Trials Unit, IDIBELL - Bellvitge Biomedical Research Institute, Hospitalet De Llobregat, Spain; 10Radiology, Hospital Universitari de Bellvitge, Hospitalet De Llobregat, Spain; 11Medical Oncology, ICO - Institut Català d’Oncologia l’Hospitalet(Hospital Duran i Reynals), L’Hospitalet De Llobregat, Spain

Background: Inhibitors of the Receptor Activator of NFkB (RANK) pathway, such as denosumab, have been shown to prevent breast cancer (BC) in preclinical models by reducing proliferation and tumor cell survival. Recent studies suggest that RANK pathway inhibition enhances the anti-tumor immune response. This study aimed to evaluate the antiproliferative, proapoptotic (primary endpoints), and immunomodulatory activity (exploratory endpoint) of denosumab in early BC.

Methods: D-BIOMARK study (NCT03691311) was a randomized window-of-opportunity trial designed to evaluate the biological effects of single-agent denosumab in early BC. Sixty patients with early HER2-negative BC were enrolled, 2:1 randomization to experimental (two doses of 120mg of denosumab separated by 7 days before surgery) or control (no treatment) group. Paired samples (core-biopsy and surgical specimen) were obtained from each patient for comparison of Ki67 (proliferation),Cleaved Caspase-3 (cell survival), and tumor inﬁltrating lymphocytes (TILS) according to international guidelines. Pre vs. post values were compared using a paired t-test.

Results: A total of 58 evaluable patients were analyzed, 10 with triple-negative breast cancer (TNBC), 27 premenopausal and 31 postmenopausal. Denosumab reduced free RANKL (sRANK) levels in patient’s serum but did not reduce tumor cell survival or proliferation. Denosumab increased TILS in all patients, except TNBC (n¼6) whiledifferences in the control group did not reach statistical signiﬁcance. When considering clinically signiﬁcant increases in TILS (5% or 10%), no differences were found between both groups. No associations were found between basal sRANKL and an increase in TILS..

Conclusions: Denosumab did not affect tumor cell survival nor proliferation in early BC but may have an immunomodulatory effect that warrants further investigation.

Clinical trial identiﬁcation: NCT03691311.

Disclosure: A. Vethencourt: Financial Interests, Personal, Invited Speaker, Presentation in clinical or research sessions as a speaker: Novartis, Eisai; Non-Financial Interests, Project Lead, GEICAM Grant“Balil-Pelegrí” 2021-2022, sponsored by theSpanish breast cancer research group GEICAM.: GEICAM;Non-Financial Interests, Advisory Board: SOLTI; Non-Financial Interests, Leadership Role, Participation in the TransGEICAM group, which is part of the Spanish breast cancer research group GEICAM(Not Paid): GEICAM; Other, Travel, Accommodations, Support for attending meetings: Pﬁzer, Lilly,Novartis, Roche. A. Stradella: Financial Interests, Personal, Advisory Board, Advisory about CAPITELLO 291 trial: AstraZeneca; Financial Interests, Personal, Advisory Board, Advisory on new activities for residents: Novartis; Financial Interests, Personal, Invited Speaker, Trastu-Deruxtecan

nse variable

Mean Pre Mean

L pg/ml N¼58

0.10

0.12

N¼58

24.52 29.19

ED-CASPASE 3 H-score N¼58

1.66

2.24

7.42

12.24

within Luminal BC N¼48

8.17

11.78

within TNBC N¼10

4.250 14.250 within premenopausal patients with luminal BC N¼26 10.68 12.60 ithin postmenopausal patients with luminal BC ¼22 8.17

11.77

clinical case meeting: Daiichi; Financial Interests, Personal, Invited Speaker, meeting on new data on cyclin inhibitors: Novartis. M.J. Gil: Financial Interests, Personal, Advisory Board: Daiichi; Pﬁzer;Novartis, Gilead; Palex; Seagen; Roche y Pierre-Fabre. S. Pernas Simon: Financial Interests, Personal,Advisory Board: SeaGen, AstraZeneca- Daiichi Sankyo, Pierre-Fabre, Pﬁzer; Financial Interests, Personal, Invited Speaker: Lilly, Novartis, Eisai, Roche; Financial Interests, Institutional, Local PI: AstraZeneca, Novartis, Daiichi Sankyo; Non-Financial Interests, Member of Board of Directors: SOLTI. E.

Gonzalez-Suarez: Financial Interests, Personal and Institutional, Coordinating PI: Amgen. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.486

290P

Post

Metabolomic proﬁling and response to neoadjuvant therapy(NAT) in early breast cancer (EBC)

A. Gennari1, E. Barberis2, V. Martini1, S. Gobbato3, R. Alsati3, R. Ben Ayed3, V. Rossi1,F. D’Avanzo1, B. Rufﬁlli3, B. Malagutti3, I. Dodaro1, E. Gallarotti1, L. Galli1,

R. Boldorini1, A. Gambaro1, A. Rampi1, C. Branni3, M. Manfredi3

1Department of Translational Medicine, AOU Maggiore della Carità di Novara,Novara, Italy; 2Translational Medicine, UPO - Università del Piemonte Orientale - DISIT,Novara, Italy; 3Dipartimento di Medicina Traslazionale - DIMET, Università degli Studi del Piemonte Orientale - Amedeo Avogadro, Novara, Italy

Background: The presence of residual disease (RD) after NAT is correlated with a poor outcome in EBC patients. New strategies are required to early identify patients who will not achieve a pathological complete response (pCR). Metabolomics may represent an innovative technology to identify host-related factors correlated with treatment outcome. In this study, we evaluated the predictive ability of metabolomics combined with machine learning in EBC patients receiving NAT.

Methods: Untargeted metabolomic analysis was performed in EBC patients candidates for NAT at our institution. Plasma samples were collected at baseline, before start of treatment. Small molecules were extracted, derivatized and then analysed using bi-dimensional gas chromatography/mass spectrometer (GCxGC-MS). The metabolomic proﬁling was then evaluated according to response to therapy (pCR versus RD). A machine learning approach was implemented with Boruta features selection algorithm combined with genetical algorithm as classiﬁer, on a training set of 69 samples and validated on the remaining 27.

Results: From 12/2020 to 05/2023, 109 EBC patients have been enrolled (26 ER+, 45 HER2+, 38 TN); surgery was performed in 96 patients so far, with an overall pCR of 51% (ER+ 19%, HER2+ 51%, TN 55%). 61 small molecules were expressed (p<0.05 and Fold Change FC >1.3) between patients in pCR or RD. By multivariate analysis patients with RD showed higher levels of unsaturated fatty acids, as eicosatrienoate(FC¼6), 9-decenoic acid (FC¼2.2) and 17-octadecynoic acid (FC¼2.2) and lower levelsof fatty acids, as hexadecenoic acid (FC >100), doconexent (FC¼69.5), 9,11-conju-gated linoleic acid (FC¼5.2), circulating glucose (FC¼71) and glucopyranose (FC¼23).Pathway analysis revealed the involvement of amino and fatty acid metabolism. A prediction model, combining metabolomics and machine learning, was implemented on 35 metabolomic probes and correctly identiﬁed the type of response with an accuracy of 95%.

Conclusions: Our data indicate that host-related metabolomic signatures may identify patients with EBC failing to achieve a pCR after NAT. We identiﬁed several fatty acids,amino acids and small molecules that can be modulated through diet. Possible effects by BC subtype are being investigated.

Legal entity responsible for the study: A. Gennari.

Disclosure: A. Gennari: Other, Advisory Board: Roche, AstraZeneca. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.487

Control p-value Mean Pre Mean Post Experimental p-value

0.25

0.01

<0.01

0.05

20.59 25.24

2.56

1.98

0.24

0.06

7.35

12.94

0.18

6.13

10.80

13.667 24.000 0.08

0.64

7.31

12.73

4.87

8.75

0.04

291P

Pts (

1 -2 -3 +4 +5 +6 +7 +8 +9 +10 +11 +12 +13 +14 +15 +16 +17 +18 +19 +20 +

F: FISH t

Prognostic implications of HER2 gain in patients with HR+/HER2- breast cancer (BC) and TNBC after neoadjuvant

chemotherapy (NAC)

E. Ferraro1, S. Chew Minmin1, D. Nemirovsky2, Y. Chen2, A.V. Barrio3, S. Modi1,A. Seidman1, H. Wen4, E. Brogi4, M. Robson5, C. Dang6

1Breast Medicine Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA;2Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 3Breast Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 4Pathology Department, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 5Medicine Dept, MSKCC - Memorial Sloan Kettering Cancer Center, New York, NY, USA;6Department of Breast Oncology, MSKCC - Memorial Sloan Kettering Westchester,West Harrison, IN, USA

Background: Residual disease (RD) after NAC is a well-established risk factor for recurrence in patients (pts) with triple-negative breast cancer (TNBC) or high-risk hormone receptor-positive (HR+)/ HER2-negative (-) BC. Biologic and prognostic signiﬁcance of HER2 gain on RD after NAC are unknown. We sought to determine invasive disease-free survival (IDFS) in patients with HER2 gain in a cohort of consecutive patients with HER2(-) BC treated with NAC.

Methods: We identiﬁed pts with HER2(-) BC treated with NAC followed by surgery at our institution between 8/2019 and 12/2021. Pathologic complete response [pCR](ypT0/is ypN0) rates and HER2 status pre- and post-NAC were assessed, the latter by 2018 ASCO/CAP guidelines. HER2-low was deﬁned as IHC 1+ or IHC 2+, FISH nonampliﬁed. IDFS was analyzed using the Kaplan-Meier method and differences assessed by log-rank test. Chi-square, Fisher’s exact, Wilcoxon rank sum test, and logistic regression were used to evalute baseline features associated with HER2 gain.

Any p-value less than 0.05 was deemed to be statistically signiﬁcant.

Results: We included 528 HER2(-) pts [274 (52%) HR+/HER2- and 252 (48%) TNBC].

Overall, pCR was achieved in 40% of TNBC and 9% of HR+/HER2(-). The median followup was 17.5 months (14.5-21.3). Among 401 pts with RD, the rate of HER2 gain was 5% (20/401) (Table). HER2-low and HR+ status assessed on initial biopsy were independently associated with HER2 gain on the surgery sample with OR¼3.05 (95%CI:1.07-10.9) and OR¼4.09 (95%CI: 1.02-27.5), respectively, while high grade was not(OR¼0.68; 0.24-1.78). After surgery, all but two pts with HER2 gain received anti-HER2 therapy. The 2-year IDFS rate was 100% in pts with HER2 gain and 85% (95%CI:81-90%) in pts with HER2(-) RD (p¼0.07).

Conclusions: HER2 gain after NAC was a rare event, more commonly occurring in pts with HR+/HER2(-) BC compared to TNBC, likely related to HER2 heterogeneity.

Optimal adjuvant regimen remains to be established..

291P Details of patients with HER2 gain

R status HER2 biopsy

HER2 surgery Post-NAC

+/-) IHC F ratio F CN IHC F ratio F CN therapy

2+ 1.6 5.6 3+ / / TH

1+ / / 2+ 3.36 7.6 Pembro/HP 2+ 1.2 3.3 2+ 1.94 7.7 AI

1+ / / 2+ 3.35 8.4 V/HP, AI

1+ / / 2+ 2.6 5.4 V/HP, AI

1+ / / 2+ 3.1 6.1 HP/AI

2+ 1.5 3.3 2+ 2.04 7.49 THP

1+ / / 2+ 2.58 5.6 T-DM1

1+ / / 2+ 3.12 8.45 Cape/HP

2+ 1.2 3.44 2+ 2.27 5.17 HP/AI

0 / / 2+ 3.72 7.67 Carbo/HP, AI 0 / / 3+ / / HP/AI

1+ / / 2+ 1.8 6.3 HP/AI

0 / / 3+ / / CMF/HP, OS/AI 1+ / / 2+ 2.7 4.14 Cape/H, AI 1+ / / 3+ / / T-DM1, HP/AI 2+ 1.7 5.4 2+ 2 5.4 HP/AI

2+ 1.5 2.9 2+ 2.9 6.1 HP/AI/OS

1+ / / 2+ 2.3 6.2 HP/AI/OS

0 / / 2+ 1.6 6.8 AI/Abema

est; CN: copy number; V: vinorelbine; T: paclitaxel.

Disclosure: S. Modi: Financial Interests, Personal, Advisory Board: Daiichi Sankyo, Genentech,AstraZeneda, Seagen, Macrogenics; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo,AstraZeneca; Financial Interests, Personal, Steering Committee Member: Daiichi Sankyo; Financial Interests, Institutional, Local PI: Daiichi Sankyo, Genentech, AstraZeneca, Seagen. A. Seidman:Financial Interests, Personal, Other: Fairmont Founds Management, Hackensack Univerisity , MJH Associates, Novartis, Parexel International , myMEDEd, Spectrum Pharmaceuticals , Ortley BIO LCC,Stemline, Afﬁnia Therapeutics, Cancer Expert Now, Merck, Envision Communications; Financial Interests, Personal and Institutional, Other: AstraZeneca, Eli Lilly, Genentech, Gilead, Pﬁzer. H. Wen:Financial Interests, Institutional, Advisory Role: AstraZeneca; Financial Interests, Institutional,

Speaker’s Bureau: Roche. M. Robson: Financial Interests, Personal, Other, Review guideline pathways: Change Healthcare; Financial Interests, Personal, Invited Speaker, Speaker at CME events (NOT speaker’s bureau): Physician’s Education Resource, MJH Holdings; Financial Interests, Personal,Advisory Board, Speaker at CME events (NOT speaker’s bureau): MyMedEd; Financial Interests,Personal, Invited Speaker, Speaker at CME events (not Speakers’ bureau): Clinical care Options;Financial Interests, Institutional, Local PI, Funding for research study (ICEBERG, dating to 2007):AstraZeneca; Financial Interests, Personal, Steering Committee Member, Steering Committee Member for CAPITELLO-290, uncompensated: AstraZeneca; Financial Interests, Institutional, Other,Co-PI for Merck IIT of neoadjuvant olaparib/pembrolizumab in BRCA carriers, no personal compensation: Merck; Financial Interests, Personal, Steering Committee Member, Steering Committee member for KEYLNK-009, no compensation: Merck; Financial Interests, Institutional, Local PI,Local PI of KEYLNK009: Merck; Financial Interests, Institutional, Other, Local co-PI of clinical trial of ZEN03694 and talazoparib in TNBC, no personal compensation: Pﬁzer; Non-Financial Interests,Advisory Role: Zenith Pharmaceuticals, Tempus Labs; Non-Financial Interests, Personal, Other,Editorial services for writing of reports for ABRAZO clinical trial: Pﬁzer; Non-Financial Interests,Personal, Other, Editorial services for medical writing of reports resulting from OlympiAD trial:AstraZeneca; Non-Financial Interests, Member: ASCO. C. Dang: Financial Interests, Personal and Institutional, Other: Daiichi Sankyo; Financial Interests, Personal, Other: Gilead, Novartis, Pﬁzer,SeaGen. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.488

292P Unlocking the potential of circulating miRNAs in predicting response to neoadjuvant chemotherapy in breast cancer: A systematic review and meta-analysis

P. Tiberio1, M. Gaudio2, S. Belloni3, C. Benvenuti2, F. Jacobs2, G. Saltalamacchia2,A. Zambelli2, A. Santoro1, R. De Sanctis1

1Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Rozzano, Italy; 2Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy; 3Educational and Research Unit, IRCCS Humanitas Research Hospital,Rozzano, Italy

Background: The potential role of circulating miRNAs as biomarkers for breast cancer(BC) has been widely reported. However, the large discrepancy between studies prevents the feasibility of implementing circulating miRNAs in routine clinical practice. In BC patients undergoing neoadjuvant chemotherapy (NAC), the ability to anticipate response could lead to improve prognosis by individualizing post-NAC approach. In this scenario, the present meta-analysis aims to quantify and clarify circulating miRNAs’ predictive role for NAC response in BC patients.

Methods: We conducted a comprehensive literature search in 5 main medical databases until 16th February 2023, along with additional research sources. The systematic review and meta-analysis were performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and we applied the Cochrane recommended methodology for prognostic factor studies.We quantitatively pooled the effect sizes of each study by applying a random-effects model to consider within and between-study variances. Cochrane Q test (signiﬁcance at 0.05) and I2 value were used to assess between-study heterogeneity. The Prediction Model Risk Of Bias Assessment Tool evaluated studies’ bias risk.

Results: The meta-analysis included 15 studies, with a total of 1521 early BC patients.

Overall, our ﬁndings support the hypothesis that circulating miR-21-5p and miR-155-5p may act as predictive biomarkers. Pooled area under the curve values were 0.72(95% conﬁdence interval (CI) 0.59-0.86, p< 0.05) and 0.67 (95% CI 0.53-0.81, p<

0.05), respectively, thus indicating an acceptable predictive ability in anticipating NAC response.

Conclusions: To our knowledge, this is the ﬁrst systematic review and meta-analysis that provides a quantitative synthesis of the predictive value of circulating miRNAs for NAC response in BC patients. However, due to the limited number of studies included in the meta-analyses and the high clinical and statistical heterogeneity, further studies are needed to conﬁrm the predictive power of circulating miR-21-5p and miR-155-5p.

Funding: The Princess Margaret Cancer Foundation, The Ontario Institute for Cancer Research (OICR), BMO Financial Group Chair in Precision Genomics, GSK.

Disclosure: P.L. Bedard: Financial Interests, Institutional, Local PI: AstraZeneca, Bicara, BMS,Amgen, Novartis, Genentech/Roche, Sanoﬁ, Merck, Pﬁzer, Zymeworks, Nektar Therapeutics, Lilly,SeaGen, Medicenna; Financial Interests, Institutional, Research Grant: Pﬁzer; Financial Interests,Institutional, Funding: Servier; Non-Financial Interests, Member of Board of Directors, Executive Board Member: Breast International Group; Non-Financial Interests, Leadership Role, Chair: AACR Project GENIE; Non-Financial Interests, Leadership Role, Past Chair IND Committee Member, Breast Site Steering Committee: Canadian Clinical Trials Group; Non-Financial Interests, Advisory Role:SeaGen, Lilly, Amgen, Merck, BMS, Pﬁzer, Gilead. E. Amir: Financial Interests, Institutional, Funding:Novartis. M. Annan, A. Silvestro, Q. Zhang, R. Cheikh, J. Kim, O. Barbash : Financial Interests, Personal, Full or part-time Employment, Recently retired: GSK; Financial Interests, Personal, Stocks/Shares: GSK. L.L. Siu: Financial Interests, Personal, Advisory Board: Merck, AstraZeneca, Roche,Seattle Genetics, Voronoi, Arvinas, Tessa, Navire, Relay Therapeutics, Amgen, Marengo, InterRNA,Medicenna, Hoopika, Coherus, Tubulis, LTZ Therapeutics; Financial Interests, Personal, Other, Spouse is co-founder: Treadwell Therapeutics; Financial Interests, Personal, Stocks/Shares, Spouse has stock ownership: Agios; Financial Interests, Institutional, Local PI: Novartis, Bristol Myers Squibb, Pﬁzer,Boerhinger-Ingelheim, Merck, GSK, Roche/Genentech, AstraZeneca, Astellas, Amgen, Shattucks,EMD Serono; Financial Interests, Institutional, Coordinating PI: Bayer, Symphogen, Intensity Therapeutics; Non-Financial Interests, Advisory Role: ICR, Dana Farber Harvard Cancer Center. D. D. Cescon:Financial Interests, Personal, Advisory Board: Pﬁzer, AstraZeneca, Novartis, GSK, Merck, Gildead Sciences, Eisai, Inﬂex Ltd, Lilly, SAGA diagnostics; Financial Interests, Institutional, Funding: Merck,Roche/Genentech, GSK, Pﬁzer, Inivata / NeoGenomics, AstraZeneca, Gilead Sciences, Knight Therapeutics; Other, Personal, Other, Patent (US62/675,228) for methods of treating cancers characterized by a high expression of spindle and kinetochore associated complex subunit 3 (SKA3): Patent. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.506

311P Multinational survey study assessing genetic testing and counselling among patients (pts) with breast cancer

(MAGENTA): Results on the genetic counselling experience

R. Kaur1, S.L. Powell2, M. Artigas3, I. Borovova4, P. Gadiya5, A. Hsu6, L. Kidd7,D. Rosenfeld8, M.M. Saeed9, E. Scarelli10, M. Wahib11

1Consultant, Breast Cancer Welfare Association Malaysia, Selangor, Malaysia; 2Pink Hope, Narrabeen, NSW, Australia; 3Private individual, Argentina, Buenos Aires,Argentina; 4Russian Association of Oncology Patients, “ZDRAVSTVUY!”, Moscow,Russian Federation; 5Nag Foundation, N Main Rd, Koregaon Park, Pune, India; 6Patient author, Taiwan, Taipei City, Taiwan; 7Victorian Department of Education, Beaconsﬁeld Primary School, Beaconsﬁeld, VIC, Australia; 8Private individual, Mexico,Mexico City, Mexico; 9Private individual, Egypt, Cairo, Egypt; 10Oncoguia Institute, Sao Paulo, Brazil; 11Medical Affairs, AstraZeneca Egypt, Cairo, Egypt

Background: Despite genetic testing (GT) and counselling (GC) being key in breast cancer (BC) risk assessment, GC uptake rates are low even among pts undergoing GT.

A global survey was conducted among pts with BC to identify the gaps in the GC experience and to propose strategies to ﬁll them.

Methods: A steering committee comprising of pts and pt advocates co-developed a 38-question survey, which was offered to pts in Argentina, Australia, Brazil, Egypt,India, Malaysia, Mexico, Russia and Taiwan in local languages, through social media.

The questions pathway was dependent on response to prior questions. Chi-square test was used to assess signiﬁcance between responses, if applicable.

Results: The ﬁnal analysis set (FAS) included responses from 1176 respondents with a> 90% completion rate of survey questions. In the FAS, 737 (63%) respondents reported having undergone GT. Most respondents in the FAS (768/1061; 71%) rated their awareness level of GT/GC (before BC diagnosis) as between ‘very low’ to‘moderate’. Among pts undergoing GT, 616 respondents responded to the question enquiring on the resources available to them to guide their GT experience, beyond their oncologist. These were the genetic counsellor (295/616; 48%), pt support groups(232/616; 38%) and websites (217/616; 35%). Among the 439 respondents who did not undergo GT, 174 (40%) were offered GT by their doctor but did not take it. The table shows the level of understanding of GC reimbursement eligibility among the respondents.

Table: 311P

Question

Population No. of

respondents

Response [n (%)]

Did you receive any GC?*

Yes

e 34

- Issue

I don’t know

Tested 737

327 (44) 266 (36) 86 (12)

Not tested 439

31 (7) 277 (63) 46 (11)

Should you qualify,is the cost of GC for breast cancer

reimbursed

in your country?

FAS 1176 302 (26) 174 (15) 372 (32)Tested 737

325 (44) 129 (18) 283 (38)

82 (19) 120 (27) 237 (54)

*Statistically signiﬁcant difference (p<0.00001) between tested and not tested pts.

Conclusions: Most pts with BC are not offered GC, which signiﬁcantly correlates with GT uptake. Since poor awareness of GC is a critical gap, improving GC services and pt education through pt advocates and online tools may increase GT rates, offering a more impactful GT experience for pts and their families.

Editorial acknowledgement: Professional medical writing assistance was provided by Madhubrata Ghosh, PhD, of Ward6 Singapore Pte Ltd, Singapore and funded by AstraZeneca.

S2 - 2023

Legal entity responsible for the study: AstraZeneca UK Limited.

Funding: AstraZeneca International (AstraZeneca UK limited).

Disclosure: R. Kaur: Financial Interests, Personal, Advisory Board: Pﬁzer, Novartis, Roche, AstraZeneca; Financial Interests, Personal, Invited Speaker: Pﬁzer, Novartis, Roche, AstraZeneca; Financial Interests, Personal, Research Grant: Pﬁzer, Novartis, Roche, AstraZeneca; Financial Interests, Institutional, Other: Pﬁzer, Novartis, Roche; Financial Interests, Personal, Advisory Board, Honoraria:Pﬁzer, Novartis, Roche, AstraZeneca; Financial Interests, Personal, Other, Congress participation,travel support, lectures: Pﬁzer, Novartis; Financial Interests, Personal, Training: Pﬁzer, Novartis;Financial Interests, Personal, Advisory Role: Pﬁzer, Novartis, Roche; Financial Interests, Personal,Speaker, Consultant, Advisor: Pﬁzer, Novartis, Roche, AstraZeneca; Financial Interests, Personal,Advisory Board, Congress participation, travel support, lectures: Roche; Financial Interests, Personal,Other, Congress participation, lectures: AstraZeneca; Financial Interests, Personal, Other: AstraZeneca. S. S.L. Powell: Financial Interests, Personal, Full or part-time Employment: Pink Hope; Financial Interests, Personal, Advisory Board, Honoraria: AstraZeneca; Non-Financial Interests, Personal, Other,Travel support: AstraZeneca. M. Artigas: Financial Interests, Personal, Advisory Board, Honoraria:AstraZeneca. I. Borovova: Financial Interests, Personal, Full or part-time Employment: Russian Association of Oncology Patients “ZDRAVSTVUY!”; Financial Interests, Personal, Advisory Board: Public Council under the Ministry of Health of the Russian Federation, Presidential Council for the Development of Civil Society and Human Rights, Public Council under Roszdravnadzor, Council for Social Welfare under the Government of the Russian Federation, AstraZeneca. P. Gadiya: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Role:AstraZeneca. A. Hsu: Financial Interests, Personal, Advisory Board, Honoraria: AstraZeneca. L. Kidd:Financial Interests, Personal, Full or part-time Employment: Victorian Department of Education,Beaconsﬁeld Primary School; Financial Interests, Personal, Advisory Board, Honoraria: AstraZeneca.

D. Rosenfeld: Financial Interests, Personal, Advisory Board: AstraZeneca. M.M. Saeed: Financial Interests, Personal, Advisory Board: AstraZeneca. E. Scarelli: Financial Interests, Personal, Full or parttime Employment: OncoGuia Institute; Financial Interests, Personal, Advisory Board: AstraZeneca,Pﬁzer, Novartis, Roche, MSD, Daiichi Sankyo, Bayer; Financial Interests, Personal, Advisory Board,Honoraria: AstraZeneca, Pﬁzer, Novartis, Roche, MSD, Daiichi Sankyo, Bayer; Financial Interests,Personal, Ofﬁcer, Congress participation, lectures: AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca, Pﬁzer, Roche, MSD, Daiichi Sankyo, Bayer; Financial Interests, Personal, Other,Congress participation, lectures: Pﬁzer, Roche, MSD, Daiichi Sankyo, Bayer; Financial Interests,Personal, Invited Speaker, Congress participation, lectures: Novartis; Financial Interests, Personal,Other: Novartis. M.Wahib: Financial Interests, Personal, Full or part-time Employment: AstraZeneca;Financial Interests, Personal, Stocks/Shares: AstraZeneca.

https://doi.org/10.1016/j.annonc.2023.09.507

312P

Prediction model of breast cancer patient’s neoadjuvant treatment outcome using breast cancer organoids cultured from core needle biopsies

D.W. Lee1, G.Y. Kim2, K.H. Park2, B.J. Chae3, J.E. Lee3, S.W. Kim3, S.Y. Jang3, J.Y. Choi3,J.M. Ryu3, S.K. Lee3, J.H. Yu3, S.J. Nam3, B. Ku4

1Biomedical Engineering, Gachon University - Global Campus, Seongnam, Republic of Korea; 2Precision Medicine Research Institute, MBD Co., Ltd, Suwon, Republic of Korea; 3Division of Breast Surgery, Department of Surgery, Samsung Medical Center(SMC)-Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 4MBD Co., Ltd, Suwon, Republic of Korea

Background: The incidence of breast cancer is steadily increasing, and many patients receive adjuvant chemotherapy before or after surgery. In particular, neoadjuvant drug therapy is commonly used to suppress microinvasive before surgery. In this study, the patient-derived organoids (PDOs) from breast cancer patient’s biopsies were used for drug sensitivity test. To predict patient’s neoadjuvant treatment outcome, we propose a new drug sensitivity evaluation method based on multifactors such as Area Under Curve (AUC) of dose response curve, organoid growth rate.

Methods: Patient cells were obtained from core needle biopsy before surgery and mechanically dissociated before being mixed with extracellular matrix (ECM) to generate PDOs. Anti-cancer drug sensitivity testing was performed on these PDOs using a pillar-based organoid system, which involved single or combination treatments with anti-cancer drug with 384 plate-based high throughput screening. Area Under Curve (AUC) values of the dose-response curves (DRC) and organoid growth rate were calculated by pillar-based organoid system.

Results: The proposed multi-factor prediction model was veriﬁed by comparing drug sensitivity test with patient’s neoadjuvant outcome. We performed drug sensitivity test of 79 breast cancer patients. So far, 13 patients have ﬁnally been evaluated for neoadjuvant treatment results. Multi-factor prediction model (Cancer Organoidbased Diagnosis Reactivity Prediction, CODRP) shows 83 % sensitivity and 85 %speciﬁcity while conventional prediction model using only AUC shows 50 % sensitivity and 71 % speciﬁcity.

Conclusions: Therefore, Multi-factor prediction model (CODRP) may provide useful supplementary diagnostic information for individual breast cancer patients by selecting optimal anticancer drug candidates for patient treatment.

Funding: Medical & Bio Decision Co., Ltd.

https://doi.org/10.1016/j.annonc.2023.09.508

313P Intrinsic subtypes in a cohort of early breast cancer patients

T. Bracht1, R. Spiller2, M. Bauer3, S. Kaufhold1, V. Hanf4, C. Uleer5, T. Lantzsch6,S. Peschel7, J. John8, M. Pöhler9, E. Weigert10, K-F. Bürrig11, J. Buchmann12,E. Kantelhardt1, C. Thomssen1, M. Vetter1

1Department of Gynaecology, Martin Luther University Halle-Wittenberg, Halle(Saale), Germany; 2Gynaecology, UKH - Universitätsklinikum Halle (Saale), Halle(Saale), Germany; 3Institute of Pathology, Martin Luther University Halle-Wittenberg,Halle (Saale), Germany; 4Department of Obstetrics and Gynaecology, Klinikum Fuerth,Fuerth, Germany; 5Department of Gynaecology, Gynäkologisch-Onkologische Praxis,Hildesheim, Germany; 6Department of Gynecology, KH St. Elisabeth und St. Barbara Halle, Halle (Saale), Germany; 7Department of Gynaecology, St. Bernward Krankenhaus GmbH, Hildesheim, Germany; 8Department of Gynaecology, Helios Hospital Hildesheim, Hildesheim, Germany; 9Department of Gynaecology and Obstretrics,Hospital Wolfenbüttel, Wolfenbüttel, Germany; 10Institute of Pathology, Gemeinschaftspraxis Amberg, Amberg, Germany; 11Institute of Pathology, Institute of Pathology Hildesheim, Hildesheim, Hildesheim, Germany; 12Institute of Pathology,Hospital Martha-Maria Halle-Doelau, Halle (Saale), Germany

Background: Breast cancer is a heterogeneous disease with regard to diagnosis,therapy and survival. Complementary to the histopathological classiﬁcations of the tumours, molecular biological tests specify individualised therapy recommendations.

Our aim was to classify tumours into intrinsic subtypes and to analyse the association of grouping with disease progression.

Methods: Intrinsic subtypes were determined from 1,070 tumours by mRNA expression proﬁling (PAM50 algorithm) from fresh tumour tissue or FFPE tissue in a prospective, multicenter cohort study (n¼1,270; NCT 01592825). mRNA expressionevaluation was performed either by nCounterNanoString or GenChip HG U133 Plus 2.0 or BioMark Fluidigm. Endpoints were recurrence free interval (RFI) and overall survival (OS). Median follow-up time was 60.3 months. Survival analyses were done by Kaplan-Meier method and Cox model adjusting for age, nodal status, tumour size, and tumour differentiation.

Results: The PAM50 analysis resulted in 44.9% in Luminal A (n¼480), 23.9% Luminal B(n¼256), 14.4% HER2-enriched (n¼154), and 16.8% in Basal-like (n¼180). In the totalcohort, 89.9% (95% CI 87.9-91.9) of patients were free of RFI event and 87.5% (95% CI

85.3-89.7) were alive at 5 years of observation. Of patients with a Luminal A tumour,93% were free of RFI event (95% CI 88.1-97.9). The remaining patients had a substantially higher risk of RFI events: Luminal B, HR¼3.3 (95% CI 1.78-6.01); HER2-enriched, HR¼3.8 (95% CI 2.01-7.21); Basal-like, HR¼4.7 (95% CI 2.53-8.7). In the Coxmodel, only tumour size (HR¼2.5) and nodal status (HR¼2.2) had a signiﬁcantadditional prognostic impact. Also with regard to OS, PAM50 subtypes, tumour size,and nodal status were the only signiﬁcant prognostic factors.

Conclusions: Even after guideline-based therapy, the intrinsic subtypes still have prognostic signiﬁcance. Nearly half the patients can be identiﬁed as Luminal A with an excellent course of disease, whilst patients with Luminal B, HER2-enriched, Basal-like still have a substatial risk of recurrence, requiring further improvement of therapy concepts.

Funding: Wilhelm Roux Program of the Medical Faculty, Martin-Luther-University Halle-Wittenberg (grant number: FKZ 25/36) German Federal Ministry of Education and Research (grant number: Med FKZ 031A429).

Disclosure: C. Thomssen: Financial Interests, Personal, Speaker, Consultant, Advisor: Amgen,AstraZeneca, Aurikamed, Daiichi Sankyo, Gilead, Jörg Eickeler, Hexal, Lilly, Medupdate, MSD,Nanostring, Novartis, Onkowiisen, Pﬁzer, Roche, Seagen, Vifor; Financial Interests, Personal, Financially compensated role: Forum Sanitas; Non-Financial Interests, Personal, Member: AGO Breast Committee, ASCO, DGGG (Germ Soc OB/GYN), DGS (Germ Soc Senology), DKG (Germ Cancer Soc),EORTC PathoBiomarker Group; Non-Financial Interests, Personal, Member of Board of Directors:AGO -B Breast Study Group; Non-Financial Interests, Personal, Ofﬁcer, representing AGO-B: BIG;Non-Financial Interests, Personal, Invited Speaker: ESO; Non-Financial Interests, Personal, Steering Committee Member: ESMO. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.509

314P Concordance of somatic variants between circulating tumor DNA and tissue in patients with breast cancer

K. Shin, M-S. Park, E.H. Cho, H. Park, H-Y. Woo, M-J. Kwon

Laboratory Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

Background: Analysis of circulating tumor DNA (ctDNA) is a noninvasive method for detecting somatic variants. However, the sensitivity of ctDNA is limited by the dilution of ctDNA with cell-free DNA from non-cancer cells. In this study, we evaluated the concordance of somatic variants between ctDNA and tissue in patients with breast cancer to assess the clinical usefulness of ctDNA testing.

Methods: Paired plasma and tissue samples at the diagnosis were collected from 29 patients with breast cancer. Next-generation sequencing targeting 49 genes was performed on both plasma and tissue samples and the concordance between plasma and tissue was evaluated.

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Results: A total of 140 variants were detected in paired tissue and plasma samples of 29 patients. Among them, 66.4% (93/140) of variants were detected only in tissue,

14.3% (20/140) of variants were detected only in plasma, and 19.3% (27/140) of variants were detected in both samples. The median variant allele frequency of concordant and discordant variants in ctDNA was 1.5% and 0.6%, respectively.

Actionable variants were detected in four genes: BRCA1, BRCA2, ERBB2, and PIK3CA.

For 29 patients, the overall concordance rate for detecting actionable variants was

65.5% (19/29), with individual gene concordance rates of 96.6% (28/29) for BRCA1,

93.1% (27/29) for BRCA2, 79.3% (23/29) for ERBB2, and 79.3% (23/29) for PIK3CA. The overall sensitivity and speciﬁcity were 41.2% and 100%, respectively.

Conclusions: ctDNA testing showed a high concordance and speciﬁcity in detecting actionable variants. It can be used as a complementary test to tissue biopsy for selecting appropriate therapeutic agents.

https://doi.org/10.1016/j.annonc.2023.09.510

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Table:Questi

How w before Should startin How w family What What a 2)

Multinational survey study assessing genetic testing and counselling among patients (pts) with breast cancer

(MAGENTA): Results on perceptions on testing

S.L. Powell1, M. Artigas2, I. Borovova3, P. Gadiya4, A. Hsu5, R. Kaur6, L. Kidd7,D. Rosenfeld8, M.M. Saeed9, E. Scarelli10, M. Wahib11

1Pink Hope, Narrabeen, NSW, Australia; 2Private individual, Argentina, Buenos Aires,Argentina; 3Russian Association of Oncology Patients, “ZDRAVSTVUY!”, Moscow,Russian Federation; 4Nag Foundation, N Main Rd, Koregaon Park, Pune, India; 5Private individual, Taiwan, Taipei City, Taiwan; 6Consultant, Breast Cancer Welfare Association Malaysia, Selangor, Malaysia; 7Victorian Department of Education,Beaconsﬁeld Primary School, Beaconsﬁeld, VIC, Australia; 8Patient author, Mexico,Mexico City, Mexico; 9Private individual, Egypt, Cairo, Egypt; 10Oncoguia Institute, Sao Paulo, Brazil; 11Medical Affairs, AstraZeneca Egypt, Cairo, Egypt

Background: Genetic testing (GT) is vital in the risk assessment of breast cancer (BC)and along with genetic counselling (GC), may inform treatment decisions. However,fewer than one-third of patients (pts) with BC undergo GT. A multinational survey was conducted for a deeper understanding of the barriers in the uptake of GT and GC.

Results from this survey, focusing on awareness and pts’ perceptions towards GT and GC have been reported here.

Methods: A steering committee comprising of pts and pt advocates co-developed a 38-question online survey, which was launched in local languages for pts in Argentina,Australia, Brazil, Egypt, India, Malaysia, Mexico, Russia and Taiwan, through different social media platforms. The questions pathway was determined based on response to certain questions on GT & GC uptake. Percentage responses to a response option was calculated against the number of respondents for that question.

Results: The ﬁnal analysis set (FAS) included responses from 1176 participants with more than 90% completion rate of survey questions. Median age among respondents in the FAS was 42 years (IQR: 35, 49) at the time of BC diagnosis. Among survey respondents, 63% (737/1176) had undergone GT, and 37% (439/1176) did not undergo GT. The table lists select questions on some aspects of the GT experience as well as perceptions of testing. .

Conclusions: There are critical gaps in the awareness of GT among pts and the public,along with gaps in perceived value and access to GT, with notable variance between the tested and the non-tested populations. Strategic action is needed to overcome the barriers to GT and to improve the pt experience.

Editorial acknowledgement: Professional medical writing assistance was provided by Madhubrata Ghosh, PhD, of Ward6 Singapore Pte Ltd, Singapore, and funded by AstraZeneca.

Response

ould you rate the awareness levels of GT/GC of yourself,diagnosis?

Moderate to v

all pts diagnosed with BC undergo GT ﬁrst before g treatment?

illing would you be to have your children and other members undergo GT?

Very willing

was your main reason for not undergoing GT?

I was not offe

re the main barriers to GT for you and your family? (Top

Cost

Lack of unders

Disclosure: S.L. Powell: Financial Interests, Personal, Full or part-time Employment: Pink Hope;Financial Interests, Personal, Advisory Board, Honoraria: AstraZeneca; Non-Financial Interests, Personal, Other, Travel support: AstraZeneca. M. Artigas: Financial Interests, Personal, Advisory Board,Honoraria: AstraZeneca. I. Borovova: Financial Interests, Personal, Full or part-time Employment:Russian Association of Oncology Patients “ZDRAVSTVUY!”; Financial Interests, Personal, Advisory Board: Public Council under the Ministry of Health of the Russian Federation, Presidential Council for the Development of Civil Society and Human Rights, Public Council under Roszdravnadzor, Council for Social Welfare under the Government of the Russian Federation; Financial Interests, Personal,Advisory Board, Honoraria: AstraZeneca. P. Gadiya: Financial Interests, Personal, Advisory Board:AstraZeneca; Financial Interests, Personal, Advisory Role: AstraZeneca. A. Hsu: Financial Interests,Personal, Advisory Board: AstraZeneca. R. R. Kaur: Financial Interests, Personal, Advisory Board: Pﬁzer,Novartis, Roche, AstraZeneca; Financial Interests, Personal, Invited Speaker: Pﬁzer, Novartis, Roche,AstraZeneca; Financial Interests, Personal, Research Grant: Pﬁzer, Novartis, Roche, AstraZeneca;Financial Interests, Institutional, Other: Pﬁzer, Novartis, Roche, AstraZeneca; Financial Interests,Personal, Advisory Board, Honoraria: Pﬁzer, Novartis, Roche, AstraZeneca; Financial Interests, Personal, Other, Congress participation, travel support, lectures: Pﬁzer, Novartis, Roche; Financial Interests, Personal, Training: Pﬁzer, Novartis, Roche; Financial Interests, Personal, Advisory Role: Pﬁzer,Novartis, Roche; Financial Interests, Personal, Speaker, Consultant, Advisor: Pﬁzer, Novartis, Roche,AstraZeneca; Financial Interests, Personal, Advisory Board, Congress participation, lectures: AstraZeneca. L. Kidd: Financial Interests, Personal, Full or part-time Employment: Victorian Department of Education, Beaconsﬁeld Primary School; Financial Interests, Personal, Advisory Board, Honoraria:AstraZeneca. D. Rosenfeld: Financial Interests, Personal, Advisory Board, Honoraria: AstraZeneca.

M.M. Saeed: Financial Interests, Personal, Advisory Board, Honoraria: AstraZeneca. E. Scarelli:Financial Interests, Personal, Full or part-time Employment: OncoGuia Institute; Financial Interests,Personal, Advisory Board: AstraZeneca, Pﬁzer, Roche, Novartis, MSD, MSD, Daiichi Sankyo, Bayer;Financial Interests, Personal, Advisory Board, Honoraria: AstraZeneca, Pﬁzer, Roche, Novartis, MSD,Daiichi Sankyo, Bayer; Financial Interests, Personal, Other, Congress participation, lectures: AstraZeneca, Roche, Novartis, Daiichi Sankyo, Bayer; Financial Interests, Personal, Invited Speaker:AstraZeneca, Pﬁzer, Roche, Novartis, Daiichi Sankyo, Bayer; Financial Interests, Personal, Advisory Board, Congress participation, lectures: Pﬁzer, MSD. M. Wahib: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca.

https://doi.org/10.1016/j.annonc.2023.09.511

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ery low

U D

red GT

tanding

Comprehensive characterization of the HER2-enriched intrinsic molecular subtype in ER-positive HER2-negative breast cancer

L. Hohmann1, K. Sigurjónsdóttir2, A. Bosch3, D.F. Nacer4, S. Veerla5, J. Häkkinen6,J. Vallon-Christersson7, Å. Borg8, Y. Memari9, H. Davies10, S. Nik-Zainal9, J. Staaf11

1Department of Clinical Sciences, Lund University, Lund, Sweden; 2Medicine Dept.,Lund University, Lund, Sweden; 3Hematology Oncology and Radiation Physiscs Department, Lund University - Faculty of Medicine, Malmo, Sweden; 4Clinical Sciences,Lund, Lund University, Lund, Sweden; 5Avdelningen för Translationell Cancerforskning,Lund University, Lund, Sweden; 6Avdelningen för Translationell Cancerforskning, Lund University - Faculty of Medicine, Malmo, Sweden; 7Division of Oncology Department of Clinical Sciences, Lund University, Lund, Sweden; 8Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden; 9MRC Cancer unit, University of Cambridge-Wellcome Trust Centre for Stem Cell Research, Cambridge, UK; 10Department of Medical Genetics, University Biomedical Services (UBS) -University of Cambridge, Cambridge, UK; 11Oncology, Lund University-Institution of Clinical Sciences-Oncology and Pathology, Lund, Sweden

Background: Breast cancer that is estrogen receptor positive (ER+) and human epidermal growth factor receptor 2 negative (HER2-) can be further stratiﬁed into intrinsic molecular subtypes by employing PAM50-based gene expression proﬁling.

Despite its association with poor outcome, the HER2-enriched (HER2E) subtype currently holds no implications for clinical treatment decisions due to a lack of insight into its distinguishing features. Therefore, we aimed to evaluate the response of patients to conventionally administered therapies and identify molecular features to inform therapy optimization.

Methods: Two primary breast cancer cohorts provided clinical, transcriptomic, and genomic data on ER+/HER2- cases: SCAN-B 4413 (HER2E: 89, Luminal A (LumA): 3049,Luminal B (LumB): 1349) and METABRIC 1227 (HER2E: 58, LumA: 601, LumB: 340),including whole genome sequencing data for 32 HER2E cases. Focal points were analyses based on overall survival and invasive disease-free survival (IDFS),

No. of respondents/Total no. of

respondents to the question (%)

758/1061 (71)

nderwent GT

603/849 (71)

460/625 (74)

id not undergo GT

143/224 (64)

371/1176 (32)

322/737 (44)

49/439 (11)

282/394 (72)210/425 (49)163/425 (38)

differential gene expression, pathway enrichment, mutational frequencies and signatures, and copy number alterations.

Results: Clinicopathological analyses highlighted HER2E breast cancer to be a small subgroup associated with worse prognoses than other luminal PAM50 subtypes,regardless of whether patients were treated with endocrine therapy (E) or both endocrine and chemotherapy (EC), independent of tumor size, grade, age, and lymph node status (IDFS; E: HR 4.0, CI95 2.0-7.8; EC: HR 2.8; CI95 1.16-6.9; LumA as reference). Furthermore, HER2E tumors were larger and higher graded than LumA tumors.

Next to highly proliferative characteristics akin to LumB, HER2E tumors were distinguished by their low ESR1 expression, high FGFR4 expression, high immune response,and high frequency of TP53 mutations.

Conclusions: The HER2E subtype within ER+/HER2- disease is a small but clinically relevant patient subgroup that is not constituted by misclassiﬁed cases and is less ER dependent than other luminal subtypes. It does not represent a distinct biological entity, but it is nevertheless associated with potentially targetable molecular features,for instance in form of a high immune response and high FGFR4 expression.

Legal entity responsible for the study: Lund University.

Funding: Breast and Lung Cancer Research Group, Faculty of Medicine, Department of Clinical Sciences, Lund University.

https://doi.org/10.1016/j.annonc.2023.09.512

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Awareness of genomic testing among patients with breast cancer in Europe

A. Cardone1, D. Bell2, C.B. Biurrun3, F. Cardoso4, L.D. Csaba5, L. Guéroult-Accolas6,M.P. Lux7, A. Ramírez Piris8, I. Rubio9, R. Simcock10, R. D’Antona Fidanzia11

1Patient Advocacy, Cancer Patients Europe, Brussels, Belgium; 2Treatment, Medicines,Genomics, Macmillan Cancer Support, London, UK; 3Cancer Patient Advocacy, Federación Española de Cáncer de Mama, Santander, Spain; 4Breast Unit, Champalimaud Clinical Centre, Lisbon, Portugal; 5Sociology and Social Work, Babes-Bolyai University,Cluj-Napoca, Romania; 6Patient Networks, Patients en Réseau, Paris, France; 7Frauenund Kinderklinik St. Louise, Klinik für Gynäkologie und Geburtshilfe, Paderborn, Germany; 8Patient Advocacy, Exact Sciences, Zurich, Switzerland; 9Mammary Pathology,Clinica Universidad de Navarra, Madrid, Spain; 10Cancer Centre, University Hospitals Sussex, Brighton, UK; 11Cancer Patient Advocacy, Europa Donna, Milan, Italy

Background: Genomic testing, involving expression proﬁling of tumour tissue removed from patients with breast cancer, is a powerful tool to help choose the most appropriate treatment for individual patients. The objective of this study was to evaluate awareness of genomic cancer testing in ﬁve European countries (France,Germany, Italy, Spain, and the United Kingdom), with a focus on women with breast cancer.

Background: Transition of HER2 status after neoadjuvant chemotherapy (NAC) has frequently been reported previously; however, few study has focused on HER2-low breast cancer. Here, we evaluated the HER2 transition proportion among HER2-zero and HER2-low breast cancer cases post-NAC and the impact of clinical outcome after our initial report on pathologic complete response, long term outcomes and recurrence pattern in between two groups after neoadjuvant chemotherapy (S Kang, European Journal of Cancer, 2022).

Methods: We retrospectively reviewed HER2-zero and HER2-low breast cancer patients who underwent NAC and surgical resection during 2014e2018 at Asan Medical Center. We included 1288 patients who had paired pre- and post-therapeutic HER2 status results. HER2-zero was deﬁned as immunohistochemistry (IHC)0, and HER2-low was deﬁned as IHC1+ or IHC2+, with in situ hybridization-negativity.

Results: Of patients who were HER2-zero pre-NAC(n¼650), 68% and 29% of patientswere HER2-zero and HER2-low, respectively, post-NAC. Among patients who were HER2-low pre-NAC(n¼638), 32% of patients showed HER2 changes, and 59% of pa-tients had a constant HER2-low status post-NAC. Patients with constant HER2-low or transitions from HER2-low to zero had a higher proportion of hormone-receptor [HR]positivity (84% and 79%) than those with changes from HER2-zero to low (77%) or with constant HER2-zero (56%), respectively. Multivariable logistic regression analysis revealed that patients with HR positivity had a higher probability of gaining HER2-low expression than those with HR negativity (Odds ratio 2.48). No signiﬁcant differences were observed in terms of overall survival and disease-free survival between patients with and without HER2-changes according to hormone receptor status, except in the post-therapeutic HER2-low HR-negative subset.

Conclusions: Temporal heterogeneity of HER2-low expression is observed in substantial portions of post-NAC breast cancer patients. Clinical outcomes show no signiﬁcant associations, except in the post-therapeutic HER2-low, HR-negative subset.

Prognostic implications of HER2 transition in HER2-low breast cancer require further investigation.

Disclosure: K.H. Jung: Non-Financial Interests, Personal, Advisory Board: Roche, AstraZeneca,Celgene, Eisai, Takeda, Novartis, Everest Medicine, Merck, Bixink. S. Kim: Non-Financial Interests,Institutional, Advisory Board: Lilly; Non-Financial Interests, Personal, Advisory Board: AstraZeneca,Daehwa Pharmaceutical, ISU Abxis, BeiGene, Daiichi Sankyo/AstraZeneca, OBI Pharma; Financial Interests, Personal, Stocks/Shares: Neogene Therapeutics, TC Corp, Genopeaks; Financial Interests,Personal, Other, Honoria: Daehwa Pharmaceutical, LegoChem Biosciences, Kalbe; Financial Interests,Institutional, Research Grant: Novartis, Dongkook Pharma, Genzyme. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.501

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Multiplexed immunoﬂuorescence (mIF) to select patients with HER2+ breast cancer (BC) having an excellent outcome without chemotherapy (chemo): A substudy of the

PERNETTA trial (SAKK22/10-UCBG-BOOG)

K. Zaman1, S. Tissot1, F. Benedetti1, D. Dietrich2, D. Tarussio1, J. Huober3,H. Bonnefoi4, P. Weder5, E. Boven6, S. Rusakiewicz7, L.E. Kandalaft1

1Department of Oncology, Lausanne University Hospital CHUV, Lausanne, Switzerland;2Oncology, SAKK - Swiss Group for Clinical Cancer Research, Bern, Switzerland;3Oncology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland; 4Medical Oncology Department, Institute Bergonié - Centre Régional de Lutte Contre le Cancer (CLCC),Bordeaux, France; 5Oncology, Tumor- und BrustZentrum Ostschweiz, St.Gallen,Switzerland; 6Oncology, Amsterdam UMC - Vrije University Medical Centre (VUmc),Amsterdam, Netherlands; 7Oncology Department /CTE, Ludwig Cancer Center of the University of Lausanne - CHUV, Lausanne, Switzerland

Background: PERNETTA trial randomized 210 HER2+ BC patients (pts) to 1st-line trasutuzmab-pertuzumab (T-P) alone or combined with chemo. In the ﬁnal analysis(median follow-up 63 months), pts with chemo had longer progression free survival(PFS), but similar overall survival (OS) at 2 years. In this ancillary study, we aimed to identify immune biomarkers predicting for long PFS in pts with the chemo-free antiHER2 strategy.

Methods: Six good and 6 poor responders were selected in each study arm, based on their PFS (total 24 pts); 77 proteins were assessed using GeoMx digital spatial proﬁling technology in these 24 samples, in the Immune Landscape Laboratory of the Ludwig Institute in Lausanne. Proteins discriminating good versus poor responders were selected to construct a panel of 7 proteins, which was then tested by mIF in the 142 available pts’ samples. After high-deﬁnition scanning, the tissue images were analyzed by IFQuant software and the results correlated with pts’ PFS and OS by stratiﬁcation cox regression.

Results: CD8, GrzB, BCL2, CD44, MET, DAPI, and CK were selected for the ﬁnal panel.

In the chemo-free arm, pts with low expression of CD8-GrzB in stroma or CD8-MET in tumor had similar PFS as pts receiving chemo (p¼0.8 and 0.4) and signiﬁcantly betterthan the pts with high expressions (p¼0.03 and 0.05). Pts without chemo and withlow expression of CD8-MET in tumor showed a better OS than the pts with high expression (p¼0.02) and even better than the pts having received chemo (p¼0.04). Inaddition, different combined expressions of these biomarkers in stroma and in tumor were able also to discriminate pts with good versus poor outcome in arm A, arm B or whole study population.

Conclusions: Immunity plays a signiﬁcant role in the efﬁcacy of anti-HER2 treatments.

mIF allowing to assess simultaneously several biomarkers presence, intensity and location seems to permit selecting pts with HER2+ advanced stage BC having an excellent outcome in terms of PFS and OS without chemo in 1st line. If validated these biomarkers may contribute to treatment de-escalation and quality of life improvement.

Clinical trial identiﬁcation: CHUV_DO_CTE_TRP_0001_2017 Ethical committe agreement: 15/07/2021.

Legal entity responsible for the study: Lausanne University Hospital, Prof. Lana Kandalaft.

Funding: Roche provided an unrestricted funding.

Disclosure: K. Zaman: Financial Interests, Institutional, Advisory Board: AstraZeneca, Daiichi, Lilly,Pierre Fabre, Gilead, MSD, Novartis, Seagen, Viatris; Financial Interests, Institutional, Funding,Translational study: Roche; Financial Interests, Institutional, Steering Committee Member: Pierre Fabre; Financial Interests, Institutional, Other, Member of the IDMC of an international trial: Roche;Financial Interests, Institutional, Steering Committee Member, Member of the Steering committee of an international study: Daiichi; Non-Financial Interests, Advisory Board: Swiss Group for Clinical Research Against Cancer (SAKK), Executive Committee of the MINDACT trial; Non-Financial Interests,Member, Representative of SAKK Breast Group: Breast International Group (BIG); Non-Financial Interests, Member: EORTC Breast Group; Other, Unrestricted funding for organization of academic symposium: Agendia, AstraZeneca-MSD, Daiichi, Eisai, Exact Sciences, Lilly, Pierre Fabre, Gilead,Novartis, Pﬁzer, Roche, Seagen, Viatris, Vifor; Other, Support for participation in international congress: AstraZeneca, Daiichi, Gilead, Pierre Fabre, Roche, Lilly. J. Huober: Financial Interests,Institutional, Research Funding: Celgene, Novartis, Lilly; Financial Interests, Personal, Invited Speaker: Lilly, Novartis, Roche, Pﬁzer, AstraZeneca, MSD, Celgene, Eisai, AbbVie, Seagen, Gilead,Daiichi; Financial Interests, Institutional, Advisory Board: Lilly, Novartis, Roche, Pﬁzer, AstraZeneca,MSD, Celgene, AbbVie, Seagen, Gilead; Financial Interests, Institutional, Other, travel grant: Roche,Pﬁzer, Novartis, Daiichi. P. Weder: Financial Interests, Institutional, Other, travel grants: Roche. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.502

307P Identifying new biological subgroups of triple-negative breast cancer using next-generation integrative clustering pipeline

X. Zhu1, J. Bayani2, M. Dewan1, H. Tovey1, L. Kilburn1, K. Taylor3, J. Banerji1, C. Toms1,A. Sadanandam4, P.J. Barrett-Lee5, J. Bliss1, D.A. Cameron6, J.M.S. Bartlett7,

M.C.U. Cheang1

1Clinical Trial and Statistics Unit, The Institute of Cancer Research, Sutton, UK;2Diagnostic Development, Ontario Institute for Cancer Research, Toronto, ON, Canada;3Edinburgh Cancer Research Centre, Cancer Research UK Edinburgh Centre, Edinburgh,UK; 4Department of Molecular Pathology, The Institute of Cancer Research, London,UK; 5Velindre Cancer Centre, Velindre NHS University Trust - NHS Wales, Cardiff, UK;6Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK; 7Diagnostic Development, University of Edinburgh, Edinburgh, UK

Background: Early triple-negative breast cancer (eTNBC) is molecularly heterogenous,with differential prognosis. We aimed to identify new biological subgroups (B-grp) of eTNBC via an integrative clustering pipeline (ICP) and evaluate the clinical value of these B-grp in a large randomised clinical trial.

Methods: TACT2 was a phase 3, randomised trial testing adjuvant accelerated versus standard Epirubicin in early breast cancer. From TACT2, 551 eTNBC tumours were stratiﬁed into training (n¼367) and testing (n¼184) by treatment arm. Expressions of758 genes (GE) and Triple-Negative Subtypes ( TNS; Burstein CCR 2015 ) of tumour were proﬁled by nCounter@ Breast Cancer 360TM. Immunohistochemistry expressions(IHC) of HER2, EGFR and CK5/6 were assessed. Clinicopathological features (ClinPath)included age, nodal status, tumour size and grade. The ICP included random forest(RF) and 9 unique clustering methods with hypergeometric test to reconcile clustering results to a ﬁnal output. Survival endpoint was time to recurrence (TTR) for multivariable cox regression (mCox), of which the goodness-of-ﬁt was assessed by chisquare, brier score and integrated calibration index.

Results: The ICP returned 4 B-grp using GE, IHC and ClinPath of the training set. GE was the main factor of clustering, summarising B-grp into immune-enriched (IM),Luminal-AR (LAR), mesenchymal like (MES) and basal like (BL). IM and LAR contained mainly TNS-BLIA and TNS-LAR, respectively. Both MES and BL comprised TNS-BLIA,TNS-BLIS and TNS-MES. The RF was trained using GE as unimodal single-sample predictor to assign the B-grp on the testing set. Adding B-grp to ClinPath yielded more accurate 5-year TTR prediction for test samples when compared to TNS (Table).

Table: 307P Comparing the goodness-of-ﬁt of three mCox models using chisquare, brier score and integrated calibration index

ClinPath ClinPath + TNS

Volume 34 - I

ClinPath + B-grp

Chi-square

19.27 59.98

32.29

Chi-square (against the ClinPath model)

- 40.71 (p < 0.0001) 16.02 (p ¼ 0.001)

Brier score

0.1477 0.1544

0.1425

Integrated calibration index 0.021 0.064

0.019

Brier score is the mean square difference between the true classes (0 ¼ no recur-rence, 1 ¼ recurrence) and the predicted probabilities at given time point. Inte-grated calibration index is the weighted absolute difference between the calibration curve and the diagonal line of best ﬁt..

Conclusions: We identiﬁed 4 eTNBC B-grp based on distinct biology which provided more accurate 5-year TTR prediction in addition to ClinPath than TNS. The association of the B-grp with survival for other treatments could be further evaluated.

Clinical trial identiﬁcation: NCT00301925.

Legal entity responsible for the study: The Institute of Cancer Research and Lothian Health Board.

Funding: The Institute of Cancer Research; Cancer Research UK; Ontario Institute for Cancer Research with funds from the Ontario Government.

Disclosure: J. Bayani: Other, Personal, Other, Gene Signature of Residual Risk Following Endocrine Treatment in Early Breast Cancer (Patent Title), National Phase Application, Patent number:2016368696 (Country: Australia, Date: Mar. 10, 2022); 2016800813945 (China, Mar. 18, 2022);3387168 (Europe, May 12, 2022); 7043404 (Japan, Mar. 18, 2022); 11,566,292 (United States, Jan.31,2023): Patent - Granted. H. Tovey: Financial Interests, Institutional, Other, Salary funded by grants to her institution: AstraZeneca UK Ltd, Eli Lilly and Company Limited, Pﬁzer Inc, Aventis Pharma Limited. J. Bliss: Financial Interests, Institutional, Research Funding: AstraZeneca, Merck Sharp &Dohme, Puma Biotechnology, Pﬁzer, Roche, Novartis (previously GSK), Eli Lilly, Janssen-Cilag, Clovis Oncology; Financial Interests, Personal, Other, Travel, accommodations, expenses: Pﬁzer. D.A.

Cameron: Financial Interests, Institutional, Funding: Aptitude Health, Roche Sweden, Pﬁzer Limited,Celldex Therapeutics Inc, Carnall Farrar, San Antonio Breast Cancer Consortium, Highﬁeld Communication, AstraZeneca Global Commercial Organisation - Egypt, Celgene Corporation, Chief Scientists Ofﬁce, Cancer Research UK, HTA, Samsung Bioepis Co Ltd (Korea), Eli Lilly & Company, Costello Medical Consulting Ltd, prIME Oncology, AstraZeneca UK Limited, Roche Products Ltd, Novartis Pharma AG, Novartis Pharmaceuticals Corporation, Pﬁzer Limited, PFS Ltd, Novartis Pharmaceuticals UK Limited, Merck Sharp Dohme Limited, PUMA Biotechnology, Inc., Pﬁzer Limited, F. Hoffmann-La Roche AG, Clovis Oncology, Breast International Group (BIG), Breast Cancer Institute, Daiichi Sankyo,USA, Eisai, Elsevier Ltd, European Cancer Organisation, Exact Therapeutics, G1 Therapeutics, Galapagos NV, Genentech Inc, GSK, ICON Clinical Research, Prima BioMED, RTI Health Solutions, Seattle Genetics, Erytech Pharma, Succinct Medical Communications, Seagen, Sapience Therapeutics Ltd ,Bexon / Zymeworks Biopharmaceuticals Inc., Make Seconds Count, Next Gen Healthcare Communications, Clarity Pharmaceuticals, Immutep, Oncolytics Biotech (U.S), Grail UK, Byondis, Gilead Sciences Ltd UK. J.M.S. Bartlett: Financial Interests, Personal, Advisory Role, Consultancy: BioNTech

ssue S2 - 2023

AG, Biotheranostics, Inc., RNA Diagnostics, Inc., oncoXchange/MedcomXchange Communications Inc, OncoCyte Corporation, Ontario Institute for Cancer Research, AstraZeneca, Cerca Biotech;Financial Interests, Personal, Advisory Board: MedcomXchange Communications Inc; Financial Interests, Personal, Other, Honoraria: MedcomXchange Communications Inc; Financial Interests, Personal, Research Funding: Thermo Fisher Scientiﬁc, Genoptix, Agendia, NanoString Technologies, Inc.,Stratifyer GmbH, Biotheranostics, Inc., Exact Sciences; Other, Personal, Other, CIN4 predicts beneﬁt from anthracycline, National Phase Application, (Canada, Jan. 11, 2017): Patent - Applied; Other,Personal, Other, Systems, Devices and Methods for Constructing and Using a Biomarker, National Phase Application, 15/328,108 (United States, Jan. 23, 2017); 15824751.0 (Europe, Jan. 12, 2017);(Canada, Jan. 12, 2017): Patent - Applied; Other, Personal, Other, Immune Gene Signature Predicts Anthracycline Beneﬁt, PCT (international application), PCT/CA2016/000305, Filing date: Dec. 7, 2016:Patent - Applied; Other, Personal, Other, Gene Signature of Residual Risk Following Endocrine Treatment in Early Breast Cancer (Patent Title), National Phase Application, Patent application number 3007118 (Country of Filing: Canada e Patent Application Date: 06/01/18): Patent - Applied;Other, Personal, Other, A Molecular Classiﬁer for Personalized Risk Stratiﬁcation for Patients with Prostate Cancer (Invention Title), PCT International Application No.: PCT/CA2021/050837, International Filing Date: June 18, 2021: Patent - Applied; Other, Personal, Other, CIN4 predicts beneﬁt from anthracycline (Invention Title), National Phase Application, Patent number: 11214836 (Country:United States, Date: Jan. 4, 2022); 3169815 (Europe, Dec. 23, 2020): Patent - Granted; Other, Personal, Other, Targeting the Histone Pathway to Detect and Overcome Anthracycline Resistance (IP Title), National Phase Application, Patent number: 2016800728463 (Country: China, Date: Aug. 27,2021); 11,015,226 (United States, May 25, 2021); 3359508 (Europe, Sept. 9, 2020); 3,000,858(Canada, Sept. 27, 2022): Patent - Granted; Other, Personal, Other, Gene Signature of Residual Risk Following Endocrine Treatment in Early Breast Cancer (Patent Title), National Phase Application,Patent number: 2016368696 (Country: Australia, Date: Mar. 10, 2022); 2016800813945 (China, Mar.

18, 2022); 3387168 (Europe, May 12, 2022); 7043404 (Japan, Mar. 18, 2022); 11,566,292 (United States, Jan.31, 2023): Patent - Granted; Other, Personal, Other, Disclosure Name: A Molecular Classiﬁer for Personalized Risk Stratiﬁcation for Patients with Prostate Cancer, Date: 21/08/2019:Invention Disclosure. M.C.U. Cheang: Financial Interests, Personal, Funding: NanoString Technologies; Financial Interests, Personal, Advisory Role: Veracyte; Other, Personal, Licencing Fees or royalty for IP, Breast Cancer Classiﬁer: US Patent No. 9,631,239.: Patent. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.503

308P

Regression-based deep-learning predicts breast cancer recurrence risk score from pathology slides

O.S.M. El Nahhas1, C.M.L. Loefﬂer1, A. Marra2, Z. Carrero1, F. Pareja2, H. Wen2,B. Weigelt2, P. Selenica2, S. Chandarlapaty3, J.S. Reis-Filho2, J.N. Kather1

1Clinical AI, EKFZ - Else Kröner Fresenius Zentrum für Digitale Gesundheit, Dresden,Germany; 2Department of Pathology and Laboratory Medicine, MSKCC - Memorial Sloan Kettering Cancer Center, New York, NY, USA; 3Department of Medicine and Human Oncology and Pathogenesis Program, MSKCC - Memorial Sloan Kettering Cancer Center, New York, NY, USA

Background: Breast cancer (BC) treatment decisions can be challenging, particularly in patients with early-stage hormone receptor-positive/HER2-negative (HR+/HER2-) tumors. Prognostic assays, such as the 21-gene recurrence score assay (Oncotype DX),are used to determine individual patient risk of recurrence and guide decision on whether to administer adjuvant chemotherapy or not. However, these tests are costly and time-intensive to perform. Deep-Learning (DL) can predict molecular biomarkers from routine hematoxylin and eosin (H&E) pathology slides, potentially serving as an inexpensive and accessible pre-screening tool. We aim to use DL for the outcome prediction of the Oncotype DX test.

Methods: We trained a DL-based regression model in a weakly-supervised manner to detect Oncotype DX risk score directly from routine H&E-stained pathology slides in a large (n¼5,303) cohort of early-stage HR+/HER2- BCs from Memorial Sloan Kettering(MSK).We then externally validated the model onto The Cancer Genome Atlas (TCGA)BC cohort for which Oncotype DX scores were available (n¼100). The model wasevaluated using the Pearson’s correlation coefﬁcient r. Moreover, the recurrence score was divided into low (<11) and intermediate/high (11) risk groups, enabling eval-uation via the area under the receiver operating characteristic curve (AUROC).

Results: The model yielded a signiﬁcant r of 0.59 (p<0.0001) on the test set of the training cohort of MSK BCs and 0.58 (p<0.0001) on the external cohort of TCGA BCs.

When binarizing the predictions into intermediate/high and low recurrence risk groups, we found that the model was particularly accurate for identifying patients with intermediate/high risk scores, reaching an AUROC of 0.87 ( 0.04) and 0.79 (0.03) in the MSK and TCGA cohort, respectively.

Conclusions: We developed a DL-model that can accurately predict Oncotype DX score from routine pathology slides, offering a cost-effective and time-efﬁcient prescreening tool for identifying a high-risk subgroup HR+/HER2- early BCs and to democratize the access to complex but clinically useful biomarkers. This approach could support informed treatment decisions by accurately determining recurrence risk, ultimately improving patient outcomes.

Legal entity responsible for the study: TU Dresden.

Funding: EKFZ.

Disclosure: J.S. Reis-Filho: Financial Interests, Personal, Other, Consultant: Goldman Sachs, Eli Lilly,Saga Diagnostics; Financial Interests, Personal, Other, Member of the Scientiﬁc Advisory Board and Consultant: Repare Therapeutics, Paige.AI; Financial Interests, Personal, Advisory Board: Personalis,Roche Tissue Diagnostics; Financial Interests, Personal, Advisory Board, Member of the Scientiﬁc Advisory Board: Bain Capital; Financial Interests, Personal, Advisory Board, Ad hoc member of the Pathology Scientiﬁc Advisory Board: Daiichi Sankyo, Merck; Financial Interests, Personal, Advisory Board, Ad hoc member of the Oncology Scientiﬁc Advisory Board: AstraZeneca; Financial Interests,Personal, Advisory Board, Member of the SAB: MultiplexDX; Financial Interests, Personal, Member of Board of Directors: Odyssey Bio, Grupo Oncoclinicas; Financial Interests, Personal, Stocks/Shares:

Repare Therapeutics; Financial Interests, Personal, Other, Stock options: Paige.AI. J.N. Kather:Financial Interests, Personal, Invited Speaker: Fresenius, Eisai, MSD; Financial Interests, Personal,Advisory Board: Owkin, DoMore Diagnostics, Panakeia, London, UK. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.504

309P Machine learning-based characterization of tumor-immune microenvironment at a spatial and multiplexed resolution in early breast cancer: A sub-study of the EORTC 10994/BIG 1-00 randomized phase III trial with long-term follow-up

I. Zerdes1, A. Matikas1, A. Mezheyeuski2, B. Acs3, H. Johansson4, G. Manikis5,C. Boyaci3, C.E. Boman1, C. Poncet6, M. Ignatiadis7, Y. Bai8, D. Rimm9,

G. MacGrogan10, D.A. Cameron11, J. Bergh12, H. Bonnefoi13, T. Foukakis1

1Department of Oncology-Pathology & Breast Center, Karolinska Institutet & Karolinska University Hospital, Comprehensive Cancer Center, Stockholm, Sweden;2Immunology, Genetics and Pathology, Uppsala University - Rudbecklaboratoriet,Uppsala, Sweden; 3Department of Oncology-Pathology & Department of Clinical Pathology and Cancer Diagnostics, Karolinska Institutet & Karolinska University Hospital,Comprehensive Cancer Center, Stockholm, Sweden; 4Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; 5Computational BioMedicine Laboratory (CBML), Foundation for Research and Technology-Hellas (FORTH), Heraklion,Greece; 6Statistical Department, EORTC AISBL/IVZW - European Organisation for Research and Treatment of Cancer, Brussels, Belgium; 7Department of Medical Oncology, Institute Jules Bordet, Brussels, Belgium; 8Department of Pathology, Yale University School of Medicine - Yale Cancer Center, New Haven, CT, USA; 9Department of Pathology, Yale University School of Medicine - Yale Cancer Center, New Haven, CT,USA; 10Department of BioPathology, Institute Bergonié - Centre Régional de Lutte Contre le Cancer (CLCC), Bordeaux, France; 11Edinburgh Cancer Centre, western General Hospital, Crewe Road south, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Midlothian, UK; 12Department of Oncology-Pathology & Breast Center, Karolinska Institutet & Karolinska University Hospital, Comprehensive Cancer Center, Stockholm, Solna, Sweden; 13Medical Oncology Department, Institute Bergonié

- Centre Régional de Lutte Contre le Cancer (CLCC), Bordeaux, France

Background: Data support the role of immune inﬁltrate in breast cancer (BC) prognosis and therapy prediction. The aim of this study was to characterize the immune landscape in early BC at a multiplex and spatial resolution using machine learning(ML)-based algorithms and investigate its potential prognostic value.

Methods: Tissue microarrays (TMA) were constructed from pretreatment samples from patients enrolled in the EORTC 10994/BIG 1-00 neoadjuvant randomized phase III trial (taxane/anthracycline vs FEC). An automated algorithm for digital TIL (dTIL)quantiﬁcation was applied on H&E stained TMA. Multiplex ﬂuorescent immunohistochemistry (mfIHC) was performed for an immune antibody panel and cell phenotyping/localization was applied with a ML-based software. TP53 mutational status was available for a subset of patients. Logistic and Cox regression models investigated the association of immune-related metrics with pathological complete response (pCR)and progression-free survival (PFS), respectively.

Results: Median follow-up was 11.4 years. 587 patients had dTIL and 478 had mfIHC data. Among the dTIL variables, easTIL [sum of TIL area (mm2)/stroma area (mm2)]were higher in the triple-negative subtype and an independent predictor of pCR(ORadj¼ 1.59, 95% CI 1.00 e 2.54, p¼0.05) in the whole cohort. No signiﬁcant as-sociation with PFS was noted. However, a signiﬁcant interaction was observed between esTIL (TIL/stromal cells) and TP53 mutational status (p¼ 0.028); higher esTILabundance was prognostic for worse PFS only in patients with TP53 wild-type tumors.

CD8+ T-cells were the most abundant cell subset in both tumor and stroma compartments. Expression of total CD4+ (ORadj¼ 1.79, 95% CI 1.07 e 2.97, p¼0.026) andintra-tumoral CD8+ T-cells (ORadj¼ 1.83, 95% CI 1.05 e 3.20, p¼0.033) was inde-pendently associated with improved pCR.

Conclusions: Our data indicate that ML-based models could be used for studying the immune inﬁltrate in BC. Abundance of dTIL and spatial distribution of immune markers contain prognostic information, which might depend on TP53 mutational status. Further validation is warranted.

Clinical trial identiﬁcation: NCT00017095.

Legal entity responsible for the study: European Organisation for Research and Treatment of Cancer (EORTC).

Funding: The clinical trial was funded by: the US National Cancer Institute (grants 2U10 CA11488-31 through 5U10 CA011488-40, Bethesda, MD, USA), French Ligue Nationale Contre le Cancer (donation through the EORTC Charitable Trust), European Union (fp6 Active p53 grant), Pharmacia (educational grant to EORTC Headquarters),and Sanoﬁ-Aventis (educational grants to EORTC Headquarters and Clinical Trial Ofﬁce at Karolinska University, and provided docetaxel for this trial). The biomarker study presented here was funded by: Region Stockholm, Percy Falks Foundation, Iris, Stig and Gerry Castenbäcks Foundation, Swedish Cancer Society and the Research Funds at Radiumhemmet.

Disclosure: A. Matikas: Financial Interests, Institutional, Coordinating PI, International co-PI of academic trial ARIADNE (EU CT: 2022-501504-95-00): AstraZeneca, Novartis, Veracyte; Non-Financial Interests, Advisory Role: Veracyte, Roche. M. Ignatiadis: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Other, Independent Monitoring Committee: Seattle Genetics; Financial Interests, Institutional, Coordinating PI: Pﬁzer, Roche, Natera, Inivata, Rejuveron;

S307

Non-Financial Interests, Ofﬁcer: EORTC; Financial Interests, Personal, Other, Travel Grants: Roche,Gilead. D. Rimm: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Cell Signaling Technology , Cepheid, Danaher, GSK, Konica/Minolta, Lilly, Merck, Monopteros, Nanostring, PAIGE.AI, Regeneron, Roche, Ventana; Financial Interests, Personal, Advisory Role: Fluidigm, Immunogen, NextCure, Odonate, Sanoﬁ, Verily; Financial Interests, Institutional, Other: Amgen, Cepheid,Navigate BioPharma, NextCure, Konica/Minolta, Akoya; Financial Interests, Personal, Royalties:Rarecyte. D.A. Cameron: Financial Interests, Institutional, Advisory Board: Roche, Pﬁzer, AstraZeneca,Daiichi Sankyo, SeaGen, Synthon, Zymeworks; Financial Interests, Institutional, Other, Have done advisory boards, spoken at a webinar and involved in a manuscript with Lilly - all recompense to my institution: Lilly; Financial Interests, Institutional, Other, Have done advisory boards and been involved in a health economic analysis and publication. All recompense to my institution: Novartis;Financial Interests, Institutional, Coordinating PI, funding and drug for UK participation in a French led Novartis funded study. Institutional funding received for consultancy work: Novartis; NonFinancial Interests, Principal Investigator, one of three PIs for the Ameera-6 trial - which has now closed early as the company have stopped all development of the drug: Sanoﬁ; Other, Chair of the board of this small Scottish charity for secondary breast cancer: Make Seconds Count; Other, Chair of the Board of B.I.G. - a group of international breast cancer research groups: Breast International Group; Other, Chair of the European Breast Cancer Council which organises the bi-annual EBCC meetings: EBCC. J. Bergh: Financial Interests, Institutional, Advisory Board: Amgen, AstraZeneca,Bayer, Merck, Pﬁzer, Roche, Sanoﬁ-Aventis; Financial Interests, Personal, Other, Co-author on a chapter in UpToDate on prognostic and predictive factors in early, non-metastatic breast cancer.

Honoraria to Asklepios Medicine HB: UpToDate; Financial Interests, Personal, Stocks/Shares,consultant for this diagnostic company in early development: Stratipath . H. Bonnefoi: Financial Interests, Personal, Advisory Board: AstraZeneca/ Daiichi Sankyo; Financial Interests, Institutional,Coordinating PI, UCBG3-06 prospective study: Bayer. T. Foukakis: Financial Interests, Institutional,Invited Speaker: Roche, AstraZeneca, Gilead Sciences; Financial Interests, Personal, Advisory Board:Novartis, Veracyte, Exact Sciences, Afﬁbody; Financial Interests, Personal, Invited Speaker: Pﬁzer;Financial Interests, Personal, Royalties, Authorship of two chapters in UpToDate: Wolters Kluwer;Financial Interests, Institutional, Coordinating PI, Clinical trial support (research grant and study drug): Pﬁzer, AstraZeneca; Financial Interests, Institutional, Coordinating PI, Clinical trial support(research grant and study drug): Novartis. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.505

310P

S308

Longitudinal evaluation of circulating tumour DNA in early breast cancer using a plasma-only methylation-based assay

M. Elliott1, J. Fuentes Antras1, A. Dou1, Z.W. Veitch2, P.L. Bedard1, E. Amir1,

M. Nadler1, E. Van de Laar3, C. Yu3, M. Annan4, A. Silvestro5, Q. Zhang6, R. Cheikh7,J. Kim6, O. Barbash8, L.L. Siu1, H. Berman9, D. Cescon1

1Division of Medical Oncology & Hematology, University Health Network e Princess Margaret Cancer Centre, Toronto, ON, Canada; 2Medical Oncology, Royal Victoria Regional Cancer Centre, Barrie, ON, Canada; 3Cancer Genomics Program, UHN -University Health Network - Princess Margaret Cancer Center, Toronto, ON, Canada;4Oncology, GSK USA, Collegeville, PA, USA; 5Experimental Medicine Division, GSK -Waltham, Waltham, MA, USA; 6Experimental Medicine Unit, GSK, New York, NY, USA;7Experimental Medicine Unit, GSK - GSK Canada, Toronto, ON, Canada; 8Oncology,GSK, Philadelphia, PA, USA; 9Department of Pathology and Laboratory Medicine,University Health Network - Princess Margaret Cancer Center, Toronto, ON, Canada

Background: Plasma-only ctDNA detection is a strategy to identify molecular residual disease (MRD) in early breast cancer (EBC). MRD-positivity in the absence of clinical/radiographic disease may have prognostic implications and enable intervention prior to clinical recurrence.

Methods: Plasma samples from baseline, perioperative, adjuvant and follow-up timepoints were collected in patients with estrogen receptor positive/HER2-negative(ER+) and triple-negative (TN) breast cancer treated with neoadjuvant chemotherapy(2015 onward). Samples were analyzed using the Guardant Reveal pan-tumor assay on the INFINITYTM platform. Clinical/pathologic characteristics and recurrence outcomes were collected. ctDNA/MRD-positivity was deﬁned as a methylation score > 0.

Results: 270 timepoints (median 3 per patient, range: 1-9) were analyzed from 83 patients with ER+ (n¼38) and TN (n¼45) EBC; 95% (256/270) produced successfulresults. Baseline positivity rate was 67.5% (54/80) in all patients (66.7% in ER+, 68.2%in TN). Nine patients had a mutation called at baseline (7 PIK3CA; 1 of TP53, FGFR1,BRAF, GATA3, or NOTCH2). Larger tumor size (p¼0.014) and nodal involvement(p¼0.011) were associated with baseline test positivity. 17/83 (20.5%) patients havehad a clinical recurrence (13 distant, 4 local). 14/17 (82.3%) patients with recurrence had a positive test at baseline (2 negative, 1 fail) and baseline methylation scores were higher in patients with recurrence (p¼0.0032). Seven of 8 patients withrecurrence had a positive sample collected at or prior to clinical recurrence with lead time of up to 5.1 months. Four patients with no documented recurrence had a positive test at their last follow up [range: 4.7-19.1 months from last test] with methylation scores lower than those of patients with recurrence (p¼0.012). AnyctDNA positivity in follow up after surgery was strongly associated with a risk of recurrence (HR ¼ 7.02, 95%CI: 1.82-27.2, p¼0.001).

Conclusions: This longitudinal evaluation of a plasma-only methylation based ctDNA assay demonstrates ctDNA detection and dynamic changes in a large EBC cohort.

Potential prognostic and predictive applications warrant further evaluation.

Clinical trial identiﬁcation: NCT03702309.

Editorial acknowledgement: Copy editing assistance was provided by Meditech Media.

Legal entity responsible for the study: University Health Network - Princess Margaret Cancer Centre - Cancer Genomics Program.

Methods: A prospective self-controlled trial compared the detection efﬁcacies of ICG and RI was conducted. Concordance (ICG and RI-positive cases divided by RI-positive cases) and reverse concordance (ICG and RI-positive cases divided by ICG-positive cases) were documented and adverse event were also assessed.

Results: Of 69 patients (median age 56.7 (range 33-85), median BMI 22.6 (range 17.0 e 44.5)) enrolled between 2019 and 2021, 71 SLN biopsies were performed. Sixty-one(85.9%) underwent upfront surgery, while ten (14.1%) were given neoadjuvant treatment. Thirty-four breast-conserving surgeries (BCS) (47.9%), 33 mastectomies(46.5%) and four cryotherapies (5.6%) were performed. No adverse event nor skin staining were reported. The SLN identiﬁcation rate was 87.3% (62/71) for ICG and

95.8% (68/71) for RI (p¼0.13). Dual tracer method resulted in 97.2% successfulidentiﬁcation, signiﬁcantly superior to ICG alone (p¼0.04, OR 5.0, CI 1.0-24.1) and andwas in line with the reported rate of 96.7% (94.3-99.1)1 by blue dye and RI.

Concordance and reverse concordance rates were 89.7% and 98.4%, respectively. A median of 2 lymph nodes was detected by both ICG (range 0 e 6) and IR (range 0e 5)with no statistical difference (p¼0.60). Of 10 cases with 13 metastatic nodesconﬁrmed by histology, both ICG and RI achieved 100% concordance rates. Breast conserving treatments had a higher ICG failure rate compared to mastectomy (21.1%vs 3.0%, p¼0.05, OR 8.5, CI 1.0-72.4). In addition, among three cases with priorsurgery, two failed ICG SLN identiﬁcation. Meanwhile, age, BMI, tumour location,multifocality, neoadjuvant treatment, and ICG volume showed no signiﬁcant correlation with ICG detection rate.

Conclusions: The combined use of ICG and RI ensures adequate SLN identiﬁcation without problems known with the use of blue dye, such as skin staining and anaphylaxis. A higher failure rate was noted in patients with breast-conserving treatments for ICG tracing.

https://doi.org/10.1016/j.annonc.2023.09.522

327P Deﬁning ‡10% radioisotope-hot stained nodes as sentinel lymph nodes by “blue dye + radioisotope” dual-tracer method for sentinel lymph node biopsy leads to the

overdetection and excessive excision

Y. Jiao, Q. Lv

Breast Surgery Department, West China School of Medicine/West China Hospital of Sichuan University, Chengdu, China

Background: Sentinel lymph node biopsy (SLNB) has been widely used to assess axillary staging. In clinical practice, it is crucial to deﬁne sentinel lymph node (SLN)and determine whether the detected nodes are SLNs during the process of SLNB. It is important to consider whether currently existing consensus on SLNB method which is dual-tracer technique may lead to the excessive and unnecessary removal of negative nodes. In addition, no uniform measurable and objective index has been established to deﬁne intra-operation palpable nodes, the excision of which may increase the random detection of SLN. The purpose of this study was to optimize the speciﬁc method of SLNB.

Methods: To propose an optimal cut-off value for “radioisotope+bule dye” dual-tracer method, the detailed information of (BC) patients who had no clinical node involvement and underwent SLNB from November 2010 to February 2021 was prospectively collected in the breast surgery department of West China Hospital. We analyzed the site and size, radioactivity, the status of blue dye and the pathological results of each node detected of each patients.

Results: A total of 4985 lymph nodes from 1595 BC patients were identiﬁed. Only

11.57% (577/4985) SLNs were deﬁned as pathologically positive, resulting in 88.43%(4408/4985) negative nodes removed excessively. By gradually increasing the threshold of radioisotope count in comparison to the hottest SLN, we found that when elevating the cut-off value from 10% to approximately 60%, 17.3% of lymph nodes were spared removal, among which only 0.88% were missed positive SLNs.

Raising the optimal cutoff value of radioisotopes to 60% and exempting palpable nodes at the same time could reduce the number of nodes detected by 30.81% with only 1.75% missed positive SLNs. Additionally, multivariate analysis in our study showed that larger tumor size and higher clinical N stage was signiﬁcantly positively associated with SLN metastasis.

Conclusions: Raising the optimal cut-off value of radioisotope to 60% and exempting palpable nodes may be considered as a potential alternative method to avoid removing excessive negative nodes in SLNB.

Legal entity responsible for the study: Q. Lv.

Funding: West China Hospital, Sichuan University.

https://doi.org/10.1016/j.annonc.2023.09.523

328P Frequency of radiotherapy-induced malignancies in

Li-Fraumeni syndrome patients with early breast cancer and inﬂuence of the radiotherapy technique

V. Petry1, R. Colombo Bonadio1, K. Moutinho2, L. Senna1, L. Testa1, M.C. Fragoso3,M.D.P. Estevez Diz1

1Clinical Oncology, ICESP - Instituto do Cancer do Estado de Sao Paulo, Sao Paulo,Brazil; 2Radiation Oncology, ICESP - Instituto do Cancer do Estado de Sao Paulo, Sao Paulo, Brazil; 3Endocrinology, ICESP - Instituto do Cancer do Estado de Sao Paulo, Sao Paulo, Brazil

Background: Breast cancer (BC) is the most common malignancy in female patients(pts) with Li-Fraumeni Syndrome (LFS). These pts are at increased risk of other malignancies, including radiotherapy-induced malignancies (RIM) that are those occurring in a previously irradiated ﬁeld. We aimed to evaluate the frequency of RIM and other oncologic outcomes of LFS pts with eBC.

Methods: We evaluated pts with a germline pathogenic/likely pathogenic variant of TP53 (LFS) diagnosed with eBC and followed by the Hereditary Cancer Team of a single cancer center between Dec/99 and Apr/23. The primary endpoint was the frequency of RIM among pts treated with adjuvant RT.

Results: Forty-nine pts were evaluated. Median age was 39 years (range 21 - 62); 79%were ER-positive; 35% HER2-positive; 35% stage I and 27% stage II; and 71% had TP53 R337H variant. Most pts (87%) were unaware of the LFS at the time of BC treatment.

Regarding treatment, 62% underwent a mastectomy, 66% (neo)adjuvant chemotherapy, and 62% RT. The use of RT was more common after conservative surgery as expected (87% vs 46% with mastectomy, P¼0.010). Oncologic outcomes are sum-marized in the table. Among 30 pts treated with RT, 4 (13.8%) developed RIM in the irradiated ﬁeld (3 soft tissue malignancies and 1 BC). The occurrence of RIM was not inﬂuenced by RT dose ( 40.8 or > 40.8), but was inﬂuenced by the type of RT. RIMwas observed in 100% with 2D RT (n¼2/2), 100% (n¼1/1) with volumetric modulatedarc therapy (VMAT), 6% (n¼1/16) with 3D RT, and 0% with intensity-modulated RT(n¼0/1) (P¼0.007).

Table: 328P

Radiotherapy (n[30)

No radiotherapy (n[18)

me 34 - Issue S2 -

Local recurrence 2 (6.7%)

1 (5.6%)

1.000

Distant recurrence 5 (16.7%)

0.388

Contralateral BC 5 (16.7%)

2 (11.1%)

0.696

Second neoplasia 15 (50%)

5 (27.8%)

0.226

RIM

4 (13.8%)

Conclusions: Our study conﬁrms an alarming rate of RIM after adjuvant RT, highlighting the need for a careful risk-beneﬁt evaluation for the indication of RT, which should be preferentially avoided if possible. Despite the small numbers in each subgroup, the risk of RIM seemed to be inﬂuenced by the RT technique, with higher rates with 2D RT and VMAT. Early TP53 testing is crucial to guide the BC treatment plan.

Disclosure: V. Petry: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo,Novartis. R. Colombo Bonadio: Financial Interests, Personal, Invited Speaker: AstraZeneca, Daiichi Sankyo, Gilead, Nestle Health, Zodiac; Financial Interests, Personal, Expert Testimony: Ache; Financial Interests, Institutional, Research Funding: Novartis, AstraZeneca. L. Testa: Financial Interests, Personal, Advisory Board: AstraZeneca, Lilly, Novartis, Daiichi Sankyo, MSD; Financial Interests, Institutional, Research Funding: Novartis; Financial Interests, Personal, Invited Speaker: AstraZeneca,

Roche, Daiichi Sankyo, MSD, Lilly, Zodiac, Pﬁzer. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.524

329P

Pulmonary function and lung ﬁbrosis up to 12 years after breast cancer radiotherapy

J. Karlsen1, T. Tandstad2, S. Steinshamn3, Ø. Salvesen4, N. Parlikar4, S. Lundgren4,R.J. Reidunsdatter3

1Cancer Clinic St Olavs Hospital, Trondheim, NTNU - Norwegian University of Science and Technology, Trondheim, Norway; 2Cancer Clinic St Olavs Hospital, Trondheim, St.

Olavs Hospital, Trondheim, Norway; 3Department of Circulation and Medical Imaging,NTNU - Norwegian University of Science and Technology, Trondheim, Norway; 4Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Trondheim, Norway

Background: Breast cancer (BC) radiotherapy (RT) may induce lung damage ranging from radiological changes only to respiratory failure. The evidence of long-term radiationﬁbrosis (RF) and its impact on lung function and patients reported dyspnea is scarce. The aim of the present study was to evaluate lung function from before RT to up to 12 years after treatment and identify predictors for long-term RF and reduced lung function.

Methods: BC patients (n¼250) referred to postoperative RT (2 Gy x 25) were enrolledin a prospective cohort study from February 2007 to October 2008. All assessments were conducted through clinical controls before RT (baseline), at 3, 6 and 12 months and at long-term follow- up ranging from 7-12 years after RT. Lung function was assessed by the pulmonary function tests (PFT) Vital capacity (VC), Forced Expiratory volume in 1second (FEV1), Forced Vital Capacity (FVC) and diffusion capacity for carbon monoxide (DLCO). RF was diagnosed by High Resolution Computer Tomography scans and graded in accordance with the CTCAE version 3.0 criteria. Patient reported dyspnea was assessed by the EORTC QLQ-C30.

Results: VC, FVC, FEV1 and DLCO declined at 3 months after RT and remained low at long-term follow-up except for DLCO which increased up to 12 years after RT. VC,FEV1, and FVC changes from baseline differed between patients treated with chemotherapy and those not treated with chemotherapy. FEV1 changes from baseline differed between locoregional and local radiated patients. A decline in VC, FEV1, and FVC 3 months after RT predicted a decline in PFT up to 12 years (p¼0.020, p¼0.004,and p¼0.020, respectively). At long-term follow-up age was the only patient andtreatment-related factor associated with RF (p¼0.021). RF was observed in 144 pa-tients (91%), of which 129 (81%) had ﬁbrosis Grade 1 and 15 (9%) had ﬁbrosis Grade

2. 61 (35%) patients reported dyspnea, mainly grade 1.

Conclusions: Pulmonary function deteriorated in the ﬁrst year and up to 12 years after BC RT. An early decline in VC, FVC and FEV1 predicted further decline at longterm follow-up. RT. Chemotherapy and locoregional RT predicted a decrease in PFT in the ﬁrst year and for up to 12 years after RT. Older age was associated with RF at longterm follow-up. Few patients reported severe dyspnea.

Legal entity responsible for the study: The Norwegian University of Science and Technology, Faculty of Medicine.

Funding: The Liaison Committee for education, research and innovation in Central Norway.

https://doi.org/10.1016/j.annonc.2023.09.525

330P Effect of radiotherapy in deep inspiration in patients with left breast cancer: Does the size of the target area affect the dose for the most crucial organs at risk?

Z. Locsei1, B. Nagy2, T. Brunner3, L. Mangel4

1Universitätsklinik für Strahlentherapie-Radioonkologie, Graz, Hungary; 2Radiotherapy, PTE-AOK - Pecs University Medical School - Institute of Oncotherapy, Pécs,Hungary; 3Radiation Oncology, Graz Medical University, Graz, Austria; 4Institute of Oncotherapy, PTE-AOK - Pecs University Medical School - Institute of Oncotherapy,Pécs, Hungary

Background: After radiotherapy (RT) to the left breast, the long-term risk of developing various cardiovascular diseases may increase. In our study, we present how deep inspiration treatment changes the doses of organs at risk (OAR), especially the heart. Furthermore, we examined if there is a relationship between the size of the irradiated target area and the dose on the heart.

Methods: From May 2016 to August 2020, 503 patients with left-sided breast cancer underwent RT at our institute. Since May 2018, we have treated our patients in deep breathing (DIBH) using the “voluntary breath-hold” technique. We compared the Dmean and Dmax values for the most critical OAR (left lung, heart, left ventricle, LADleft anterior descending artery) based on the two treatment methodologies. Subsequently, both groups were then further subdivided into whether the treatment was given by standard fractionation or hypofractionation and created 3-3 groups based on the size of the target area (PTV).

Results: In patients treated with normal fractionation in DIBH vs. without, the doses of the OARs were the following: lung Dmean: 9.3 Gy vs. 9.96 Gy (p¼0.029), left ventricleDmean: 3.52 Gy vs. 7.56 Gy (p¼2.69E-27), heart Dmean: 2.78 vs. 5.31 (p¼1.11E-24), LADDmean 12.17 vs. 25.91 Gy (p¼4.63E-24) respectively. In the hypofractionated group withvs. without DIBH the values were lung Dmean: 7.43 Gy vs. 8.08 Gy (p¼0.17), leftventricle Dmean: 3.48 Gy vs 6.4 Gy (p¼2.64E-10), heart Dmean: 2.64 vs 4.62 (p¼2.96E-08), LAD Dmean 11.46 vs 18.35 Gy (p¼3.37E-06) respectively. In the standard fraction-ated group, the average doses for each structure decreased mostly in women with large breast sizes after DIBH treatment. Generally, as the breast size increases, the values of the left ventricle, heart, and LAD increase, whilst the values of the lungs decrease.

Although, a signiﬁcant difference could only be detected in a few categories.

Conclusions: DIBH RT of the left breast signiﬁcantly reduces radiation exposure to crucial OAR than free-breathing radiation therapy. At the same time, the coverage of the target area does not change, and our results suggest that this beneﬁt is most pronounced in patients with large breast sizes.

https://doi.org/10.1016/j.annonc.2023.09.526

331P miR-21 and miR-34a as biomarkers of radiotherapy skin adverse events in ductal carcinoma in situ

T. Marinko1, A. Cvetkoska2, S. Redensek Trampuz3, V. Dolzan3, K. Goricar3

1Radiotherapy Department, Institute of Oncology Ljubljana, Ljubljana, Slovenia;2Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia; 3Pharmacogenetics Laboratory, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine,Ljubljana, Slovenia

Background: Ductal carcinoma in situ (DCIS) is a non-invasive type of breast cancer treated with surgery and adjuvant radiotherapy (RT). RT improves local disease control, but also causes adverse effects. Molecular factors could contribute to interindividual variability in the incidence of skin adverse events after RT. Radiation exposure can affect expression of miRNAs, small non-coding RNAs involved in posttranscriptional regulation of gene expression. Our aim was to evaluate whether miR21 and miR-34a expression changes after RT and if miRNA expression is associated with skin adverse events of RT in patients with DCIS.

Methods: Our prospective study included 119 patients with DCIS treated with adjuvant RT. Skin adverse events were assessed using Common Terminology Criteria for Adverse Events (CTCAE) v.5 immediately after RT and six months after RT. MiRNA was isolated from plasma before and after RT and quantitative PCR was used to determine miR-21 and miR-34a expression. Non-parametric tests and logistic regression were used in statistical analysis.

Results: Immediately after RT, 5.7% patients had grade 2 skin adverse events, while

26.1% patients experienced grade 2 adverse events after six months. More skin adverse events after six months were observed in smokers (p¼0.036). After RT, theexpression of miR-21 (p¼0.001) and miR-34a (p<0.001) was signiﬁcantly increased.Patients with a greater increase in miR-34a expression after RT were more likely to have a higher grade of skin adverse events immediately after RT, even after adjustment for clinical parameters (ORadj¼1.13; 95% CIadj¼1.02-1.26; padj¼0.026). Similarly,greater increase in miR-34a expression was associated with more adverse events six months after RT, but the association was only signiﬁcant adjustment for clinical parameters (ORadj¼1.13; 95% CIadj¼1.01-1.27; padj¼0.035). Expression of miR-21 wasnot associated with skin adverse events.

Conclusions: Our results suggest that miR-21 and miR-34a expression increases after RT and miR-34a expression might serve as a biomarker of RT skin adverse events.

Research grants: ARRS J3-1753, ARRS J3-2527, P1-0170 and P3-0321.

Funding: Slovenian Research Agency.

https://doi.org/10.1016/j.annonc.2023.09.527

332P Early prediction of residual cancer burden to neoadjuvant chemotherapy in breast cancer by longitudinal MRI-based multitask learning: A multicenter cohort study

W. Li1, Y. Huang2, T. Zhu2, K. Wang2

1Breast Cancer, The First People’s Hospital of Foshan, Foshan, China; 2Breast Cancer,Guangdong Provincial People’s Hospital, Guangzhou, China

Background: Neoadjuvant chemotherapy (NAC) has been a standard treatment for locally advanced breast cancer (BC). However, the high heterogeneity of BC results in various tumor response. Therefore, there is a growing need for early assessment of tumor response, particularly for insensitive BC, to guide personalized treatment. We

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aim to develop a longitudinal radiomics multitask model to accurately predict RCB score in the early stage of NAC for breast cancer.

Methods: A total of 1048 patients with breast cancer receiving NAC across four institutions were retrospectively enrolled. We collected longitudinal MRI sequences at the pre-NAC and mid-NAC timepoints, and extracted 21804 radiomics features per patient. We used a multitask learning strategy to predict RCB score (RCB 0-I, II and III).

The Mann-Whitney U-test, Spearman analysis, the least absolute shrinkage and selection operator regression and Boruta method were used to perform feature selection. We developed various base machine learning models, followed by an ensemble stacking method to integrate the base model outputs. The multitask learning model was subsequently veriﬁed in three independent external validation cohorts.

Results: Of the total patients, 442 (42.18%) reached RCB 0-I, 462 (44.08%) reached RCB II and 144 (13.74%) reached RCB III. 17 and 19 signiﬁcant features were selected for two independent tasks. For identifying RCB 0-I and RCB II-III, the multitask model reached an area under the curve (AUC) of 0.932 in primary cohort, and AUCs of 0.890,

0.919 and 0.911 in the external validation cohorts. It also identiﬁed RCB II and RCB III with an AUC of 0.916 in primary cohort, and AUCs of 0.870, 0.899 and 0.871 in external validation cohorts.

Conclusions: The longitudinal radiomics multitask learning model is a noninvasive tool to predict RCB score for breast cancer, and help clinical decision-making in the early stage of NAC.

https://doi.org/10.1016/j.annonc.2023.09.528

333P

Evaluation of a composite PET/CT and HER2 tissue-based biomarker to predict response to neoadjuvant HER2-directed therapy in early breast cancer (TBCRC026)

M.A. Hennessy1, A. Cimino-Mathews2, J. Carter3, J. Kachergus4, Y. Ma4, J. Leal2,L. Solnes2, V. Abramson5, L.A. Carey6, M. Rimawi7, J. Specht8, A.M. Storniolo9,C. Vaklavas10, A.C. Wolff2, R. Wahl11, E.A. Perez12, C-Y. Huang13, V. Stearns2,A. Thompson4, R.M. Connolly1

1Cancer Research @UCC, University College Cork, Cork, Ireland; 2Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, MD, USA; 3Department of Pathology, University of Alberta, Edmonton, AB, Canada; 4Dept. of Cancer Biology,Mayo Clinic - Florida, Jacksonville, FL, USA; 5Hematology/Oncology, Vanderbilt Ingram Cancer Center, Nashville, TN, USA; 6Medicine - Hematology/Oncology Division, UNC -The University of North Carolina at Chapel Hill - School of Medicine, Chapel Hill, NC,USA; 7College of Medicine, Baylor, Houston, TX, USA; 8Medicine Department, University of Washington Seattle Cancer Care Alliance, Seattle, WA, USA; 9Medical Oncology Dept., Indiana University Simon Cancer Center, Indianapolis, IN, USA;10Medical Oncology Dept, University of Alabama at Birmingham, Birmingham, AL,USA; 11Dept. of Nuclear Medicine, Washington University School of Medicine in St.

Louis - Siteman Cancer Center, St. Louis, MO, USA; 12Dept. of Cancer Biology, Mayo Clinic - Florida, Jacksonville, FL, USA; 13Dept of Epidemiology and Biostatistics, UCSF -University of California San Francisco, San Francisco, CA, USA

Background: Early metabolic change on FDG PET/CT was predictive of response to neoadjuvant trastuzumab/pertuzumab (HP) in TBCRC026, with high negative predictive value (NPV) suggesting a lack of decline in SULmax at cycle 1 day 15 (C1D15) best predicts those who will not achieve pathological complete response (pCR) with HP alone.We hypothesized that a composite biomarker incorporating both PET and HER2 tissue-based biomarkers could improve biomarker performance in this setting.

Methods: Patients with stage II-III ER-negative/HER2-positive breast cancer received neoadjuvant HP. PET/CT was performed at baseline and C1D15. Promising imaging biomarkers included 40% SULmax decline between baseline and C1D15, and C1D15SULmax 3 (n¼83 evaluable). Baseline tissue-based biomarkers included HER2-enriched intrinsic subtype (72%, 46/64 available; Nanostring [NS] BC360), log2 tumor HER2 protein abundance (median 13.5, range 7.1-15.9; NS GeoMxTM DSP), HER2 3+(83%, 64/77; immunohistochemistry central review). Logistic regressions were used to construct prediction models for pCR with the composite HER2/PET biomarker. Overall discriminatory power of the predictive model was evaluated using the C statistic.

Sensitivity and speciﬁcity were evaluated at the optimal cut-off point determined by maximizing Youden’s index in the receiver operating characteristic (ROC) analysis.

Results: Factors most predictive for response (pCR 22%, PMID 33999652) in single predictor models included D15 SULmax (OR 0.43; p¼0.007, c¼0.77), % reduction inSULmax (OR 1.03, p¼0.006, c¼0.72) and tumor HER2 protein abundance (OR 1.75;p¼0.01, c¼0.76). The composite of D15 SULmax and % reduction in SULmax com-bined with their interaction term, had improved probability (c¼0.89 from c¼0.78),with high sensitivity (100%) and NPV (100%). The addition of tumor HER2 protein did not further improve prediction power (c¼0.90).

Conclusions: The composite HER2/PET biomarker had high prediction power for pCR,however was not superior to the prediction power of PET/CT alone. These data suggest clinical trials informed by early FDG PET/CT biomarkers warrant further evaluation to personalize breast cancer care.

Clinical trial identiﬁcation: NCT01937117.

Legal entity responsible for the study: Translational Breast Cancer Research Consortium.

Funding: TBCRC and its foundation partners (The Breast Cancer Research Foundation and Susan G. Komen for the Cure) ASCO CCF CDA 2013 Genentech (ML28190) SKCCC Core Grant (P30-CA006973) AVON Center of Excellence (01-2017-007) NCI Quantitative Imaging Network (QIN) contract (5U01CA140204) Breast Cancer Research Foundation (grant 21-161) Breakthrough Cancer Research.

Disclosure: M.A. Hennessy: Financial Interests, Personal, Sponsor/Funding: Roche, MSD, AstraZeneca. A. Cimino-Mathews: Financial Interests, Personal, Research Grant: BMS; Financial Interests,Personal, Other, Consultant Honoraria: BMS. J. Carter: Financial Interests, Personal, Other, Honorarium: AstraZeneca, Merck, Dako-Agilent, Roche. J. Leal: Financial Interests, Personal, Other,Consultant: PlenaryAI. V. Abramson: Financial Interests, Institutional, Other, Grants: Pﬁzer, Genentech, Gilead, AstraZeneca, Zentalis; Financial Interests, Personal, Other, Consulting: FirstThought,Daiichi Sankyo, SeaGen, AstraZeneca; Financial Interests, Personal, Other: Eisai. L.A. Carey: Financial Interests, Institutional, Funding, research funding: Syndax, Immunomedics, Novartis, Nanostring Technologies, AbbVie, Seattle Genetics, Veracyte; Non-Financial Interests, Advisory Role, uncompensated relationship - all monies go to UNC. Dr. Carey does not have any signatory authority over any UNC account: Sanoﬁ, Novartis, G1 Therapeutics, Genentech/Roche, GSK, AstraZeneca/ Daiichi Sankyo, Apitude Health, Exact Sciences. M. Rimawi: Financial Interests, Personal, Other, Consulting:SeaGen, Genentech, AstraZeneca, Novartis, Macrogenics. J. Specht: Financial Interests, Personal,Other, Consultant: Volastra; Financial Interests, Personal, Advisory Board, and Consultant: GE Healthcare; Financial Interests, Personal, Advisory Board: Sensei Biotherapeutics, GSK, Daiichi Sankyo; Financial Interests, Personal, Royalties, ROR1 royalties: UW CoMotion; Financial Interests,Institutional, Research Grant: Celcuity, Pﬁzer, Xencor, Merck, Seagen, Seattle Genetics, Minerva,Myriad Pharmaceuticals, Novartis, Genentech, Cascadian Therapeutics, Abbvie, Nektar. A. A.M. Storniolo: Financial Interests, Personal, Other, Member of DSMB for phase III trials, no involvement with HER2 positive breast cancer trials or compounds used in this study: AstraZeneca. C. Vaklavas:Financial Interests, Personal, Other, Wife: Flatiron Health; Financial Interests, Personal, Other,Consultation: Guidepoint, Novartis, SeaGen; Financial Interests, Personal, Other, Consultant: Daiichi Sankyo; Financial Interests, Personal, Other, Consultant Honoraria: Gilead Sciences; Non-Financial Interests, Personal, Other, Non-compensated consultation: Genentech; Financial Interests, Personal,Other, Participation in non CME activity: Pﬁzer, Daiichi Sankyo/AstraZeneca. A.C. Wolff: Financial Interests, Personal, Other, DSMB for Impassion030 Alexandra trial (Roche trial led by BIG, received honorarium from BIG): Roche. R. Wahl: Financial Interests, Personal, Advisory Board: Clarity Pharmaceuticals, Voximetry , Seno Medical; Financial Interests, Personal, Stocks/Shares: Clarity Pharmaceuticals; Financial Interests, Personal, Stocks/Shares, Stock options: Voximetry; Financial Interests, Personal, Other, Honoraria: BMS, Actinium Pharmaceuticals, Jubilant Draximage, Abderra,Radiopharm Therapeutics, ITM; Financial Interests, Personal, Ofﬁcer, Honoraria: Siemens; Financial Interests, Personal, Other, Research support: Actinium Pharmaceuticals, BMS, Bayer, ITM, Siemens,White Rabbit AI. V. Stearns: Financial Interests, Institutional, Research Grant: AbbVie, Biocept,Novartis, Pﬁzer, Puma Biotechnology, QUE Oncology; Other, Personal, Advisory Board: Novartis;Other, Personal, Advisory Board, DSMB: AstraZeneca; Other, Personal, Other: Foundation Medicine Study Assays. A. A. Thompson: Non-Financial Interests, Personal and Institutional, Other, Involved in beta testing both GeoMx and CosMx technology for NanoString Technologies, Inc. The nature of this work involves instrument training and analytical support from NanoString, focused upon developing and deploying analytical solutions for data analysis. No ﬁnancial remuneration was involved.:NanoString Technologies. R.M. Connolly: Financial Interests, Institutional, Other, Unrestricted Education Grant: Pﬁzer; Financial Interests, Institutional, Research Funding: MSD Ireland, Daiichi Sankyo,AstraZeneca; Financial Interests, Personal, Other, Travel/Educational support: Novartis; Non-Financial Interests, Personal, Advisory Board: Roche; Non-Financial Interests, Personal, Advisory Board, Chair:SeaGen; Financial Interests, Personal, Advisory Board: AstraZeneca/Daiichi, AstraZeneca, Gilead;Financial Interests, Personal, Steering Committee Member: AstraZeneca/Daiichi Sankyo; NonFinancial Interests, Personal, Steering Committee Member: Develop Med UCD, ACRI, Decrescendo.

Methods: The survey was initiated by Cancer Patients Europe (CPE) as part of its my Cancer my Concern (myC) initiative and was developed with a panel of oncologists and patient association representatives. Participants were recruited by e-mail and through a social media campaign. They responded to a 42-question internet survey(Survey Monkey) which took w10 minutes to complete..

Results: Of 1,383 participants completing the survey, 566 women with HR+ and HER2-breast cancer who were eligible for genomic testing were analysed. 245 (43.3%) were aged 50-59 years and 381 (67.3%) had received higher education. 238 participants(42.1%) had heard about genomic testing; only 122 (21.6%) were told that they were eligible for it and 104 (18.4%) were told the reasons for the test. The majority (N ¼479; 84.6%) considered that they did not have sufﬁcient information to make a decision about genomic testing and only 139 (24.6%) actually decided to take a test.

Overall, 234 (41.3%) would have liked to have received more information on treatment options, and 246 (43.5%) more information on additional testing. 464 participants (82.0%) sought more information on their disease. The principal sources of information on breast cancer management were healthcare professionals (N ¼ 363;64.1%), internet (N ¼ 351; 62.0%), and patient associations (N ¼ 117; 20.7%). For themajority (N ¼ 398; 70.3%), the healthcare professional did not provide advice onwhere to ﬁnd more information.

Conclusions: This study demonstrates that awareness of and access to genomic testing for breast cancer in Europe is sub-optimal. Healthcare professionals need to improve communication with patients regarding genomic testing and involve them in shared decision-making. Patient associations should also act as a portal for providing information on genomic testing.

Legal entity responsible for the study: Cancer Patients Europe (CPE).

Funding: Exact Sciences.

Disclosure: L.D. Csaba: Other, Institutional, Other: UEFISCDI; Non-Financial Interests, Other: ECO,IPOS, APSCO. L. Guéroult-Accolas: Other, Other: Exact Science, Veracyte. M.P. Lux: Financial Interests,Personal, Advisory Board: Exact Sciences , Agendia. A. Ramírez Piris: Financial Interests, Personal,Other, Employee: Exact Sciences. R. Simcock: Financial Interests, Institutional, Other: Novartis,Seagen , Exact Sciences. R. D’Antona Fidanzia: Non-Financial Interests, Other, advocacy group: Exact Sciences, Agendia, Quimark. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.513

318P Evaluation of novel diagnostic kits using the semi-dry dotblot method combined for detecting metastases in sentinel lymph nodes of patients with breast cancer: A multi-center prospective study

R. Otsubo1, M. Matsumoto1, E. Inamasu1, A. Tanaka1, S. Kuba2, M. Morita2,F. Kaseida3, S. Maeda4, M. Nakashima5, H. Ikari6, S. Ohno7, H. Takei8, S. Eguchi2,T. Nagayasu1

1Surgical Oncology, Nagasaki University Hospital, Nagasaki, Japan; 2Surgery, Nagasaki University Hospital, Nagasaki, Japan; 3Laboratory Medicine, Nagasaki University Hospital, Nagasaki, Japan; 4Breast and Endocrine Surgery, National Hospital Organization Nagasaki Medical Center, Omura, Japan; 5Tumor and Diagnostic Pathology,Nagasaki University Atomic Bomb Disease Institute, Nagasaki, Japan; 6Surgery,Sasebo Chuo Hospital, Sasebo, Japan; 7Breast Oncology Center, The Cancer Institute Hospital of JFCR, Koto-ku, Japan; 8Breast Surgery, Nippon Medical School Main Hospital, Tokyo, Japan

Background: The semi-dry dot-blot (SDB) method, a diagnostic procedure for detecting lymph node (LN) metastases using anti-cytokeratin (CK) antibody, is based on the theory that epithelial components such as CK are not found in normal LNs.

Thus, metastases are diagnosed on basis of the presence of CK in lavage ﬂuid of sectioned LNs. We prospectively evaluated novel SDB kits that use a newly developed anti-CK19 antibody and an automatic reader for diagnosing sentinel LN metastases in patients with breast cancer as a multi-center study.

Methods: We obtained 924 sentinel LNs dissected between January 2021 and December 2021 at six institutes in Japan. We excluded patients with neoadjuvant chemotherapy and neoadjuvant endocrine therapy. These LNs were sliced at 2-mm intervals and washed with PBS. Cells suspended in the lavage ﬂuid of sliced LNs were centrifuged and lysed to extract protein. The extracted protein was applied to the SDB kit to diagnose LN metastasis using an automatic reader that evaluates absorbance.

Washed LNs were blindly examined using intraoperative and permanent histological examination. Diagnoses based on SDB kit were compared with diagnoses made by permanent histological examination of the LNs. Primary endpoints were sensitivity,speciﬁcity, and overall agreement of the SDB kit for distinguishing macrometastases from non-macrometastases.

Results: Ninety-four of the 924 LNs were assessed as macrometastases, 40 as micrometastases and 790 as negative by histological examination. With a borderline CK19 absorbance of 11.9 milli-absorbance for detecting macrometastases with 0.989 Area Under the Curve, the sensitivity, speciﬁcity, and overall agreement of the SDB kit were 94.7%, 98.3%, and 97.9%, respectively. Furthermore, the kits and the automatic reader yielded diagnoses in approximately 20 min at a cost of less than 30 EUR for the SDB kit and less than 3,000 EUR for the automatic reader.

Conclusions: The kits with an automatic reader used in our study were accurate,quick, and cost-effective in diagnosing LN metastases without loss of LN tissue, and were especially useful for detecting distinguish macrometastases.

https://doi.org/10.1016/j.annonc.2023.09.514

319P The impact of low HER2 expression on clinical signiﬁcances and outcomes in patients with HER2-negative early breast cancer

Y. Koi1, W. Tajiri1, J. Kawasaki1, S. Akiyoshi1, C. Koga1, Y. Nakamura1, K. Taguchi2,E. Tokunaga1

1Breast Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka,Japan; 2Department of Pathology, National Kyushu Cancer Center, Fukuoka, Japan

Background: HER2-low, deﬁned by immunohistochemically (IHC) 1+ or 2+ with negative in situ hybridization (ISH), has recently attracted attention as a novel classiﬁcation in determining treatment strategies in HER2-negative metastatic breast cancer (BC). However, clinical signiﬁcance of this new subcategory in early-stage BC and testing methodologies of HER2-low remain unclear.

Methods: We retrospectively reviewed the clinical data of 1,359 patients with HER2-negative BC at stage I-III between January 2008 and December 2017 in our institute.

They were classiﬁed into HER2-low (n¼455) and HER2-0 (n¼904) subgroups ac-cording to IHC assay or gene ampliﬁcation on ISH. We compared the difference in clinicopathological characteristics, recurrence-free survival (RFS), and overall survival(OS) between these subgroups. Since three different immunostaining kits (HercepTest; Dako (i), Bond III stainer (Leica Biosystems) (ii), Ventana ultra View PATHWAY HER2/neu (4B5) (iii)) were used in deﬁning HER2 expression depending on period, we also evaluated the frequency of HER2 expression level by immunostaining kits.

Results: The median age was 57 (range 24e87) and the median follow-up period was 77 months (range 1.1e175.6). The number of patients at clinical stage I, II, and III was 790, 462, and 107, respectively. The HER2-low subgroup tended to have lower histological grade (p < 0.01) and higher frequency of hormone receptor positivity (p <

0.01) compared to the HER2-0 subgroup. There were no statistically signiﬁcant

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differences in RFS (p ¼ 0.95) or OS (p ¼ 0.87) between two subgroups. Intriguingly,there were signiﬁcant differences in the percentages of HER2-low and HER2-0,depending on the immunostaining kits (42.2% vs 57.8% (i), 84.5% vs 15.5% (ii), 87.9%vs 12.1% (iii)).

Conclusions: In this study, there was no prognostic difference based on HER2 expression status in HER2-negative early-stage BC, but there was a frequency difference in determining HER2-low and HER2-0 depending on the immunostaining kits.

While there are many assays for HER2 evaluation approved in the practice, an appropriate companion diagnosis for HER2-low seems to be critical to select patients who may beneﬁt from newer treatment such as Trastuzumab Deruxtecan.

https://doi.org/10.1016/j.annonc.2023.09.515

320P

Clinical and pathological characteristics of breast cancers switching from early luminal-like to metastatic triplenegative phenotype

M. Ivanova1, A. Marra2, S. Morganti3, K. Venetis1, E. Sajjadi4, L. Ascione2,

B. Taurelli Salimbeni2, P. Zagami2, P.P.M. Berton Giachetti2, G. Curigliano2, N. Fusco1,C. Criscitiello2

1Division of Pathology, IEO - Istituto Europeo di Oncologia IRCCS, Milan, Italy; 2Division of New Drugs and Early Drug Developement, IEO - Istituto Europeo di Oncologia IRCCS, Milan, Italy; 3Breast Oncology Center, Dana Farber Cancer Institute, Boston,MA, USA; 4Oncology and Hematology-Oncology Department, UNIMI - Università degli Studi di Milano Statale, Milan, Italy

Background: Loss of hormone receptors (HR) at breast cancer (BC) metastatic relapse has been reported. Few data are available on the clinicopathologic features associated with HR loss and its prognostic impact.

Methods: We retrospectively identiﬁed a cohort of 51 patients (pts) with primary HR+/HER2- BC and triple-negative (TN) metastasis (LUM-TN) along with two control cohorts of paired HR+/HER2- and TN on both primary and metastatic samples (LUMLUM, n¼50; TN-TN, n¼49). Clinical features and outcomes were retrieved frommedical charts. HR and HER2 status were independently reviewed by two pathologists on all archival samples. Estrogen receptor (ER) expression between 1% and 10% was considered as ER-low. Cox-proportional hazard models were used to assess the impact of variables on distant metastasis-free survival (DMFS) and overall survival (OS).

Results: The three cohorts had no difference in median age, menopausal status nor stage at diagnosis. Pts in LUM-TN cohort had a higher frequency of invasive lobular(20% vs 10% vs 2%, p¼.03), primary ER-low BCs (22% vs 0% vs 0%, p<.001) andlocoregional relapse (18% vs 0% vs 2%, p<.001) than pts in the LUM-LUM and TN-TN cohorts. Metastatic samples from pts in LUM-TN and LUM-LUM cohorts were more frequently HER2-low than those in TN-TN cohort (57% vs 66% vs 24%, p<.001). At univariate analysis, pts with LUM-TN switch had a longer DMFS compared to the TNTN (median DMFS 62 vs 18 months; HR 3.35, 95%CI 2.2-5.1, p<.001), but similar to the LUM-LUM cohort (median DMFS 62 vs 64 months; HR 0.95, 95%CI 0.6-1.41,p<.8). The DMFS difference was not signiﬁcant after adjusting for other variables,including grade and ER-low status. Median OS was signiﬁcantly lower for pts in LUMTN (median OS 93 vs 139 months; HR 2.3, 95%CI 1.3-4.1, p<0.004) and TN-TN cohorts(median OS 47 vs 139 months; HR 3.4, 95%CI 1.1-10.7, p<0.03) when compared to the LUM-LUM cohort, independently from other clinicopathologic features.

Conclusions: HR loss at metastatic relapse is frequent in lobular and ER-low primary BCs. Pts with HR loss have similar DMFS compared to pts with maintained HR expression, but apparently reduced OS. Further investigation on biological mechanisms underpinning the LUM-TN phenotype switch is ongoing.

Funding: Fondazione Umberto Veronesi, Fondazione IEO e MONZINO, Italian Ministry of Health with Ricerca Corrente 5 x 1000.

Disclosure: M. Ivanova: Financial Interests, Institutional, Research Funding: Fondazione Umberto Veronesi. K. Venetis: Financial Interests, Institutional, Research Funding: Fondazione IEO e MONZINO. G. Curigliano: Financial Interests, Institutional, Speaker, Consultant, Advisor: Bristol Myers Squibb, Lilly, Novartis, Pﬁzer, Roche, Seagen, Daiichi Sankyo. N. Fusco: Financial Interests, Institutional, Speaker, Consultant, Advisor: MSD, Boehringer Ingelheim, Novartis, AstraZeneca, Daiichi Sankyo; Financial Interests, Institutional, Funding: Italian Ministry of Health with Ricerca Corrente 5 x 1000 funds. C. Criscitiello: Financial Interests, Institutional, Speaker, Consultant, Advisor: Pﬁzer, Lilly,Novartis, Roche, Bristol Myers Squibb, Seagen, Daiichi Sankyo. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.516

321P Non-BRCA variants in hereditary breast and ovarian cancer patients in the northern Mexico population

D. Aguilar1, M.D.L. Garza Rodriguez2, D.C. Pérez-Ibave2, C.M. Villarreal Garza3,O. Vidal-Gutierrez2, C.H. Burciaga Flores2

1Breast Cancer Center, Hospital Zambrano Hellion TecSalud, San Pedro Garza Garcia,Mexico; 2Oncology Service, CUCC - Centro Universitario Contra el Cáncer - Universidad Autónoma de Nuevo León (UANL), Monterrey, Mexico; 3Breast Cancer Center, Hospital Zambrano Hellion, Tecnologico de Monterrey, San Pedro Garza Garcia, Tlalpan. D.F.,Mexico

Background: Hereditary cancer syndromes explain 5-10% of all cancer cases. Germline pathogenic variants in BRCA1 and BRCA2 genes (BRCA) are present in 2-3% of all breast cancer (BC), and 15% of all ovarian cancer (OC) cases. BRCA1 and BRCA2 pathogenic variants (PV) represent 25-28% of BC and 40% of OC patients with a positive familial history. BRCAs are the most studied genes for the prevalence, family history, preventive surgeries, and target treatment options in both BC and OC. There are other genes, important in the diagnosis, pathogenesis, and treatment options of the patients: TP53, PALB2, CHEK2, among others. This study aims to identify the prevalence of non-BRCA genes related to the development of hereditary breast and ovarian cancer syndrome in patients of Northeast Mexico.

Methods: This is a multicenter study that recruited patients from two reference oncology centers in Nuevo Leon, Mexico: the CECIL (The CUCC Early Cancer Detection Clinic) Hereditary Cancer Registry and Hereditary Cancer Program from Tec Salud.

From March of 2016 to March of 2023, a total of 872 patients meeting NCCN criteria were evaluated by Medical Geneticists from both centers and were tested with NGS multigene cancer panels.

Results: A total of 665 (76.26%) patients with a clinical diagnosis of HBOC (Hereditary Breast Hereditary Cancer Syndrome) were included. We found 310 (46.6%) patients had at least one variant, 180 (58%) with at least one pathogenic variant, and 130(41%) with a VUS (a variant of uncertain signiﬁcance). BRCA1 was found in 79 (43.8%)and BRCA2 in 32 (17.7%) of all PV. Non-BRCA PV were found in 69 (38.3%) patients: 4 ATM, 2 BLM, 3 BRIP1, 22 CHEK2, 4 CDKN2A, 5 MUTYH, 10 PALB2, 4 RAD51C, 2 SDHA,2 TP53, 2 WRN, CDH1, CDK4, DICER, MSH3, NBN, PTEN, RAD50, USH2A one of each. Is remarkable that 19 of the 22 patients with CHEK2 and 5 of the 10 patients with PALB2 had the recurrent PV c.707T>C and c.2167_2168del, respectively.

Conclusions: Non-BRCA PV in Northern Mexico correspond to one-third of the BC and OC cases, including HRD (homologous recombination deﬁciency) genes. HDR patient carriers are potential targets of iPARP therapies. This project reinforces the fact that multigene panels should be employed to ensure a complete diagnosis in hereditary cancer patients.

Legal entity responsible for the study: Centro de Cáncer de Mama, Hospital Zambrano Hellion, Tec Salud. Centro Universitario Contra el Cancer, Hospital Dr Jose Eleuterio Gonzalez, UANL.

https://doi.org/10.1016/j.annonc.2023.09.517

322P Clinicopathological characteristics and genomic proﬁling of pure mucinous breast cancer

S. Wang1, Q. Lu2, H. Zhou1, P. Sun3, K. Shao4, K. Lee5, F. Xu1, W. Xia1, K. Jiang1

1Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China;2Department of Radiology, Sun Yat-sen University Cancer Center, Guangzhou, China;3Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China; 4Joint institute of Medicine, BGI-Shenzhen - Headquarters, Shenzhen, China; 5Department of Ultrasound, First Afﬁliated Hospital of Sun Yat-Sen University, Guangzhou, China

Background: Pure mucinous breast cancer (PMC) is a rarely seen histological type with favorable prognosis. Nevertheless, cases with recurrence have been reported and diagnosed in clinical practice. The recurrent patterns and mechanisms of PMC are unknown. Thus, in this study, we aim to discover the prognostic factors of PMC and reveal the genomic proﬁling of PMC with positive lymph nodes.

Methods: A total of 166 cases diagnosed as PMC were included. We compared the clinicopathologic characteristics across different groups using Mann-Whitney U test or chi square test according to variables. 21-gene assay was done in 10 patients with recurrence and 20 TNM staging-matched patients. Whole-exon sequencing was done in 12 PMC primary tumor and 4 positive lymph nodes. We compared the genomic alterations between two groups in single nucleotide polymorphism, copy number variation and enriched pathways.

Results: The median age at diagnosis was 45 years old in total 166 patients. After median follow-up of 84 months, 21/166 patients developed recurrence with/without distant metastasis. The signiﬁcant different factors between patients with recurrence and without recurrence were tumor size, lymph node status and TNM staging. 21-gene recurrence scores were not statistically signiﬁcant between two groups. Wholeexon sequencing showed that lymph node-positive(LNP) PMC primary tumors were more recurrently with mutations of ADCY10 (3/6) and SHANK3 (3/6), while lymph node-negative(LNN) PMC did not harbor these genes. Moreover, LNP group

prevalently harbored gains of 15q23, 17q23.2, 20p11.21 and loss of 21p11.2, while LNN group did not harbored any of these copy number variations. In terms of pathway enrichment, LNP group was involved in several pathways but LNN group was not enriched in any pathways.

Conclusions: Overall prognosis is good in PMC. TNM staging is an important prognostic factor of PMC. PMC with positive lymph node more recurrently harbored gains of 15q23,17q23.2, 20p11.21 and loss of 21p11.2. More researches, especially integration of multi-omics studies, are needed in revealing the underlying mechanism of lymph node metastasis in PMC.

Funding: The Guangdong Basic and Applied Basic Research Foundationthe Sun Yatsen University Clinical Research 5010 Program Guangdong Provincial Key Laboratory of Human Disease Genomics.

https://doi.org/10.1016/j.annonc.2023.09.518

323P

Macrophage population analysis of the breast cancer

microenvironment within the context of seroma formation after mastectomy (SerMa pilot study)

F. Schneider1, M. Köpke1, C. Kuhn1, M. Wild2, M. Schneider1, C. Dannecker1,L.C. Hinske3, U. Jeschke1, N. Ditsch1

1Department of Obstetrics and Gynecology, Universitätsklinikum Augsburg, Augsburg,Germany; 2Department of Obstetrics and Gynecology, Data Management and Clinical Decision Support, Universitätsklinikum Augsburg, Augsburg, Germany; 3Data Management and Clinical Decision Support, Universitätsklinikum Augsburg, Augsburg,Germany

Background: The primary goal of the SerMa pilot study was to identify possible immunological/inﬂammatory factors related to seroma formation after mastectomy and ﬁrst diagnosis of breast cancer. CD68 is a common marker for tumor-associated monocytes and macrophages in general. CD163 is used to detect M2-polarized macrophages. Both are known to have an inﬂuence on defense reactions and wound healing due to their immunomodulatory effect. Thus, the aim of this evaluation was to evaluate whether a correlation can be shown within the context of postoperative seroma formation.

Methods: From 100 patients meeting the criteria of the study, tumor tissue of 80 patients was available for evaluation. Immunohistochemical antibody staining against CD68 and CD163 was performed, and two groups were compared: Patients with and without seroma formation. The number of macrophages in the tumor microenvironment was manually quantiﬁed at three sites representative of each specimen in the entire ﬁeld of view at a magniﬁcation of 40x lens. The mean value of the three areas was used for further analysis.

Results: For CD68, the range of the mean value was from 0 to 354 macrophages. The number of CD68-positive macrophages was signiﬁcantly increased (p¼0.036) in pa-tients with seroma development (mean¼45.31) compared to those without(mean¼34.31). For CD163, the range extends from 0 to 309 macrophages. Again, thenumber of CD163-positive macrophages was signiﬁcantly increased (p¼0.027) inpatients with postoperative seroma formation (mean¼45.57) compared to patientswithout (mean¼33.99).

Conclusions: These data demonstrate a signiﬁcant correlation of CD68 and CD163 positive macrophages in the tumor microenvironment and seroma formation in the breast after mastectomy. This study was the ﬁrst to investigate these possible relationships. As highly associated with immunological processes, the signiﬁcant higher detection of CD68 and CD163 within the population of “Seroma developers” supports our study group’s previously published results on the identiﬁcation of immunological markers in seroma ﬂuid and thus the hypothesized relationship of seroma formation based on immunological/inﬂammatory processes.

Legal entity responsible for the study: N. Ditsch, U. Jeschke.

Funding: This study is funded by a research grant of the Medical Faculty of the University of Augsburg (“Projektförderung-Intramurale Forschungsförderung Medizinische Fakultät”) for N.D (190,000 Euro).

https://doi.org/10.1016/j.annonc.2023.09.519

324P Nodal underestimation rate in early-stage ER+/HER2- breast cancer patients with limited positive sentinel lymph nodes in the era of precise medicine: A real-world multicenter analysis from 40 institutions in China

Y. Zong1, Y. Lu2, Y. Tong2, X. Fei3, Y. Zhu4, Z. Wang2, X. Zhang2, Y. Zhu2, J. Huang2,J. Hong2, S. Zhu2, W. Gao2, X. Chen2, O. Huang2, J. He2, W. Chen2, Y. Li2, K. Shen2,J. Wu2

1Department of Internal Medicine, Wayne State University, Detroit, MI, USA;2Comprehensive Breast Health Center, Ruijin Hospital - Shanghai Jiao Tong University School of Medicine, Shanghai, China; 3Department of Pathology, Ruijin Hospital -Shanghai Jiao Tong University School of Medicine, Shanghai, China; 4Department of Ultrasonographic, Ruijin Hospital - Shanghai Jiao Tong University School of Medicine,Shanghai, China

Background: Emerging data show more estrogen receptor-positive/ human epidermal growth factor receptor 2-negative (ER+/HER2-) early breast cancer patients with 1-3 positive sentinel lymph nodes (SLNs) omitted axillary lymph node dissection (ALND)but received adjuvant radiation therapy, which led to equivalent locoregional and distant disease control. In this study, we aimed to evaluate whether sentinel lymph node biopsy (SLNB) only can provide accurate lymph node staging to select candidates for multigene assay testing and adjuvant CDK4/6 inhibitor treatment in ER+/HER2-breast cancer patients with 1-3 positive SLNs.

Methods: Consecutive patients with cT1-3N0, ER+/HER2- disease, and 1-3 positive SLNs were retrospectively included from the multicenter Shanghai Jiao Tong University-Breast Cancer Database. The nodal underestimation rate (NUR) was calculated in patients receiving SLNB+ALND in the overall population and in potential candidates for multigene assays and CDK4/6 inhibitors according to the RxPONDER, MINDACT,and monarchE trials.

Results: Among the 3672 patients included, 24.1% received SLNB only. The overall NUR was 9.5%. For those who met the inclusion criteria for the RxPONDER, MINDACT,and monarchE trials, positive non-SLNs were found in 3.0%, 3.5%, and 3.7% of the patients, respectively. The low NUR was not inﬂuenced by breast surgery modality.

Additional ALND upon SLNB brought no survival beneﬁt for eligible patients of these trials (RFI P¼0.090; OS P¼0.772).

Conclusions: ALND can be safely omitted in cT1-3N0, ER+/HER2- breast cancer patients with 1-3 positive SLNs when selecting candidates for multigene assays testing and adjuvant CDK4/6 inhibitor treatment.

https://doi.org/10.1016/j.annonc.2023.09.520

325P Impact of breast tumour location on axillary nodal involvement, chemotherapy use, and survival

Y. Xu, J. Cao, L. Barbera

Oncology, Tom Baker Cancer Centre, Calgary, AB, Canada

Background: Axillary level I-II node (ALN) status is used to stratify breast cancer risk and inform systemic therapy decisions. We sought to investigate the association of breast tumour location with ALN involvement, use of chemotherapy, and breast cancer-speciﬁc survival (BCSS).

Methods: Patients diagnosed with stage T1-2 M0 breast cancer from 2004 to 2019 were identiﬁed from the SEER 17 registries database. Tumour locations were classiﬁed as outer quadrant, inner quadrant, or central. Covariates were age, race, median household income, year of diagnosis, tumour size, histology, grade, and ER/PR/HER2 status. Propensity score weighting with Bayesian additive regression trees was used to balance covariates between tumour locations. Doubly robust estimation was then performed with multivariable logistic and Cox regressions to assess the association of tumour location with binary outcomes and BCSS, respectively.

Results: A total of 453,387 patients with a median follow-up of 70 months were eligible for analysis, of whom 293,070 (65%) had outer quadrant tumours, 127,237(28%) had inner quadrant tumours, and 33,560 (7%) had central tumours. After propensity score weighting, the rates of ALN metastases for outer quadrant, inner quadrant, and central tumours were 28.2%, 20.2%, and 32.6%, respectively.

Chemotherapy was given to 38.0%, 36.5%, and 38.8% of patients. Ten-year BCSS were

91.6%, 91.0%, and 90.5%. Compared to outer quadrant tumours, inner quadrant tumours had lower odds of ALN metastases (OR 0.62; 95% CI 0.61-0.63; P<0.001) and central tumours had higher odds (OR 1.30; 95% CI 1.26-1.33; P<0.001). Similarly,inner quadrant tumours had lower odds of receiving chemotherapy (OR 0.90; 95% CI

0.88-0.91; P<0.001) while central tumours had higher odds (OR 1.07; 95% CI 1.04-1.10; P<0.001). BCSS was worse in both inner quadrant (HR 1.07; 95% CI 1.04-1.10;P<0.001) and central (HR 1.10; 95% CI 1.04-1.15; P<0.001) tumours.

Conclusions: The risk of ALN metastases from breast cancer varies with tumour location. Inner quadrant tumours have worse BCSS than outer quadrant tumours despite a lower risk of ALN metastases. Reliance on ALN staging without consideration

S313

of tumour location may lead to treatment decisions that are inconsistent with breast cancer risk.

https://doi.org/10.1016/j.annonc.2023.09.521

326P

S314

Sentinel lymph node mapping in breast cancer: Evaluating the dual-tracer method with indocyanine green and

radioisotope

A. Kwong1, B.H.H. Cheung2, V.C.M. Man2

1Surgery Department, The University of Hong Kong - Li Ka Shing Faculty of Medicine,Hong Kong, China; 2Surgery, HKU - The University of Hong Kong, Hong Kong, China

Background: Indocyanine green (ICG) has the potential to improve sentinel lymph node (SLN) mapping. This current cohort study was designed to assess the value of ICG using a new ICG handheld system with radioisotope (RI) in patients with early breast cancer undergoing SLN biopsy.

https://doi.org/10.1016/j.annonc.2023.09.529

334P The contribution of nurses in early detection of breast cancer in Cameroon

N. Calvin1, M. Florence1, J.F. Domgue2, T. Gracious1, K. Mireille1, N. Marious1,C. Claudette1, D. Bonghaseh3, N. Kathleen1, S. Manga1

1Women’s Health Program, Cameroon Baptist Convention Health Services, Bamenda,Cameroon; 2Epidemiology, The University of Texas M. D. Anderson Cancer Center,Houston, TX, USA; 3Georgetown Global Health, Georgetown University, Yaounde,Cameroon

Background: Compared to global ﬁgures, breast cancer mortality to incidence ratio is worst in Sub Saharan Africa where about 80% of patients present with locally advanced and metastatic disease at diagnosis. In Cameroon, breast cancer is the commonest cancer with 4,170 cases recorded each year constituting 20.1% of all cancers diagnosed. Late disease presentation is attributed to poor awareness,absence of organized early detection programs, and inadequate facilities for accurate and timely diagnosis and treatment. Our objective was to investigate the role that nurses involved in cervical cancer screening/prevention can play in early detection of breast cancer in Cameroon.

Methods: The nurses involved in cervical cancer screening/prevention in a large faithbased healthcare organization called the Cameroon Baptist Convention Health Services (CBCHS) were trained to do clinical breast exams (CBE) for women aged 21 years and over, and also trained on breast tissue collection for pathology processing and examination. Clients with abnormal breast ﬁndings were provided Fine Needle Aspirations (FNA), TruCut biopsies or referred for ultrasound and/or mammography depending on the clinical presentation.

Results: Between January 2020 and December 2022, a total of 16,038 women age range (14-99) years were provided CBE with a mean and median age of 40.4 and 39,respectively. Among these, 750 (4.7%) had abnormal ﬁndings. Among those with

abnormal ﬁndings, 397(52.9%) had breast masses for which 213 (53.7%) had TruCut biopsies and FNA and the others were either referred or had previously established diagnosis. From the 213 Tru-Cut biopsies and FNA’s done, 76 (35.7%) showed a pathology diagnosis of invasive breast cancer while the others showed: acute mastitis 3(2.9%), ﬁbroadenoma 25 (11.7%), benign mass 83 (39.0%), non-diagnostic 12 (5.6%)and other diagnosis 19 (8.9%).

Conclusions: Nurses can play a key role in early detection of breast cancer if they are trained, and this can greatly reduce the number of women seen with late stage disease and also reduce mortality rates.

https://doi.org/10.1016/j.annonc.2023.09.530

335P

Real-world data: Correlation of radiological and pathologic complete response after neoadjuvant treatment of breast cancer

K. Cular, D. Gudelj, L. Toula, M. Krizic, M. Soce, N. Dedic Plavetic, M. Popovic,T. Silovski

Department of Oncology, KBC - University Hospital Centre Zagreb, Zagreb, Croatia

Background: Neoadjuvant chemotherapy (NAC) of newly diagnosed breast cancer is used to improve resectability, reduce the extent of breast and axillary surgery and improve overall survival. Accurate assessment of locoregional response to NAC is important for surgical planning. Radiological method of choice is post-treatment breast magnetic resonance imaging (MRI), which determines the rate of response according to RECIST criteria. The primary indicator of outcome of NAC is pathologic complete response (pCR). This study aimed to compare radiologic and pathologic complete response rates after neoadjuvant treatment of early breast cancer.

Methods: A retrospective study of 259 breast cancer cases who received NAC between 01.01.2020 and 31.12.2021 at University Hospital Centre Zagreb was conducted with prior Ethics Committee approval. Radiological and pathohistological characteristics of the tumor at the time of diagnosis and after neoadjuvant treatment were analyzed using the Hospital information system (BIS). Furthermore, post-neoadjuvant therapy MRI ﬁndings were correlated with the postoperative pathohistological ﬁndings. Sensitivity, speciﬁcity, accuracy, and positive predictive value of radiologic complete response (rCR) as a predictor of pCR were calculated.

Results: Complete data was available for 94.98% (246/259) of patients. In 62 (25.20%)patients, rCR was recorded, radiologic partial response (rPR) in 150 (60.98%), stable disease in 22 (8.94%), and progressive disease in 9 patients. In 78 (31.71%) patients pCR was achieved, 46 (58.97%) were also classiﬁed as rCR, while 32 (41.03%) of those showed a radiological stable disease or rPR. Out of the 62 patients with rCR, 16(25.81%) did not achieve pCR. The sensitivity and speciﬁcity of rCR were 90.48% and

58.97%, respectively, while positive predictive value was 82.61%. The overall accuracy of breast MRI in predicting pCR was 80.49%.

Conclusions: Although the sensitivity of breast MRI in predicting pCR was high, the speciﬁcity was low with only moderate overall accuracy. Low speciﬁcity can lead to an incorrect choice of breast surgery, therefore a better method of evaluation is necessary.

Disclosure: M. Krizic, N. Dedic Plavetic, T. Silovski: Financial Interests, Personal, Research Funding:Roche. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.531

336P Dual-mode near-infrared multispectral imaging system equipped with deep learning models improves the identiﬁcation of cancer foci in breast cancer specimens

Y. Liu1, L. Zhang1, J. Liao2, M. Zhang1, Y. Liu1, D. Han1, Z. Jia1, S. Niu1, H. Bu3, J. Yao2

1Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China; 2AI Lab, Tencent, Shenzhen, China; 3Department of Pathology, West China Hospital, Sichuan University, Chengdu, China

Background: For surgically resected breast cancer samples, it is challenging to perform specimen sampling by visual inspection, especially when the tumor bed shrinks after neoadjuvant therapy in breast cancer.

Methods: We developed a dual-mode near-infrared multispectral imaging system(DNMIS) to obtain richer sample tissue information by acquiring reﬂection and transmission images covering visible to NIR-II spectrum range (400e1700 nm).

Additionally, artiﬁcial intelligence (AI) was used to segment the rich multispectral data. 80 breast cancer samples were collected to verify the advantage of DNMIS in assisting pathologists to identify tumor beds.

Results: DNMIS demonstrated better tissue contrast and eliminated the interference of surgical inks on the breast tissue surface, helping pathologists ﬁnd the tumor area which is easy to be overlooked with visual inspection. Statistically, AI-powered DNMIS provided a higher tumor sensitivity (95.9% vs visual inspection 88.4% and X-rays

92.8%), especially for breast samples after neoadjuvant therapy (90.3% vs visual inspection 68.6% and X-rays 81.8%).

Conclusions: We infer that DNMIS can improve the breast tumor specimen sampling work by helping pathologists avoid missing out tumor foci.

https://doi.org/10.1016/j.annonc.2023.09.532

337P Comparison of fused diffusion-weighted imaging using unenhanced MRI and abbreviated post-contrast-enhanced MRI in patients with breast cancer

K. Lee

Diagnostic Radiology, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea

Background: To determine the percentage of breast cancers detectable by fused diffusion-weighted imaging (DWI) using unenhanced magnetic resonance imaging(MRI) and abbreviated post-contrast-enhanced MRI.

Methods: Between October 2016 and October 2017, 194 consecutive women (mean age, 54.2 years; age range, 28-82 years) with newly diagnosed unilateral breast cancer who underwent preoperative 3.0 T breast MRI with DWI were evaluated. Both fused DWI and abbreviated MRI images were independently reviewed by two radiologists for the detection of index cancer (which showed the most suspicious ﬁndings in both breasts), location, lesion conspicuity, lesion type, and lesion size. Moreover, the relationship between cancer detection and histopathological results of surgical specimens were evaluated.

Results: Index cancer detection rates were comparable between fused DWI and abbreviated MRI (radiologist 1: 174/194 [89.7%] vs. 184/194 [94.8%], respectively, P¼ 0.057; radiologist 2: 174/194 [89.7%] vs. 183/194 [94.3%], respectively, P ¼ 0.092).In both radiologists, abbreviated MRI showed a signiﬁcantly higher lesion conspicuity than fused DWI (radiologist 1: 9.37 2.24 vs. 8.78 3.03, P < 0.001; radiologist 2:9.16 2.32 vs. 8.39 2.93, P < 0.001). The k value for the interobserver agreementof index cancer detection was 0.67 on fused DWI and 0.85 on abbreviated MRI. For lesion conspicuity, the intraclass correlation coefﬁcients were 0.72 and 0.82 on fused DWI and abbreviated MRI, respectively. Among the histopathological factors, tumor invasiveness was associated with cancer detection on both fused DWI (P ¼ 0.011) andabbreviated MRI (P ¼ 0.004, radiologist 1), lymphovascular invasion was associatedwith cancer detection on abbreviated MRI (P ¼ 0.032, radiologist 1), and necrosis wasassociated with cancer detection on fused DWI (P ¼ 0.031, radiologist 2).

Conclusions: Index cancer detection was comparable between fused DWI and abbreviated MRI, although abbreviated MRI showed a signiﬁcantly better lesion conspicuity.

Disclosure: The author has declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.533

338P Breast cancer follow-up: A population-based cohort study

S. Di Cosimo1, R. Miceli2, S. Ljevar2, G. Tinè2, P. Baili3, V. Cappelletti1, G. Apolone3

1Advanced Diagnostics, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy;2Clinical Epidemiology and Trial Organization, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy; 3Scientiﬁc Directorate, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy

Background: Breast cancer (BC) survivorship guidelines recommend follow-up (F/U)with a schedule of physician visits and annual mammography. However, literature reﬂects an increasing reliance on advanced imaging. Our goal was to analyze BC F/U practice with its roots and effects at a population level.

Methods: We included women 18 years with early BC undergoing surgery between2012-2014. We accessed the data warehouse of Lombardy Region in Italy. After calculating the annual frequency of each imaging per patient, we included the derived covariates in unsupervised clustering to set three statistically different groups with increasing F/U intensity, ie minimal, moderate and maximal.We used the Kaplan-Meier method for overall survival (OS) estimates and the Coxmodel for multivariable analysis.

Results: Overall 28,775 women entered the study, median age was 61 years (IQR 49-72), median time since diagnosis 87.6 months (IQR 77.7-97.9), 69.7% had breastS317

conservative surgery. Of the 862,955 exams prescribed in the 5 years after surgery,

12.8% were mammograms. Ultrasound (64.7%) was the most common non recommended imaging, followed by computed tomography (11.7%), magnetic resonance(6.2%), and bone scan (4.6%). Intensive F/U was more likely after triple negative(30.1%) and HER2 positive (27.8%) than luminal-like BC (13.1%). Surveillance intensity decreased over time, resulting in 56% of BC survivors having minimal F/U from the third year after surgery onwords. At a 12 month landmark analysis, OS was 80.8%,

87.4% and 66.2% in women having minimal, medium, and maximal intensive F/U. The survival beneﬁt of medium intensive F/U was signiﬁcant in luminal-like; whereas, the negative effect of maximal intensive F/U extended to all subtypes and was independent of age, surgery, adjuvant and radiotherapy (HR 2.16, 1.99-2.36).

Conclusions: Use of non recommended imaging is common after BC surgery and increases with increasing risk of relapse. Due to the retrospective nature of our study,survival ﬁndings are only hypotheses generating. While intensive F/U possibly included women with poor prognostic factors not accounted for by the adjustment,medium intensive F/U might have allowed for timely/curative intervention of recurrent BC. Data overall offers an opportunity to discuss current F/U strategies.

Funding: This study is part of the project “I controlli periodici (follow-up) dopo la diagnosi e le terapie in pazienti liberi damalattia e asintomatici: verso una personalizzazione delle strategie di follow-up” supported by Grant n. RR33 of Lombardy Region, Italy.

Disclosure: S. Di Cosimo: Financial Interests, Personal, Other, Ad hoc project/protocol reviewer:MEDSIR; Financial Interests, Personal, Advisory Board, Treatment of HER2-positive breast cancer:Pier Fabre; Financial Interests, Personal, Other, Medical meeting material setup and distribution;Speaker Bureau: IQVIA. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1067

339P

An online mindfulness-based stress-reduction (MBSR)

intervention for breast cancer (BC) survivors: A randomized trial

M.G. Salazar-Alejo1, A.S. Ferrigno2, J. Gutiérrez-Ornelas3, F. Mesa-Chavez1,A. Platas4, H.C. Verduzco-Aguirre5, C.M. Villarreal Garza1

1Breast Cancer Center, Hospital Zambrano Hellion TecSalud, San Pedro Garza Garcia,Mexico; 2Department of Medicine, Yale University, New Haven, CT, USA; 3Mindfulness Training, Centro Mindfulness Monterrey, San Pedro Garza García, Mexico; 4Clinical Research, Médicos e Investigadores en la Lucha contra el Cáncer de Mama, Mexico City, Mexico; 5Departamento de Hemato-Oncologia, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico

Background: Recent literature has proposed MBSR as an intervention that can decrease symptom burden in oncologic patients. However, there is paucity of data on the effect of online-delivered interventions despite the potential of this modality to improve access and adherence to treatment. The aim of this study was to study the effects of an online MBSR intervention on BC survivors.

Methods: Women aged18 years, diagnosed with stage 0-III BC at least 1 year prior toinclusion and not undergoing active treatment were invited to participate. Those with mild anxietywere randomized to an onlineMBSR intervention orwaitlist (WL).TheMBSR intervention consisted of 8weekly sessions ofmeditation guided by a certiﬁed instructor.

Measured outcomes included anxiety (GAD-7), depression (PHQ-9), worry about disease recurrence (CWS), fatigue (FACIT-F), insomnia (ISI), and vasomotor symptoms (MENQOL). Assessments were done at baseline, 2 months, 5 months, and 8 months.

Results: A total of 97 patients with a median age of 45 years (IQR: 40-51) and a median of 24 months (IQR: 15-36) after diagnosis were included. 66 were randomized to MBSR and 31 to WL. Most participants were married (54%), had public health insurance (49%), and were diagnosed with stage III (33%) or II (32%) BC. Linear mixed models controlling for health insurance, education, and stage showed that MSBR led to signiﬁcant reductions in anxiety (GAD-7 -3.76, p<0.01), depression (PHQ-9 -4.17 points, p<0.01), cancer worry (CWS -2.59 points, p<0.05), fatigue (FACIT-F -4.15 points, p<0.05), and insomnia (ISI -4.10 points, p<0.01) at the 8 months follow-up,but not vasomotor symptoms (MENQOL score +0.51 points, p¼0.42). Adjusted meanscores are shown in the Table.

Table: 339P

Questionnaire

Group

Baseline

8 months

GAD-7

MSBR

10.3

5.6

11.1

9.4

PHQ-9

11.3

6.1

12.8

FACIT-F

13.7

8.5

14.9

12.7

CWS

14.4

11.0

14.0

13.6

ISI

13.9

8.2

13.1

12.3

MENQOL

4.4

3.1

3.9

2.6

Conclusions: An online MBSR intervention demonstrated a statistically signiﬁcant and persistent reduction in anxiety and depression symptoms in BC survivors. This modality offers BC patients better access to interventions with the potential to improve their quality of life.

Disclosure: J. Gutiérrez-Ornelas: Financial Interests, Personal, Financially compensated role, Director: Centro Mindfulness Monterrey. A. Platas: Non-Financial Interests, Personal, Member of Board of Directors: MILC - Médicos e Investigadores en la Lucha contra el Cáncer de Mama. H.C. VerduzcoAguirre: Financial Interests, Personal, Other, Research honoraria: Celulicity; Financial Interests,Personal, Other, Travel grants: Asofarma, AstraZeneca. C.M. Villarreal Garza: Financial Interests,Personal, Invited Speaker: MSD Oncology, Novartis, Pﬁzer, AstraZeneca Mexico, Lilly; Financial Interests, Personal, Research Grant: Pﬁzer; Financial Interests, Personal, Advisory Board: Lilly, AstraZeneca Mexico, MSD Oncology; Non-Financial Interests, Personal, Member of Board of Directors:MILC - Médicos e Investigadores en la Lucha contra el Cáncer de Mama. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1068

340P Novel application of spatial analyses to investigate environmental factors and hormone receptor-positive breast cancer

A. Thomas1, A. Zorn2, K.M. Conway2, A. Rhoads2, J.J. Oleson2, J. Pakish-Darby3,C.F. Lynch2, P.A. Romitti2

1Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC,USA; 2Epidemiolgy, Biostatistics, Toxicology Department, S416 CPHB, The University of Iowa - College of Public Health, Iowa City, IA, USA; 3Obstertrics and Gynecology,Wake Forest University School of Medicine, Winston-Salem, NC, USA

Background: Incidence of hormone receptor-positive (HR+) breast cancer (BC) is increasing. With environmental factors associated with HR+ tumors, we used spatial analysis to identify regions with excess HR+ BC.

Methods: Surveillance data for 38,944 women with a primary diagnosis of BC with reported HR status during 2000-18 and no prior cancers were obtained from the Iowa Cancer Registry. HR+ tumors were deﬁned as those that were estrogen receptorpositive or progesterone receptor-positive. Spatial patterns in HR+ BC/1,000 women and as a proportion of all women with BC with known HR status were examined by county (n¼99) for premenopausal aged (15-49 years; n¼7,935) and post-menopausalaged (50 years; n¼31,009) women; proportions were analyzed using logisticregression with spatial correlation via intrinsic conditional auto-regressive models at the county level and general additive models (GAMs) at the residence level (premenopausal, n¼7,930; postmenopausal, n¼30,988).

Results: HR status was classiﬁed for 38,944 women (premenopausal: 6,188 HR+, 1,747 HR-; postmenopausal: 26,190 HR+, 4,819 HR-). Across all counties, rates of HR+ BC ranged from 4.9-17.1/1,000 premenopausal women, representing 57.6-96.8% of BC cases among these women and a state average of 78.0%. Respective values were

29.3-61.1/1,000 postmenopausal women, 75.6-92.6%, and 84.5%. The top 21 counties with the highest estimated proportions of HR+ BC after spatial smoothing within each age group represented 25.3% of all premenopausal women and 21.2% of all postmenopausal women in Iowa. Twelve (57.1%) of these counties overlapped between age groups; two counties were elevated above the respective state averages for both age groups, with 95% probability. GAMs indicated similar areas of increased probability of HR+ BC.

Conclusions: Findings suggest some spatial overlap in proportions of incident HR+ BC between pre- and postmenopausal women. This overlap may indicate shared environmental risk factors for HR+ BC between age groups in these regions. Our analytical approach provides a model that can be applied across broader geographic regions.

Future analyses will explore temporal differences in these incident cancers.

Legal entity responsible for the study: University of Iowa.

Funding: University of Iowa.

Disclosure: A. Thomas: Financial Interests, Personal, Advisory Board, One time Ad Board: AstraZeneca, Genentech; Financial Interests, Personal, Stocks/Shares: Pﬁzer, Bristol Myers Squibb, Gilead Sciences, Johnson and Johnson, Doximity; Financial Interests, Personal, Royalties, Husband: UpToDate; Financial Interests, Institutional, Local PI: Sanoﬁ, Merck. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1069

341P

Table:Region(n)

Cold (7

Warm

Impact of environmental temperature on clinical outcomes of early-stage breast cancer (BC)

A.M. Roy1, A. George2, K. Attwood2, A. Gupta1, B. Czerniecki3, J. Carpten4,V.F. Borges5, B. Schneider6, J. Kolesar7, C. Moskaluk8, C. Shriver9, C. Matsen10,S. Ganesan11, S. Phadke12, W. Razaq13, S. Gandhi1

1Medical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA;2Biostatistics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA; 3Surgical Oncology, Mofﬁtt Cancer Center, Tampa, FL, USA; 4Clinical Genomics, Keck School of Medicine - University of Southern California USC, Los Angeles, CA, USA; 5Medical Oncology, UCHealth Cancer Care - Anschutz Medical Campus - University of Colorado Cancer Center, Aurora, CO, USA; 6Medical Oncology, Indiana University Simon Cancer Center, Indianapolis, IN, USA; 7Pharmacy, UK - University of Kentucky - Markey Cancer Center, Lexington, KY, USA; 8Pathology, The University of Virginia, Charlottesville, VA,USA; 9Surgical Oncology, Murtha Cancer Center, Bethesda, MD, USA; 10Surgical Oncology, University of Utah Health - Huntsman Cancer Institute, Salt Lake City, UT,USA; 11Medicine Dept., Rutgers Cancer Institute of New Jersey, New Brunswick, NJ,USA; 12Medical Oncology, University of Iowa Holden Comprehensive Cancer Center,Iowa City, IA, USA; 13Medical Oncology, Stephenson Cancer Center, Oklahoma University Health Science Center, Oklahoma City, OK, USA

Background: Preclinical evidence using mouse model suggests that thermal/cold stress increases tumor growth by modulating the tumor microenvironment; however,the clinical relevance of temperature on BC outcomes is unknown. Studies show that residing in cold regions is associated with higher incidence of BC. We aim to study the impact of environmental temperature on the pathological complete response (pCR)and survival of early-stage BC patients (pts).

Methods: A multi-institutional study was conducted within the Oncology Research Information Exchange Network. We analyzed the clinical and genomic data for earlystage BC pts from 12 centers in the United States from different environment zones (5 warm (W) and 7 cold (C)) (based on average annual regional temperature obtained from National Centers for Environmental Information). Cox regression was used to measure the association of climate and overall/relapse-free survival (OS/RFS) after adjusting for confounders.

Results: Out of the 1,304 early-stage BC pts, 271 pts received neoadjuvant chemotherapy (NAC) (186 W, 85 C). Higher clinical T- and N-stages were observed in pts from W compared to C regions (p<0.001). Pts residing in C regions had more comorbidities(57.6% vs 48%, p<0.001). Pts in W regions had higher pCR, though not statistically signiﬁcant (8% vs 2.5%, p¼ 0.1). The OS (univariate (UV) HR¼ 0.48, 95% CI 0.27-0.64,p <0.001; multivariate (MV) aHR¼ 0.56, 95% CI 0.32 - 0.96, p¼ 0.03) and RFS (UVHR¼ 0.51, 95% CI 0.38 - 0.68, p<0.001; MV aHR¼ 0.52, 95% CI 0.36 - 0.75, p¼0.0005) were higher in pts from W compared to C regions (Table). The OS (aHR¼ 0.35,p¼ 0.02) and RFS (aHR¼ 0.49, p¼ 0.02) of pts who received NACT were also higher inW regions.

s 5-yr OS

(95% CI)

Median OS(months)(95% CI)

5-yr RFS(95% CI)

RFS (95% CI)

82) 83 (76-86) % 157.7

(116.6-NR)

69 (62-76) % 108.4

(88.9-147.8)

(522) 95 (92-97) % 214.7

(205.3-NR)

83 (79-87) % 250.4

(129.9-250.4)

Conclusions: Early-stage BC pts living in cold have worse OS and RFS compared to warm regions. Larger studies are warranted to validate these interesting ﬁndings and further research focusing on therapeutic strategies to abrogate this outcome disparity by temperature is needed.

Legal entity responsible for the study: A.M. Roy.

https://doi.org/10.1016/j.annonc.2023.09.1070

342P Fertility preservation in young breast cancer patients:Patient’s knowledge and perception

Z. Naimi, A. Riahi, M. Bohli, R. Ben Amor, A. Hamdoun, R. Haddad, G. Bouguerra,L. Kochbati

Department of Radiation Oncology, Abderrahmen Mami Hospital, Ariana, Tunisia

Background: This study aimed to assess breast cancer (BC) patients’ knowledge and perception of fertility risks and preservation, and to determine factors that impact fertility preservation(FP) patient decision making.

Methods: We performed a cross-sectional study including 70 BC patients 45 year-old. Patients were surveyed using a 29 item questionnaire assessing their personal

experience and knowledge about fertility risks and FP treatments. A knowledge score(0-12) was calculated with 1 point awarded for each correct answer. Statistical associations between socio-demographic characteristics, personal experience and knowledge score were analyzed.

Results: Mean age was 34 year-old. Thirty-seven patients had a college degree and 80% were married. Previous pregnancy/live birth were reported in 77%/72% of patients. Twenty-seven percent of patients had prior contact with infertility. Fifty-ﬁve patients were informed about infertility risks related to BC treatment. Only 62.8% of patients received information about FP treatments. Thirty-ﬁve patients were referred to FP consultation of whom 12 patients received FP treatments. Embryos/oocytes freezing were the main used options. The main reasons for skipping FP treatments were lack of pregnancy desire (38.6%) and insufﬁcient provided information (30%).

“Complexity of FP procedure” and “fear of delaying cancer treatment” were reported in 8.6% and 4.3% of cases respectively. Mean knowledge score was 6(3 -11). Forty-six percent of patients believed that “FP treatment is related to an increased risk of cancer recurrence”. Only 61.4% of patients were aware that “freezed eggs remain available in the future whenever the patient is ready to use them”. Most of the patients (81.4%) were aware that having a spouse was not a prerequisite for FP treatment. Knowledge about FP treatments availability and costs was poor with more than half of patients overestimating costs and assuming the lack of FP treatment options. Only 60% of patients were aware of an operational legal framework for FP in Tunisia.

Conclusions: This study showed that FP baseline knowledge in BC patients is generally poor. Patient’s access to clear and concise fertility information is the key for effective interventions for fertility preservation.

https://doi.org/10.1016/j.annonc.2023.09.1071

343P Modulation of the immune system (ImS) during moderate physical activity (mPA) in breast cancer (BC) patients (pts)treated with neoadjuvant chemotherapy (NACT)

O. Garrone1, A. Abbona2, M. Paccagnella2, F. Ruatta1, P. Vanella3, G. Tomasello1,F. Barbin1, M.G. Rossino1, N. Croce3, M.C. Merlano4

1Medical Oncology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico,Milan, Italy; 2Medical Oncology, Fondazione ARCO - Cuneo, Cuneo, Italy; 3Medical Oncology, Azienda Ospedaliera S. Croce e Carle Cuneo, Cuneo, Italy; 4Medical Oncology, Candiolo Cancer Institute FPO - IRCCS, Candiolo, Italy

Background: The link between mPA and ImS is known. We studied the effect of mPA on a panel of circulating cytokines (Cy) during NACT in BC pts.

Methods: Pts underwent epirubicin and cyclophosphamide, followed by weekly paclitaxel trastuzumab. Blood samples were collected in pts underwent mPA (TR,Nordic or ﬁt walking, 3 workouts/week, 1 hour each in the 10-12 weeks before surgery) and in pts who declined mPA (UN) at T0, at day 1 of week 6 of paclitaxel (T1,starting point of mPA) and before surgery (T2). 22 Cy: IL1b, IL2, IL4, IL5, IL6, IL7, IL8,IL10, IL12, IL13, IL15, IL17a, IL18, IL21, CCL2, CCL4, CXCL10, CCL22, IFNg, TGFb, TNFa,VEGF were measured by Simple Plex EllaTM. Differences between the median Cy values were analyzed with Mann-Whitney U test. Comparisons between time points within the same group were analyzed with Wilcoxon signed-rank test. ROC analysis was performed to highlight relevant variables for TR and UN. PCA and PERMANOVA evaluated the impact of mPA on Cy at T1 and T2.

Results: 91 pts have been accrued. 88 pts have been analysed, 68 TR and 20 UN. At T0 IL4 was higher (p < 0.01) in UN pts. At T1 IL4 and IL17 were higher (p < 0.01) in UN.

At T2 higher values (p < 0.01) of IL4, IL7, IL17, VEGF in UN. Higher IL21 (p < 0.01) in TR. Longitudinal analysis (LA) between T0 and T1 in TR and UN showed increase of INF-g, IL5, IL15, CCL2, CXCL10, IL17a. UN pts showed also increase of IL6. TR pts showed increase of IL7, IL18 and decrease of IL4, IL13, CCL22. LA between T1 and T2 showed increase of IL21, CCL22, TNFa and decrease of IL6, IL8, IL15 TGFb in TR pts.

UN showed increase of CXCL10 and decrease of IFNg, IL6, IL8, CCL2, TGFb. PCA discriminated TR from UN pts at T2 (p¼0.045 PERMANOVA analysis).

Conclusions: TR and UN pts were similar at T0. LA between T0-T1 showed that CT induced prominent changes in TR suggesting a more plastic ImS. LA between T1-T2 showed signiﬁcant changes of Cy only in TR supporting a role of mPA in the modulation of the ImS. Overall, CT induced weak changes in UN and more consistent changes in TR pts, suggesting a more efﬁcient ImS and a possible additional effect derived from mPA in TR. PCA at T2 supports these hypotheses showing a signiﬁcant grouping of TR clearly separate from UN.

Legal entity responsible for the study: O. Garrone.

Funding: Fondazione IRCCS Ca’ Granda Ospedale maggiore Policlinico, Milan.

Disclosure: O. Garrone: Financial Interests, Personal, Advisory Board: Eisai, Daiichi Sankyo;Financial Interests, Personal, Speaker, Consultant, Advisor: Pﬁzer; Financial Interests, Personal,Invited Speaker: Novartis, Lilly. G. Tomasello: Financial Interests, Personal, Advisory Board: Novartis,Lilly, Amgen. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1072

S319

344P

S320

Epidemiological analysis and overall survival of female breast cancer in a developing middle eastern country over 18 years

M. Abunasser1, A. Alhajahjeh2, Z. Abdulelah3, A. Abdulelah4, A. Ghazzawi4,D. Murshedi4, H. Abdel-Razeq5

1Medical Oncology, KHCC - King Hussein Cancer Center, Amman, Jordan; 2Internal Medicine, IAU - The University of Jordan, Amman, Jordan; 3Internal Medicine, St.

Bartholomew’s Hospital - Barts Health NHS Trust, London, United Kingdom; 4Internal Medicine, KHCC - King Hussein Cancer Center, Amman, Jordan; 5Lung Cancer, Genitourinary Cancers, Breast Cancer, KHCC - King Hussein Cancer Center, Amman, Jordan

Background: Breast cancer imposes a signiﬁcant regional and global health burden not only due to being the most prevalent malignancy in females in the Middle East and worldwide, but due to the associated substantial morbidity and mortality.

Therefore, the determination of the epidemiological features of breast cancer in the Middle East is of prominent interest given the signiﬁcant resultant burden associated with breast cancer as it enables for the efﬁcient introduction of effective interventions.

Methods: Data on 20,046 female patients of different nationalities and residing in Jordan diagnosed with breast cancer during the period of 2000-2018 were obtained from the Jordan Cancer Registry. Consequently, comprehensive statistical analysis was performed to establish the epidemiological characteristics of breast cancer in Jordan,including the overall survival and crude incidence.

Results: A total of 20,046 female patients with a mean age of 51.5 12.5 years oldwere included in the analysis. Only 6.54% of the enrolled patients were smokers at the time of diagnosis. Breast cancer was more commonly affecting the left breast,

46.9% of the patients, than the right breast, 43.5% of the patients, whereas 1.18% of the patients had breast cancer bilaterally. The upper outer quadrant of the breast was the most commonly reported site of tumour location. Moderately differentiated carcinoma was the most commonly encountered grade in 31.4% of the patients,whereas 28.9% had poorly differentiated carcinoma. Regional spread to the lymph nodes was observed in 19.0% of the sample and 13.1% of the patients had distant metastasis, while localized breast cancer was noted in 16.6% of the patients. A statistically signiﬁcant increase in the crude incidence of breast cancer in females has been observed in Jordan over the 18 years period with a crude incidence estimated effect of 0.46 (P-value<0.001). The overall survival rate was determined to be 95.8%,

83.2%, and 62.8% at 1-year, 3-year, and 5-year interval, respectively.

Conclusions: Breast cancer in Jordan imposes a signiﬁcant burden due to the signiﬁcant increase in the crude incidence over the 18-year period, and thus mandating vigorous and vigilant screening and preventative measures.

https://doi.org/10.1016/j.annonc.2023.09.1073

345P The effect of early post-operative exercise on shoulder

function in breast cancer patients: A randomised controlled trial

J. Min1, J. Ryu2, S. Yeon2, S. Park3, J.Y. Kim3, S.I. Kim3, J.W. Kang4, S. Jun4, R. Park5,Y.J. Lee5, T.H. Lee4, E. Kim2, C. Oh4, K. Chiho5, D-H. Park2, J. Jeon2

1Convergence Medicine, Yonsei University College of Medicine - Wonju Severance Christian Hospital, Wonju, Republic of Korea; 2Sports Industry Studies, Yonsei University, Seoul, Republic of Korea; 3Division of Breast Surgery, Department of Surgery,Severance Hospital - Yonsei University College of Medicine, Seoul, Republic of Korea;4Sports Medicine, Yonsei University, Seoul, Republic of Korea; 5Sports Industry, Yonsei University, Seoul, Republic of Korea

Background: Breast cancer surgery can impair shoulder function, and the effects of rehabilitation exercise during early recovery remain uncertain. This study aims to assess the effectiveness of tailored exercise intervention on shoulder function recovery at one and six months post-surgery.

Methods: A total of 122 breast cancer patients (Stage 0-3) scheduled for surgery were evaluated, and 58 patients (mean age 50.26.6 years) were randomly assigned to anexercise or usual care group (1:1). The exercise group underwent ﬁve tailored exercise education sessions, starting one day before hospital discharge and continuing for four weeks after surgery. Participants received exercise diaries, online links, and QR codes for home-based workouts. The primary outcome measured the proportion of participants achieving 90% of their pre-surgery shoulder ROM and strength at one and six months post-surgery. Secondary measures included DASH and SPADI scores,physical activity levels, and body composition.

Results: Out of 58 participants, 56 (96.6%) completed the trial, with a 96.6% exercise compliance rate one month after surgery. In the exercise group, 92.9% and 96.2%achieved pre-surgery shoulder strength levels at one and six months post-surgery,

respectively, compared to 3.7% and 32.1% in the control group. The exercise group also exhibited signiﬁcantly lower shoulder pain and disability scores (SPADI) at one and six months after surgery, as well as higher physical activity levels at six months.

Table: 345P Change in shoulder strength among postoperative breast cancer patients

Affected arm

EPET (n¼25)

Usual Care (n¼26)

lume 34 - Issue S2

Sum of

strength (Ib)T0

44.110.2

47.511.1

0.36

23.210.3*** 23.89.4***

0.80

40.411.9

28.511.9***

0.001

45.914.7

32.011.2***

51.314.0

32.09.2***

61.017.1*** 38.38.4***

MeanSD, P¼represented the results of independent T-test (the p-valueadjusted for Bonferroni method (0.05/6¼0.0083), *¼represented paired t-test[**p<0.01 vs. baseline, ***p<0.001 vs. baseline (p-value adjusted for Bonferroni method)] Abbreviation: early postoperative exercise therapy; EPET.

Conclusions: Early implementation of tailored exercise during rehabilitation signiﬁcantly improved shoulder function beyond pre-surgery levels. This study provides essential insights into the efﬁcacy and safety of early rehabilitation exercises for breast cancer patients during the post-surgery recovery phase.

Clinical trial identiﬁcation: The Institutional Ethics Review Board of Severance Hospital and WHO International Clinical Trials Registry Platform (ICTRP; KCT0006997)approved the trial.

Funding: This research was supported by the Ministry of Education of the Republic of Korea, the National Research Foundation of Korea (NRF-2020S1A5B5A17090332) and Korea Breast Cancer Foundation (KBCF-2020U002).

https://doi.org/10.1016/j.annonc.2023.09.1074

346P Quality of life (QoL) and toxicity in patients (pts) with hormone receptor-positive, HER2-negative early breast cancer (HR+, HER2e eBC) treated with adjuvant (adj)endocrine therapy (ET) in the CANcer TOxicities (CANTO)study

A. Bertaut1, T. Badovinac Crnjevic2, A-L. Martin3, C. Gaudin4, L. Chen5

1Methodology and Biostatistics Unit, Centre Georges François Leclerc Cancer Center,Dijon, France; 2Clinical Science Oncology, F. Hoffmann-La Roche AG - Switzerland,Basel, Switzerland; 3Health Data and Partnership Department, Unicancer, Paris,France; 4CANcer TOxicity (CANTO), Unicancer, Paris, France; 5Product DevelopmentData Science- RWD Enabling Platform, Genentech, Inc., South San Francisco, CA, USA

Background: ET is the mainstay treatment (tx) for HR+ eBC but they have persistent side effects that negatively affect QoL, leading to early tx discontinuation and compromising outcomes. We describe the incidence of ET toxicity and its QoL impact in CANTO.

Methods: CANTO (NCT01993498) is a prospective, longitudinal cohort study enrolling pts with invasive (cT0-cT3, cN0-3, no metastases) BC from 26 French cancer centres.

Pts with HR+, HER2e eBC treated with adj ET were followed for the ﬁrst 3 years (yrs)after eBC diagnosis. Pt demographics, clinical data, adherence, symptoms and QoL were collected. Questionnaires were administered at baseline (BL), 3e6 months (mo;M0) after primary surgery, chemotherapy or radiotherapy completion (whichever came last), and 12 mo, 36 mo and 60 mo after M0. Descriptive analyses were conducted for frequency of symptoms and mean/median QoL questionnaires summary scores.

Results: Of the 5564 pts who met the inclusion criteria (median age: 57 yrs), 63%were post-menopausal and 52% had stage I eBC at diagnosis. The table shows QoL and toxicity data. Global and functioning QoL remained high at BL and during tx. BCspeciﬁc symptoms persisted during tx. Pain was the most prevalent toxicity in the ﬁrst 3 yrs; prevalence of muscular and joint pain increased over time. Mean intensity of global, muscular and joint pain all remained high over the course of ET (median intensity: w6 [0e10 scale]). ET adherence was 81e93% over time; in the ﬁrst 3 yrs,23% switched ET and 7% discontinued adj ET; toxicity was the main reason cited.

Table: 346P

M0 12 mo 36 mo

Mean EORTC QLQ-C30

83 80 79

Global health status

68 68 66

Physical functioning

91 85 84

Role functioning

87 80 82

Emotional functioning

65 72 70

Cognitive functioning

82 79 77

Social functioning

91 83 85

Insomnia

43 41 43

Fatigue

28 36 35

Pain

15 28 30

Mean EORTC QLQ-BR23

Body image

88 75 77

Future perspective

49 56 61

Sexual functioning

26 26 26

Breast symptoms

13 26 20

Systemic therapy side effects 11 20 19

Arm symptoms

9 21 19

Toxicity, %

Global and back pain

- 71 74

Muscular and back

- 32 36

Joint and back

- 59 68

Conclusions: While global and functional QoL remained high in the ﬁrst 3 yrs after eBC diagnosis, BC-speciﬁc symptoms slightly increased/persisted during ET. This study conﬁrmed long-term toxicity of ET, particularly pain. Better management of symptoms and supportive interventional strategies are needed to further improve QoL in eBC.

Clinical trial identiﬁcation: NCT01993498, ﬁrst posted November 25, 2013.

Disclosure: A. Bertaut: Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd: F. Hoffmann-La Roche Ltd. T. Badovinac Crnjevic: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd/ Genentech; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd; NonFinancial Interests, Personal, Other, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd: F. Hoffmann-La Roche Ltd. A. Martin, C. Gaudin: Non-Financial Interests,Personal, Other, Research funding: Support for third-party writing assistance: F. Hoffmann-La Roche Ltd. L. Chen: Financial Interests, Personal, Full or part-time Employment: Genentech, Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd; Non-Financial Interests, Personal,Other, Research funding: Support for third-party writing assistance: F. Hoffmann-La Roche Ltd.

https://doi.org/10.1016/j.annonc.2023.09.1075

348P Long-term opioid use following treatment of localized breast cancer: A real-world analysis

A. Shai1, E. Granot-Hershkovitz2, S. Amar-Farkash2, K. Rosenberg-Katz2, D. Aran3

1Breast Cancer Unit, RAMBAM Health Care Campus, Haifa, Israel; 2Data Science and Research Department, Carelon Digital Platforms Israel, Tel Aviv, Israel; 3Faculty of Biology, Technion - Israel Institute of Technology, Haifa, Israel

Background: Chemotherapy for early breast cancer (BC) increases the risk of chronic opioid use. Factors associated with new opioid use after (neo)adjuvant chemotherapy for BC are poorly understood.

Methods: We analyzed Elevance Health administrative claims and Cancer Care Quality Program data between 2017-2022. BC patients who underwent surgery and(neo)adjuvant chemotherapy were included. Patients that had claims for either opioids or for medications used to treat neuropathic pain before BC diagnosis were excluded. Long-term use was deﬁned as opioid drug claims lasting at least 3 months within 1 year of follow-up. We explored factors associated with this outcome via logistic regressions, with additional stratiﬁcation to adjuvant/neoadjuvant groups.

Results: Among 3,353 BC patients, 156 (4.56%) were prescribed long-term opioids during the ﬁrst year following chemotherapy. Young age, advanced stage, mastectomy(vs. lumpectomy), and higher comorbidity score were associated with long-term opioid usage (Table). Of patients aged 45 (N¼442), 8.6% had long-term opioidclaims, while patients aged 65-75 (N¼653), 2.45% had such claims. When analyzingspeciﬁc comorbidities, signiﬁcant associations with opioid use were found for chronic obstructive pulmonary disease (COPD), liver disease, and peptic ulcer in patients treated with neoadjuvant chemotherapy. Rheumatic disease and congestive heart failure were associated with opiod use in patients treated with adjuvant chemotherapy.

Table: 348P Factors associated with long term opioid use

OR Conﬁdence interval p value

Age

0.66 0.55-0.78

1.40E-06*

Lymph node +

1.51 1.02-2.24

4.13E-02

Social determinant index

1.07 0.91-1.26

4.17E-01

Charlson’s comorbidity

1.4 1.21-1.64

1.29E-05*

Stage II (ref stage I)

2.16 1.33-3.52

1.93E-03*

Stage III (ref stage I)

1.35 0.72-2.54

3.52E-01

Mastectomy (ref lumpectomy) 2.41 1.52-3.81

1.77E-04*

Mastectomy and lumpctomy(ref lumpectomy)

5.72 3.33-9.8

2.34E-10*

Radiotherapy

0.64 0.43-0.96

2.87E-02*

Hormonal

0.71 0.5-1

5.27E-02

Anti HER2

0.91 0.63-1.31

6.09E-01

Immunotherapy

2.29 0.75-6.97

1.45E-01

Taxans

1.09 0.59-1.99

7.87E-01

Conclusions: This study offers valuable real-world insights into the prevalence and potential risk factors for chronic opioid use during the ﬁrst year following chemotherapy for BC. Young age, mastectomy and higher comorbidity index were associated with chronic opiod use in this cohort.

Disclosure: E. Granot-Hershkovitz, S. Amar-Farkash, K. Rosenberg-Katz: Financial Interests, Personal, Full or part-time Employment: Elevance Health. D. Aran: Financial Interests, Personal, Other,Consultant: Carelon Digital Platforms, Link Therapeutics, CytoReason. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.1076

349P The inﬂuence of diabetes on taxane-induced neurotoxicity and quality of life in breast cancer patients

E. Cimbro1, M. Dessi1, P. Ziranu1, C. Madeddu1, F. Atzori1, E. Lai1, A. Pretta1,S. Mariani1, C. Donisi1, D. Spanu1, M. Pozzari1, S. Murgia1, C. Codipietro1,E. Palmas1, G. Sanna1, F. Semonella1, S. Sardo2, G. Finco2, M. Scartozzi1

1Medical Oncology Department, University Hospital of Cagliari, Monserrato, Italy;2Anesthesiology Department, University of Cagliari, Monserrato, Italy

Background: Peripheral neuropathy is one of the long-term complications of diabetes.

In breast cancer diabetic patients, this condition can worsen neurotoxic symptoms induced by taxane-based therapy administration. Chemotherapy induced peripheral neuropathy (CIPN) and its inﬂuence on patient’s quality of life (QoL) is evaluated through certiﬁed questionnaires (NCI-CTC, EORTC QLQ-CIPN20, FACT-TAXANE).

Methods: Data from stage I-III breast cancer patients treated with taxane-based therapy between 2018 and 2022 were retrospectively analyzed at the Medical Oncology of the University Hospital of Cagliari. 300 patients, median age 57 years (32-85), followed a schedule of PCT 80mg/m2 30 weekly per maximum 12 adminis-trations; 43 patients had diabetes (14,3%). Peripheral neuropathy was evaluated by the NCI-CTC scale at every drug administration. QLQ-CIPN20 and FACT-TAXANE questionnaires were collected at baseline, at 4 and 12 weeks of treatment. KruskalWallis test was used to assess relation between neurotoxicity grade and QoL; ANOVA for repeated measures was used to test differences at different timing. Student’s Ttest was used to analyze differences in diabetic and non-diabetic population.

Results: Neurotoxicity inﬂuenced QoL, in both populations, at cycle IV (p<0.001) and cycle XII (p¼0.008). Patients with grade 0, 1 and 2 neurotoxicity reported a QLQ-CIPN20 median score of 32, 34 and 43 at cycle IV respectively, and a median value of 27, 33 and 34 at cycle XII respectively. ANOVA test showed a signiﬁcant worsening of QLQ-CIPN20 and FACT-TAXANE scores at 4 and 12 weeks vs. baseline (p<0.001 for both). Values of QLQ-CIPN20 remained signiﬁcantly higher in comparison to baseline also at 3 (p<0.001), 6 (p<0.001) and 12 months (p<0.001) follow up. In diabetic population, scores were signiﬁcantly higher (p<0.05) in all neurotoxicity questionnaires, but no difference in QoL was highlighted by FACT-TAXANE, compared to non diabetic patients.

Conclusions: The use of QLQ-CIPN20 and FACT-TAXANE questionnaires identiﬁed neurotoxicity onset and its correlation to QoL, yet at an initial phase of treatment.

Diabetic patients presented more severe neurotoxicity, without inﬂuencing overall QoL.

https://doi.org/10.1016/j.annonc.2023.09.1077

S321

350P

Quality of life data on sexual relations in early breast cancer patients

M.L. Garrido, B.I. Tavara, L. Lopez, S. Pérez, M. Vázquez, M. Lopez Flores,C. Castañón, S. Abella Alvarez, A. López

Medical Oncology Department, Complejo Asistencial Universitario de León, León,Spain

Background: The diagnosis and treatment of breast cancer involves changes in personal, family, social, professional and sexual relationships. In this study we assessed sexual satisfaction in patients with early breast cancer using the validated SEXSAT-Q scale.

Methods: We used the SEXSAT-Q quality of life questionnaire in 60 patients diagnosed with early breast cancer at our centre. Six dimensions were studied: 1. Loss of sexual desire. 2. Alteration of body image. 3. Psychological coping. 4. Discomfort during sexual intercourse. 5. Satisfaction during sexual intercourse. 6. Satisfaction with breast reconstruction. Data were collected in Medical Oncology Department during March 2023.

Results: A sample of 60 patients was selected, aged 26-72 years old, with a median age of 52 years, who had undergone breast cancer surgery, 73.33% by conservative surgery. 20% were premenopausal, 10% were perimenopausal and 70% were menopausal. 35% were being treated with chemotherapy, 56.67% with hormonoterapy and 8.33% with anti-HER2. 78.33% had a stable partner and did not use contraception. 30% of patients were quite or very sad and depressed since starting treatment. 50% of patients believe that the treatment has worsened their body image. 75% reported that during treatment their sexual relations were not satisfactory. 61.67% believe that their sexual desire has decreased and 45% admit having more problems reaching orgasm since diagnosis.

Conclusions:Women with curable breast cancer it is important to know the impact of diagnosis and treatment on the sexual sphere. The SEXSAT-Q questionnaire is a validated scale capable of measuring the sexual satisfaction of our patients.

Legal entity responsible for the study: M.L. Garrido Onecha.

https://doi.org/10.1016/j.annonc.2023.09.1078

351TiP EORTC BCG 1984 e NOBLE: Noeoadjuvant olaparib and durvalumab for patients with BRCA-associated triplenegative breast cancer

E. Buhrer1, E. Xenophontos1, A.-S. Hamy-Petit2, J. Casas1, C. Callens3, A. Lanzi4,T. Meyskens5, C. Poncet6, E.G.C. Brain2

1Medical Department, EORTC AISBL/IVZW - European Organisation for Research and Treatment of Cancer, Brussels, Belgium; 2Medical Oncology Department, Hopital René Huguenin - Institut Curie, Saint-Cloud, France; 3Genetics Department, Institut Curie,Paris, France; 4Breast Cancer Medico-Scientiﬁc Program, Institut Curie, Paris, France;5Medical Oncology Department, AZ Klina, Brasschaat, Belgium; 6Statistical Department, EORTC AISBL/IVZW - European Organisation for Research and Treatment of Cancer, Brussels, Belgium

Background: The standard of care for patients with early triple-negative breast cancer(TNBC) is neoadjuvant chemotherapy followed by surgery. Recently, immune checkpoints inhibitors (ICI) added to neoadjuvant chemotherapy have shown efﬁcacy.

Among TNBC, BRCA mutations and other homologous recombination deﬁciency(HRD) signals are relatively frequent. As opposed to other types of breast cancer, HRD TNBC show a high neoantigen load, a large number of tumour inﬁltrating lymphocytes(TILs), and a high PD-L1 expression. In BRCA/HRD breast cancer, PARP inhibitors(PARPi) exhibit a distinct anticancer activity. In addition, they show immunomodulatory effects by promoting PD-L1 expression and DNA damage, increasing neoantigen load. Chemotherapy-free regimens combining PARPi and ICI result in promising synergistic activity as shown in the metastatic setting, supporting investigation in the neoadjuvant setting.

Trial design: NOBLE is an EORTC phase 2, randomized, multicentre, open label, clinical trial. It includes a minimax Simon’s two-stage design with an early feasibility step.

Eligible patients must have early TNBC harbouring a tumoral (t)BRCA1/2 mutation, or another HRD signal based on methylation. Following central screening for tumoral BRCA/HRD (Institute Curie, 455 patients), 152 patients will be randomized between olaparib vs olaparib and durvalumab for 4 cycles of neoadjuvant treatment. Thereafter, patients will undergo surgery. All patients will be followed-up to 2 years (y) after surgery. The trial will be conducted in 3 steps (screening/randomization): Step 1 e Feasibility (60/20): to assess the central testing failure rate, the turn-around time for central testing and the prevalence of tBRCA/HRD; Step 2 (193/64) e Futility; and Step 3 (202/152) e Expansion of recruitment. The primary endpoint is the rate of pathologic complete response at the time of surgery, deﬁned as ypT0/is ypN0. Secondary endpoints are response based on RECIST v1.1, surgery rate, 2-y event-free-survival, 2-y overall survival, safety, and quality of life. The study is expected to be activated in early autumn 2023 and the primary endpoint will be available approximately 5 years after the screening of the ﬁrst patient.

Clinical trial identiﬁcation: EudraCT 2022-003594-33. NCT05209529.

Funding: EORTC is the legal sponsor of the study. AstraZeneca provided an educational grant.

Disclosure: C. Callens: Financial Interests, Institutional, Advisory Board: AstraZeneca. E.G.C. Brain:Financial Interests, Personal, Invited Speaker, Webinars, optimized endocrine therapy for older breast cancer patients: Eli Lilly; Financial Interests, Personal, Advisory Board, Palbociclib and older breast cancer patients: Pﬁzer; Financial Interests, Personal, Invited Speaker, Symposium HER2+ MAO conference 03/21: SEAGEN; Financial Interests, Personal, Invited Speaker, ELEVATE 10/2021 and ABC 11/2021 meeetings: Pﬁzer; Financial Interests, Personal, Other, IDMC DESTINY 05: DAIICHI; Financial Interests, Personal, Advisory Board, GCSF and FN in older patients: SANDOZ; Financial Interests,Personal, Advisory Board, Underserved Patients Populations with breast cancer, advisory board:Pﬁzer; Financial Interests, Personal, Invited Speaker, Management of older patients with cancer,series of seminars in Canada for HCP: Pﬁzer; Financial Interests, Institutional, Coordinating PI,APPALACHES study EORTC 1745: Pﬁzer; Financial Interests, Institutional, Coordinating PI, TOUCH study (IBCSG 55/GERICO study): Pﬁzer; Financial Interests, Institutional, Local PI, DEESTINY 09:DAIICHI; Financial Interests, Institutional, Local PI, DESTINY 06: Daiichi; Financial Interests, Institutional, Local PI, SERENA 06: AstraZeneca; Financial Interests, Institutional, Coordinating PI, AMEERA 6: Sanoﬁ. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2828

352TiP Neoadjuvant chemo-immunotherapy plus/minus fasting-like approach in stage II-III triple-negative breast cancer

patients: The phase II randomized BREAKFAST-2 trial

C. Vernieri1, F. Ligorio1, M.V. Dieci2, M. Lambertini3, C. De Angelis4, M. Iorﬁda5,A. Botticelli6, C. Strina7, A. Vingiani8, L. Provenzano1, G.V. Bianchi1, S. Folli9,

D. Generali7, A. Zambelli10, S. de Placido4, L. Del Mastro3, V. Guarneri2, G. Capri1,G. Pruneri8, F.G.M. De Braud1

1Medical Oncology and Hematology Department, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy; 2Department of Surgery, Oncology and Gastroenterology,University of Padova, Padua, Italy; 3Department of Medical Oncology, IRCCS AOU San Martino - IST-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy; 4Department of Clinical Medicine and Surgery, Azienda Ospedaliera Universitaria Federico II, Naples,Italy; 5Division of Medical Senology, IEO - European Institute of Oncology, Milan, Italy;6Department of Radiological, Oncological and Pathological Science, Sapienza University of Rome, Rome, Italy; 7Multidisciplinary Unit of Breast Pathology and Translational Research, ASST Cremona, Cremona, Italy; 8Department of Advanced Diagnostics, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy; 9Breast Unit, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy; 10Department of Biomedical Sciences, Humanitas University, Milan, Italy

Background: Despite remarkable improvements in early-stage Triple-Negative Breast Cancer (TNBC) treatment with neoadjuvant chemoimmunotherapy (CT-IO), a considerable proportion of TNBC patients (pts) still experience tumor relapse after surgery. Preclinical studies indicate that TNBC is exquisitely sensitive to fasting-like approaches (FLAs),and we have recently shown that cyclic FLA boosts systemic and intratumor immunity in cancer patients.We hypothesize that combining FLA with preoperative CT-IO can increase pathologic complete response (pCR) rates in pts with stage II-III TNBC.

Trial design: This phase 3 randomised, open-label study is enrolling women (pre- or postmenopausal) and men with ER+/HER2e (IHC 0/1+/2+/ISHe) early BC who have completed deﬁnitive locoregional therapy and standard adjuvant ET ( CDK4/6i) for2 and 5 years (+ 3 months) without disease recurrence. Pts must be considered atintermediate or high risk of recurrence based on clinical, biological and genomic factors. Pts are randomised (1:1) to continue standard ET of the investigator’s choice(tamoxifen or aromatase inhibitor LHRH agonist) or camizestrant LHRH agonistfor up to 60 months. The primary endpoint is invasive BC-free survival (STEEP 2.0 criteria). Secondary endpoints include invasive disease-free survival and distant relapse-free survival (STEEP 2.0 criteria), overall survival, safety, and health-related quality of life. Approximately 4300 pts will be randomised; enrollment is ongoing.

Clinical trial identiﬁcation: NCT05774951.

Editorial acknowledgement: Medical writing assistance was provided by Suzanne Patel at BOLDSCIENCE Inc., funded by AstraZeneca.

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Pharmaceuticals, K-Group Beta, Kind Pharmaceuticals, Loxo Oncology, Oncothyreon, Orum Therapeutics, Prelude Therapeutics, Profound Bio, Relay Therapeutics, Tolmar, Torque Therapeutics. S.

Loibl: Financial Interests, Institutional, Advisory Board, Member: Amgen, AstraZeneca, BMS, Celgene,EirGenix, GSK, Lilly, Pierre Fabre, Roche, SeaGen, Abbvie, Sanoﬁ, Gilead, Merck, Novartis, Relay Therapeutics; Financial Interests, Institutional, Invited Speaker: AstraZeneca, DSI, Novartis, Pﬁzer,Roche, Gilead, Seagen; Financial Interests, Institutional, Advisory Board: DSI, Pﬁzer, Olema; Financial Interests, Personal, Invited Speaker: Medscape; Financial Interests, Personal, Full or part-time Employment, CEO: GBG Forschungs GmbH; Financial Interests, Institutional, Invited Speaker, Ki67:VM Scope GmbH; Financial Interests, Institutional, Research Grant: AstraZeneca, Celgene, Novartis,Immunomedics/Gilead, Pﬁzer, Roche, Daiichi-Sankyo; Financial Interests, Institutional, Funding:AbbVie, Molecular Health; Financial Interests, Personal, Other, PIPenelope/Padma: Pﬁzer; Financial Interests, Personal, Other, SC PALOMA3: Pﬁzer; Financial Interests, Personal, Other, SC SOLAR1:Novartis; Financial Interests, Personal, Other, SC HERCLIMB: SeaGen; Financial Interests, Personal, Other, SC Katherine: Roche;Financial Interests, Personal, Other, SC Capitello; EC Cambria 1: AstraZeneca; Financial Interests,Personal, Other, SC Inavo: Roche; Financial Interests, Personal, Other, SC Destiny B05; SC Destiny B09: Daiichi Sankyo; Non-Financial Interests, Principal Investigator, After publication of primary endpoint: PI Aphinity; Non-Financial Interests, Advisory Role, Group in Germany responsible for breast cancer guidelines: AGO Kommission Mamma; Non-Financial Interests, Member, Member guideline committee; past chair in ESMO Breast: ESMO; Non-Financial Interests, Member, German Gynaecological Oncology society: AGO; Non-Financial Interests, , Member, German Cancer Society:DKG; Non-Financial Interests, Member: ASCO; Other, Other, EP14153692.0No ﬁnancial interest,Institutional: Patent; Other, Other, EP21152186.9No ﬁnancial interest, institutional: Patent; Other,Other, EP15702464.7No ﬁnancial interest, institutional: Patent; Other, O N. Niikura: Financial Interests, Personal, Invited Speaker:

AstraZeneca, Pﬁzer, Daiichi Sankyo, Chugai, Eli Lilly, MSD; Financial Interests, Personal and Institutional, Research Grant: Chugai, Eisai, Nippon Kayaku; Financial Interests, Personal and Institutional,Coordinating PI: Daiichi Sankyo. K.S. Saini: Financial Interests, Personal, Full or part-time Employment: Fortrea Inc.; Financial Interests, Personal, Stocks/Shares: Fortrea Inc., Labcorp Inc.; Financial Interests, Personal, Advisory Board: European Commission; Financial Interests, Personal, Ownership Interest: Quantum Health Analytics (UK) Ltd.; Non-Financial Interests, Personal, Other, Honorary Clinical Fellow: Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust,Cambridge, UK. I. Gioni: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. T.

Klinowska: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. I. Mayer: Financial Interests, Personal, Advisory Board:AstraZeneca, Lilly, Puma, Macrogenics, Sanoﬁ; Financial Interests, Personal, Full or part-time Employment, since 12/2021: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca;Financial Interests, Institutional, Research Grant: Genentech, Pﬁzer; Non-Financial Interests, ,Member: ASCO, AACR. M. Stuart: Financial Interests, Personal and Institutional, Other, I provided consultancy support for AZ: AstraZeneca. E.I. Syta: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. A. Walding: Financial Interests, Personal, Full or part-time Employment:AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. T. Bachelot: Financial Interests, Personal, Advisory Board: Roche, Novartis, AstraZeneca, Pﬁzer, Seagen, Daiichi Sankyo;Financial Interests, Institutional, Advisory Board: Lilly; Financial Interests, Institutional, Research Grant: Novartis, Roche, AstraZeneca, SeaGen, Pﬁzer; Financial Interests, Personal, Invited Speaker:Roche; Financial Interests, Institutional, Invited Speaker: AstraZeneca. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.3100

BREAST CANCER, LOCALLY ADVANCED

355P

Reduction of anthracycline use with a combined imaging and pathology prediction model in the neoadjuvant I-SPY2 trial

A. DeMichele1, E. Price2, S. Venters3, W. Li4, D. Wolf5, J. Gibbs4, L. Brown-Swigart5,M. Klein6, N. Onishi7, C. Yau8, D. Yee9, C. Isaacs10, J. Perlmutter11, H.S. Rugo12,L.J. Van’t Veer13, J. Boughey14, F. Symmans15, N. Hylton4, L. Esserman16

1Hemato-Oncology Dept., Hospital of the University of Pennsylvania, Philadelphia, PA,USA; 2Breast Imaging, UCSF - University of California San Francisco, San Francisco, CA,USA; 3Department of Neurosurgery, UCSF - University of California San Francisco, San Francisco, CA, USA; 4Department of Radiology and Biomedical Imaging, UCSF - University of California San Francisco, San Francisco, CA, USA; 5Department of Laboratory Medicine, UCSF - University of California San Francisco, San Francisco, CA, USA;6Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA;7Radiology, UCSF - University of California San Francisco, San Francisco, CA, USA;8Surgery, UCSF - University of California San Francisco, San Francisco, CA, USA;9Oncology, Masonic Cancer Center - University of Minnesota, Minneapolis, MN, USA;10Oncology Department, Lombardi Cancer Center Georgetown University,Washington,DC, USA; 11Gemini Group, Philadelphia, PA, USA; 12Helen Diller Family Comprehensive Cancer Center, UCSF - University of California San Francisco, San Francisco, CA, USA;13Laboratory Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; 14Division of Breast and Melanoma Surgical Oncology, Mayo Clinic, Rochester, NY, USA; 15Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA; 16Surgery & Radiology, UCSF - University of California San Francisco, San Francisco, CA, USA

Background: The I-SPY2 Trial is a randomized phase II platform trial testing novel neoadjuvant therapies. Serial MRI and pathology are used to evaluate response. New agents (+/- taxane) are tested in a 12 week (wk) treatment block, followed by Adriamycin/Cytoxan (AC). We sought to determine whether MRI functional tumor volume (FTV)-based predictive models, in conjunction with breast core biopsy, could identify early responders who had reached pCR and thus proceed to surgery without receiving AC, sparing them additional toxicity. The “predicted Residual Cancer Burden” (preRCB) models were developed using retrospective I-SPY data and prospectively tested in I-SPY2.

Methods: Eligible patients (pts) were required to be on preRCB-designated treatment arms and consented to participate in the optional preRCB process. PreRCB included breast MRI at baseline, wk 3 and wk 12 of the initial I-SPY2 treatment block and a clinical core biopsy of the tumor bed at 12-weeks. Pts who met combined preRCB criteria (predicted probability of pCR above threshold in a subtype speciﬁc FTV model and no invasive tumor on breast biopsy) were eligible to proceed to surgery without AC after return of results (ROR) and consultation with their clinician.

Results: From 1/20-6/22, 172 pts underwent preRCB and completed surgery. 51/172(30%) met combined MRI/biopsy preRCB criteria and 40/51 proceeded to surgery without AC (Table). 96% (49/51) pts who met preRCB criteria had RCB0/1 vs. 48% (57/120) of pts who did not meet criteria (OR 27 [6.5-235]; Fisher’s exact test p¼1.04E-10). Overall, preRCB led to a 24% reduction in AC use without signiﬁcant difference in RCB0/1 rate between those with and without AC (p¼1).

Conclusions: Implementation of preRCB in I-SPY2 identiﬁed patients with pCR prior to AC. High uptake of early surgery recommendations led to reduced use of AC while maintaining optimal outcome. I-SPY 2.2 is testing next-generation models to enable further optimization.

Table: 355P

PreRCB met (n[51)

PreRCB not met (n[120)

No AC

40/51 (78%)

Received AC 11/51 (22%)

22/120 (18%)

Received AC 98/120 (82% )

RCB 0/1 RCB 2/3 RCB 0/1 RCB 2/3 RCB 0/1 RCB 2/3 RCB 0/1 RCB 2/3

38 (95%) 2 (5%) 11 (100%) 0 (0%) 12 (55%) 10 (45%) 45 (46%) 53 (54%)

Clinical trial identiﬁcation: NCT01042379.

Legal entity responsible for the study: Quantum Leap Healthcare Collaborative.

Funding: Research reported in this abstract was supported by the National Cancer Institute of the National Institutes of Health under award number P01CA210961. The authors wish to acknowledge the generous support of the study sponsors, Quantum Leap Healthcare Collaborative ( QLHC, 2013 to present) and the Foundation for the National Institutes of Health (2010 to 2012).

Disclosure: D. Yee: Financial Interests, Personal, Research Funding, unrelated to this work:Boehringer Ingelheim. C. Isaacs: Financial Interests, Institutional, Research Grant: Tesaro/GSK,Seattle Genetics, Pﬁzer, AstraZeneca, BMS, Genentech, Novartis; Financial Interests, Personal, Licencing Fees or royalty for IP: UptoDate, McGrawHill; Financial Interests, Personal, Speaker,

Consultant, Advisor: AstraZeneca, Genentech, ION, Novartis, Pﬁzer, Seagen; Financial Interests,Personal, Advisory Board: Novartis; Non-Financial Interests, Personal, Leadership Role: SideOut Foundation . H.S. Rugo: Financial Interests, Personal, Other, Consultancy/advisory support: PUMA,NAPO, Mylan, Daiichi Sankyo, Eisai; Financial Interests, Institutional, Local PI: Novartis, Lilly, Pﬁzer,Daiichi, AstraZeneca, Gilead Sciences, Inc., GSK, Sermonix Pharmaceuticals Ins., Pionyr Immunotherapeutics, Taiho Oncology, Inc., Veru Inc; Financial Interests, Institutional, Coordinating PI: OBI Pharma, Astellas Pharma Inc., F. Hoffmann-La Roche AG/Genentech, Inc., Merck; Financial Interests,Personal, Other, Travel support to academic meetings: Merck, AstraZeneca, Gilead; Non-Financial Interests, Advisory Role, I advise a number of companies without compensation: various. L.J. Van’t Veer: Financial Interests, Personal, Stocks or ownership: Agenda NV. N. Hylton: Financial Interests,Institutional, Research Funding: NIH. L. Esserman: Financial Interests, Institutional, Research Funding: Merck; Financial Interests, Personal, Advisory Board: Blue Cross Blue Shield; Financial Interests,Personal, Other, Website Author: UpToDate. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.534

356P Prognostic value of the residual cancer burden after neoadjuvant chemotherapy for invasive lobular breast cancer: An international pooled cohort study

S. Gottipati1, H.M. Earl2, C. Yau1, D.A. Cameron3, J. Abraham2, L. Hayward4,F. Reyal5, M. Osdoit5, G.S. Sonke6, J. Wesseling7, J. Boughey8, M.P. Goetz9,A. DeMichele10, L. Pusztai11, P. Sharma12, M. Martin Jimenez13,

S. Lopez-Tarruella Cobo14, M. Del Monte-Millan15, F. Symmans16, R. Mukhtar1

1Department of Surgery, UCSF - University of California San Francisco, San Francisco,CA, USA; 2Department of Oncology, Addenbrooke’s Hospital, Cambridge, UK;3Department of Oncology, Institute of Genetics and Cancer, University of Edinburgh,Edinburgh, UK; 4Department of Oncology, ECC - Edinburgh Cancer Centre - SCAN,Edinburgh, UK; 5Department of Surgery, Institut Curie, Paris, France; 6Department of Medical Oncology, NKI-AVL - Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands; 7Divisions of Diagnostic Oncology & Molecular Pathology, NKI-AVL - Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital,Amsterdam, Netherlands; 8Department of Surgery, Mayo Clinic Cancer Center,Phoenix, AZ, USA; 9Department of Oncology, Mayo Clinic, Rochester, NY, USA;10Hemato-Oncology Dept., Hospital of the University of Pennsylvania, Philadelphia,PA, USA; 11Department of Medical Oncology, Yale University School of Medicine, New Heaven, TX, USA; 12Internal Medicine Department, University of Kansas Medical Center, Westwood, CA, USA; 13Servicio de Oncologia Médica Department, Hospital General Universitario Gregorio Marañon, Madrid, Spain; 14Dept. Medical Oncology,Hospital General Universitario Gregorio Maranon, Madrid, Spain; 15Medical Oncology Dept., Hospital General Universitario Gregorio Marañon - Fundación Investigación Biomedica, Madrid, Spain; 16Department of Pathology and Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

Background: Residual Cancer Burden (RCB) after neoadjuvant chemotherapy (NAC)has been validated to predict event-free survival (EFS) across breast cancer subtypes but its prognostic ability has not been speciﬁcally studied for invasive lobular carcinoma (ILC).

Methods: We studied patient-level data (histologic subtype, RCB, and EFS) from a previously published pooled cohort from 12 institutions in the US and Europe. ILC was deﬁned by local institutional protocols. Characteristics in pure ILC vs. non-ILC were compared using t-test or chi-squared test. Associations between continuous RCB index and EFS were assessed in both groups with mixed effect Cox models and multivariable analyses. Recursive partitioning was used in an exploratory model to stratify prognosis by individual clinicopathologic variables and the components of RCB.

Results: Of 5161 patients, the diagnosis was ILC in 216 (4.2%) and non-ILC in 4945. ILC cases were older, had lower grade, higher tumor (T) category, and more hormone receptor (HR) positive HER2 -negative subtype (73.6% vs 36.4%) (all p-values <0.05).

Pathologic complete response (pCR/RCB 0) was achieved in 10.6% of ILCs and 33.4%of non-ILC (2.5% and 11.8% respectively among HR+HER2- cases, p<0.0005).

Increased RCB index was signiﬁcantly associated with worse EFS in both ILC and nonILC (p<0.05) and remained prognostic when adjusted for age, grade, T category,baseline nodal status, and receptor subtype. While continuous RCB index had a linear relationship with probability of EFS event (log scale) in non-ILC, this relationship was non-linear in ILC cases; for ILC, prognosis was similar for RCB index 1.9, withincreasing risk for RCB index >1.9. Recursive partitioning demonstrated residual tumor cellularity as most prognostic in ILC, followed by number of positive nodes and tumor dimensions.

Conclusions:While pCR rate after NAC is low in ILC, RCB retains prognostic value, with residual cellularity providing the most information. RCB index values 1.9 had similarprognosis to pCR. These results underscore the utility of RCB for evaluating NAC response in those with ILC for clinical management and as an endpoint for clinical trials.

S325

Funding: National Institutes of Health (United States), National Cancer Institute,Award #: K08CA256047.

Disclosure: H.M. Earl: Financial Interests, Institutional, Research Funding, Grants from Roche and Sanoﬁ-Aventis: Roche and Sanoﬁ-Aventis; Financial Interests, Speaker, Consultant, Advisor, Consultant for Daiichi Sankyo, AstraZeneca, Intas Pharmaceuticals, and prIME Oncology: Daiichi Sankyo,AstraZeneca, Intas Pharmaceuticals, prIME Oncology; Financial Interests, Other, Travel support from Daiichi Sankyo, AstraZeneca, Intas Pharmaceuticals, Pﬁzer, and Amgen: Daiichi Sankyo, AstraZeneca,Intas Pharmaceuticals, Pﬁzer, Amgen. C. Yau: Financial Interests, Full or part-time Employment,Salary from Quantum Leap Healthcare Collaborative: Quantum Leap Healthcare Collaborative. D.A.

Cameron: Financial Interests, Institutional, Advisory Board: Roche, Pﬁzer, AstraZeneca, Daiichi Sankyo, SeaGen, Synthon, Zymeworks; Financial Interests, Institutional, Other, Have done advisory boards, spoken at a webinar and involved in a manuscript with Lilly - all recompense to my institution: Lilly; Financial Interests, Institutional, Other, Have done advisory boards and been involved in a health economic analysis and publication. All recompense to my institution: Novartis; Financial Interests, Institutional, Coordinating PI, funding and drug for UK participation in a French led Novartis funded study. Institutional funding received for consultancy work: Novartis; Non-Financial Interests, Principal Investigator, one of three PIs for the Ameera-6 trial - which has now closed early as the company have stopped all development of the drug: Sanoﬁ; Other, Chair of the board of this small Scottish charity for secondary breast cancer: Make Seconds Count; Other, Chair of the Board of B.I.G. - a group of international breast cancer research groups: Breast International Group; Other,Chair of the European Breast Cancer Council which organises the bi-annual EBCC meetings: EBCC. J.

Abraham: Financial Interests, Research Grant: AstraZeneca; Financial Interests, Other, Lecture fees:Pﬁzer, Eisai. L. Hayward: Financial Interests, Research Grant, Grants from Roche and Sanoﬁ-Aventis:Roche and Sanoﬁ-Aventis; Financial Interests, Other, Travel expenses from Roche, AstraZeneca, Pﬁzer and Sanoﬁ-Aventis, all outside the submitted work.: Roche, AstraZeneca, Pﬁzer , Sanoﬁ-Aventis. G.S.

Sonke: Financial Interests, Institutional, Research Funding, Institutional research funding from AstraZeneca, Merck, Novartis, Roche.: AstraZeneca, Merck, Novartis, Roche. J. Boughey: Financial Interests, Institutional, Research Funding, Research funding to institution from Eli Lilly: Eli Lilly. M.P.

Goetz: Financial Interests, Institutional, Advisory Board: ARC Therapeutics, Biotheranostics, Blueprint Medicines, Rna Diagnostics, Sanoﬁ Genzyme; Financial Interests, Institutional, Other, Consulting:AstraZeneca, Seattle Genetics; Financial Interests, Institutional, Other, General Consulting: Lilly;Financial Interests, Personal, Invited Speaker, CME Activity: Research to Practice, Clinical Education Alliance, Medscape, MJH Life Sciences; Financial Interests, Personal, Invited Speaker, CME Panel Discussant: Total Health Conferencing; Financial Interests, Personal, Other, Moderator for CME Activity: Curio Science; Financial Interests, Institutional, Local PI: Lilly, Pﬁzer, LOXO, ATOSSA Therapeutics, AstraZeneca, Sermonix. L. Pusztai: Financial Interests, Personal, Advisory Board, Advisory Board, Trial Steering Committee membership: AstraZeneca; Financial Interests, Personal, Advisory Board: Pﬁzer, Roche Genentech, Novartis, Exact Sciences, Natera; Financial Interests, Personal,Advisory Board, advisory board, trial steering committee: Merck; Financial Interests, Personal,Advisory Board, advisory board: Biotheranostics; Financial Interests, Personal, Advisory Board,investigator meeting: Biovica; Financial Interests, Institutional, Trial Chair, clinical trial support to institution: Pﬁzer, Merck; Financial Interests, Institutional, Local PI, clinical trial support to institution:Seagen, AstraZeneca; Financial Interests, Institutional, Research Grant, research grant: Bristol Myers Squibb; Non-Financial Interests, Advisory Role, member of the scientiﬁc advisory board: Breast Cancer Research Foundation; Non-Financial Interests, Member of Board of Directors: SWOG Hope Foundation; Non-Financial Interests, Institutional, Product Samples, material transfer agreement:Pﬁzer. P. P. Sharma: Financial Interests, Institutional, Research Funding: Novartis, Merck, BMS; Financial Interests, Advisory Board, Consulting/advisory board from Merck, Novartis, Seattle genetics, Gilliad/Immunomedics, AstraZaneca, ExactSciences.: Merck, Novartis, Seattle genetics, Gilliad/Immunomedics, AstraZaneca, ExactSciences. M. Martin Jimenez: Financial Interests, Personal, Advisory Board: AstraZeneca, Lilly, Roche/Genentech, Daiichi Sankyo, Menarinio-Stemline; Financial Interests,Personal, Invited Speaker: Pﬁzer, AstraZeneca, Lilly, Novartis, Roche/Genentech; Financial Interests,Institutional, Research Grant: Novartis, Roche, Puma; Non-Financial Interests, Member of Board of Directors: TRIO; Non-Financial Interests, Leadership Role: Geicam; Non-Financial Interests, Member:ASCO; Non-Financial Interests, Advisory Board: SEOM. S. Lopez-Tarruella Cobo: Financial Interests,Personal, Advisory Board: Asra Zeneca, Daiichi Sankyo, Pﬁzer, Novartis, Lilly, Gilead, GSK, Roche,Pierre Fabre, Seagen, Menarini_Stemline, Gebro Pharma; Non-Financial Interests, Member of Board of Directors: Geicam, Seom. F. Symmans: Financial Interests, Ownership Interest, Shares intellectual property: Delphi Diagnostics. All other authors have declared no conﬂicts of interest.

Trial design: BREAKFAST-2 (NCT05763992) is an open-label, multicentric, randomized,phase 2 trial aimed at investigating the antitumor activity of experimental FLA in combination with standard preoperative CT-IO in pts with treatment-naïve, localized (T1c and N1-2, or T2-4 and N0-2) TNBC. Pts will be randomized in a 1:1 ratio to: a) control arm(standard CT-IO), consisting of 12 administrations of weekly paclitaxel + carboplatin concomitant with 4 triweekly cycles of Pembrolizumab, followed by 4 triweekly cycles of doxorubicin/epirubicin + cyclophosphamide + Pembrolizumab every three weeks; b)experimental arm, consisting of CT-IO + 5-day FLA every three weeks, up to 8 FLA cycles.

Then pts will undergo surgery. Key eligibility criteria are: age of 18-75 years, ECOG PS 0-1,BMI > 19 kg/m2, absence of malnutrition, diabetes, uncontrolled autoimmune disorders,or severe comorbidities. The primary study endpoint is pCR. Hypothesizing that the experimental treatment is able to increase the pCR rate from 65% (historical data with CTIO alone) to 85%, and assuming an a error of 5% and a power of 85%, a total of 145 patients will be enrolled. Secondary endpoints include: safety and tolerability, compliance, Event-Free Survival (EFS) and Overall Survival (OS). We will combine plasma metabolomics and bulk/single cell RNA-seq analyses to explore the impact of the experimental treatment on systemic and intratumor immunometabolic pathways, as well as to assess the association between immunometabolic changes and clinical outcomes.

The trial has started to enroll pts on May 2nd, 2023.

Clinical trial identiﬁcation: NCT05763992.

Legal entity responsible for the study: Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.

Funding: Giuliani Foundation e Fondazione Gianmaria e Sabrina Giuliani; Fondazione IRCCS Istituto Nazionale dei Tumori; AIRC.

Disclosure: C. Vernieri: Financial Interests, Personal, Advisory Board: Novartis, Pﬁzer, Lilly, Daiichi Sankyo, Lilly, Istituto Gentili; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Institutional, Research Grant: Roche. M.V. Dieci: Financial Interests, Personal, Invited Speaker: Eli Lilly, Exact sciences, Gilead, Seagen, Daiichi Sankyo, Novartis; Financial Interests, Personal, Advisory Board: Novartis, Eli Lilly, Seagen, Exact Science, Daiichi Sankyo, Gilead; Financial Interests, Personal, Other, Consultancy: Pﬁzer; Financial Interests, Personal, Other, Consultancy on educational project: Roche. M. Lambertini: Financial Interests, Personal, Advisory Board: Roche,AstraZeneca, Lilly, Novartis, Pﬁzer, Exact Sciences, MSD, Seagen, Gilead; Financial Interests, Personal,Invited Speaker: Takeda, Sandoz, Ipsen, Libbs, Knight, Daiichi Sankyo, Lilly, Pﬁzer, Novartis, Roche;

Financial Interests, Personal, Other, Travel grant to attend ASCO 2022: Gilead; Financial Interests,Institutional, Coordinating PI, 2-year research grant paid to my Institution: Gilead. C. De Angelis:Financial Interests, Personal, Advisory Board: Roche, Eli Lilly, GSK, Novartis, Pﬁzer, AstraZeneca;Financial Interests, Institutional, Funding: Novartis. G.V. Bianchi: Financial Interests, Personal,Advisory Board: Novartis, Eli Lilly, Daiichi Sankyo, AstraZeneca, Roche, MSD, Seagen. D. Generali:Financial Interests, Personal, Other, Educational events: Novartis, Lilly, Pﬁzer, Daiichi Sankyo, Roche;Financial Interests, Personal and Institutional, Research Grant: AstraZeneca , Novartis , LILT. L.Interests, Personal, Advisory Board, Her2+ and TN breast cancer: Roche; Financial Interests, Personal,Writing Engagement, Consultancy for TNBC text: Roche; Financial Interests, Personal, Advisory Board, denosumab: Amgen; Financial Interests, Personal, Advisory Board, Early and metastatic BC: Eli Lilly; Financial Interests, Personal, Invited Speaker, CDK4-6 inhibitors: Eli Lilly; Financial Interests,Personal, Advisory Board, tucatinib: Seagen Int; Financial Interests, Personal, Advisory Board,Oncotype dx: Exact sciences, Havas life; Financial Interests, Personal, Advisory Board, Neratinib:Pierre Fabre; Financial Interests, Personal, Invited Speaker, Internal training: MSD; Financial Interests,Personal, Invited Speaker, Educational meetings: Accademia Nazionale Medicina; Financial Interests,Personal, Writing Engagement, Author for BC text: Pensiero Scientiﬁco Editore; Financial Interests,Personal, Advisory Board, Breast cancer: Uvet; Financial Interests, Personal, Other, Author slide kits and interviews: Think2it; Financial Interests, Personal, Advisory Board, Palbociclib: Pﬁzer; Financial Interests, Personal, Invited Speaker, Breast cancer: Aristea, Meeting SrL; Financial Interests, Personal,Other, Author slide kits: Forum service; Financial Interests, Personal, Other, Author text about biosimilars: Edizioni Minerva Medica; Financial Interests, Personal, Other, consultant: Kardo srl;Financial Interests, Personal, Invited Speaker, Breast cancer meetings: Delphi international, Over srl;Financial Interests, Personal, Invited Speaker: Prex Srl, Editree; Financial Interests, Personal, Advisory Board: Uvet, Collage SpA, Daiichi Sankyo, AstraZeneca, Agendia, Gilead; Financial Interests, Personal,Other, Interview: Infomedica srl; Financial Interests, Personal, Other, Consultant: Sharing progress in cancer care - Switzerland; Financial Interests, Personal, Other, Consultancy: Eli lilly; Financial Interests, Institutional, Funding, National coordinating PI: Roche; Financial Interests, Institutional,Funding, Local PI: AstraZeneca, Roche, Eli Lilly, Daiichi Sankyo, Novella Clinical, Novartis; NonFinancial Interests, Institutional, Product Samples, Genomic Test: FoundationOne. Del Mastro: Financial Interests, Personal, Invited Speaker, Educational meeting: Novartis, Symposia,Andromeda E20, Vyvamed srl; Financial Interests, Personal, Invited Speaker, Lecture: Ipsen; Financial Interests, Personal, Advisory Board, Her2+ and TN breast cancer: Roche; Financial Interests, Personal,Writing Engagement, Consultancy for TNBC text: Roche; Financial Interests, Personal, Advisory Board, denosumab: Amgen; Financial Interests, Personal, Advisory Board, Early and metastatic BC: Eli Lilly; Financial Interests, Personal, Invited Speaker, CDK4-6 inhibitors: Eli Lilly; Financial Interests,Personal, Advisory Board, tucatinib: Seagen Int; Financial Interests, Personal, Advisory Board,Oncotype dx: Exact sciences, Havas life; Financial Interests, Personal, Advisory Board, Neratinib:Pierre Fabre; Financial Interests, Personal, Invited Speaker, Internal training: MSD; Financial Interests,Personal, Invited Speaker, Educational meetings: Accademia Nazionale Medicina; Financial Interests,Personal, Writing Eng s and interviews: Think2it; Financial Interests, Personal, Advisory Board, Palbociclib: Pﬁzer; Financial Interests, Personal, Invited Speaker, Breast cancer: Aristea, Meeting SrL; Financial Interests, Personal,Other, Author slide kits: Forum service; Financial Interests, Personal, Other, Author text about biosimilars: Edizioni Minerva Medica; Financial Interests, Personal, Other, consultant: Kardo srl;Financial Interests, Personal, Invited Speaker, Breast cancer meetings: Delphi international, Over srl;Financial Interests, Personal, Invited Speaker: Prex Srl, Editree; Financial Interests, Personal, Advisory Board: Uvet, Collage SpA, Daiichi Sankyo, AstraZeneca, Agendia, Gilead; Financial Interests, Personal,Other, Interview: Infomedica srl; Financial Interests, Personal, Other, Consultant: Sharing progress in cancer care - Switzerland; Financial Interests, Personal, Other, Consultancy: Eli lilly; Financial Interests, Institutional, Funding, National coordinating PI: Roche; Financial Interests, Institutional,F V. Guarneri:Financial Interests, Personal, Invited Speaker: Eli Lilly, Novartis, Amgen, GSK; Financial Interests,Personal, Advisory Board: Eli Lilly, Novartis, MSD, Gilead, Eli Lilly, Sanoﬁ, Merck Serono, Exact Sciences, Eisai, Olema Oncology; Financial Interests, Institutional, Local PI: Eli Lilly, Roche, BMS,Novartis, AstraZeneca, MSD, Synton Biopharmaceuticals, Merck, GSK, Daiichi Sankyo, Nerviano; NonFinancial Interests, Member: ASCO. G. Pruneri: Financial Interests, Personal and Institutional,Advisory Role: Roche, Bayer, AstraZeneca. F.G.M. De Braud: Financial Interests, Personal, Advisory Board: Roche, EMD Serono, NMS Nerviano Medical Science, Sanoﬁ, MDS, Incyte, BMS, Menarini,AstraZeneca, Pierre Fabre, Mattioli 1885 , MCCann Health, Taiho, IQVIA; Financial Interests, Personal,Speaker’s Bureau: BMS, Healthcare Research & Pharmacoepidemiology, Merck Group, MSD, Pﬁzer,Servier, Sanoﬁ, Roche, Amgen, Incyte , Dephaforum, Seagen, Nadirex, Ambrosetti, Itanet; Financial Interests, Personal and Institutional, Sponsor/Funding: Novartis, F Hoffmann-LaRoche Ltd, BMS,Ignyta Operating INC, Merck Sharp&Dohme Spa, Kymab, Pﬁzer, Tesaro, MSD, MedImmune LCC,Exelis Inc., LOXO Oncology Incorporated, Daiichi Sankyo, Basilea Pharmaceutica International AG,Janssen-Cilag International NV, Merck KGAA. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2829

353TiP

Phase III study to evaluate the efﬁcacy and safety of GLSI100 (GP2 + GM-CSF) in breast cancer patients with residual disease or high-risk PCR after both neo-adjuvant and

postoperative adjuvant anti-HER2 therapy, Flamingo-01

S. Patel1, J. Thompson1, M. Patel1, F.J. Daugherty1, M. Rimawi2

1Clinical and Regulatory, Greenwich LifeSciences, Inc., Stafford, TX, USA; 2Hematology and Oncology, Baylor College of Medicine, Houston, TX, USA

Background: GP2 is a biologic nine amino acid peptide of the HER2/neu protein delivered in combination with Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF)that stimulates an immune response targeting HER2/neu expressing cancers, the combination known as GLSI-100. In a prospective, randomized, single-blinded, placebocontrolled, multicenter phase IIb study, no recurrences were observed in the HER2+population after 5 years of follow-up, if the patient was treated with GLSI-100, survived,and was followed for more than 6 months (p¼ 0.0338). Immunotherapy elicited a potentresponse measured by skin tests and immunological assays. Of the 146 patients that have been treated with GLSI-100 over 4 clinical trials, GLSI-100 was well-tolerated and no serious adverse events observed were considered related to the immunotherapy.

Trial design: This phase III trial is a prospective, randomized, double-blinded, multi-center study. After 1 year of trastuzumab-based therapy, 6 intradermal injections of GLSI-100 or placebo will be administered over the ﬁrst 6 months and 5 subsequent boosters will be administered over the next 2.5 years. The participant duration of the trial will be 3 years treatment plus 1 additional year follow-up. Approximately 498 patients will be enrolled.

To detect a hazard ratio of 0.3 in invasive breast cancer free survival (IBCFS), 28 events will be required. An interim analysis for superiority and futility will be conducted when at least 14 events have occurred. This sample size provides 80% power if the annual rate of events in placebo patients is 2.4% or greater. Up to 100 non-HLA-A*02 subjects will be enrolled in an open-label arm. The patient population is deﬁned by these key eligibility criteria: 1) HER2/neu positive and HLA-A*02 and 2) Residual disease or High risk pCR(Stage III at presentation) post neo-adjuvant therapy. The trial objectives are to: 1)Determine if GP2 therapy increases IBCFS, 2) Assess the safety proﬁle of GP2, and 3)Monitor immunologic responses to treatment and assess relationship to efﬁcacy and safety. The study has been initiated in the US with plans to open in Europe.

Clinical trial identiﬁcation: NCT05232916.

Legal entity responsible for the study: Greenwich LifeSciences. Inc.

Funding: Greenwich LifeSciences, Inc.

Disclosure: S. Patel: Financial Interests, Personal, Ownership Interest: Greenwich LifeSciences, Inc.;Financial Interests, Personal, Stocks/Shares: Greenwich LifeSciences, Inc.; Financial Interests,

Personal, Member of Board of Directors: Greenwich LifeSciences, Inc.; Financial Interests, Personal,Ofﬁcer: Greenwich LifeSciences, Inc.; Financial Interests, Personal, Full or part-time Employment:Greenwich LifeSciences, Inc.. J. Thompson: Financial Interests, Personal, Ownership Interest:Greenwich LifeSciences, Inc.; Financial Interests, Personal, Stocks/Shares: Greenwich LifeSciences,Inc.; Financial Interests, Personal, Ofﬁcer: Greenwich LifeSciences, Inc.; Financial Interests, Personal,Full or part-time Employment: Greenwich LifeSciences, Inc.. M. Patel: Financial Interests, Personal,Ownership Interest: Greenwich LifeSciences, Inc.; Financial Interests, Personal, Stocks/Shares:Greenwich LifeSciences, Inc.; Financial Interests, Personal, Full or part-time Employment: Greenwich LifeSciences, Inc.. F.J. Daugherty: Financial Interests, Personal, Ownership Interest: Greenwich LifeSciences, Inc.; Financial Interests, Personal, Stocks/Shares: Greenwich LifeSciences, Inc.; Financial Interests, Personal, Member of Board of Directors: Greenwich LifeSciences, Inc.; Financial Interests,Personal, Ofﬁcer: Greenwich LifeSciences, Inc.; Financial Interests, Personal, Full or part-time Employment: Greenwich LifeSciences, Inc.. M. Rimawi: Other, Personal, Speaker’s Bureau: Daiichi Sankyo, Genentech, Macrogenics, Seattle Genetics; Other, Personal, Other, Contracted Research: F.

Hoffmann-La Roche Ltd., Pﬁzer; Other, Personal, Principal Investigator: Greenwich LifeSciences, Inc.

https://doi.org/10.1016/j.annonc.2023.09.3080

354TiP A phase III randomised open-label study of extended

adjuvant therapy with camizestrant vs standard endocrine therapy (ET) in patients with ER+/HER2e early breast cancer(BC) and an intermediate or high risk of recurrence

(CAMBRIA-1)

E. Hamilton1, S. Loibl2, N. Niikura3, P. Rastogi4, K.S. Saini5, I. Gioni6, T. Klinowska6,I. Mayer7, M. Stuart6, E. Syta8, A. Walding6, T. Bachelot9

1Medical Oncology Department, Sarah Cannon Research Institute at Tennessee Oncology, Nashville, TN, USA; 2Medicine and Research Department, German Breast Group (GBG) Forschungs GmbH, Neu-Isenburg, Germany; 3Breast Oncology Department, Tokai University School of Medicine, Isehara, Japan; 4Oncology Department,University of Pittsburgh, Pittsburgh, PA, USA; 5Global Clinical Development, Fortrea Inc., Durham, NC, USA; 6Late Development Oncology R&D, AstraZeneca, Cambridge,United Kingdom; 7Late Development Oncology R&D, AstraZeneca, Gaithersburg,United States of America; 8Late Development Oncology, AstraZeneca Canada, Inc.,Toronto, ON, Canada; 9Medical Oncology Department, Centre Léon Bérard, Lyon,France

Background: Deﬁnitive locoregional (surgery radiotherapy) and standard adjuvantET ( chemotherapy or cyclin-dependent kinase 4/6 inhibitor [CDK4/6i]) can achievecure in many patients (pts) with ER+/HER2e early BC. Nevertheless, a signiﬁcant proportion of pts with stage IeIII disease will experience recurrence to metastatic,incurable disease (5- and 10-year cumulative incidences of recurrence of 8.3% and

14.0%, respectively). There is evidence that incorporating a more effective endocrine therapy after 2 years of standard adjuvant ET can result in clinical beneﬁt for high-risk individuals. Camizestrant is a next-generation oral selective ER degrader and pure ER antagonist. In SERENA-2, camizestrant 75 mg and 150 mg signiﬁcantly prolonged progression-free survival vs fulvestrant in postmenopausal women with ER+/HER2e advanced BC with disease recurrence or progression after ET. The CAMBRIA-1 study(NCT05774951) is evaluating the potential of extended adjuvant therapy with camizestrant to improve outcomes in pts with ER+/HER2e early BC with an intermediate or high risk of recurrence after deﬁnitive locoregional therapy and standard adjuvant ET.

Conclusions: Our DR was 95%, FNR was 8%, mortality was 5%, and overall survival with SLNB(-) was 127 months.

Legal entity responsible for the study: Hospital Universitario Cruces.

https://doi.org/10.1016/j.annonc.2023.09.545

368P Impact of PET-CT-determined sarcopenia on survival and pathological complete response in breast cancer patients with neoadjuvant chemotherapy

G. Tahtaci1, B. Yildiz2, U. Aydos3

1Medical Oncology Department, Gazi University - Faculty of Medicine, Ankara, Turkey;2Internal Medicine, Gazi University - Faculty of Medicine, Ankara, Turkey; 3Nuclear Medicine, Gazi University - Faculty of Medicine, Ankara, Turkey

Background: Neoadjuvant chemotherapy (NACT) is a frequently used treatment method in breast cancer. Achieving pathological complete response (pCR) is one of the surrogate marker for long-term survival. Sarcopenia is considered a poor prognostic factor in breast cancer. The association between pCR and sarcopenia has not been fully elucidated in neoadjuvant setting in breast cancer. It was aimed to evaluate the effect of sarcopenia on pCR and overall survival (OS) in breast cancer patients with NACT.

Methods: Patients with NACT between 2014 and 2021 were included in the study.

SMI (skeletal muscle index), VFA (visceral fat tissue area), sarcopenic obesity (VFA/SMI) were determined at the level of the third lumbar vertebra on PET-CT images before and after NACT. Patients were categorized according to pCR. The relationship between pCR and clinicopathological features and PET-CT parameters were evaluated by logistic regression analysis. Kaplan-Meier method was used for survival analysis.

Results: The medical records of 56 patients who received NACT were reviewed and twenty-three patients who met the inclusion criteria were included in the study. They were classiﬁed as sarcopenic according to the previously determined cutoff value for sarcopenia (SMI: 38.9 cm2/m2). Sarcopenia was present in 50% of patients. PostNACT sarcopeni was found in 20% of the patients. The rate of post -NACT sarcopenic obesity was %27.3. pCR was achieved in 28.3% of patients. Sarcopenia was not associated with clinicopathologic features, pCR and OS. There was no association between clinicopathologic factors and pCR. Recurrence, post treatment high VFA, and post treatment sarcopenic obesity were signiﬁcantly associated with survival. In multivariate analysis post treatment high VFA level was signiﬁcantly associated with increased mortality (HR: 3.278 CI: 95% (1.143-9.401), p¼ 0.027).

https://doi.org/10.1016/j.annonc.2023.09.535

357P

Prediction of pathologic response to neoadjuvant

chemotherapy (NAC) using diffuse optical breast scanner(DOB-Scan) in patients with locally advanced breast cancer(LABC)

P.T. Nguyen1, S. Momtahen2, M. Momtahen2, P. Atwal3, W.W. Yap4, B. Bradshaw5,A. Chinnadurai6, H.M. Abusin1, A. Gurjal1, S. Gilmour1, M.A. Shaikh1,

R. Ramaseshan2, F. Golnaraghi2, J. Ko1

1Medical Oncology Dept., BC Cancer - Abbotsford, Abbotsford, BC, Canada;2Mechatronics, Simon Fraser University, Surrey, BC, Canada; 3Physics, BC Cancer -Abbotsford, Abbotsford, BC, Canada; 4Diagnostic Imaging, Surrey Memorial Hospital,Surrey, BC, Canada; 5Anatomic Pathology, ARHCC - Abbotsford Regional Hospital and Cancer Centre, Abbotsford, Canada; 6Medicine, University of Western Ontario, London, ON, Canada

Background: No modality exists to accurately predict pathologic response to chemotherapy prior to surgery in patients with LABC receiving NAC. The objective of this study is to use the novel DOB-scan to evaluate the pathologic response of breast cancer to NAC before surgery.

Methods: The study aims to enroll 90 patients and recruitment is ongoing. An eligible patient had a diagnosis of LABC and was recommended NAC followed by resection.

DOB-Scan used near-infrared light to examine healthy and breast cancer tissue prior to NAC, at clinic visit prior to each WNAC cycle, and after NAC was completed.

Palpated tumour size was measured at the same time; ultrasound (US) was performed prior to NAC start, halfway, and after ﬁnal NAC. After surgery, the specimens were reviewed by reference pathologist and assigned the pathologic Residual Cancer Burden (pRCB) class (Symmans et al. JCO 2007 ; Yau et al. SABCS 2019 ). We

calculated the optical RCB (oRCB) class by determining the minimum reﬂectance that correlated with maximum absorption on DOB-Scan after the last NAC prior to surgery.

Correlation between pRCB and oRCB was modelled to ﬁt a linear regression.

Results: 60 patients have been enrolled; data from 30 patients who completed NAC and surgery were included in this interim analysis. Median age was 58 (range 29-72);all but 1 had ductal carcinoma; 22 had axillary lymph node(s) involved. Median longest diameter of the primary tumour on US was 2.3 cm (range 0.7-18). Final size by palpation or US indicated response to NAC, but did not correlate with pRCB. The oRCB clustered linearly with pRCB (pRCB ¼ 4.4 x oRCB), with a sensitivity of 97% and aspeciﬁcity of 100%. Artiﬁcial-intelligence rendered noise reduction of oRCB increased the sensitivity to nearly 100%.

Conclusions: Early results suggest that the oRCB can predict ﬁnal pathologic response more accurately than palpation or US during NAC. Lower oRCB indicated better response to NAC, with the ability to predict pRCB and pathologic complete response prior to resection. DOB-Scan can be used as a point-of-care hand-held instrument to assess tumour response and assist with treatment decisions in patients receiving NAC.

Funding: Michael Smith Foundation; Crystal Gala Foundation.

Disclosure: J. Ko: Financial Interests, Personal, Advisory Board: AstraZeneca, Astellas, Pﬁzer,Takeda; Financial Interests, Personal, Invited Speaker: BMS, Merck; Financial Interests, Personal,Research Grant: Janssen, Bayer. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.536

358P Major adverse cardiovascular event outcomes of adjuvant taxane + anthracycline versus taxane-based chemotherapy in older adults with triple-negative breast cancer: A SEERMedicare study

S.C. Roy1, S. Lakritz2, A. Schreiber2, E. Molina3, C. Bradley4, L. Kondapalli5,J.R. Diamond6

1Internal Medicine, University of Colorado Denver - Anschutz Medical Campus, Aurora,CO, USA; 2Division of Medical Oncology, University of Colorado Denver - Anschutz Medical Campus, Aurora, CO, USA; 3Population Health Shared Resource, UCHealth Cancer Care - Anschutz Medical Campus - University of Colorado Cancer Center,Aurora, CO, USA; 4Department of Health Systems, Management, and Policy, University of Colorado Denver - Anschutz Medical Campus, Aurora, CO, USA; 5Department of Cardiology, University of Colorado Denver - Anschutz Medical Campus, Aurora, CO,USA; 6Medical Oncology Dept., UCHealth Cancer Care - Anschutz Medical Campus -University of Colorado Cancer Center, Aurora, CO, USA

Background: Triple-negative breast cancer (TNBC) is regarded as relatively more aggressive compared to other subtypes of breast cancer with characteristic metastatic patterns and poor prognosis. The standard of care for TNBC has historically been anthracycline and taxane-based chemotherapy (ATAX). Despite its effectiveness,anthracyclines carry a small but important risk of cardiotoxicity, which is a concern in older women. The purpose of this study was to evaluate major adverse cardiovascular events in older women with TNBC.

Methods: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we identiﬁed 2,215 women with TNBC diagnosed at age > 65 between 2010-2015. We compared patient and clinical characteristics according to adjuvant chemotherapy regimen (ATAX versus TAX). Logistic regression was performed to estimate the odds ratios (OR) and 95% conﬁdence intervals (CIs), Kaplan Meier survival curves were generated to estimate three-year overall survival (OS) and cancer speciﬁc survival (CSS). Cox proportional hazards models were used to analyze OS and CSS while controlling for patient and tumor characteristics. MACE was deﬁned as acute myocardial infarction, heart failure, potentially fatal arrhythmia, and cerebral vascular incidence. Few patients experienced a cardiac death and therefore this was excluded in the analysis.

Results: Of the 2,215 patients in our cohort, a majority of patients 1334 (60.26%)received TAX compared to ATAX 881 (39.78%). Patients who received ATAX were not more likely to experience cardiac outcomes such as acute myocardial infarction (OR

1.10, 95% CI [0.66, 1.82], p¼0.724), heart failure (OR 0.73, 95% CI [0.52, 1.05],p¼0.09), CVA (OR 0.76, 95% CI [0.45, 1.29], p¼0.31), or potentially fatal arrhythmia(OR 0.66, 95% CI [0.29, 1.50], p¼0.32) when controlling for traditional risk factors.Among patients who experienced a cardiac outcome, there was no difference in OS or CSS in patients who received TAX vs ATAX (HR 1.18, 95% CI [0.46-2.98], p¼0.74 andHR 1.39, 95% CI [0.38 e 5.11] p¼0.62).

Conclusions: Among older women with TNBC, receipt of adjuvant chemotherapy with ATAX was not associated with increased risk of adverse cardiac outcomes. For those who experienced a cardiac event, there was no difference in survival amongst those who received TAX compared to ATAX.

Funding: Women’s Cancer Developmental Therapeutics Program, University of Colorado Cancer Center.

https://doi.org/10.1016/j.annonc.2023.09.537

359P

Table:Catego

Physic

Psycho resista

Unveiling the factors inﬂuencing exercise engagement in breast cancer patients: Insights from the early recovery phase

S. Yeon1, J. Min2, J.Y. Kim3, S.I. Kim3, T.H. Lee4, D-H. Park1, R. Park5, J.W. Kang4,Y.J. Lee6, C. Oh4, E. Kim1, S. Jun4, K. Chiho6, J. Jeon1

1Sport Industry Studies, Yonsei University, Seoul, Republic of Korea; 2Convergence Medicine, Yonsei University College of Medicine - Wonju Severance Christian Hospital,Wonju, Republic of Korea; 3Division of Breast Surgery, Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea; 4Sports Medicine, Yonsei University, Seoul, Republic of Korea; 5Sports Industry, Yonsei University, Seoul, Republic of Korea; 6Department of Sports Industry, Yonsei University, Seoul, Republic of Korea

Background: Although engaging in exercise after breast cancer surgery (BCS) has been shown to facilitate faster recovery, factors inﬂuencing exercise participation during the early recovery phase remain unclear in breast cancer patients. Therefore, this study aimed to explore the perceptions, attitudes, and barriers to exercise in breast cancer patients immediately after surgery and up to 4 weeks post-surgery.

Methods: A descriptive qualitative research method was employed to investigate this topic. A purposive sample of 33 breast cancer patients was selected, and each participant was interviewed three times over a one-month period after surgery.

Results:We found physical constraints and psychological resistance were identiﬁed as barriers to exercise. Postoperative physical symptoms (pain, range of motion, lack ofﬁtness, and seroma) and surgical drains were identiﬁed as physical constraints. Participants also faced psychological resistance such as concerns about side effects, lack of willpower, and fear of pain. Furthermore, a lack of trustworthy information regarding the timing of exercise initiation and proper types of exercise after surgery was identiﬁed as a psychological resistance.

Conclusions: The identiﬁed barriers, both physical and psychological, should be taken into consideration when developing strategies to motivate and support patients in engaging in exercise. The identiﬁed barriers, both physical and psychological, should be taken into consideration when developing strategies to motivate and support patients in engaging in exercise.

Clinical trial identiﬁcation: This study involves human participants and was approved by the Institutional Review Board of Severance Hospital (IRB No. 4-2018-1094).

Funding: This work was supported by the National Research Foundation of Korea grant number NRF-2017S1A5A2A01024689, NRF-2021S1A5B5A16077404, the National R&D Programme for Cancer Control, Ministry of Health and Welfare, Republic of Korea (HA21C0067000021) and the Yonsei Signature Research Cluster Programme

2021220009.

359P Themes, codes, and categories from the interviews

ries

%(n)

Codes

al constraints 100% (33)

Postoperative physical symptoms

Operation derived condition

logical nce

48.5% (16) Perception and attitude

Concerns due to lack of

trustworthy exercise information

https://doi.org/10.1016/j.annonc.2023.09.538

360P

100%

45.4%

54.5%

Neoadjuvant inetetamab combined with pertuzumab,

paclitaxel and carboplatin for locally advanced HER2-

positive breast cancer: Primary analysis of a phase II study

Y. Chai1, M. Jiang1, J. Liu1, M. He1, X. Wang2, Y. Wang2, X. Yang2, J. Wang2, B. Xu3,Q. Li4

1Medical Oncology Dept., Chinese Academy of Medical Sciences and Peking Union Medical College - National Cancer Center, Cancer Hospital, Beijing, China; 2Surgical Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College -National Cancer Center, Cancer Hospital, Beijing, China; 3Medical Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College - National Cancer Center, Cancer Hospital, Beijing, China; 4Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College - National Cancer Center, Cancer Hospital,Beijing, China

Background: Inetetamab is a neotype HER2-targeted monoclonal antibody with amino acids modiﬁed Fc segment which optimizes the antibody-dependent cellular cytotoxicity effect. However, robust evidence evaluating the combination of inetetamab combined with pertuzumab, paclitaxel and carboplatin (TCbIP) for neoadjuvant therapy is still lacking. This study aimed to evaluate the efﬁcacy and safety of TCbIP as a neoadjuvant therapy for patients with locally advanced (LA) HER2-positive breast cancer.

Methods: This phase II trial included female patients with histologically conﬁrmed stage IIA to IIIC HER2-positive primary invasive breast cancer. Eligible patients received TCbIP treatment every three weeks for a maximum of six cycles followed by surgery. The primary endpoint was pathologic complete response (pCR, ypT0/is ypN0)rate. Key secondary endpoints included near pCR (npCR, residual breast disease<1cm) rate, objective response rate (ORR) and safety.

Results: From November 2021 to May 2023, 28 patients were enrolled in the trial.

One patient received one cycle of the study treatment and was lost to follow-up without surgery, and four patients received one cycle of the study treatment and were still in treatment, leaving 23 patients in the ITT population. Among these 23 patients (82.6% in stage III), 16 patients completed the study treatment and surgery(PP population) and six patients were still undergoing neoadjuvant treatment. The ORR was 91.3% (21/23) in the ITT population and 93.8% (15/16) in the PP population.

Among the 16 patients in the PP population, 10 patients (62.5%) achieved pCR. A total of 14 patients (87.5%) achieved npCR. For patients with hormone receptor (HR)negative and positive tumors, the pCR rates were 88.9% (8/9) and 28.6% (2/7),respectively. The most common grade 3 adverse event was neutropenia (25.0%). No signiﬁcant reduction in the left ventricular ejection fraction was observed in any patient.

Conclusions: Neoadjuvant therapy with TCbIP has shown promising efﬁcacy and manageable toxicity in patients with HER2-positive LA breast cancer.

Clinical trial identiﬁcation: NCT05749016.

https://doi.org/10.1016/j.annonc.2023.09.539

Theme

(33)

Pain at the surgery site

87.9% (29)

Limited range of motion

66.6% (22)

Lack of ﬁtness

33.3% (11)

Seroma

12.2% (4)

(15) Drain

45.5% (15)

(18) Concerns about side effects

42.4% (13)

Lack of willpower

15.2% (5)

Fear of pain

(18) Concerns regarding the exercise timing being inappropriate

42.4% (14)

Discouragement from others

18.2% (6)

S327

361P

A phase II study of fulvestrant combined with chemotherapy in the neoadjuvant treatment of HR+/HER2- locally

advanced breast cancer

J. Wu, Q. Shao, X. Pan, W. Zhou, Y. Wang, N. Zhang, X. Zhou, W. Li, F. Xu, X. Zeng

Department of Breast Center, Chongqing University Cancer Hospital, Chongqing, China

Background: HR+/HER2- breast cancer are less sensitive to neoadjuvant chemotherapy (NCT), with a low objective response rate (ORR) of approximately 65% and a much lower pathological complete response (pCR) rate ranging from 5% to 10%. This phase 2 study aims to evaluate the efﬁcacy and safety of adding fulvestrant to NCT in patients (pts) with HR+/HER2- breast cancer, and to investigate the predictive value of 18F-FES PET/CT for effectiveness.

Methods: In this single-arm phase 2 study, eligible pts were female with histologically conﬁrmed HR+/HER2- locally advanced breast cancer (IIB-IIIC). Pts received fulvestrant (500 mg, on days 0, 14, 28, then every 28 days thereafter, every 4 weeks for six cycles) plus AC-T regimen, followed by surgery. Premenopausal women received a concomitant GnRH analogue. Pts underwent 18F-FES PET/CT examination at baseline.

The primary endpoint was ORR. Secondary endpoints include tpCR (ypT0/is ypN0),overall survival (OS), and safety.

Results: From Dec 2020 to Sep 2022, 36 pts were enrolled. The median age was 53 years (range, 35-67), 78% were ECOG PS 1, 69% were postmenopausal, 92% were nodal involved, and 83% had stage III. After neoadjuvant therapy, the ORR and DCR were 86.1% (95% CI, 70.5%-95.3%) and 100% (95% CI, 90.3%-100.0%), respectively. All pts completed surgery, with a tpCR rate 8.3% (3/36; 95% CI, 1.8%-22.5%). 29 (80.6%;95% CI, 64.0%-91.8%) pts had pathological tumor response [Miller-Payne (MP) grade 3]. Grade 3 treatment-emergent adverse events (TEAEs) occurred in 22% (8/36).The most common TEAEs were neutropenia (13.9%) and leukopenia (8.3%). Among the 36 pts, 24 completed 18F-FES PET/CT scan at baseline. The average SUVmax in primary breast lesions was 4.17 (range 1.00-12.80). The SUVmax was signiﬁcantly associated with MP grade (R¼0.82, p¼8.4e-07). The SUVmax of the primary tumorfrom pts with MP grade 2/3 was signiﬁcantly lower than those in pts with MP grade 4/5 (p¼2.33e-05).

Conclusions: The addition of fulvestrant to NCT showed manageable toxicity and promising antitumor activity for pts with HR+/HER2- locally advanced breast cancer.

The SUVmax of18F-FES PET/CT was positively correlated with patient efﬁcacy.

Clinical trial identiﬁcation: ChiCTR2000041235.

https://doi.org/10.1016/j.annonc.2023.09.540

362P CYBERNEO trial: Update of results at 14 years of follow-up

S. Ben Dhia1, R. Schiappa2, J. Gal3, J-M. Ferrero4, P. Bahadoran5, C. Chapellier6,P-Y. Bondiau1

1Radiation Oncology, Centre Antoine Lacassagne, Nice, France; 2Epidemiology,Biostatistics and Data, Centre Antoine Lacassagne, Nice, France; 3Biostatistics Unit,Centre Antoine Lacassagne, Nice, France; 4Medical Oncology, Centre Antoine Lacassagne, Nice, France; 5Dermatology, CHU Nice - Hopital Pasteur, Nice, France; 6Radiology, Centre Antoine Lacassagne, Nice, France

Background: The purpose of the phase I “CYBERNEO” trial was to deﬁne the efﬁcacy of the CyberKnife(CK) for locally advanced (stage III) breast tumors combined to a neo-adjuvant treatment with chemotherapy for patients for whom a conservative surgery could not be considered at the onset. Neoadjuvant chemotherapy (NAC)consisted of 6 cycles: 3 cycles of docetaxel and 3 cycles of 5-ﬂuorouracil-epirubicincyclophosphamide (FEC). CK was performed during the second cycle of chemotherapy. Breast surgery was performed six to eight weeks later and conventional breast irradiation without boost, afterwards. The main objective was to deﬁne the maximum tolerated dose of hypofractionated radiotherapy concurrent with NAC.We present an updated survival data for patients included in this trial and we evaluate the late toxicities of this combination.

Methods: We updated the survival data of 25 patients treated for a stage III breast cancer between 2007 and 2009 at the Antoine Lacassagne Center in Nice and included in the CYBERNEO trial by recording late toxicities and esthetic results.

Results: With a median follow-up of 12 years, 95% CI [10-14], 19 patients (76%) were in remission, 1 patient had a controlled axillary lymph node relapse (4%) band 5 patients (20%) died due to metastatic progression within a median of 5 years after treatment (min: 1, max: 9). Nine patients (36%) had a complete histological response(pCR). The highest percentage of pCR was in the group of patients treated in the 4th stage (28.5 Gy in 4 fractions). Overall survival at 14 years was 71%, 95% CI [53%-94%].

Two patients developed chronic radiation toxicity during follow-up with a ﬁbrosis(8%), of which one was in the 4th stage and one in the 5th stage (31.5 Gy). Three patients (12%) had a change of prosthesis after treatment which for one patient was 24 months after the end of support.

Conclusions: The updated results of the CYBERNEO trial with 14 years of follow-up conﬁrm the satisfactory results in terms of local control with an excellent long-term safety proﬁle.

https://doi.org/10.1016/j.annonc.2023.09.541

363P High adipocytokines and IL-18bp serum levels are associated with lower objective response rate after neoadjuvant treatment in breast cancer patients with metabolic syndrome

L. Mont’Alverne Arruda1, G. de Lima Freitas2, L. Guimarães Franco da Silva2,

J. Sales Bonﬁm da Silva2, I. de Fátima Vieira Camelo Maia2, A. Gomes Cajado2,C. Choquenaira Quispe2, B.G. Alves1, L.D.C.A. Guimaraes1, A.B. Lustosa1, I. Rocha1,A.B.T. Filgueiras1, L.F. Oliveira Torres1, J.P. Holanda Soares1, F. Bitencourt4,

P. Goberlanio5, M.D.P.S.S. Cunha6, R.C. Pereira Lima-Jr2, D.V. Tenazoa Wong2

1Oncologia Clinica, HHJ - Hospital Haroldo Juacaba - Instituto Do Cancer do Ceara(ICC), Fortaleza, Brazil; 2Department of Physiology and Pharmacology, Center for Drug Research and Development (NPDM), Federal University of Ceará, Fortaleza, Brazil;4Pesquisa Clinica, HHJ - Hospital Haroldo Juacaba - Instituto Do Cancer do Ceara (ICC),Fortaleza, Brazil; 5Biologia Molecular, HHJ - Hospital Haroldo Juacaba - Instituto Do Cancer do Ceara (ICC), Fortaleza, Brazil; 6Patologia, HHJ - Hospital Haroldo Juacaba -Instituto Do Cancer do Ceara (ICC), Fortaleza, Brazil

Background: Metabolic syndrome (MetS) has been identiﬁed as a factor related to a worse prognosis in breast cancer. However, the association between adipocytokines and IL-18bp serum levels, MetS, and breast cancer is not demonstrated.

Methods: We prospectively evaluated 151 women with breast cancer eligible for neoadjuvant chemotherapy (NAC). We studied adipocytokines (resistin and leptin)and IL-18bp serum levels and their association with MetS, patients’ clinical and laboratory data, and clinical and pathological responses after NAC. Data analysis used the Fisher/Chi-Square and Mann-Whitney Tests (SPSS v20.0, p<0.05). Study approval number 5.332.237.

Results: 134 subjects (95.7%) achieved clinical objective response (complete + partial). Among the 151 patients evaluated, 82 (54.3%) had MetS, with HDL-C <50 mg/dl being the most frequent criterion (n¼72, 87,8%). Age>45 years, postmenopausalstatus, obesity, NAC dose reduction, and delay in performing surgery were more associated with the MetS group (p<0.01). MetS breast cancer patients with high resistin levels presented with positive lymph nodes (97%), >¼88 cm waist circum-ference (94%), and invasive breast carcinoma of no special type (100%) versus the group with low levels of resistin (p<0.05). Additionally, high IL-18bp levels were associated with non-luminal A breast cancers (94%) versus 73% of patients with IL18bp low levels (p<0.05). Leptin was elevated in patients with hyperglycemia and hypertriglyceridemia, while IL18-bp levels increased in subjects with HDL-C < 50md/dl (p<0.05). The higher frequency of objective response was associated with no need for dose reduction and low serum IL-18bp concentration (p<0.05).

Conclusions: High adipocytokines and IL-18bp serum levels are associated with lower objective response rates after neoadjuvant treatment in breast cancer patients with metabolic syndrome.

Legal entity responsible for the study: L. Mont’Alverne Arruda.

Funding: Funcap, CNPq, Ebserth, Capes.

https://doi.org/10.1016/j.annonc.2023.09.542

365P Effectiveness and safety of human type 5 recombinant adenovirus (H101) in malignant tumor with malignant pleural effusion and ascites: A multicenter, observational,real-world study

B. Wang1, C. Zhong1, Z. Liao2, H. Wang3, X. Cai4, Y. Zhang2, J. Wang5, T. Wang6,H. Yao7

1Department of Oncology, No. 960 Hospital of PLA, Jinan, China; 2Department of Medical Oncology, Shaanxi Provincial Cancer Hospital, Xi’an, China; 3Department of Oncology, The Second Hospital of Tianjin Medical University, Tianjin, China; 4Department of General Internal Medicine, Sun Yat-Sen University Cancer Center, Guangzhou,China; 5Department of Oncology, The First Afﬁliated Hospital of Shandong First Medical University/ Shandong Provincial Qianfoshan Hospital, Jinan, China; 6Hepatobiliary Pancreatic Center, Beijing Tsinghua Chang Gung Hospital, Beijing, China;7Department of Medical Affairs, Guangdong Techpool Bio-pharma Co., Ltd, Guangzhou, China

Background: Human type 5 recombinant adenovirus (H101) has shown promising efﬁcacy in malignant serous effusion (MSE), but evidence is limited. The purpose of this study was to analyze the effectiveness and safety of H101 in Chinese patients

with malignant pleural effusion and ascites (MPE/MA) in the real world, so as to guide clinical use of H101.

Methods: This multicenter, observational, real-world study recruited patients with MPE or MA caused by malignant tumor receiving H101-containing treatment between January 2020 and June 2022 across 5 hospitals. Effectiveness was evaluated by overall remission rate (ORR), and safety was evaluated based on adverse events (AEs).

Subgroup analysis was performed on patients grouped according to tumor type, the volume of MPE and MA, and dosage of H101.

Results: A total of 653 eligible patients were enrolled in this study, among whom 467 received H101 monotherapy and 176 received H101 combined with chemotherapy. In H101 monotherapy group, the decrease of MPE or MA was achieved in 282 (60.4 %)patients, 176 (37.7%) patients showed no change in volume of MPE or MA, and 9(1.9%) patients showed an increase, yielding an ORR of 60.4% (282/467). The ORR for the combination therapy group was 60.2% (106/176), with 106 cases of PR, 69 cases of NC and 1 case of PD. Subgroup analyses based on tumor type, volume of MPE and MA, and dosage of H101 all showed high ORR, approximately 60%. The main AEs associated with H101-containing regimens were fever, nausea and vomiting. No serious AEs occurred in both groups.

Conclusions: Encouraging clinical beneﬁts and manageable toxicity of H101 against MPE and MA were observed in the real-world clinical setting, indicating that the H101-containing regimen is reliable, safe, and feasible, providing a novel and effective option for the treatment of this disease.

https://doi.org/10.1016/j.annonc.2023.09.543

366P

Artiﬁcial intelligence (AI)-powered assessment of complete and intense human epidermal growth factor receptor 2(HER2)-positive tumor cell proportion in breast cancer:

Predicting ﬂuorescence in situ hybridization (FISH) positivity and response to HER2-targeted therapy

M. Jung1, S-W. Kim2, S.G. Song3, S.K. Baek4, S.I. Cho5, S. Shin5, S. Kim5, H. Song5,S. Park5, S. Pereira5, D. Yoo5

1Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea; 2Department of Pathology, Kyung Hee University College of Medicine, Seoul,Republic of Korea; 3Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea; 4Department of Internal Medicine, Kyung Hee University College of Medicine, Seoul, Republic of Korea; 5Oncology, Lunit Inc., Seoul,Republic of Korea

Background: The level of expression of HER2 is important in predicting response to HER2-targeted therapies. HER2 expression level is classiﬁed in groups (3+ positive, 2+equivocal, and 1+ or 0 negative) or quantiﬁed as an H-score based on the proportion of tumor cell intensity (complete and intense [strong positive], weak to moderate complete [moderate positive], incomplete and faint/barely perceptible [weak positive]). If the case is classiﬁed as 2+ equivocal, an additional test such as Fluorescence In Situ Hybridization (FISH) test is performed to conﬁrm the positivity. In this study,we aim to ﬁgure out that the complete and intense HER2-positive tumor cell proportion can predict both FISH positivity and response to HER2-targeted therapy,compared to the H-score.

Methods: Lunit SCOPE HER2, an AI-powered HER2 analyzer that identiﬁes and quantiﬁes HER2 IHC according to staining intensity of tumor cells, was used to evaluate the HER2 status of breast cancer cases (n¼205) from Kyung Hee UniversityHospital. They consisted of 41 3+, 163 2+, and 1 1+, as interpreted by pathologists. Of these, 171 had FISH results, and 44 received HER2-targeted therapy as neoadjuvant(n¼25) or as palliative (n¼19). The proportion of strong positive tumor cells or the H-score by the AI-powered HER2 analyzer was assessed to predict clinical outcomes.

Conclusions: Dynamic follow-up for sarcopenic obesity and visceral adipose tissue increase may improve the survival in breast cancer with NACT. Further prospective studies will be elucidated the relationship between breast cancer and sarcopenia.

S329

Legal entity responsible for the study: G. Tahtacı.

https://doi.org/10.1016/j.annonc.2023.09.546

369P

The impact of germline BRCA mutations in locally advanced,triple-negative breast cancer (TNBC) treated with platinumbased neoadjuvant chemotherapy

H. Goldvaser1, I. Kuchuk2, R. Yerushalmi3, A. Goldshtein4, O. Rotem3, A. Lotan5,A.A. Gabizon1, R. Mutai3

1Oncology Department, Shaare Zedek Medical Center, Jerusalem, Israel; 2Oncology,Meir Medical Center, Kfar Saba, Israel; 3Oncology Dept., Rabin Medical Center Davidoff Cancer Centre, Beilinson Campus, Petah Tikva, Israel; 4Faculty of Medicine,The Hebrew University of Jerusalem, Jerusalem, Israel; 5Plastic Surgery, Shaare Zedek Medical Center, Jerusalem, Israel

Background: Whether germline BRCA (gBRCA) mutation affects prognosis and whether it has implications on treatment decision in the neoadjuvant setting is unclear.

Methods: Two centers retrospective cohort study comprising all women with earlystage TNBC who completed genetic testing and were treated with neoadjuvant chemotherapy with dose-dense chemotherapy containing carboplatin, between

10.2014 and 3.2020. Clinico-pathological features and data on dose reduction and delays were collected. Data on outcomes including pathological complete response(pCR), overall-survival (OS) and disease-free survival (DFS) were also calculated. Differences of these variables by gBRCA status were investigated.

Results: Sixty-four 64 women were included in the ﬁnal analysis, of which 31 had pathogenic gBRCA mutation and 33 were gBRCA wild-type. Clinico-pathological characteristics and dose density and intensity were similar between both groups.

Among gBRCA mutated patients, 23/31 (74%) achieved pCR, compared to 17/33(51%) in the non-mutated, p¼0.035. At a median follow-up of 30 months, gBRCAmutated women had signiﬁcantly favorable OS (HR¼8.64, 95% CI 1.08-69.21,p¼0.042) and a trend for a favorable DFS (HR¼7.4, 95% CI 0.91-60.27; p¼0.062). Thefavorable OS for gBRCA mutated women remained signiﬁcant in multivariate analysis(p¼0.029) and was noted regardless to pathological response (p¼0.01).

Conclusions: Compared to non-mutated, gBRCA mutated women with locally advanced TNBC treated with neoadjuvant chemotherapy containing carboplatin had a higher pCR rate and better outcome. Whether gBRCA mutation has a role in deescalating treatment in this population, should be further investigated.

Disclosure: H. Goldvaser: Financial Interests, Personal, Speaker, Consultant, Advisor, Not related to the submitted work: Gilead, Oncotest , Novartis ; Financial Interests, Personal, Advisory Board, Not related to the submitted work: Pﬁzer; Financial Interests, Personal, Invited Speaker, Not related to the submitted work: Roche , AstraZeneca; Financial Interests, Personal, Speaker, Consultant, Advisor:MSD. R. Yerushalmi: Financial Interests, Personal, Speaker, Consultant, Advisor, outside the submitted work: Roche, Eli-Lilly ; Financial Interests, Institutional, Research Grant, outside the submitted work: Roche; Financial Interests, Personal, Advisory Board, outside the submitted work: Pﬁzer,Novartis, Gilead; Financial Interests, Personal, Invited Speaker, outside the submitted work: Medison,MSD, AstraZeneca. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.547

370P LYMPHA surgery to reduce lymphedema following axillary node clearance: A new study at a London plastics centre

D. Hobday, L. Ioannidi, M. Kanapathy, S. Hamilton, A. Mosahebi, N. Naderi

Plastic Surgery Dept., Royal Free London NHS Foundation Trust, London, UK

Background: LYMPHA is a relatively new surgical technique that dramatically reduces the incidence of lymphedema following axillary node clearance in breast cancer patients. The technique identiﬁes dominant lymph vessels draining the arm with the aid of dye and, following clearance of the axillary nodes, anastomosing lymphatic vessels to a branch of the axillary vein to enable free drainage of lymphatic ﬂuid. Not currently widely available to breast cancer patients in the UK, this simple surgical procedure carried out at the time of axillary node clearance has been shown to reduce the incidence of lymphedema from 25% to 4%. We report on the establishment of a LYMPHA service at a major London Plastics Centre and ﬁrst 2 years of its outcomes.

Methods: Suitable patients were referred to plastics by the breast surgery team and seen preoperatively to discuss LYMPHA. Upon agreeing to the procedure, pre-operative measurements of arm volume and arm bioimpedance were completed as well as screening questionnaires on symptoms of lymphedema. Subsequent to the procedure the two measurements and the questionnaires were repeated at 1, 3, 6, 12 and 24 month intervals.

Results: Of 16 patients that have undergone the LYMPHA procedure 0 have experienced signs or symptoms of lymphedema to date. One patient suffered temporary swelling of the arm 1-month post-op which subsequently resolved. No patients have suffered any complications relating to LYMPHA. 1 patient withdrew due to metastatic disease recurrence. The patients enrolled have been followed up for between 3-23 months with a current mean follow up time of 12.61 months.

Conclusions: Our ﬁndings thus far support current evidence that LYMPHA surgery is both safe and effective in reducing the incidence of lymphedema. This pilot study is currently being developed into an RCT which will add to the evidence base of this relatively niche area of plastic surgery.

https://doi.org/10.1016/j.annonc.2023.09.548

371P Adherence to standardized and structured electronic

symptom reporting (ePRO) via mobile app in HER2-positive breast cancer treated with HER2 biosimilar trastuzumab

A. Trojan1, M.K. Kiessling1, M.S. Aapro2, A. Eniu3

1Breast Oncology, Brustzentrum Zürichsee, Horgen, Switzerland; 2Cancer Center,Clinique de Genolier, Genolier, Switzerland; 3Department Service Interdisciplinaire de Cancerologie, HRC - Hopital Riviera-Chablais - Site de Rennaz, Rennaz, Switzerland

Background: The treatment of HER2+ breast cancer (BC) patients with Herceptin was the standard for more than a decade. Development of trastuzumab biosimilars has prompted the demonstration of clinical equivalency to the reference biosimilar and safety. So far, adherence to dynamic standardized and structured real-world assessment of wellbeing and symptoms, via ePROs in patients treated with the HER2 biosimilar Ogivri has not been reported. We assess the adherence of ePROs using the medidux app (previously: consilium care) and perform a comparative analysis of ePROs obtained from HER2+ BC patients in two studies where Herceptin was administered (NCT02004496, NCT03578731).

Methods: In this 6 week observational study, patients were treated with trastuzumab(Ogivri) +/- Pertuzumab, +/- Chemotherapy +/- anti-hormones. Patients used the mediduxTM app to record well-being, symptoms (according to CTCAE), EQ-5D-5L, trail maker test and vital parameters and intake of medication in a standardized manner.

Patients also received a pop-up reminder in case of missing data entries after 3 days.

Previously obtained ePROs from 38 patients treated with Herceptin similar therapeutic settings were used for comparative analysis.

Results: From 53 female patients included in this trial so far, there was only one drop out. About 60% of patients continued to use the app after the observational 6 weeks period. Close to 10`000 symptom entries were recorded with an average of > 2 symptoms/day. Of the more than 90 individual symptoms, the most common reported were fatigue, taste disorder, diarrhea, nausea, dry mucosa, joint discomfort,tingling, headache and appetite loss. Results available from >70% of all data sets suggests that patients symptoms were reported in a similar incidence and score as from the comparative analysis of Herceptin. Adherence to the app use and electronic recording of symptoms was continued in average for another 3 months after the end of observation without clear correlation to age or symptom severity.

Conclusions: The majority of patients continued the ePRO app use after end of study participation. Only 1 drop out (from 53 pats) was noted in this propsective observational study.

Clinical trial identiﬁcation: SNCTP000004711.

Legal entity responsible for the study: Mobile Health AG, Zurich.

Funding: Mylan Pharma GmbH (a Viatris Company).

Disclosure: A. Trojan: Other, Personal, Stocks or ownership: Mobile Health AG. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.549

372P

Prevalence of BRCA1 and BRCA2 mutation among Indian breast cancer patients: A multicentre cross-sectional study

S. Nag1, D. Arya2, S.J. Rajappa3, N.K. Warrier4, A. Kapoor5, J. Ghosh6, A. Batra7,S.S. Panda8, S. Kate9, G. Prakash10, C. Goswami11, S.V. Almel12, S. Aggarwal13,R. Kodagali14, K. Bhatt15, S. Gupta16

1Medical Oncology Department, Sahyadri Hospital, Pune, India; 2Medical Oncology Dept, Max Super Speciality Hospital, Saket, New Delhi, Uttar Pradesh, India;3Oncology Department, Basavatarakam Indo American Cancer Hospital & Research Institute, Hyderabad, Andhra Pradesh, India; 4Medical Oncology Dept, MVR Cancer Centre & Research Institute, Kozhikode, India; 5Medical Oncology Dept., Mahamana Pandit Madan Mohan Malviya Cancer Centre and Homi Bhabha Cancer Hospital,Varanasi, Uttar Pradesh, India; 6Medical Oncology Dept, TMC - Tata Medical Center,Kolkata, India; 7Medical Oncology Dept, AIIMS - All India Institute of Medical Sciences,New Delhi, Delhi, India; 8Medical Oncology, IMS & SUM Hospital SOA University,Bhubaneswar, India; 9Medical Oncology Department, HCG Manavata Cancer Centre,Nashik, India; 10Internal Medicine Department, PGIMER - Postgraduate Institute of Medical Education and Research, Chandigarh, Chandigarh, India; 11Medical Oncology Dept, Ruby General Hospital, Kolkata, West Bengal, India; 12Medical Oncology, P. D.

Hinduja National Hospital and Medical Research Centre, Mumbai, Maharashtra, India; 13Medical Oncology Department, Sir Ganga Ram Hospital, New Delhi, India;14Medical Affairs, AstraZeneca India, Bangalore, India; 15Medical Affairs Department,AstraZeneca India, Bangalore, India; 16Medical Oncology Department, Tata Memorial Centre - Homi Bhabha National Institute, Mumbai, India

Background: Germline mutations in breast cancer susceptibility genes 1 or 2(gBRCA1/2mut) increase predisposition to breast cancer. Previous Indian breast cancer studies suggest gBRCAmut prevalence of 18.6-36.2%, but data are either single-centre or in patients selected by family history, histopathological subtype or age.

Methods: This was a prospective,cross-sectional,multicentre, study conducted in 14 institutions across India among patients with newly diagnosed stage I to IV breast cancer who had not yet completed 1st- line treatment and were not enriched for gBRCAmut. Based on previous Indian data, a sample size of 313 was estimated to be adequate. Germline BRCA 1/2 testing was performed in a single central laboratory in blood sample-derived DNA by next-generation sequencing (NGS), with reﬂex multiplex ligation probe ampliﬁcation (MLPA) in patients who were -ve on NGS or were detected with Variant of Unknown Signiﬁcance (VUS).

Results: Between June 2022 and Feb 2023, 304 patients were recruited in the study with a median age of 46 (22-83) years.The prevalence of pathogenic or likely pathogenic (P/LP) gBRCA 1/2 mutation was 27 (8.8%, 95%CI 6.18-12.61%) in the full study population. P/LP gBRCAmut prevalence in patients with ER/PR+/HER2 negative, HER2 positive and TNBC were 10/123 (8.13%, 95% CI 4.48-14.32), 2/80 (2.5%, 95% CI 0.69-8.66), and 15/102 (14.8%, 95% CI 9.12-22.85) respectively; in patients 50 years and>50 years were 20/194 (10.31%, 95% CI 6.77-15.39) and 7/110 (6.37%, 95% CI 3.12-12.56) respectively; in patients with and without relevant family history were 10/35(28.57%, 95% CI 16.33-45.05) and 17/269 (6.32%, 95% CI 2.57-7.63 ), respectively;and in patients with stage I-III and stage IV disease were 22/235 (9.36%, 95% CI 6.26-13.77) and 5/68 (7.35%, 95% CI 3.18-16.09), respectively. The majority of P/LP gBRCAmut were in BRCA1 (16/304, 5.26%, 95%CI 3.04-8.4%), of whom 12/16 (75.0%)patients had TNBC, while 11/304 (3.62%) patients had gBRCA2mut of whom 7/11(63.63%) had ER/PR+/HER2 -negative disease and 4/11 (36.37%) were TNBC.

Conclusions: Less than 10% of unselected newly diagnosed Indian breast cancer patients have P/LP gBRCA mutations. Younger age, TNBC subtype and positive family history enrich for such mutations.

Legal entity responsible for the study: AstraZeneca Pharma India Ltd.

Funding: AstraZeneca Pharma India Ltd.

Disclosure: S. Nag: Financial Interests, Personal, Invited Speaker: Dr Reddys Pﬁzer Roche; Financial Interests, Institutional, Local PI: AstraZeneca. Roche; Non-Financial Interests, Advisory Role: NGO s like WCI. IMA; Non-Financial Interests, Member: ASCO. ISMPO. R. Kodagali: Financial Interests,Personal, Full or part-time Employment: AstraZeneca Pharma India Ltd. K. Bhatt: Financial Interests,Personal, Full or part-time Employment: AstraZeneca Pharma India Ltd. S. Gupta: Financial Interests,Personal, Other, Member of various committees related to guidelines, drug pricing, others: Indian Council of Medical Research, Government of India; Financial Interests, Personal, Other, Member of Scientiﬁc Committee on nano-biosensors for healthcare applications: Council of Scientiﬁc and Industrial Research, Government of India; Financial Interests, Personal, Other, Scientiﬁc committee member for appraisal of scientiﬁc projects submitted to DBT for funding.: Department of Biotechnology, Government of India; Financial Interests, Personal, Other, Scientiﬁc committee member for appraisal of scientiﬁc projects submitted to India Alliance for funding. India Alliance is a partnership between Wellcome Trust and Department of Biotechnology (Government of India) to fund healthcare related research in India.: India Alliance; Financial Interests, Institutional, Other, Steering Committee member for a global clinical trial (CLEE011A2207). Honorarium to institution.: Novartis;Financial Interests, Institutional, Other, Steering Committee member for a global clinical trial.

Honorarium to institution.: AstraZeneca; Financial Interests, Institutional, Advisory Board, Advisory Board member on ovarian cancer. Honorarium to institution.: AstraZeneca UK Limited; Financial Interests, Institutional, Advisory Board, Advisory Board member on metastatic breast cancer. Honorarium to institution.: Eli Lilly & Company (India) Limited; Financial Interests, Institutional, Invited Speaker, Invited speaker on cervical cancer at an academic conference. Honorarium to institution:Seoul National University Hospital; Financial Interests, Institutional, Invited Speaker, Chairperson at a conference. Honorarium to institution: Lupin Limited; Financial Interests, Institutional, Invited Speaker, Chairperson, speaker, or panelist at 5 conferences/meetings. Honoraria to institution.:Roche Products (India) Private Limited; Financial Interests, Institutional, Invited Speaker, Chairperson, panelist, or speaker at a 3 meetings/roundtable. Honoraria to institution: Novartis Healthcare Pvt. Ltd.; Financial Interests, Institutional, Invited Speaker, Chairperson at 2 conferences/meetings. Honoraria to institution: Eli Lilly & Company (India) Limited; Financial Interests, Institutional, Invited Speaker, Invited speaker in a conference. Nag Foundation is a not-for-proﬁt registered

society working in the ﬁeld of cancer: Nag Foundation; Financial Interests, Institutional, Invited Speaker, Invited panelist in a meeting. Honorarium to institution.: Eisai Company Limited; Financial Interests, Institutional, Invited Speaker, Invited speaker. Honorarium to institution: Omnicuris Healthcare Private Limited; Financial Interests, Institutional, Invited Speaker, Invited panelist at a conference. Honorarium to institution.: Cipla Limited, Cadila Pharmaceuticals; Financial Interests,Institutional, Invited Speaker, Invited chairperson at a conference. Honorarium to institution.: Intas Pharmaceuticals Limited; Financial Interests, Institutional, Local PI, CO40016 Titled - A Double Blind,Placebo- Controlled, Randomized Phase III Study of IPATASERTIB in combination with Paclitaxel As a treatment for patients with PIK3CA/AKT1/PTEN-Altered, Locally Advanced or Metastatic, Triple Negative Breast cancer or Hormone Receptor e Positive, HER2 e Negative Breast Cancer: F. Hoffmann-La Roche Ltd; Financial Interests, Institutional, Coordinating PI, National coordinating PI of a multi-omics study in ER positive breast cancer: Department of Biotechnology, Government of India;Financial Interests, Institutional, Local PI, EGC002: Phase III, Randomized, Multicenter, Double-blind Study to Compare Efﬁcacy and Safety of EG12014 (EirGenix Trastuzumab) with Herceptin as Neoadjuvant Treatment in Combination with Anthracycline/Paclitaxel-based Systemic Therapy in Patients with HER2-positive Early Breast Cancer: EirGenix Inc.; Financial Interests, Institutional, Local PI, Protocol No. - CLEE011A3201C : A phase II randomized study of the combination of Ribociclib plus goserelin acetate with Hormonal Therapy versus physician choice chemotherapy in premenopausal or perimenopausal patients with hormone receptor positive/HER2-negative inoperable locally advanced or metastatic breast cancer - RIGHT Choice Study: Novartis Healthcare Pvt. Ltd.; Financial Interests, Institutional, Local PI, Protocol No. - D9100C00001 : A Phase III, Randomized, Multi-Center,Double-Blind, Global Study to Determine the Efﬁcacy and Safety of Durvalumab in Combination With and following Chemoradiotherapy Compared to Chemoradiotherapy Alone for Treatment in Women With Locally Advanced Cervical Cancer (CALLA): AstraZeneca Pharma India limited.; Financial Interests, Institutional, Local PI, Protocol No. - CLEE011A2207 : A phase II, multicenter, randomized,open-label study to evaluate the safety and efﬁcacy of 400 mg of ribociclib in combination with nonsteroidal aromatase inhibitors for the treatment of pre- and postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer who received no prior therapy for advanced disease: Novartis Healthcare Pvt. Ltd.; Financial Interests, Institutional, Local PI: Glenmark Pharmaceuticals Ltd.; Financial Interests, Institutional, Coordinating PI, Protocol No. - D0816R00025 :A Prospective, Multicentre, Phase-IV Clinical Trial of Olaparib in Indian Patients with Platinum Sensitive Relapsed Ovarian Cancer who are in Complete or Partial Response Following Platinum Based Chemotherapy and Metastatic Breast Cancer with Germline BRCA1/2 Mutation (SOLI Study):AstraZeneca Pharma India Limited; Financial Interests, Institutional, Local PI, Protocol No. -D9670C00001 : A Phase 3, Randomized, Multi-center, Open-label Study of Trastuzumab Deruxtecan(T-DXd) Versus Investigator’s Choice Chemotherapy in HER2-low, Hormone Receptor Positive Breast Cancer Patients whose Disease has Progressed on Endocrine Therapy in the Metastatic Setting(DESTINY-Breast06): AstraZeneca Pharma India Ltd.; Financial Interests, Institutional, Local PI, Protocol No. - D3614C00001 : A Phase III Double-blind Randomised Study Assessing the Efﬁcacy and Safety of Capivasertib + Paclitaxel Versus Placebo + Paclitaxel as First-line Treatment for Patients with Histologically Conﬁrmed, Locally Advanced (Inoperable) or Metastatic Triple-Negative Breast Cancer(TNBC).: AstraZeneca Pharma India Limited; Financial Interests, Institutional, Local PI, PIK3CA Registry- A descriptive study of PIK3CA mutations in patients with HR+/Her2- advanced breast cancer.:NOVARTIS HEALTHCARE PRIVATE LIMITED; Financial Interests, Institutional, Local PI, Protocol No. -D967JC00001 : A Phase 1b/2 Multicentre, Open-label, Modular, Dose-ﬁnding and Dose-expansion Study to Explore the Safety, Tolerability, and Anti-tumour Activity of Trastuzumab Deruxtecan (T-DXd)in Combination with other Anti-cancer Agents in Patients with HER2-positive Metastatic Breast Cancer (DESTINY-Breast07): AstraZeneca Pharma India Ltd.; Financial Interests, Institutional, Local PI,D9311C00001 ’’A Randomised, Multicentre, Double-blind, Placebo-controlled, Phase III Study of First-line Carboplatin and Paclitaxel in Combination with Durvalumab, Followed by Maintenance Durvalumab with or without Olaparib in Patients with Newly Diagnosed Advanced or Recurrent Endometrial Cancer (DUO-E): AstraZeneca; Financial Interests, Institutional, Local PI, WO42633 A phase III, randomized, double-blind,placebo-controlled clinical trial to evaluate the efﬁcacy and safety of adjuvant atezolizumab or placebo and trastuzumab emtansine forher2-positive breast cancer at high risk of recurrence following preoperative therapy (ASTEFANIA study): Roche Products(India) Pvt. Ltd.; Financial Interests, Institutional, Local PI, MO42921 A multi-country observational retrospective study to evaluate the prevalence of pd-l1 and its role in patients with tnbc treated with systemic therapy (VANESSA): Roche Products India Pvt Ltd. ; Financial Interests, Institutional,Local PI, Cost-effectiveness Analysis & Value-Based Pricing for Anti-Cancer Drugs: Implications for Patients, Industry, Insurer and Regulator: Department of Health Research, Ministry of Health and Family Welfare, New Delhi; Financial Interests, Institutional, Coordinating PI, Coordinating PI for Multi-Omics Analysis to Decipher Mechanisms of Hormone Resistance in Breast Cancer: Department of Biotechnology, Government of India; Financial Interests, Institutional, Coordinating PI, Mapping of Breast Cancer: Department of Science and Technology, Government of India; Financial Interests,Institutional, Local PI, Protocol No. - ECTS/16/002 : A multicentric open label phase II safety and efﬁcacy study of ormeloxifene in tamoxifen resistant metastatic/recurrent breast cancer patients.:HLL Lifecare Limited (A Government of India Enterprises); Financial Interests, Institutional, Coordinating PI, Protocol No. - D0818R0000 : Protocol no. D0818R00001- A Non-interventional, multicentre study to assess prevalence of BRCA1 and BRCA2 mutation among ovarian, primary peritoneal and fallopian tube cancer patients in India (BRCA study): AstraZeneca Pharma India Ltd.; Financial Interests, Institutional, Local PI, Protocol No. - 1000-16 : An Open Label, Single Arm, Multicentric,Phase IV study to evaluate the safety and efﬁcacy of Bevacizumab of Intas Pharmaceuticals Limited in approved indications: Intas Pharmaceuticals Ltd; Financial Interests, Institutional, Local PI, Protocol No. - Protocol no: 471-13 : “A Prospective, Adaptive, Randomized, Open-Label, Multicenter Clinical Trial to assess the Efﬁcacy and Safety of Fixed Dose Combination of Capecitabine & Cyclophosphamide in Patients of Metastatic Breast Cancer with failure of Anthracycline and/or Taxane Chemotherapy: Intas Pharmaceuticals Ltd; Financial Interests, Institutional, Local PI, Protocol No. -MO39196: A phase III, Multicentre, randomised, double-blind, placebo controlled study of Atezolizumab ( anti-PD-L1 antibody) in combination with paclitaxel compared with placebo in combination with paclitaxel for patients with previously untreated, inoperable locally advanced or metastatic Triple Negative Breast Cancer.: Roche Products (India) Pvt. Ltd; Financial Interests, Institutional, Local PI, Protocol No. - CBYL719C2301 : A phase III randomized double-blind, placebo controlled study of alpelisib (BYL719) in combination with fulvestrant for men and postmenopausal women with hormone receptor positive, HER2-negative advanced breast cancer which progressed on or after aromatase inhibitor treatment: Novartis Healthcare Pvt. Ltd.; Non-Financial Interests, Member of Board of Directors, This is a not-for-proﬁt registered organization which aims to create large databases of genomic and other ’omic’ data in breast and other cancers.: Indian Cancer Genome Atlas; NonFinancial Interests, Leadership Role, General Secretary of this non-governmental organization (It is a not-for-proﬁt) which aims to help underprivileged patients with breast and gynecological cancers and promotes research and educational activities in these themes.: Women’s Cancer Initiative - Tata Memorial Hospital; Non-Financial Interests, Leadership Role, President-Elect of ISMPO which is the largest professional organization of medical oncologists in India. It is a not-for-proﬁt registered society.: Indian Society of Medical and Paediatric Oncology (ISMPO). All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.550

S331

373P

Impact of comorbidities on real-world (rw) clinical outcomes of patients (pts) with hormone receptor-positive/human epidermal growth factor 2-negative (HR+/HER2-) advanced breast cancer (ABC) treated with palbociclib and enrolled in POLARIS

D. Tripathy1, J.L. Blum2, M.S. Karuturi1, S. McCune3, S. Kurian4, M.M. Moezi5,D.M. Anderson6, Y. Wang7, M.Z. Montelongo8, Z. Zhang9, E. Gauthier10, G. Rocque11

1Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Department of Oncology, Baylor-Sammons Cancer Center, Texas Oncology, US Oncology, Dallas, TX, USA; 3William S. Gibbons Cancer Research Institute, Northwest Georgia Oncology Centers Wellstar, Marietta, GA, USA;4Hematology/Oncology, West Virginia University Cancer Institute, Morgantown, VA,USA; 5Medical Oncology, Cancer Specialists of North Florida, Fleming Island, FL, USA;6Oncology & Hematology, Health Partners Institute, Saint Paul, MN, USA; 7Oncology Medical Group, Pﬁzer Inc, New York, NY, USA; 8Biostatistics and Medical Writing, ICON Commercialisation and Outcomes, ICON plc, Blue Bell, PA, USA; 9Oncology Clinical Statistics, Pﬁzer Inc, San Diego, CA, USA; 10Global Medical Affairs, Pﬁzer Inc, San Francisco, CA, USA; 11Division of Hematology/Oncology, Department of Medicine,University of Alabama at Birmingham, Birmingham, AL, USA

Background: Palbociclib is used to treat HR+/HER2 ABC with an aromatase inhibitoras ﬁrst line of therapy (1LOT) or with fulvestrant in pts whose disease progressed on endocrine therapy. Limited information exists on comorbidities’ impact on rw clinical outcomes in these pts.

Methods: POLARIS is a prospective observational study of pts with HR+/HER2 ABCreceiving palbociclib in clinical practice in the US and Canada. Rw progression-free survival (rwPFS) and overall survival (OS) for pts with clinically relevant comorbidities and by Charlson Comorbidity Index (CCI) score were descriptively summarized.

Results: 1250 pts were enrolled (median age 64 y; 99% female; 27% de novo metastatic diagnosis; 32% bone-only; 40% visceral metastases). Of these, 908 (73%)received palbociclib as 1LOT and 342 (27%) as 2LOT. Pts had a median (range) of 2(0e9) comorbidities; 5% had 0, 56% had 1e2, 32% had 3e4, and 7% had >4. Median OS (months; 95% CI) for pts with CCI scores of 0, 1e2, and 3+ were 48.8 (37.3eNE),NR (43.0eNE), and 34.3 (29.1e44.1) in 1LOT and 39.5 (30.6e50.5), 35.2 (26.5e41.6),and 31.6 (20.9e45.2) in 2LOT, respectively. Median rwPFS for CCI scores andcertain comorbidities are shown (Table).

Results: Among all cases, FISH positivity was 20.5%, pathologic complete response(pCR) after neoadjuvant therapy was 40.0%, and complete/partial response during palliative therapy was 68.4%. The proportion of strong positive tumor cells was a better predictor of FISH positivity and response compared to H-score (Area under the curve: 0.784 vs. 0.688 for FISH, and 0.872 vs. 0.859 for response). Prediction of pCR was equivalent for both (0.773). The DeLong test showed a signiﬁcant difference in the prediction of FISH positivity (p¼0.023).

Conclusions: This study showed that AI analysis of breast cancer HER2 expression,speciﬁcally the proportion of strong positive tumor cells, can predict FISH and therapy response better than the H-score.

Disclosure: S.I. Cho, H. Song, S. Park, S. Pereira, D. Yoo: Financial Interests, Personal, Full or parttime Employment: Lunit Inc.; Financial Interests, Personal, Stocks/Shares: Lunit Inc. S. Shin, S. Kim:Financial Interests, Personal, Full or part-time Employment: Lunit Inc. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.544

367P Sentinel lymph node biopsy (SLNB) in patients with locally advanced breast cancer (LABC): Descriptive, inferential and survival analysis

J.M. Espejo Niño

Medicina Nuclear, Hospital Universitario Cruces, Barakaldo, Spain

Background: The objective was to perform a descriptive, inferential and overall survival analysis of patients with LABC who underwent SLNB.

Methods: Retrospective study(January/12-December/22) in patients with LABC selected for SLNB with: initial clinical and radiological tumor and lymph node staging(TNM-AJCC-7&8-Edition), histological types, prognostic tumor markers, with evaluation of the response(radiological & pathological) of the tumor and lymph nodes after neoadjuvant chemotherapy(NACT). We performed a descriptive, inferential and survival analysis.

Results: 141patients with LABC met inclusion criteria: 128(91%)Inﬁltrating Ductal Carcinoma, 7(5%)Inﬁltrating Lobular Carcinoma, 2(1%) Inﬁltrating Ductal Carcinoma in-situ, and 1case(1% each) of: tubular, medullary, mucinous and colloid carcinoma.

The TNM staging before NACT was: T1:14(9.9%)patients; T2:95(67.4%); T3:27(19.2%)and T4:5(3.5%). 89(63.1%)patients were cN(+) and 52(36.9%) were cN(0). Intrinsic subtypes were: Luminal-A 10(7.1%) patients, Luminal-B 26(18.4%); Luminal-B-Her2 34(22%); Her2 31(28.4%) and 40(24.1%)Triple negative. Histological grades (HG) were:grade I 5(3.5%)patients, grade II 53(37.6%), and grade III 83(58.9%). We obtained 46(32.6%)SLNB(+), 85(60.3%)SLNB(-) and in 10(7.1%)there was no migration (NM).

We performed 93 lymphadenectomies(LDN): 44 SLNB(+); 39 SLNB(-) and 10-NM. We obtained 29LDN(+):19SLNB(+), 6NM and 4SLNB(-). We obtained 64LDN(-): 25SLNB(+),4NM and 35SLNB(-). 8-patients died: 3LDN(+): 2SLNB(+) and 1NM; 4-LDN(-): 2SLNB(+)and 2SLNB(-); and 1 SLNB(-) without LDN. 46-patients(51.7%) went from cN(+) to pN0.

In the inferential analysis we found a statistically signiﬁcant correlation between the SLNB result and the intrinsic subtype (p<0.001), with Luminal-B-Her2 subtypes and triple negative patients as those with the most SLNB(-) results. Detection rate(DR) was

95.3%. False negative rate (FNR) was 8%, considering SLNB(+) as a true positive. The survival time for patients with SLNB(+) was 111 months, for SLNB(-) it was 127 months (2.4) and for patients with NM it was 95 months.

L. Cavalcante1, L.L. Siu2, J. Toso3, D. Mires3, R. Shiga3, J. Maruca4, G. Ayele3,P. Kumar Vuppala3, Y. Cheng3, L. Huang3, J.E. Connolly3, Y. Ishimoto5, M. Sue5,P.L. Bedard6

1Hematology/Medical Oncology, Winship Cancer Institute of Emory University,Atlanta, GA, USA; 2Medical Oncology and Hematology Department, Princess Margaret Cancer Centre, Toronto, ON, Canada; 3Daiichi Sankyo, Inc., Basking Ridge, NJ, USA;4Daiichi Sankyo, Inc., Basking Ridge, NJ, USA, Rutgers University, New Brunswick, NJ,USA; 5Daiichi Sankyo Co., Ltd., Tokyo, Japan; 6Division of Medical Oncology & Hematology, Princess Margaret Cancer Center, Toronto, ON, Canada

Background: Immune checkpoint inhibitors have improved outcomes for patients with various cancer types, yet most experience disease progression. Growing evidence supports that myeloid cells, such as macrophages, play a major role in inhibiting tumor progression. Macrophage and cancer cell interaction can be inhibited by the SIRPa-CD47 pathway. Blocking this pathway may restore antitumor immune functions of macrophages and reduce tumor growth. DS-1103a, a recombinant humanized IgG4 anti-SIRPa antibody, blocks this pathway by binding to the major human variants of SIRPa. T-DXd, an antibody-drug conjugate consisting of an anti-HER2 antibody and topoisomerase I inhibitor payload, is approved for various cancers. In nonclinical studies, DS-1103a enhanced the trastuzumab-induced antibody-dependent cellular phagocytosis, suggesting a potential beneﬁt of the combination. This study will assess the preliminary safety and efﬁcacy of DS-1103a + T-DXd in advanced solid tumors.

Trial design: This phase 1, global, multicenter, ﬁrst-in-human, 2-part, dose-escalation,and dose-expansion study (NCT05765851) plans to enroll up to 78 patients. Part 1(dose-escalation [based on BOIN design]) will enroll patients with pathologically documented HER2-expressing (IHC1+ or greater) or HER2-mutated (activating mutation) advanced solid tumors not amenable to standard of care. Part 2 (dose34 - Issue S2 - 2023

expansion) will enroll patients with HER2-low (IHC2+/ISH- or IHC1+ [ISH- or untested])breast cancer who received 1-2 prior lines of chemotherapy in the recurrent or metastatic setting. DS-1103a monotherapy will be administered for Cycle 1 of Part 1,DS-1103a + T-DXd for all other 21-day cycles and during Part 2. The evaluation period for dose limiting toxicity will be before Cycle 3 in Part 1. Primary endpoints include the safety and tolerability of the combination in both parts, determining the recommended dose of DS-1103a in combination for expansion in Part 1, and assessing the objective response rate in Part 2. Secondary endpoints include the antitumor activity of DS-1103a + T-DXd, pharmacokinetic proﬁle of DS-1103a, and incidence of antidrug antibodies against DS-1103a.

Clinical trial identiﬁcation: NCT05765851.

Editorial acknowledgement: Writing support was provided by Kim Caldwell, PhD and Danyang Zhou, PharmD, of Lumanity Communications Inc., and was funded by Daiichi Sankyo, Inc.

Legal entity responsible for the study: Daiichi Sankyo, Inc.

Funding: Daiichi Sankyo, Inc.

Disclosure: L. Cavalcante: Financial Interests, Personal, Advisory Board: Pliant Therapeutics;Financial Interests, Personal, Full or part-time Employment, Employment ended February 2022:Actuate Therapeutics. L.L. Siu: Financial Interests, Personal, Advisory Board: Merck, AstraZeneca,Roche, Seattle Genetics, Voronoi, Arvinas, Tessa, Navire, Relay Therapeutics, Amgen, Marengo,InterRNA, Medicenna, Hoopika, Coherus, Tubulis, LTZ Therapeutics; Financial Interests, Personal,Other, Spouse is co-founder: Treadwell Therapeutics; Financial Interests, Personal, Stocks/Shares,Spouse has stock ownership: Agios; Financial Interests, Institutional, Local PI: Novartis, Bristol Myers Squibb, Pﬁzer, Boehringer-Ingelheim, Merck, GSK, Roche/Genentech, AstraZeneca, Astellas, Amgen,Shattucks, EMD Serono; Financial Interests, Institutional, Coordinating PI: Bayer, Symphogen, Intensity Therapeutics; Non-Financial Interests, Advisory Role: ICR, Dana Farber Harvard Cancer Center. J. Toso: Financial Interests, Personal, Advisory Board, Employment and equity: Daiichi Sankyo.

D. Mires, G. Ayele, Y. Cheng, L. Huang, J.E. Connolly, M. Sue: Financial Interests, Personal, Other,Employment and equity: Daiichi Sankyo. R. Shiga, Y. Ishimoto: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. P.L. Bedard: Financial Interests, Institutional, Local PI:AstraZeneca, Bicara, BMS, Amgen, Novartis, Genentech/Roche, Sanoﬁ, Merck, Pﬁzer, Zymeworks,Nektar Therapeutics, Lilly, SeaGen, Medicenna; Financial Interests, Institutional, Research Grant:Pﬁzer; Financial Interests, Institutional, Funding: Servier; Non-Financial Interests, Member of Board of Directors, Executive Board Member: Breast International Group; Non-Financial Interests, Leadership Role, Chair: AACR Project GENIE; Non-Financial Interests, Leadership Role, Past Chair IND Committee Member, Breast Site Steering Committee: Canadian Clinical Trials Group; Non-Financial Interests, Advisory Role: SeaGen, Lilly, Amgen, Merck, BMS, Pﬁzer, Gilead. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.2830

S333

BREAST CANCER, METASTATIC

376O

mOS, m mOS H OS rat OS rat mPFS b mPFS H

m, media Estimated

Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice (TPC) in patients (pts) with HER2-low unresectable and/or metastatic breast cancer (mBC):Updated survival results of the randomized, phase III DESTINY-Breast04 study

S. Modi1, W. Jacot2, H. Iwata3, Y.H. Park4, M.J. Vidal Losada5, W. Li6, J. Tsurutani7,K. Zaman8, N.T. Ueno9, A. Prat10, K. Papazisis11, H.S. Rugo12, N. Harbeck13, S-A. Im14,M. De Laurentiis15, C.M.A. Orbegoso16, L. Yung17, F-C. Cheng18, Y. Cheng19,

D.A. Cameron20

1Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 2Medical Oncology, Institut du Cancer de Montpellier, Montpellier, France; 3Breast Oncology,Aichi Cancer Center Hospital, Nagoya, Aichi, Japan; 4Hematology-Oncology, Samsung Medical Center, Seoul, Republic of Korea; 5Oncologia Médica, Hospital Clínic de Barcelona, Barcelona, Spain; 6Tumor Center, The First Hospital of Jilin University,Changchun, Jilin, China; 7Advanced Cancer Translation Research Institute, Showa University, Shinagawa, Japan; 8Oncology, Lausanne University Hospital CHUV, Lausanne, Switzerland; 9Medicine, University of Hawaii Cancer Center, Honolulu, HI, USA;10Medical Oncology, Translational Genomics and Targeted Therapies Group, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; 11Oncology,Euromedica General Clinic, Thessaloniki, Greece; 12Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; 13Breast Center, Obstetrics and Gynecology, LMU University Hospital, Munich, Germany; 14Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul,Republic of Korea; 15Breast Oncology Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy; 16Global Oncology Research and Development, Daiichi Sankyo, Inc., Rueil-Malmaison, France; 17Global Oncology R&D, Daiichi Sankyo, Inc.,Basking Ridge, NJ, USA; 18Biostatistics & Data Management, Daiichi Sankyo, Inc.,Basking Ridge, NJ, USA; 19Clinical Safety and Pharmacovigilance, Daiichi Sankyo, Inc.,Basking Ridge, NJ, USA; 20Edinburgh University Cancer Centre, University of Edinburgh, Edinburgh, UK

Background: DESTINY-Breast04 (NCT03734029) assessed T-DXd vs TPC in pts with HER2-low mBC (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization). Atprimary data cutoff (DCO; January 11, 2022), median overall survival (mOS) for the full analysis set (FAS ¼ hormone receptor-positive [HR+] and hormone receptor-negative[HR]) was 23.4 months (mo) for T-DXd vs 16.8 mo for TPC (hazard ratio, 0.64; P ¼0.001), with 18.4 mo median follow-up (F/U). Here, we report results from a preplanned further F/U (DCO, March 1, 2023).

Methods: Pts were randomly assigned 2:1 to T-DXd or TPC. At the updated DCO,analyses of OS (HR+ and FAS), progression-free survival (PFS) by investigator (HR+ and FAS), and safety were conducted.

Results: At DCO, median F/U was 32 mo. Median treatment duration was 8.2 mo(range, 0.2-39.1 mo) for T-DXd and 3.5 mo (range, 0.3-19.7 mo) for TPC. Efﬁcacy results are shown in the table. Grade 3 treatment-emergent adverse events (TEAEs)were lower in T-DXd vs TPC (54.4% vs 67.4%). The most common TEAEs were gastrointestinal or hematological in nature; all-grade nausea (T-DXd: 76.0%; TPC:

30.2%) and vomiting (T-DXd: 40.7%; TPC: 13.4%) were most common for T-DXd and decreased neutrophil count (T-DXd: 22.1%; TPC: 36.0%) was most common for TPC.

Exposure-adjusted incidence rates for any-grade TEAEs were 1.2 and 2.6 for the T-DXd vs TPC arm, respectively. No new adjudicated drug-related interstitial lung disease/pneumonitis events were reported with longer F/U (primary DCO: 45 pts [12.1%] for T-DXd; 1 pt [0.6%] for TPC).

Conclusions: Results from the 32-mo median F/U for DESTINY-Breast04 conﬁrms the sustained clinically meaningful improvement for T-DXd vs TPC previously demonstrated in HER2-low mBC, regardless of HR status. Similar to the primary analysis, the overall safety proﬁle was generally manageable with longer duration of treatment exposure.

376O Summary of efﬁcacy results

HR+

T-DXd n ¼ 331

o (95% CI)

23.9 (21.7-25.2)

azard ratio (95% CI)

0.69 (0.55-0.87)

e at 24 mo, %a (95% CI)

49.0 (43.3, 54.5)

e at 36 mo, %a (95% CI)

26.5 (20.7-32.7)

y investigator, mo (95% CI)

9.6 (8.4-10.0)

0.37 (0.30-0.46)

and CI for OS rate at the speciﬁed time point are from Kaplan-Meier analysis.

Clinical trial identiﬁcation: NCT03734029.

Editorial acknowledgement: Under the guidance of authors, assistance in medical writing and editorial support was provided by Lauren Carroll, MS, MPH, and Soniya Patel, PhD, of ApotheCom, and was funded by Daiichi Sankyo, Inc.

Disclosure: S. Modi: Financial Interests, Personal, Advisory Board: Daiichi Sankyo, Genentech,AstraZeneca, Seagen, Macrogenics; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo,AstraZeneca; Financial Interests, Personal, Steering Committee Member: Daiichi Sankyo; Financial Interests, Institutional, Local PI: Daiichi Sankyo, Genentech, AstraZeneca, Seagen. W. Jacot: Financial Interests, Personal, Advisory Board: AstraZeneca, Eisai, Novartis, Roche, Pﬁzer, Eli Lilly, MSD, BMS,Chugai, Seagen, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca, Pﬁzer,Seagen, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: AstraZeneca, Daiichi Sankyo; Financial Interests, Coordinating PI: Roche, Daiichi Sankyo; Financial Interests, Local PI: Roche,Novartis, Daiichi Sankyo. H. Iwata: Financial Interests, Personal, Advisory Board: Chugai, Daiichi Sankyo, AstraZeneca, Lilly, Sanoﬁ; Financial Interests, Personal, Invited Speaker: Chugai, Daiichi Sankyo, AstraZeneca, Lilly, Pﬁzer, Sanoﬁ, Taiho; Financial Interests, Personal and Institutional,Steering Committee Member: Chugai, Daiichi Sankyo, AstraZeneca, MSD, Amgen, Sanoﬁ, Novartis,Pﬁzer, Kyowa Hakko Kirin; Financial Interests, Personal and Institutional, Local PI: Lilly, Bayer, Behringer, Nihon Kayaku. Y. Y.H. Park: Financial Interests, Personal, Advisory Board: AstraZeneca, Pﬁzer,Roche, Novartis, MSD, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca,Pﬁzer, Roche, Novartis, MSD; Financial Interests, Institutional, Other, Research Grant: AstraZeneca,Pﬁzer, Roche, MSD; Non-Financial Interests, Principal Investigator: AstraZeneca, Pﬁzer, Novartis,MSD, Lilly, Roche, Daiichi Sankyo. M.J. Vidal Losada: Financial Interests, Personal, Advisory Board:Novartis/Pﬁzer, Roche, Pﬁzer, AstraZeneca/Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Novartis/Pﬁzer, Roche/Genentech, AstraZeneca/Daiichi Sankyo, Gilead Sciences; Financial Interests, Personal, Other, Travel, Accommodations, expenses: Pﬁzer; Financial Interests, Personal,Other, Travel, Accommodations, Expenses: Gilead Sciences. J. Tsurutani: Financial Interests, Personal,Invited Speaker: Daiichi Sankyo, AstraZeneca; Financial Interests, Institutional, Research Grant: Eisai,Eli Lilly, Ono. K. Zaman: Financial Interests, Institutional, Advisory Board: AstraZeneca, Daiichi, Lilly,Pierre Fabre, Gilead, MSD, Novartis, Seagen, Viatris; Financial Interests, Institutional, Funding,Translational study: Roche; Financial Interests, Institutional, Steering Committee Member: Pierre Fabre; Financial Interests, Institutional, Other, Member of the IDMC of an international trial: Roche;Financial Interests, Institutional, Steering Committee Member, Member of the Steering committee of an international study: Daiichi; Non-Financial Interests, Advisory Board: Swiss Group for Clinical Research Against Cancer (SAKK), Executive Committee of the MINDACT trial; Non-Financial Interests,Member, Representative of SAKK Breast Group: Breast International Group (BIG); Non-Financial Interests, Member: EORTC Breast Group; Other, Unrestricted funding for organization of academic symposium: Agendia, AstraZeneca-MSD, Daiichi, Eisai, Exact Sciences, Lilly, Pierre Fabre, Gilead,Novartis, Pﬁzer, Roche, Seagen, Viatris, Vifor; Other, Support for participation in international congress: AstraZeneca, Daiichi, Gilead, Pierre Fabre, Roche, Lilly. N.T. Ueno: Financial Interests,Personal, Research Funding: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Daiichi Sankyo. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal,Invited Speaker, Lecture fees: Novartis, Daiichi Sankyo; Financial Interests, Personal, Advisory Board,Advisory role/consultancy: Novartis, Pﬁzer, Oncolytics Biotech, Guardant Health, Peptomyc; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Institutional, Other, Contracted research: Boehringer Ingelheim, Medica Scientia inno. Research; Financial Interests, Personal, Advisory Board: AstraZeneca, 1TRIALSP, S.L.; Financial Interests, Personal,Member of Board of Directors, Leadership role: Reveal Genomics, SL.; Financial Interests, Personal,Stocks/Shares: Reveal Genomics, Oncolytics Biotech; Financial Interests, Personal, Royalties: Reveal Genomics, International Oncology Bureau, S.L.,; Financial Interests, Institutional, Local PI: Roche,AstraZeneca; Financial Interests, Personal and Institutional, Steering Committee Member: Daiichi Sankyo; Financial Interests, Institutional, Coordinating PI: Novartis; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation, Actitud Frente al Cáncer Foundation; Non-Financial Interests, Personal, Other, Asociación Española de Investigación sobre el Cáncer: ASEICA. K. Papazisis: Financial Interests, Personal, Invited Speaker: MSD, Gilead, AstraZeneca, Novartis, Novartis, Genesis, Eli Lilly, Roche; Financial Interests, Personal, Advisory Board: MSD,Eli Lilly, GSK; Financial Interests, Personal, Research Grant: MSD, AstraZeneca, Novartis, Eli Lilly,Daiichi Sankyo, Roche, GSK, NEKTAR, BMS, Boehringer Ingelheim, Sanoﬁ, Eisai; Financial Interests,Personal, Advisory Role: Novartis, Ipsen. H.S. Rugo: Financial Interests, Personal, Other, Consultancy/advisory support: PUMA, NAPO, Mylan, Daiichi Sankyo, Eisai; Financial Interests, Institutional, Local PI: Novartis, Lilly, Pﬁzer, Daiichi, AstraZeneca, Gilead Sciences, Inc., GSK, Sermonix Pharmaceuticals Ins., Pionyr Immunotherapeutics, Taiho Oncology, Inc., Veru Inc; Financial Interests, Institutional,Coordinating PI: OBI Pharma, Astellas Pharma Inc., F. Hoffmann-La Roche AG/Genentech, Inc.,Merck; Financial Interests, Personal, Other, Travel support to academic meetings: Merck, AstraZeneca, Gilead; Non-Financial Interests, Advisory Role, I advise a number of companies without

FAS

PC n ¼ 163

T-DXd N ¼ 373

TPC

N ¼ 184

7.6 (15.1-20.2)

22.9 (21.2-24.5)

16.8 (14.1-19.5)

0.69 (0.55-0.86)

5.1 (27.3, 43.0)

47.3 (41.9, 52.4)

32.0 (24.8, 39.3)

6.9 (10.2-25.0)

26.2 (20.8-31.9)

16.3 (10.3-23.6)

.2 (3.4-4.9)

8.8 (8.3-9.8)

4.2 (3.0-4.5)

0.36 (0.29-0.45)

compensation: various. N. Harbeck: Financial Interests, Personal and Institutional, Other, Honoraria for lectures and/or consulting; Clinical Trials: Amgen, AstraZeneca, Daiichi Sankyo, EPG Communication, Gilead, Eli Lilly, Medscape, MSD, Novartis, Pierre-Fabre, Pﬁzer, Roche, Sandoz, Seagen, Sanoﬁ,Springer, Zuelligpharma, Viatris. S. Im: Financial Interests, Personal, Advisory Board, no payment:AstraZeneca, Novartis, Eisai, Roche, Hanmi, Pﬁzer, Lilly, MSD, GSK, Daiichi Sankyo; Financial Interests,Institutional, Advisory Board: Bertis; Financial Interests, Personal, Advisory Board: Idience; Financial Interests, Institutional, Research Grant: AstraZeneca, Pﬁzer, Roche, Eisai, Dae Woong; Financial Interests, Institutional, Local PI, Clinical Trial Budget: AstraZeneca, Hanmi, Novartis, Roche, Pﬁzer,Daiichi Sankyo, MSD, Lilly; Financial Interests, Institutional, Coordinating PI, Clinical Trial Budget:Eisai; Financial Interests, Institutional, Research Grant, Clinical Trial Budget: Boryung Pharm. C.M.A.

Orbegoso, L. Yung, F. Cheng, Y. Cheng: Financial Interests, Personal, Full or part-time Employment:Daiichi Sankyo. D.A. Cameron: Financial Interests, Institutional, Advisory Board: Roche, Pﬁzer,AstraZeneca, Daiichi Sankyo, SeaGen, Synthon, Zymeworks; Financial Interests, Institutional, Other,Have done advisory boards, spoken at a webinar and invovled in a manuscript with Lilly - all recompense to my institution: Lilly; Financial Interests, Institutional, Other, Have done advisory boards and been involved in a health economic analysis and publication. All recompense to my institution: Novartis; Financial Interests, Institutional, Coordinating PI, funding and drug for UK participation in a french led Novartis funded study.Insitutional funding recieved for consultancy work: Novartis; Non-Financial Interests, Principal Investigator, one of three PIs for the Ameera-6 trial

- which has now closed early as the company have stopped all development of the drug: Sanoﬁ;Other, Chair of the board of this small Scottish charity for secondary breast cancer: Make Seconds Count; Other, Chair of the Board of B.I.G. - a group of international breast cancer research groups:Breast International Group; Other,Chair of the European Breast Cancer Council which organises the bi-annual EBCC meetings: EBCC. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.553

377O

Best o

CR PR

Stable Progre NE Missing

IC-ORR IC-DoR CNS-PF

NE, not e

A pooled analysis of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-positive (HER2+) metastatic breast cancer (mBC) with brain metastases (BMs) from DESTINYBreast (DB) -01, -02, and -03

S.A. Hurvitz1, S. Modi2, W. Li3, Y.H. Park4, W. Chung5, S-B. Kim6, J. Cortés7,T. Yamashita8, J. Pedrini9, S-A. Im10, L-M. Tseng11, N. Harbeck12, I. Krop13,G. Curigliano14, E. Mathias15, J. Cathcart16, A. Cagnazzo15, S. Ashfaque15,A. Egorov15, F. André17

1Medicine/Hematology Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; 2Medicine, Memorial Sloan Kettering Cancer Center, New York, NY,USA; 3Tumor Center, The First Hospital of Jilin University, Changchun, Jilin, China;4Hematology-Oncology Dept, Samsung Medical Center, Seoul, Republic of Korea;5Medical Oncology, National Cheng Kung University, Tainan City, Taiwan; 6Oncology Dept., Asan Medical Center, Seoul, Republic of Korea; 7Oncology, International Breast Cancer Center, Barcelona, Spain; 8Breast and Endocrine Surgery, Kanagawa Cancer Center, Yokohama, Japan; 9Medical Oncology, Hospital Nossa Senhora da Conceicao,Porto Alegre, Brazil; 10Internal Medicine, Seoul National University Hospital, Seoul,Republic of Korea; 11Surgery, Taipei Veterans General Hospital, Taipei City, Taiwan;12Breast Center, Obstetrics & Gynecology, and Comprehensive Cancer Center Munich,LMU University Hospital, Munich, Germany; 13Medical Oncology, Yale Cancer Center,New Haven, CT, USA; 14Oncology and Hemato-Oncology, European Institute of Oncology, IRCCS, and University of Milan, Milan, Italy; 15Oncology, Daiichi Sankyo,Inc., Basking Ridge, NJ, USA; 16Oncology, Daiichi Sankyo Inc., Basking Ridge, NJ, USA;17Breast Cancer Unit, Medical Oncology Department, Institiut Gustave Roussy, Villejuif,France

Background: T-DXd is approved for treatment of pts with HER2+ unresectable or mBC

who have received 1 prior anti-HER2-based regimens.We report exploratory pooledefﬁcacy and safety data of T-DXd vs comparator (comp) in pts from DB-01, DB-02, and

DB-03 with treated/stable (treated) and untreated/active (untreated; from DB-02/-03)

BMs at baseline, as deﬁned by the US FDA (FDA 2020).

Methods: DB-01/-02 enrolled pts who were resistant/refractory to trastuzumab

emtansine (T-DM1); DB-03 included pts previously treated with trastuzumab and

taxane. T-DXd data and ad hoc exploratory intracranial analyses were pooled from DB01/-02/-03. Comp data, physician’s choice chemotherapy and T-DM1, were pooled

from DB-02 and -03, respectively. Endpoints were intracranial (IC) objective response

rate (ORR; complete [CR] or partial response [PR] in brain) per blinded independent

central review (BICR) by RECIST, IC duration of response (DoR), central nervous system-progression-free survival (CNS-PFS) by BICR, and safety.

377O IC efﬁcacy summary

T-DXd (N [ 148)

Treated/stable BMs (n ¼ 104) Untreated/active verall IC response, n (%)

17 (16.3)

7 (15.9)

30 (28.8)

13 (29.5)

disease

48 (46.2)

15 (34.1)

ssive disease

3 (2.9)

1 (2.3)

4 (3.8)

5 (11.4)

2 (1.9)

3 (6.8)

(CR + PR in brain), n (%) 47 (45.2)

20 (45.5)

, median, mo (95% CI) 12.3 (9.1-17.9)

17.5 (13.6-31.6)

S, median (95% CI)

12.3 (11.1-13.8)

18.5 (13.6-23.3)

valuable.

Results: Of the 148 pts with BMs at baseline who received T-DXd, 104 (70.3%) had treated and 44 (29.7%) had untreated BMs. Pts had a median of 3 (range, 1.0-14.0)prior regimens in the metastatic setting. Median treatment duration was 12.7 mo(range, 0.7-45.1) with T-DXd and 5.6 mo (range, 0.1-43.0) with comp. Efﬁcacy data are in the Table. Any-grade drug-related treatment-emergent adverse events (TEAEs),drug-related grade 3 TEAEs, and serious drug-related AEs were observed in 94.5%,43.2%, and 13.0% of pts with T-DXd, vs 94.0%, 36.1%, and 7.2% with comp,respectively.

Conclusions: T-DXd exhibited robust IC responses in pts with treated and, notably,untreated BMs vs comp. Although pt numbers were small and not statistically tested,numerically longer median IC-DoR and CNS-PFS were observed in pts with untreated BMs with T-DXd. Safety was acceptable and generally manageable with T-DXd.

Clinical trial identiﬁcation: NCT03248492; NCT03523585; NCT03529110.

Editorial acknowledgement: Under the guidance of authors, assistance in medical writing and editorial support was provided by Andre Wang, PharmD, and Laura Halvorson, PhD, of ApotheCom, and was funded by Daiichi Sankyo, Inc.

Funding: This study was funded by Daiichi Sankyo, Inc., and AstraZeneca.

Conclusions: Pts with HR+/HER2 ABC receiving palbociclib and CCI scores 0 and 1e2had similar rwPFS and OS regardless of LOT. Pts with CCI score 3+ had shorter rwPFS and OS in the 1LOT, and similar rwPFS but shorter OS in the 2LOT than pts withscore 0e2. Pts with cardiac disorders in the 1LOT and blood and lymphatic disorders in the 2LOT had shorter rwPFS, while other subgroups achieved generally com-parable clinical outcomes. Understanding potential impact of comorbidities on clinical outcome in the rw is important for treatment decision-making. Larger rw studies may be needed to further assess the true impact of these comorbidities.

Table: 373P rwPFS in pts with HR+/HER2L ABC by comorbidities and LOT

Subgroups 1LOT (n[908)

‡ 2LOT (n[342)

n (%) Median rwPFS,months (95% CI)

CCI score 0

276 (30) 20.3 (17.1e24.8) 101 (30) 13.9 (7.4e19.7)

1e2

493 (54) 24.7 (20.2e29.5) 189 (55) 13.1 (9.0e17.5)

139 (15) 16.8 (12.4e21.9) 52 (15) 13.2 (8.0e24.0)

Comorbidities Vascular

496 (55) 23.7 (19.5e28.1) 183 (54) 13.1 (8.7e17.2)Psychiatric 240 (26) 19.6 (15.2e27.2) 92 (27) 13.2 (9.4e24.0)Metabolic and

nutritional

173 (19) 19.6 (14.8e24.0) 55 (16) 14.9 (6.7e23.7)

Blood and lymphatic system

147 (16) 16.8 (12.2e20.8) 83 (24) 8.6 (4.8e11.7)

Cardiac

32 (4) 12.5 (8.5e34.1) 12 (4) 11.6 (2.9e42.8)

Clinical trial identiﬁcation: NCT03280303.

Editorial acknowledgement: Medical writing support, conducted in accordance with Good Publication Practice (GPP3) and the International Committee of Medical Journal Editors (ICMJE) guidelines, was provided by Heather Caballes, PhD, of Oxford PharmaGenesis Inc., Newtown, PA, USA, with funding provided by Pﬁzer Inc., USA.

Legal entity responsible for the study: Pﬁzer Inc.

Funding: Pﬁzer Inc.

Disclosure: D. Tripathy: Financial Interests, Personal, Advisory Board, Serving on Steering Committee for TrialsEducational Lectures: Novartis; Financial Interests, Personal, Advisory Board,Steering Committee for and ongoing trial: Pﬁzer; Financial Interests, Personal, Advisory Board,Advisory council for design and interpretation of trials: GSK; Financial Interests, Personal, Invited Speaker, Educational Lectures: AstraZeneca; Financial Interests, Personal, Advisory Board, To discuss and interpret clinical trial data: Immunomedics; Financial Interests, Personal, Advisory Board, Advice on clinical trial design: OncoPep; Financial Interests, Personal, Invited Speaker, Lecture on gene proﬁling: Exact Sciences; Financial Interests, Personal, Advisory Board, Consulting: Sermonix;

Financial Interests, Personal, Advisory Board, Consultant: Personalis, Puma Biotechnology, Gilead;Financial Interests, Institutional, Research Grant, Funding for laboratory experiments on the inhibition of CXCR4 in breast cancer cells: Polyphor; Financial Interests, Institutional, Invited Speaker,Global PI on one trial and local PI on another trial: Novartis. J.L. Blum: Financial Interests, Personal,Advisory Role: Puma Biotechnology, Athenix, Inc., OncLIve, Biotheranostics, AstraZeneca, Immunomedics, Inc., Research to Practice, Sanoﬁ, Pﬁzer, Tempus, TD2; Financial Interests, Personal, Speaker’s Bureau: Pﬁzer, Tempus. S. McCune: Financial Interests, Personal, Speaker’s Bureau: BMS; NonFinancial Interests, Institutional, Principal Investigator: BMS, Merck, Roche/Genentech. Y. Wang:Financial Interests, Personal and Institutional, Full or part-time Employment: Pﬁzer; Financial Interests, Personal, Stocks/Shares: Pﬁzer. M.Z. Montelongo: Financial Interests, Personal and Institutional, Full or part-time Employment: ICON plc; Financial Interests, Personal and Institutional,Sponsor/Funding: Pﬁzer. Z. Zhang, E. Gauthier: Financial Interests, Personal and Institutional, Full or part-time Employment: Pﬁzer; Financial Interests, Personal and Institutional, Stocks or ownership:Pﬁzer. G. Rocque: Financial Interests, Institutional, Research Grant: Genentech, Pﬁzer, Carevive;Financial Interests, Institutional, Advisory Role: Pﬁzer; Financial Interests, Personal, Advisory Role:Gilead, Flatiron. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.551

374P Evaluation of symptom severity, tolerability, and physical function in the I-SPY2 trial

A. Basu1, S. Umashankar2, M. Musthafa2, T. Jones2, K. Blevins2, T. Brown3,

D. Heditsian4, B. Parker3, S. Brain5, C. Simmons5, T.J. Hieken6, K. Ruddy7, C. Mainor8,S. Tevis9, A. Blaes10, H.S. Rugo11, I. Dunn12, M. Melisko13, L. Esserman14,

D.L. Hershman15

1Surgery, UCSF - University of California San Francisco, San Francisco, CA, USA;2Department of Medicine, UCSF - University of California San Francisco, San Francisco,CA, USA; 3UCSF - University of California San Francisco, San Francisco, CA, USA;4DeClarity, Emerald Hills, CA, USA; 5Breast Science Advocacy Core, UCSF - University of California San Francisco, San Francisco, CA, USA; 6Surgery Department, Mayo Clinic,Rochester, NY, USA; 7Department of Oncology, Mayo Clinic, Rochester, NY, USA; 8Internal Medicine Department, Lombardi Cancer Center Georgetown University,Washington, DC, USA; 9Department of Surgery, University of Colorado Denver, Denver,CO, USA; 10Division of Hematology/Oncology, University of Minnesota, Minneapolis,MN, USA; 11Breast Department, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; 12Department of Data Management, QLHC - Quantum Leap Healthcare Collaborative, San Francisco, CA, USA; 13Department of Medicine,University of California San Francisco, San Francisco, CA, USA; 14Department of Surgery, UCSF - University of California San Francisco, San Francisco, CA, USA;15Department of Oncology, Columbia University Medical Center College of Physicians& Surgeons - New York Presbyterian Hospital, New York, NY, USA

Background: Patient-reported outcomes (PROs) are a valuable component to understand treatment tolerability and toxicity. We have implemented an electronic system for monitoring PROs and quality of life (QOL) for patients enrolled in the ISPY2 trial, a phase II trial evaluating the effect of novel neoadjuvant therapies for breast cancer. We associated patient demographic factors with symptoms, decline in physical function (PF), and tolerability to treatment.

Methods: Study population for this analysis includes 259 enrolled patients receiving combinations of experimental immunotherapy and chemotherapy. Patients completed PRO-CTCAE/PROMIS/FACT surveys reﬂecting symptom severity, symptom frequency, tolerability of drug, and physical function at baseline through follow up (12 months). CTCAE 5.0 was collected weekly at these timepoints to assess adverse events (AE). Odds ratio and regularized multi-variate regression was used to evaluate early symptoms predictive of a clinically signiﬁcant decline in PF from baseline to post-treatment follow-up.

Results: Of 259 patients, 160 (58%) were White, 13 (5%) were Asian, 26 (10%) were African American (AA), and 25 (9.3%) were Hispanic. 25% of all patients had a clinically signiﬁcant decline in PF between baseline and pre-surgery/follow-up. Symptom predictors of decline included high frequency of diarrhea and severity of joint pain.

African American (AA) patients had higher severity of joint pain than White patients(OR ¼ 14.9, P < 0.05). Within the ﬁrst 12 weeks of treatment, AA patients and non-white (NW) patients were more likely to report severe vomiting than White patients(OR ¼13.22 and 12.72, P< 0.05 and P< 0.03 respectively). Overall, patients thatreported lower tolerance to therapy had higher grade of AE. While patients with lowgrade adverse events were less bothered by their side effects at follow-up, higher grade adverse events such as hypothyroidism impacted distress levels by more than double.

Conclusions: Among I-SPY2 participants, when higher grade of symptoms is persistent through follow up, it impacts physical function and tolerability even after end of therapy. Our study can allow physicians to be more diligent in active and post treatment monitoring.

Legal entity responsible for the study: I-SPY2 Trial Investigators.

Funding: Research reported in this manuscript was supported by the National Cancer Institute of the National Institutes of Health under award number P01CA210961. The authors wish to acknowledge the generous support of the study sponsors, Quantum Leap Healthcare Collaborative ( QLHC, 2013 to present) and the Foundation for the National Institutes of Health (2010 to 2012). The authors sincerely appreciate the ongoing support for the I-SPY2 Trial from the Safeway Foundation , the William K.

Bowes, Jr. Foundation, Give Breast Cancer the Boot, QLHC and the Breast Cancer Research Foundation.

Disclosure: L. Esserman: Financial Interests, Institutional, Research Funding: Merck; Financial Interests, Personal, Advisory Board: Blue Cross Blue Shield; Financial Interests, Personal, Other,Website Author: UpToDate. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.552

375TiP

A phase I, 2-part, multicenter, ﬁrst-in-human dose-escalation and dose-expansion study of DS-1103a with trastuzumab deruxtecan (T-DXd) in patients with advanced solid tumors

Disclosure: S.A. Hurvitz: Financial Interests, Personal, Invited Speaker: Clinical Care Options, axis medical, cancer expert now, ICHE, MJH Associates, PER, Primo, Projects in Knowledge, Prova Education, Research to Practice, Ultimate Medical Academy, Vaniam,WebMD, Peer Education, PrecisCA;Financial Interests, Personal, Stocks/Shares, spouse owns: ROM Tech; Financial Interests, Personal,Ownership Interest, spouse: Ideal Implant; Financial Interests, Personal, Royalties, author medical book: McGraw; Financial Interests, Personal, Royalties: Elsevier, Springer, Sage, Wolters Kluwer,Wiley; Financial Interests, Institutional, Local PI: Ambrx, AstraZeneca, Arvinas, Genentech/Roche,Gilead, GSK, Immunomedics, Eli Lilly, Macrogenics, Novartis, Pﬁzer, OBI Pharma, Pieris, PUMA,Radius, sanoﬁ, Seattle Genetics, Dignitana, Zymeworks, Phoenix Molecular Designs, Ltd, cytomx,Dantari, G1 Therapeutics, Greenwich Life Sciences, Loxo Oncology, Orinove, Orum; Financial Interests, Institutional, Coordinating PI: Daiichi Sankyo, Celcuity; Financial Interests, Institutional,Research Grant: Samumed, Ambrx; Financial Interests, Steering Committee Member: Greenwich Life Sciences, Orum; Financial Interests, Principal Investigator: Genentech, Daiichi Sankyo, Seattle Genetics; Financial Interests, Advisory Role: Daiichi Sankyo, Novartis, Ambrx, 4DPharma, Dantari,Macrogenics, Lilly, Artios, Roche, Pyxis, Amgen, Pieris, Arvinas, Immunomedics/Gilead; Financial Interests, Member: ASCO, AACR; Financial Interests, Other, speaker: National Breast Cancer Coalition; Financial Interests, Member, site representative for breast cancer guidelines: National Comprehensive Cancer Network. S. S. Modi: Financial Interests, Personal, Advisory Board: Daiichi Sankyo, Genentech, AstraZeneca, Seagen, Macrogenics; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, AstraZeneca; Financial Interests, Personal, Steering Committee Member:Daiichi Sankyo; Financial Interests, Institutional, Local PI: Daiichi Sankyo, Genentech, AstraZeneca,Seagen. Y.H. Park: Financial Interests, Personal, Advisory Board: AstraZeneca, Pﬁzer, Roche, Novartis,MSD, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca, Pﬁzer, Roche,Novartis, MSD; Financial Interests, Institutional, Other, Research Grant: AstraZeneca, Pﬁzer, Roche,MSD; Financial Interests, Principal Investigator: AstraZeneca, Pﬁzer, Novartis, MSD, Lilly, Roche,Daiichi Sankyo. W. Chung: Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Pﬁzer, Roche, Sanoﬁ, Viatris; Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, MSD, Novartis, Pﬁzer. S. S. Kim: Financial Interests, Personal, Advisory Board: Novartis, AstraZeneca, Lilly, DaeHwa Pharma, ISU Abx, DaiichSankyo, Beigene, HLB Life Science, Samsung Bioepics, OBI pharma; Financial Interests, Personal,Invited Speaker: Legochem Bioscience; Financial Interests, Personal, Ownership Interest: Genopeaks,Neogene TC; Financial Interests, Institutional, Research Grant: Novartis, Sanoﬁ-Genzyme, DongKook Pharm Co. J. Cortés: Financial Interests, Personal, Advisory Board: Roche, Celgene, Cellestia,AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp&Dohme, GSK, LEUKO, Bioasis, Clovis oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent,Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics; Financial Interests, Personal, Invited Speaker: Roche, Novartis, Celgene, Eisai, Pﬁzer, Samsung Bioepis, Lilly, Merck Sharp & Dohme,Daiichi Sankyo; Financial Interests, Personal, Other, Consulting/advisor: Expres2ion Biotechnologies;Financial Interests, Personal, Stocks/Shares: MedSIR, Nektar Therapeutics; Financial Interests,Institutional, Research Grant: Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, Guardant health, Merck Sharp & Dohme, Pﬁzer, Piqur Therapeutics,Puma B, Queen Mary University of London; Other, Travel cost and expenses: Roche, Novartis, Eisai,Daiichi Sankyo, Pﬁzer, Gilead, AstraZeneca. T. T. Yamashita: Financial Interests, Personal, Invited Speaker: Chugai, Eisai, Pﬁzer, Daiichi Sankyo, AstraZeneca, Taiho, Kyowa Kirin, Novartis Pharma,Nippon Kayaku, Eli Lilly . J. Pedrini: Financial Interests, Institutional, Principal Investigator: AstraZeneca, Roche, Daiichi Sankyo, Sanoﬁ, PPD, Seagen, MSD. S. Im: Financial Interests, Personal, Advisory Board, no payment: AstraZeneca, Novartis, Eisai, Roche, Hanmi, Pﬁzer, Lilly, MSD, GSK, Daiichi Sankyo; Financial Interests, Institutional, Advisory Board: Bertis; Financial Interests, Personal,Advisory Board: Idience; Financial Interests, Institutional, Research Grant: AstraZeneca, Pﬁzer, Roche,Eisai, Dae Woong; Financial Interests, Institutional, Local PI, Clinical Trial Budget: AstraZeneca,Hanmi, Novartis, Roche, Pﬁzer, Daiichi Sankyo, MSD, Lilly; Financial Interests, Institutional, Coordinating PI, Clinical Trial Budget: Eisai; Financial Interests, Institutional, Research Grant, Clinical Trial

Comp (N [ 83)

BMs (n ¼ 44) Treated/stable BMs (n ¼ 58) Untreated/active BMs (n ¼ 25)

2 (3.4)

14 (24.1)

3 (12.0)

28 (48.3)

15 (60.0)

7 (12.1)

5 (20.0)

1 (1.7)

2 (8.0)

6 (10.3)

16 (27.6)

11.0 (5.6-16.0)

2.8 (2.7-NE)

8.7 (6.3-11.8)

4.0 (2.7-5.7)

S335

Budget: Boryung Pharm. N. Harbeck: Financial Interests, Personal and Institutional, Other, Honoraria for lectures and/or consulting; Clinical Trials: Amgen, AstraZeneca, Daiichi Sankyo, EPG Communication, Gilead, Eli Lilly, MEDSCAPE, MSD, Novartis, Pierre-Fabre, Roche, Sandoz, Sanoﬁ, Seagen,Springer, Viatris, Zuelligpharma. I. Krop: Financial Interests, Personal, Advisory Board: Genentech/Roche, AstraZeneca, Daiichi Sankyo, Macrogenics, Seagen; Financial Interests, Personal, Other, DSMB member: Novartis; Financial Interests, Personal, Other, DSMC member: Merck; Financial Interests,Personal, Full or part-time Employment, Spouse: PureTech, Freeline; Financial Interests, Personal,Stocks/Shares, Spouse: PureTech, Freeline; Financial Interests, Institutional, Coordinating PI: Pﬁzer,Macrogenics, Genentech/Roche. G. Curigliano: Financial Interests, Personal, Invited Speaker: Roche,AstraZeneca, Daiichi Sankyo, Novartis, Pﬁzer; Financial Interests, Personal, Advisory Board: Roche,AstraZeneca, Daiichi Sankyo, Lilly, Pﬁzer, Veracyte, BMS, Merck, Exact Sciences, Celcuity; Financial Interests, Personal, Writing Engagement: Pﬁzer; Financial Interests, Personal, Other, Advisory Board:Ellipsis; Financial Interests, Institutional, Research Grant, Investigator Initiated Trial: Merck; Financial Interests, Institutional, Funding, Phase I studies: BMS, Novartis, AstraZeneca, Daiichi Sankyo, Roche,Blueprint Medicine, Kymab, Astellas, Sanoﬁ, Philogen; Financial Interests, Institutional, Coordinating PI, Phase I clinical basket trial: Relay Therapeutics; Non-Financial Interests, Member of Board of Directors, No compensation for this role. This a public national company for cancer prevention: Lega Italiana Lotta ai Tumori; Non-Financial Interests, Ofﬁcer, Italian National Health Council as Advisor for Ministry of Health: Consiglio Superiore di Sanità; Non-Financial Interests, Advisory Role, Member of the Scientiﬁc Council. Patient advocacy association: Europa Donna; Non-Financial Interests, Advisory Role, Cancer Research Foundation: Fondazione Beretta; Non-Financial Interests, Ofﬁcer, Member of the Advisory Council: EUSOMA; Non-Financial Interests, Ofﬁcer, ESMO Clinical Practice Guidelines Chair: ESMO. E. Mathias, J. Cathcart, A. Cagnazzo, S. Ashfaque : Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. A. Egorov: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo; Financial Interests, Personal, Stocks/Shares: Daiichi Sankyo. F. André:Financial Interests, Institutional, Research Grant: AstraZeneca, Lilly, Novartis, Pﬁzer, Roche, Daiichi;Financial Interests, Institutional, Other, advisory board: Guardant Health; Financial Interests, Institutional, Other, Advisory board: Medimmune, Gilead, Relay therapeutics; Other, Founder: Pegacsy.

https://doi.org/10.1016/j.annonc.2023.09.554

378O

Persistence under abemaciclib and endocrine treatment(ABA+ET) in patients with advanced breast cancer (aBC):First results of the randomized IMPACT trial comparing patient coaching with the MASCC oral agent teaching tool(MOATT) versus local routine patient coaching (LC)

M.K. Welslau1, P. Fasching2, L. Mueller3, E. Belleville4, L. Rieger5, M-O. Zahn6,B. Lex7, L. Häberle8, H. Tesch1

1Oncology Department, Klinikum Aschaffenburg, Aschaffenburg, Germany; 2Department of Gynecology and Obstetrics, Universitätsklinikum Erlangen, Erlangen, Germany; 3Leer, Onkologie Untere Ems - Leer Papenburg Emden, Leer, Germany;4Womens Health Department, ClinSol, Wuerzburg, Germany; 5Gynaecologic Oncology Department, Praxis Dr. Vehling-Kaiser, Landshut, Germany; 6Oncology and Haematology Department, MVZ Onkologische Kooperation Harz, Goslar, Germany; 7Department of Gynecology and Obstetrics, Department of Gynecology and Obstetrics,Kulmbach, Germany; 8Frauenklinik, Universitätsklinik Erlangen, Erlangen, Germany

Background: Recent studies showed the positive impact of supportive care programs on patients. Possible beneﬁts include the prevention of incorrect medication intake, a decrease of treatment-related symptoms and the reduction of hospitalization due to adverse events. MOATT is a standardized patient coaching program which might be suitable to improve the therapy management of BC patients with oral treatments.

Aim of this study was to investigate the impact of MOATT on persistence and therapy management under ABA+ET.

Methods: IMPACT (NCT04030728) was a prospective randomized, controlled trial in patients with hormone receptor positive, HER2-negative aBC treated with ABA+ET.

Patients were randomized to LC vs. MOATT. Primary endpoint was the persistence rate after 24 weeks of treatment. Further endpoints included compliance rate, the number of dose reduction and dose interruptions.

Results: A total of 211 patients were randomized between 06/20 and 02/22.

Persistence probability after 24 weeks was 0.71 (95%CI 0.63-0.81) with LC and 0.82(95%CI: 0.74-0.90) with MOATT (hazard ratio: 0.59 (95%CI: 0.32-1.07; plog-rank ¼0.078). Disease progression or death were the main reasons for therapy discontinuation in 14 cases in the LC arm and in 10 cases in the MOATT arm. A decision for a permanent discontinuation of ABA in the ﬁrst 24 weeks was seen in 14 patients(14.1%) in the LC arm and 8 Patients (7.8%) in the MOATT arm. Dose reductions were planned in 24.5% of patients with LC and in 17.2% of patients in the MOATT arm.

Therapy interruptions were planned in 14.9% of LC-patients and 10.1% in the MOATT arm.

Conclusions: The risk of therapy discontinuation within the ﬁrst 24 weeks of treatment is clinically relevant. Coaching with MOATT reduced the probability for permanent therapy discontinuations by about 40% during the ﬁrst 6 months of therapy.

Standardized patient coaching improved therapy management of oral cancer therapies like abemaciclib. Patient coaching might be very useful to improve therapy management also in the adjuvant breast cancer setting.

Clinical trial identiﬁcation: NCT04030728 and July 24, 2019.

Legal entity responsible for the study: Onco Medical Consult GmbH, Tennelbachstr.

59, D-65193 Wiesbaden.

Funding: Lilly.

Disclosure: P. Fasching: Financial Interests, Personal, Advisory Board: Roche, Novartis, Pﬁzer,Daiichi Sankyo, Eisai, Merck, Sharp & Dohme, AstraZeneca, Hexal, Lilly, Pierre Fabre, Seagen,Agendia, Sanoﬁ Aventis; Financial Interests, Personal, Invited Speaker: Novartis, Daiichi Sankyo, Eisai,Merck, Sharp & Dohme, AstraZeneca, Lilly, Seagen, Gilead; Financial Interests, Personal, Other,

Medical Writing Support: Roche; Financial Interests, Institutional, Local PI: BionTech, Cepheid; NonFinancial Interests, Member: ASCO, Arbeitsgemeinschaft für Gynäkologische Onkologie e.V., Translational Research in Oncology, Deutsche Gesellschaft für Senologie e.v.. L. Mueller: Financial Interests, Institutional, Invited Speaker: Iomedico. E. Belleville: Financial Interests, Institutional, Other,Research Support/Medical Education Support: Novartis, Lilly, MSD; Financial Interests, Personal,Other, Clinical Research Management/Medical Education: ClinSol; Financial Interests, Institutional,Other, Medical Education Support: Gilead, Daiichi Sankyo, Pﬁzer, Astra Zenca, Hexal, Sandoz, Roche,Amgen, Ipsen, Eisai, SUN Pharma, Sanoﬁ, Immunocore, Takeda, BMC, SERVIER, Janssen, Stemline;Financial Interests, Institutional, Other, Clinical Research Support / Medical Education Support:Seagen; Financial Interests, Personal, Ofﬁcer: Onkowissen, Clinsol, High5md; Financial Interests,Institutional, Funding, Research Support: Lilly, Novartis, Seagen, Bayer, Pﬁzer, Daiichi. L. Rieger:Financial Interests, Personal, Stocks/Shares: Pﬁzer. H. H. Tesch: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi, Exact Science, Gilead, GSK, Lilly, MSD, Myan, Novartis, Pﬁzer, Piere Fabre, Roche Pharma GmbH, Seagan; Financial Interests, Personal, Other, Reporting SABSC, ESMO 2022 : ClinSol; Financial Interests, Personal, Other, Travel Expenses: GSK, Pﬁzer; Financial Interests,Personal, Writing Engagement: Novartis; Financial Interests, Personal, Other, Clinical trial manager:Novartis; Financial Interests, Personal, Invited Speaker, SABCS 2020 : Onkowissen; Financial Interests,Personal, Other, ownership of shares: CHOP GmbH, Onco Medical Consul, VISION MED GmbH, Care and Coach GmbH; Financial Interests, Personal, Other, Medical Co-Lead Impact: Lilly; Non-Financial Interests, Member: ASCO. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.555

381O First-in-human/phase I trial of HS-20089, a B7-H4 ADC, in patients with advanced solid tumors

J. Wu1, J. Zhang2, H. Li3, X. Wang4, Q.Y. Zhang5, Y. Shi6, M. yan7, Y. Pan8, A. Shen9,Q. Chen10, Q. Rao10, H. Wei11, C. Li12, L. Yang12, Q. Huang12, Z. Cao12, Q. Wu12

1Department of Medical Oncology, Fudan University Cancer Institute, Shanghai, China;2Department of Medical Oncology, Fudan University Shanghai Cancer Center,Shanghai, China; 3Medical Oncology, Peking University Cancer Hospital and Institute,Beijing, China; 4Medical Oncology, Zhejiang Cancer Hospital - Cancer Research Institute, Hangzhou, China; 5Medical Oncology, 3rd Afﬁliated Hospital of Harbin Medical University, Harbin, China; 6Medical Oncology Department of Breast Cancer, TMUCIH -Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; 7Medical Oncology, Henan Cancer Hospital/Afﬁliated Cancer Hospital of Zhengzhou University,Zhengzhou, China; 8Oncology Dept, Anhui Provincial Hospital, Hefei, Anhui, China;9Clinical Research, The First Afﬁliated Hospital of USTC/ Anhui Provincial Hospital,Hefei, China; 10Medical Oncology, Sun Yat-Sen Memorial Hospital, Guangzhou, China;11Department of Oncology Medicine, Hansoh Pharma Group CO.,LTD., Shanghai,China; 12Department of Medical Oncology, Hansoh Pharma Group CO.,LTD., Shanghai,China

Background: B7-H4, a transmembrane glycoprotein in the B7 superfamily, has limited expression in normal tissues but is highly expressed in various cancers. HS-20089 is a novel B7-H4 directed antibody-drug conjugate (ADC) with a drug to antibody ratio of

6. We conducted a ﬁrst-in-human phase I trial to evaluate the dose-limiting toxicity(DLT), safety, tolerability, pharmacokinetics, and efﬁcacy of HS-20089 in patients (pts)with advanced solid tumors refractory to standard therapy.

Methods: Eligible pts were enrolled in sequentially escalating dose cohorts (0.7 to 7.2 mg/kg) of HS-20089 administered intravenously every 3 weeks. The accelerated titration combined with Bayesian optimal interval (BOIN) was used as the dose escalation schedule in this phase I dose escalation trial.

Results: As of Apr. 11th, 2023, 44 pts with advanced solid tumors (41 breast cancers, 2 ovarian cancers, and 1 endometrial cancer) received HS-20089 treatment. Three DLTs were observed in 2 pts (both in 7.2 mg/kg). The most common treatment-emergent adverse events (20%) were leukopenia, neutropenia, nausea, anemia, thrombocy-topenia, vomiting, fatigue, increased alanine aminotransferase, anorexia, increased aspartate aminotransferase and hyponatremia. No interstitial lung disease and infusion reaction were reported. Of 33 response-evaluable pts, 8 partial responses (PRs)were observed in pts treated with HS-20089 (response rate: 24.2%), including 3 conﬁrmed PRs and 5 PRs awaiting conﬁrmation. The disease control rate was 63.6%.

In the subset of 16 triple-negative breast cancer (TNBC) pts, 6 PRs were observed(response rate: 37.5%), including 2 conﬁrmed PRs and 4 PRs awaiting conﬁrmation. At potential target therapeutic dose (4.8 and 5.8 mg/kg), 5 PRs of 12 pts were observed(response rate: 41.7%) in TNBC. The patient achieving PR with the longest treatment duration of 403 days remains on treatment in 0.7 mg/kg cohort.

Conclusions: Based on data from the ongoing study, HS-20089 was well tolerated and showed antitumor activities in advanced solid tumors, with encouraging clinical ef-ﬁcacy in TNBC.

Clinical trial identiﬁcation: NCT05263479.

Legal entity responsible for the study: Hansoh Pharmaceutical Group Co. Ltd.

Funding: Hansoh Pharmaceutical Group Co. Ltd.

Disclosure: H. Wei, C. Li, L. Yang, Q. Huang, Z. Cao, Q. Wu: Financial Interests, Institutional, Full or part-time Employment, Medical staff: Hansoh Pharmaceutical Group Co, Ltd. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.558

379MO

Datopotamab deruxtecan (Dato-DXd) + durvalumab (D) asﬁrst-line (1L) treatment for unresectable locally advanced/metastatic triple-negative breast cancer (a/mTNBC):

Updated results from BEGONIA, a phase Ib/II study

P. Schmid1, P.J. Wysocki2, C.X. Ma3, Y.H. Park4, R. Fernandes5, S. Lord6, R.D. Baird7,C. Prady8, K.H. Jung9, J. Asselah10, R. Huisden11, R. Stewart12, K. Heider13,

P. Vukovic14, N. Denduluri15, Z. Nowecki16

1Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, London, UK; 2Department of Oncology, Jagiellonian University Medical College, Krakow, Poland; 3Division of Oncology, Department of Medicine,Washington University School of Medicine, St. Louis, MO, USA; 4Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 5Division of Medical Oncology,Department of Oncology, Schulich School of Medicine & Dentistry, Western University,London Health Sciences Centre, London, ON, Canada; 6Department of Oncology,Medical Sciences Division, University of Oxford, Oxford, Oxfordshire, UK; 7Department of Oncology, Cancer Research UK Cambridge Centre, Cambridge, Cambridgeshire, UK;8Oncology, Sherbrooke University, Centre Intégré de Cancérologie de la Montérégie,CISSS Montérégie Centre, Greenﬁeld Park, QC, Canada; 9Surgical Oncology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Songpa-gu, Republic of Korea; 10Medical Oncology, McGill University Health Centre, Montreal, QC, Canada;11Statistics, AstraZeneca, Cambridge, UK; 12Translational Medicine, Oncology, AstraZeneca, Cambridge, UK; 13Late Phase Oncology R&D, AstraZeneca, Cambridge, UK;14Late Phase Oncology, AstraZeneca, Cambridge, UK; 15Late Phase Oncology R&D,AstraZeneca, Gaithersburg, MD, USA; 16Breast Surgery, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Poland

Background: BEGONIA (NCT03742102) is an ongoing 2-part, open-label platform study in 1L a/mTNBC, evaluating D, an antiePD-L1 antibody, plus novel therapies,including Dato-DXd, an antibody-drug conjugate made of a anti-TROP2 antibody covalently linked via a cleavable linker to a topoisomerase I inhibitor payload. Early data from BEGONIA Arm 7, Dato-DXd + D, showed promising responses. Updated results, including response duration (DoR), are reported.

Methods: Patients (pts) with unresectable a/mTNBC eligible for 1L treatment were enrolled, regardless of PD-L1/TROP2 expression, and received Dato-DXd 6 mg/kg IV +D 1120 mg IV Q3W until progression or unacceptable toxicity. PD-L1, assessed by the VENTANA PD-L1 (SP263) Assay, was high if 10% of the tumor area was populated byPD-L1eexpressing tumor or immune cells. Primary endpoints were safety and tolerability. Secondary endpoints included investigator-assessed ORR, PFS (RECIST v1.1),and DoR.

Results: As of 2 Feb 2023, 62 pts received Dato-DXd + D (29 ongoing). Median followup was 11.7 (range 2e20) months (mos). At baseline, median pt age was 53 years;60% had visceral metastases; 87% had PD-L1elow expression. Conﬁrmed ORR was 79% (95% CI, 67e88); 6 (10%) pts had complete and 43 (69%) had partial responses.

Response to treatment was irrespective of PD-L1 expression level. Median DoR was

15.5 mos (95% CI, 9.9enot calculable [NC]). Median PFS was 13.8 mos (95% CI, 11e NC). Nausea and stomatitis were the most common adverse events (AEs; 40 [65%]each). Any Grade (G) 3/4 AEs occurred in 35 (57%) pts and serious AEs in 14 (23%).

Low rates of anemia (9 [15%]), diarrhea (8 [13%]), and neutropenia (3 [5%]) occurred.

Adjudicated treatment-related interstitial lung disease/pneumonitis occurred in 3(5%) pts (2 G2; 1 G1). No deaths due to treatment-related AEs occurred. 10 (16%) pts discontinued any study drug due to AEs. No new safety signals were reported.

Conclusions: Dato-DXd combined with D continues to demonstrate manageable safety and compelling high, durable response rates in 1L a/mTNBC. Further investigation is warranted. Translational data analysis is ongoing. Funding: AstraZeneca/Daiichi Sankyo.

Clinical trial identiﬁcation: NCT03742102; November 15, 2018.

Editorial acknowledgement: Medical writing and editorial support, which was in accordance with Good Publication Practice ( GPP 2022 ) guidelines, was provided by Nicole Seneca, PhD, of Parexel and was funded by AstraZeneca.

Legal entity responsible for the study: AstraZeneca/Daiichi Sankyo.

Funding: AstraZeneca/Daiichi Sankyo.

Disclosure: P. Schmid: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Novartis, Pﬁzer,Roche, Puma Biotechnology; Financial Interests, Personal, Speaker, Consultant, Advisor, Consulting or Advisory Role: AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Eisai, Roche, Merck, Novartis,Pﬁzer, Puma Biotechnology; Financial Interests, Institutional, Research Funding: Astellas Pharma,AstraZeneca, Medivation Inc, OncoGenex; Financial Interests, Personal, Research Funding: Genentech, Novartis, Roche. P.J. Wysocki: Financial Interests, Personal, Other, Honoraria: AstraZeneca,Astellas, Amgen, BMS, Gilead, IPSEN, Immunicom, Janssen, MSD, Merck, Pierre Fabre, Pﬁzer, Roche,Sanoﬁ; Financial Interests, Personal, Speaker, Consultant, Advisor, Consulting or Advisory Role:AstraZeneca, Astellas, Amgen, BMS, IPSEN, Immunicom, Janssen, MSD, Merck, Pierre Fabre, Pﬁzer,Roche, Sanoﬁ; Financial Interests, Institutional, Research Funding: Immunicom, Merck, Pierre Fabre,Roche. C.X. Ma: Financial Interests, Institutional, Research Funding: Puma, Pﬁzer; Financial Interests,Personal, Speaker, Consultant, Advisor, Consulting Fees: AstraZeneca, Natera, Biovica, Novartis,Sanoﬁ, Pﬁzer. Y.H. Park: Financial Interests, Personal, Other, Honoraria: Merck, Novartis, Pﬁzer;Financial Interests, Personal, Speaker, Consultant, Advisor, Consulting or Advisory Role: AstraZeneca,Daiichi Sankyo, Eisai, Pﬁzer, Roche; Financial Interests, Institutional, Research Funding: AstraZeneca,Merck, Novartis, Pﬁzer; Financial Interests, Personal, Other, Travel, accommodation, expenses:Merck, Novartis. R. Fernandes: Financial Interests, Personal, Speaker, Consultant, Advisor, Consulting Fees: Canadian Agency for Drugs and Technologies in Health (CADTH); Financial Interests, Personal,Other, Honoraria: Bayer, Pﬁzer, Ipsen, BMS, Merck, Novartis, and Janssen . S. S. Lord: Financial Interests, Institutional, Other, Reports funding for clinical trial activities from AstraZeneca, during the conduct of the study: AstraZeneca; Financial Interests, Personal, Other, Honoraria: Eisai, Prosigna,

and Roche; Financial Interests, Personal, Advisory Board: Shionogi; Financial Interests, Institutional,Research Grant: Pathios Therapeutics; Financial Interests, Personal, Other, Travel, accommodation,and expenses paid by Piqur Therapeutics, Pﬁzer, Roche, and Synthon, outside the submitted work:Piqur Therapeutics, Pﬁzer, Roche, and Synthon; Financial Interests, Personal, Other, Dr Lord holds patents associated with his role as cofounder of Mitox Therapeutics: Mitox Therapeutics. R.D. Baird:Financial Interests, Institutional, Research Funding: AstraZeneca, Boehringer-Ingelheim, Carrick Therapeutics, Genentech, G1T Therapeutics, Janssen, Molecular Partners, Roche, Shionogi, Taiho;Financial Interests, Institutional, Speaker, Consultant, Advisor, Consulting or Advisory Role: AstraZeneca, Daiichi Sankyo, Molecular Partners, Novartis, Roche. C. Prady: Financial Interests, Institutional, Research Funding, Clinical Trial Activity: AstraZeneca, Sanoﬁ, Roche, Novartis. K.H. Jung:Financial Interests, Personal, Speaker, Consultant, Advisor, Consulting or Advisory Role: AstraZeneca,Celgene, Eisai, MSD, Novartis, Pﬁzer, Roche, Takeda, Daiichi Sankyo, Bixink, Everest Medicine. J.

Asselah: Financial Interests, Personal, Speaker, Consultant, Advisor, Consulting or Advisory Role:AstraZeneca, Pﬁzer, Eisai, Novartis, BMS. R. Huisden, K. Heider, P. Vukovic, N. Denduluri: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. R. Stewart: Financial Interests,Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Other, Reports personal fees from AstraZeneca and Pﬁzer, outside the submitted work: AstraZeneca, Pﬁzer.. Z.

Nowecki: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Sanoﬁ-Aventis, MSD, Roche.

https://doi.org/10.1016/j.annonc.2023.09.556

380MO SKB264 (MK-2870) in previously treated hormone receptorpositive (HR+)/ HER2-negative metastatic breast cancer(mBC): Results from a phase I/II, single-arm, basket trial

Q. Ouyang1, Y. Yin2, L. Song3, M. Yan4, X. Wu5, Z. Tong6, Y. Liu7, X. Wang8, X. Jin9,Y. Diao9, G. Liu9, J. Ge9, J. Li10

1Breast Internal Medicine Department, Hunan Cancer Hospital, Changsha, China;2Oncology Department, Jiangsu Province Hospital/The First Afﬁliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; 3Breast Internal Medicine Department, Shandong Cancer Hospital and Institute, Jinan, China; 4Breast Department, Henan Cancer Hospital, Zhengzhou, China; 5Breast Surgery, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology and Hubei Provincial Clinical Research Center for Breast Cancer, Wuhan, China; 6Department of Breast Oncology, TMUCIH - Tianjin Medical University Cancer Institute and Hospital, Tianjin, He Xi District, China; 7Oncology, The First Hospital of China Medical University, Shenyang, China; 8Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; 9Clinical Department, Sichuan KelunBiotech Biopharmaceutical Co., Ltd., Chengdu, China; 10Department of Medical Oncology, Shanghai East Hospital, Shanghai, China

Background: TROP2 is commonly overexpressed in HR+/HER2- mBC and associated with poor prognosis. SKB264 is a novel anti-TROP2 ADC developed using sulfonyl pyrimidine-CL2A-carbonate linker to conjugate its payload, a belotecan-derivative topoisomerase I inhibitor, to achieve an average Drug-to-antibody Ratio (DAR) of 7.4.

This is the ﬁrst report of results from a phase II cohort in patients (pts) with HR+/HER2- mBC.

Methods: Pts with HR+/HER2- (including HER2-low and HER2-zero) mBC received SKB264 at a dose of 5 mg/kg Q2W until progression or unacceptable toxicity. Eligibility included progression on endocrine-based therapy and at least one prior chemotherapy for mBC. Tumor assessment was performed every 8 weeks per RECIST v1.1 assessed by investigator.

Results: As of data cut-off (April 12, 2023), 41 pts (median age 50 yrs [34-66], 61%ECOG PS 1) were enrolled. Median follow-up was 8.2 months (mo). Treatment-related adverse events (TRAEs) of Grade 3 were reported in 48.8% (20/41) of pts. The mostcommon Grade 3 TRAEs ( 5%) were neutrophil count decreased (36.6%), whiteblood cell count decreased (22%), anemia (14.6%), platelet count decreased (9.8%)and GGT increase (7.3%). TRAEs led to dose reduction in 17.1% (7/41) of pts. No neuropathy or drug-related ILD/pneumonitis was reported. No TRAEs led to treatment discontinuation or death. Of 38 pts evaluable for response assessment, 47% of pts had primary endocrine resistance; 79% of pts had received 2 prior chemo-therapy for metastatic disease, and prior treatments included taxane (100%), and CDK 4/6 inhibitors (65.8%). The ORR was 36.8% (14/38, 12 conﬁrmed PR and 2 uncon-ﬁrmed PR) and DCR was 89.5%, median DoR was 7.4 mo (range, 4.2 to 14.9+), 6-mo DoR rate was 80%. Median PFS was 11.1 mo (95% Cl: 5.4, 13.1), and 6-mo PFS rate was 61.2%.

Conclusions: SKB264 at 5 mg/kg demonstrates a manageable safety proﬁle and promising antitumor activity in pts with pre-treated HR+/HER2- mBC. Two phase 3 studies are currently planned in HR+/HER2- mBC, one in China for pts after at least one chemo for mBC and a second global for pts previously untreated with chemo for mBC, both comparing SKB264 vs investigator selected chemo.

Clinical trial identiﬁcation: NCT04152499.

Legal entity responsible for the study: Sichuan Kelun-Biotech Biopharmaceutical Co.,Ltd.

Funding: Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd.

Disclosure: X. Jin, Y. Diao, G. Liu, J. Ge: Financial Interests, Personal, Full or part-time Employment:Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.557

S337

382MO

Updated results from the phase I/II study of OP-1250, an oral complete estrogen receptor (ER) antagonist (CERAN) and selective ER degrader (SERD) in patients (pts) with advanced or metastatic ER-positive, HER2-negative breast cancer

N.U. Lin1, V.F. Borges2, M.R. Patel3, M. Okera4, J. Meisel5, R. Wesolowski6, T. Pluard7,K.D. Miller8, N.J. McCarthy9, A.K. Conlin10, R. Mahtani11, D. Sabanathan12,

K.E. McCann13, E. Roesch14, G. Mathauda-Sahota15, J. Schroeder16, E.P. Hamilton17

1Medical Oncology Department, Dana Farber Cancer Institute, Boston, MA, USA;2Medical Oncology, UCHealth Cancer Care - Anschutz Medical Campus - University of Colorado Cancer Center, Aurora, CO, USA; 3Drug Development, Florida Cancer Specialists/Sarah Cannon Research Institute, Fort Myers, FL, USA; 4Oncology Department,Cancer Research SA, Adelaide, SA, Australia; 5Hematology and Medical Oncology,Winship Cancer Institute, Emory University, Atlanta, GA, USA; 6Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH,USA; 7Medical Oncology Department, Saint Luke’s Hospital of Kansas City - Saint Luke’s Health System, Kansas City, MO, USA; 8Hematology and Oncology Department,Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA;9Medical Oncology, ICON Cancer Center - Wesley Medical Centre, Auchenﬂower, QLD,Australia; 10Medical Oncology, Providence Cancer Institute, Portland, OR, USA;11Medical Oncology Department, Miami Cancer Institute - Baptist Health South Florida, Miami, FL, USA; 12Clinical Medicine Department, Macquarie University,Macquarie Park, NSW, Australia; 13Medicine, Jonsson Comprehensive Cancer Center,University of California Los Angeles, Los Angeles, CA, USA; 14Medical Oncology,Cleveland Clinic, Taussig Cancer Center, Cleveland, OH, USA; 15Clinical Science, Olema Pharmaceuticals, Inc., San Francisco, CA, USA; 16Biostatistics, Olema Pharmaceuticals,Inc., San Francisco, CA, USA; 17Drug Development Unit, Sarah Cannon Research Institute at Tennessee Oncology, Nashville, TN, USA

Background: OP-1250 is a small molecule CERAN/SERD with antitumor activity in breast cancer (BC) xenograft models, including ESR1/PIK3CA mutations and brain metastasis. OP-1250 was administered at 30e300 mg daily (qd) in the dose-escalation part of a phase 1 study. Maximum tolerated dose was not reached and no doselimiting toxicities occurred. OP-1250 at 60 mg and 120 mg was assessed in the doseexpansion part. Based on safety, pharmacokinetics, and preliminary antitumor activity, 120 mg qd was selected as the recommended phase 2 dose. Here we present the phase 1/2 study data (phase 2 is ongoing).

Methods: Pts with measurable and nonmeasurable disease were included. Eligible women (any menopausal status) and men had received 4 lines of endocrine therapy(ET) and 1 line of chemotherapy for metastatic disease. Pts with stable brainmetastasis had to have 1 prior line of ET and 3 prior lines of chemotherapy (bothfor metastatic disease). Tumor assessment (RECIST v1.1) occurred every 8 weeks(NCT04505826).

Results: By March 17, 2023, of 86 pts on OP-1250 (120 mg), 66% had 2 prior lines ofET, 30% prior chemotherapy, 67% prior fulvestrant, and 98% prior cyclin-dependent kinase 4/6 inhibitors (CDK4/6i); 45% (34/75) of pts with available baseline ctDNA had ESR1 mutations. The most common (15% of pts) all-grade treatment-emergentadverse events (AEs) were nausea, vomiting, neutropenia, fatigue, headache, constipation, and diarrhea. The most common grade 3/4 treatment-related AEs were neutropenia (9%), nausea (3%), and vomiting (3%). Neutropenia was reversible; 3 pts with grade 4 neutropenia were rechallenged at a lower dose without recurrence.

There were 4 partial responses (3 conﬁrmed) with a clinical beneﬁt rate of 40% (23/57). In pts with an ESR1 mutation, CBR was 50% (11/22). D[NZ1] [NZ2] ata continue to mature and updated data will be presented.

Conclusions: OP-1250 (120 mg qd) was well tolerated with promising efﬁcacy in heavily pretreated pts, including pts progressing on fulvestrant and CDK4/6i. A phase 3 monotherapy study in metastatic BC (second/third line) is planned in 2023.

Clinical trial identiﬁcation: NCT04505826.

Legal entity responsible for the study: Olema Pharmaceuticals, Inc.

Funding: Olema Pharmaceuticals, Inc.

Disclosure: N.U. Lin: Financial Interests, Personal, Advisory Board, Ad board participation: Seattle Genetics, Daiichi Sankyo, Prelude Therapeutics; Financial Interests, Personal, Advisory Board, Ad board/Steering Committee participation; consultant: AstraZeneca; Financial Interests, Personal,Other, Consultant: Denali Therapeutics, Blueprint Medicines, Janssen, Afﬁnia Therapeutics; Financial Interests, Personal, Advisory Board, Ad board/Steering committee participation: Olema Pharmaceuticals; Financial Interests, Personal, Other, High level Consulting: Artera Inc.; Financial Interests,Personal, Other, Steering committee: Stemline/Menarini; Financial Interests, Personal, Other,Consulting: Voyager Therapeutics; Financial Interests, Personal, Royalties, Royalties for book chapter(s): Up to Date; Financial Interests, Institutional, Funding, Trial funding to institute (and steering committee): Olema Pharmaceuticals, AstraZeneca, Seattle Genetics; Financial Interests, Institutional,Funding, Trial funding to institute: Zion Pharmaceuticals; Financial Interests, Institutional, Funding,trial funding to institute: Pﬁzer, Genentech. V. V.F. Borges: Financial Interests, Personal, Speaker,Consultant, Advisor: Seagen, AstraZeneca, Gilead; Financial Interests, Institutional, Principal Investigator: Olema Pharmaceuticals, AstraZeneca, Gilead. M.R. Patel: Financial Interests, Personal,Leadership Role: ION Pharma; Financial Interests, Personal, Speaker, Consultant, Advisor: Janssen Onocology; Financial Interests, Personal, Advisory Board: Olema Pharmaceuticals; Financial Interests,Institutional, Research Funding: Acerta Pharma, ADC Therapeutics, Agenus, Aileron Therapeutics,AstraZeneca, BioNTech AG, Boehringer Ingelheim, Celgene, CicloMed, Clovis Oncology, Cyteir Therapeutics, Daiichi Sankyo, Lilly, Evelo Therapeutics, Genentech/Roche, Gilead Sciences, GSK, H3 Biomedicine, Hengrui Therapeutics, Hutchinson MediPharma, Jacobio, Janssen, Klus Pharma, Kymab,Loxo, LSK Biopartners, Lycera, Macrogenics, Merck, Millennium, Mirati Therapeutics, Moderna Therapeutics, Pﬁzer, Prelude Therapeutics, Ribon Therapeutics, Seven and Eight Biopharmaceuticals,Syndax, Taiho Pharmaceutical, Tesaro, TopAlliance BioSciences Inc, Vigeo, ORIC, Artios, Treadwell,Mabspace, IgM Biosciences, Puretech, BioTheryX, Black Diamond Therapeutics, IgM Biosciences,NGM Biopharmaceuticals, Novartis, nurix, PureTech, Relay Therapeutics, Samumed, Silicon

Therapeutics, TeneoBio, Zymeworks, Olema Pharmaceuticals, Adagene, Astellas, Accutar Biotech,Compugen, Immunogen, Blueprint Pharmaceuticals, Bayer, Bicycle Therapeutics, Cullinan Oncology,Erasca, Inc, Immune-Onc Therapeutics, Immunitas, Jazz Pharmaceuticals, Pionyr, Revolution Medicines, Step Pharma, Syndax, Synthorx, Xencor. M. Okera: Financial Interests, Institutional, Local PI,Institution receives payment for research activities conducted as per the clinical trial agreements:Cancer Research SA. J. Meisel: Financial Interests, Personal, Advisory Board: Pﬁzer, Puma; Financial Interests, Institutional, Research Grant: Pﬁzer, Seattle Genetics, Eli Lilly. R. Wesolowski: Financial Interests, Personal, Invited Speaker, Gave an update about targeted therapies for breast cancer with focus on antibody drug conjugates at Precision Oncology Forum in Cincinnati, OH organized by the company on 3/11/23: Innovative Healthcare Institute; Non-Financial Interests, Principal Investigator,Site Principal Investigator: Olema, Dragonﬂy Therapeutics, Celcuity, Bayer, Oncorus, Treadwell Therapeutics; Non-Financial Interests, Advisory Role, Scientiﬁc Steering Committee: Celcuity; NonFinancial Interests, Advisory Role, Tucatinib Advisory Board: Seagen. T. T. Pluard: Financial Interests,Personal, Speaker, Consultant, Advisor: Pﬁzer, MacroGenics, Genentech, Seattle Genetics, Novartis,H3 Biomedicine, AstraZeneca/Daiichi Sankyo, Gilead Sciences; Financial Interests, Institutional,Research Funding: Seattle Genetics, Zymeworks, HiberCell, Pﬁzer, H3 Biosciences, DAEHWA Pharmaceutical, G1 Therapeutics, Olema Pharmaceuticals, Dantari, AstraZeneca/Daiichi Sankyo, Orinove,Sanoﬁ. K.D. Miller: Financial Interests, Personal, Other, IDMC member: Celcuity, Roche, AstraZeneca,Merck and Company, Inc.; Financial Interests, Institutional, Coordinating PI, Clinical trial funding:Pﬁzer, Astex; Financial Interests, Institutional, Local PI, Clinical trial funding: Olema. N.J. McCarthy:Financial Interests, Personal, Speaker, Consultant, Advisor: Roche, Pﬁzer, Novartis, Lilly. A.K. Conlin:Financial Interests, Personal, Advisory Board: SeaGen, AstraZeneca. R. Mahtani: Financial Interests,Personal, Other, Consultant: Agendia, Amgen, Biotheranostics, Daiichi Sankyo, Genentech, Immunomedics, Lilly, Merck, Novartis, Pﬁzer, Puma, Sanoﬁ, SeaGen; Financial Interests, Personal, Advisory Board, Consultant and served on advisory boards: AstraZeneca; Financial Interests, Personal, Advisory Board, Consultant: Eisai, Stemline. K.E. McCann: Financial Interests, Personal, Other, Speaker’s bureau for abemaciclib: Eli Lilly; Financial Interests, Institutional, Local PI, Phase I/Ib trial: Olema;Non-Financial Interests, Advisory Role, Strategic council: Puma Biotech. E. Roesch: Financial Interests, Personal, Writing Engagement, I provide monthly expert commentary on journal articles related to breast cancer.: MDedge Hematology & Oncology. G. G. Mathauda-Sahota: Financial Interests,Personal, Full or part-time Employment: Olema Pharmaceuticals. J. Schroeder: Financial Interests,Personal, Full or part-time Employment: Olema Pharmaceuticals. E.P.Cancer Inst, Hutchinson MediPharma, MedImmune, SeaGen, Compugen, TapImmune, Lilly, Pﬁzer, H3 Biomedicine, Merus, Regeneron, Arvinas, StemCentRx, Verastem, eFFECTOR Therapeutics, CytomX,InventisBio, Lycera, Mersana, Radius Health, Abbvie, Nucana, Leap Therapeutics, Zenith Epigenetics,Harpoon, Orinove, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, PharmaMar, Olema, Immunogen, Plexxicon, Amgen, Akesobio Australia, Shattuck Labs,ADC Therapeutics, Aravive, Atlas MedX, Ellipses Pharma, Incyte, Jacobio, Mabspace Biosciences,ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Repertoire Immune Medicine, Treadwell Therapeutics, Accutar Biotechnology, Artios, BeiGene, Bliss BioPharmaceuticals,Cascadian Therapeutics, Context Therapeutics, Cullinan, Dantari, Duality Biologics, Elucida Oncology,Inﬁnity Pharmaceuticals, K-Group Beta, Kind Pharmaceuticals, Loxo Oncology, Oncothyreon, Orum Therapeutics, Prelude Therapeutics, Profound Bio, Relay Therapeutics, Tolmar, Torque Therapeutics All other authors have declared no conﬂicts of interest.

Hamilton: Financial Interests,Institutional, Other, Consulting/Advisory Role: Genentech/Roche, Novartis, Lilly, Pﬁzer, Mersana,iTeos, Janssen, Loxo, Relay Therapeutics, Olema Pharmaceuticals, Orum Therapeutics, Stemline Therapeutics, AstraZeneca, Daiichi Sankyo, SeaGen, Ellipses Pharma, Greenwich LifeSciences, Tubulis,Verascity Science, Theratechnologies; Financial Interests, Institutional, Research Grant: Oncomed,Genentech/Roche, Zymeworks, Rgenix, Arqule, Clovis, Millennium, Acerta Pharma, Sermonix Pharmaceuticals, Black Diamond, Karyopharm, Curis, Syndax, Novartis, Boehringer Ingelheim, Immunomedics, FujiFilm, Taiho, Deciphera, Molecular Templates, Onconova Therapeutics, Dana Farber Cancer Inst, Hutchinson MediPharma, MedImmune, SeaGen, Compugen, TapImmune, Lilly, Pﬁzer, H3 Biomedicine, Merus, Regeneron, Arvinas, StemCentRx, Verastem, eFFECTOR Therapeutics, CytomX,InventisBio, Lycera, Mersana, Radius Health, Abbvie, Nucana, Leap Therapeutics, Zenith Epigenetics,Harpoon, Orinove, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, PharmaMar, Olema, Immunogen, Plexxicon, Amgen, Akesobio Australia, Shattuck Labs,ADC Therapeutics, Aravive, Atlas MedX, Ellipses Pharma, Incyte, Jacobio, Mabspace Biosciences,ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Repertoire Immune Medicine, Treadwell Therapeutics, Accutar Biotechnology, Artios, BeiGene, Bliss BioPharmaceuticals,Cascadian Therapeutics, Context Therapeutics, Cullinan, Dantari, Duality Biologics, Elucida Oncology,Inﬁnity Pharmaceuticals, K-Group Beta, Kind Pharmaceuticals, Loxo Oncology, Oncothyreon, Orum Therapeutics, Prelude Therapeutics, Profound Bio, Relay Therapeutics, Tolmar, Torque Therapeutics All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.559

383MO Imlunestrant with or without everolimus or alpelisib, in ER+,HER2- advanced breast cancer (aBC): Results from the phase Ia/b EMBER study

K. Jhaveri1, R. Jeselsohn2, C.X. Ma3, E. Lim4, K. Yonemori5, E.P. Hamilton6,K. Harnden7, S-A. Im8, T. Beck9, S. Sammons10, M. Bhave11, P.A. Kaufman12,C. Saura Manich13, T. Meniawy14, F. Bacchion15, R. Ismail-Khan15, Y. Li16,S.T. Estrem15, B. Nguyen15, M. Beeram17

1Medicine Dept, Memorial Sloan Kettering Evelyn H. Lauder Breast Center, New York,NY, USA; 2Dana Faber Cancer Institute, Boston, MA, USA; 3Division of Oncology,Department of Medicine, Washington University School of Medicine, St. Louis, MO,USA; 4Cancer Ecosystem Program, Garvan Institute of Medical Research, Darlinghurst,NSW, Australia; 5Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan; 6Drug Development Unit, Sarah Cannon Research Institute,Nashville, TN, USA; 7Breast Oncology Program, Inova Schar Cancer Institute, Fairfax,VA, USA; 8Medical Oncology, Seoul National University Hospital, Seoul, Republic of Korea; 9Department of Medicine, Highlands Oncology Group - Rogers, Fayetteville, AZ,USA; 10Duke University Medical Center, Duke Cancer Institute, Boston, MA, USA;11Hematology and Medical Oncology, Winship Cancer Institute of Emory University,Atlanta, GA, USA; 12Medicine, University of Vermont - Larner College of Medicine,Burlington, VT, USA; 13Medical Oncology Service, Vall d’Hebron University Hospital,Barcelona, Spain; 14Medicine Dept, Sir Charles Gairdner Hospital and Linear Research Institute, Subiaco, WA, Australia; 15Medical Oncology, Loxo@Lilly, Lilly Corporate Center, Indianapolis, IN, USA; 16Statistics - Oncology, Eli Lilly and Company, New York,NY, USA; 17Medicine Dept, South Texas Accelerated Research Therapeutics (START),San Antonio, TX, USA

Background: Imlunestrant is an investigational, next-generation, oral SERD designed to deliver continuous ER target inhibition, including in ESR1-mutant BC. In the ﬁrst-inhuman phase 1a/b EMBER study, imlunestrant demonstrated favorable safety, pharmacokinetics (PK), and clinical beneﬁt rate when administered as monotherapy(Jhaveri ASCO 2022) or with abemaciclib (Jhaveri SABCS 2022). We present the ﬁrst clinical data of imlunestrant with everolimus or alpelisib and updated imlunestrant monotherapy data from the EMBER study (NCT04188548).

Methods: Patients (pts) received imlunestrant alone as part of the phase 1a (escalation) or 1b (expansion), or with everolimus or alpelisib in 1b. Key phase 1b eligibility

included ER+, HER2- aBC, prior endocrine therapy (ET) sensitivity, 2 prior therapies,and a PIK3CA mutation (alpelisib arm only). Assignment to phase 1b treatment arms was made by investigators. Men and premenopausal women received GnRH agonist.

Key endpoints included RP2D, safety, PK, ORR (complete response [CR] plus partial response [PR]) and CBR (CR or PR, or stable disease 24 weeks) per RECIST v1.1.

Results: As of 6 Oct 2022, 114 pts received imlunestrant monotherapy, 42 pts received imlunestrant + everolimus, and 21 pts received imlunestrant + alpelisib.

Baseline characteristics were similar across combination cohorts; 46% pts had visceral disease and 46% had an ESR1 mutation at baseline. Median number of prior aBC therapies in combination cohorts was: 1 (range 1-2); including prior ET (100%), CDK4/6i (100%), fulvestrant (35%) and chemo (17%). No cardiac or ocular toxicity was seen.

Safety and preliminary efﬁcacy are presented (Table).

Table: 383MO Safety and preliminary efﬁcacy

Endpoint

Imlunestrant monotherapy(n[114)

Imlunestrant +everolimus(n[42)

Imlunestrant +alpelisib

(n[21)

All-grade treatment emergent AEs

(TEAEs) - %

Nausea e 40 Fatigue e 32 Diarrhea e 31

Diarrhea e 55 Fatigue e 45

AST increase e 38

Diarrhea e 86 Rash e 67

Hyperglycaemia

- 62

Grade 3 treatmentrelated AEs (TRAEs) - %

Fatigue e 2

Neutropenia e 2

Hypertriglyceridemia e 5

AST increase e 5

Rash e 43 Hyperglycemia

- 10

Dose reductions due to TRAEs - %Imlunestrant alone Everolimus/alpelisib alone

Both

2 N/A N/A

0 12 2

0 24 14

Discontinuations due to TRAEs - %

Imlunestrant alone Everolimus/

alpelisib alone Both

0 N/A N/A

0 2 0

0 29 0

ORR (%)

7/75 (9)

6/28 (21)

6/12 (50)

CBR (%)

48/114 (42) 26/42 (62)

13/21 (62)

AEs ¼ adverse events.

Conclusions: Imlunestrant alone or in combination with everolimus or alpelisib demonstrated robust efﬁcacy in pts with pre-treated ER+, HER-2 aBC. Toxicities were consistent with the known safety proﬁle of both alpelisib and everolimus.

Clinical trial identiﬁcation: NCT04188548.

Disclosure: K. Jhaveri: Financial Interests, Personal, Speaker, Consultant, Advisor: AbbVie; AstraZeneca; Biotheranostics; Blueprint Medicine; BMS, Daiichi Sankyo; Genetech/Roche; Intellisphere;Jounce Therapeutics; Eli Lilly and Company; Novartis; Pﬁzer; Seattle Genetics; Sanoﬁ; Sun Pharma;Synthon; Taiho Oncology; Financial Interests, Institutional, Research Funding: ADC Therapeutics;AstraZeneca; Clovis Oncology; Debiopharm; Eli Lilly and Company; Genetech Inc.; Gilead; Immunomedics; Merck; Novartis; Novita Pharmaceuticals; Pﬁzer; Puma Biotechnology; Zymeworks;Financial Interests, Personal, Other, Travel and accommodation expenses: AstraZeneca; Intellisphere;Jounce Therapeutics; Pﬁzer; Taiho Pharmaceutical. R. Jeselsohn: Financial Interests, Personal,Advisory Role: GE Health; Carrick therapeutics; Financial Interests, Institutional, Research Funding:Eli Lilly and Company; Pﬁzer. C.X. Ma: Financial Interests, Personal, Speaker, Consultant, Advisor:Agendia; AstraZeneca; Biovica; Inivata; Natera; Novartis; Olaris; Puma Biotechnology; Sanoﬁ;Financial Interests, Institutional, Research Funding: Pﬁzer; Puma Biotechnology. E. E. Lim: Financial Interests, Institutional, Advisory Board: Gilead, Novartis, Pﬁzer, Roche, AstraZeneca, MSD, Lilly;Financial Interests, Institutional, Invited Speaker: Roche, Gilead, Novartis, Lilly, AstraZeneca; Financial Interests, Institutional, Research Grant: Pﬁzer, Novartis; Financial Interests, Institutional, Steering Committee Member: Roche, Lilly, AstraZeneca; Financial Interests, Institutional, Local PI: Novartis,Gilead; Non-Financial Interests, Leadership Role, Scientiﬁc Advisory Committee: Breast Cancer Trials Australia; Non-Financial Interests, Leadership Role, Principal Cancer Theme Lead, Faculty of Medicine: University of New South Wales; Non-Financial Interests, Leadership Role, Faculty: Garvan Institute of Medical Research; Non-Financial Interests, Leadership Role, Director Cancer Research: St Vincent’s Hospital Sydeny. K. Yonemori: Financial Interests, Personal, Advisory Board: Eisai, AstraZeneca, Sanoﬁ, Genmab, Gliad, OncoXerna, Takeda, Novartis, MSD; Financial Interests, Personal,Invited Speaker: Pﬁzer, Eisai, AstraZeneca, Eli Lilly, Takeda, Chugai, Fuji Film Pharma, PDR Pharma,MSD, Ono, BMS, Boeringer Ingerheim, Daiichi Sankyo, Bayer, Jansen, Sanoﬁ; Financial Interests,Institutional, Local PI: MSD, Daiichi Sankyo, AstraZeneca, Taiho, Pﬁzer, Novartis, Takeda, Chugai, Ono,Sanoﬁ, Seagen, Eisai, Eli Lilly, Genmab, Boehringer Ingelheim, Kyowa Hakko Kirrin, Nihon Kayaku,Haihe. E. E.P. Hamilton: Financial Interests, Institutional, Other, Consulting/Advisory Role: Genentech/Roche, Novartis, Lilly, Pﬁzer, Mersana, iTeos, Janssen, Loxo, Relay Therapeutics, Olema Pharmaceuticals, Orum Therapeutics, Stemline Therapeutics, AstraZeneca, Daiichi Sankyo, SeaGen, Ellipses Pharma, Greenwich LifeSciences, Tubulis, Verascity Science, Theratechnologies; Financial Interests,Institutional, Research Grant: Oncomed, Genentech/Roche, Zymeworks, Rgenix, Arqule, Clovis,Millennium, Acerta Pharma, Sermonix Pharmaceuticals, Black Diamond, Karyopharm, Curis, Syndax,Novartis, Boehringer Ingelheim, Immunomedics, FujiFilm, Taiho, Deciphera, Molecular Templates,Onconova Therapeutics, Dana Farber Cancer Inst, Hutchinson MediPharma, MedImmune, SeaGen,

Compugen, TapImmune, Lilly, Pﬁzer, H3 Biomedicine, Merus, Regeneron, Arvinas, StemCentRx,Verastem, eFFECTOR Therapeutics, CytomX, InventisBio, Lycera, Mersana, Radius Health, Abbvie,Nucana, Leap Therapeutics, Zenith Epigenetics, Harpoon, Orinove, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, PharmaMar, Olema, Immunogen,Plexxicon, Amgen, Akesobio Australia, Shattuck Labs, ADC Therapeutics, Aravive, Atlas MedX, Ellipses Pharma, Incyte, Jacobio, Mabspace Biosciences, ORIC Pharmaceuticals, Pieris Pharmaceuticals,Pionyr Immunotherapeutics, Repertoire Immune Medicine, Treadwell Therapeutics, Accutar Biotechnology, Artios, BeiGene, Bliss BioPharmaceuticals, Cascadian Therapeutics, Context Therapeutics, Cullinan, Dantari, Duality Biologics, Elucida Oncology, Inﬁnity Pharmaceuticals, K-Group Beta, Kind Pharmaceuticals, Loxo Oncology, Oncothyreon, Orum Therapeutics, Prelude Therapeutics,Profound Bio, Relay Therapeutics, Tolmar, Torque Therapeutics K. Harnden: Financial Interests,Personal, Speaker, Consultant, Advisor: Daiichi Sankyo; Merck; SeaGen; Financial Interests, Personal,Other, Honoraria: AstraZeneca; Daiichi Sankyo; Merck; SeaGen. S. Im: Financial Interests, Personal,Advisory Board, no payment: AstraZeneca, Novartis, Eisai, Roche, Hanmi, Pﬁzer, Lilly, MSD, GSK,Daiichi Sankyo; Financial Interests, Institutional, Advisory Board: Bertis; Financial Interests, Personal,Advisory Board: Idience; Financial Interests, Institutional, Research Grant: AstraZeneca, Pﬁzer, Roche,Eisai, Dae Woong; Financial Interests, Institutional, Local PI, Clinical Trial Budget: AstraZeneca,Hanmi, Novartis, Roche, Pﬁzer, Daiichi Sankyo, MSD, Lilly; Financial Interests, Institutional, Coordinating PI, Clinical Trial Budget: Eisai; Financial Interests, Institutional, Research Grant, Clinical Trial Budget: Boryung Pharm. T. Beck: Financial Interests, Institutional, Local PI: Lilly, AZ, Novartis, DSI,AbbVie, Pﬁzer, johnson and Johnson, BMS, Merck, EMD Serono, Tesaro, Mersano, ascentage pharma,Gritstone, Gilead. S. Sammons: Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca; Daiichi Sankyo; Eli Lilly and Company; Foundation Medicine; Novartis; Pﬁzer; Seagen; Sermonix Pharmaceuticals; Financial Interests, Institutional, Research Funding: AstraZeneca/MedImmune; Eli Lilly and Company; Seagen, Sermonix Pharmaceuticals. M. Bhave: Financial Interests, Personal, Speaker, Consultant, Advisor: Daiichi Sankyo; Merck; Pﬁzer. P.A. Kaufman: Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca; Eisai; Eli Lilly and Company; H3 BioMedicine; Pﬁzer; Polyphor; Roche/Genetech; Sanoﬁ; Seagen; Financial Interests, Personal, Stocks or ownership: Amgen; Financial Interests, Institutional, Research Funding: AstraZeneca; Eisai;Macrogenics; Sanoﬁ; Seagen; Financial Interests, Personal, Other, Travel and accommodation expenses: Eli Lilly and Company; Polyphor; Seagen. C. C. Saura Manich: Financial Interests, Personal,Advisory Board: AstraZeneca, Boehringer Ingelheim, Bristol Meyers Squibb, Daiichi Sankyo, Eisai,Exact Sciences, Exeter Pharma, F. Hoffmann - La Roche Ltd, Gilead, Lilly, Merck Sharp & Dohme,Novartis, Pﬁzer, Philips, Piere Fabre, PintPharma, Puma, Roche Farma, Sanoﬁ-Aventis, SeaGen,Zymeworks, Genentech, Innoup, Millenium, Pharmalex Spain SLU; Financial Interests, Personal,Other, SC: Byondis B.V., Glaxo, Macrogenics, Menarini, Merus, Synthon Biopharpaceuticals; Financial Interests, Institutional, Research Grant: AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Bristol Myers Squibb (BMS), Cytomx Therapeutics, Daiichi Sankyo, Eli Lilly and Company, F. Hoffmann-La RocheLtd, Genentech, GSK, Immunomedics, Innoup Farma, Macrogenics, Menarini Ricerche, Merus,Novartis, Pﬁzer, Puma, Roche, Sanoﬁ-Aventis, Seattle Genetics; Financial Interests, Institutional,Coordinating PI: Byondis B.V.; Non-Financial Interests, Member: Spanish Society of Medical Oncology(SEOM), American Society for Clinical Oncology (ASCO), Geicam (Spanish Breast Cancer Research Group), European Society for Medical Oncology (ESMO), Sinology Society of the Ofﬁcial College of Physicians of Barcelona (COMB); Non-Financial Interests, Member, Junta Directiva y Comité Cientíﬁco: SOLTI group (Academic research group in breast cancer). T. Meniawy: Financial Interests,Personal, Other, Honoraria: AstraZeneca/MedImmune; Financial Interests, Personal, Speaker,Consultant, Advisor: AstraZeneca/MedImmune; Bristol Myers Squibb; GSK; Novartis; Financial Interests, Institutional, Research Funding: AstraZeneca/MedImmune; Bayer; BeiGene; Bristol Myers Squibb; Incyte; Merck Serono; Regeneron; Roche/Genentech; Financial Interests, Personal, Other,Travel, Accommodations, Expenses: Bristol Myers Squibb. F. Bacchion, R. Ismail-Khan, Y. Li, S.T.

Estrem, B. Nguyen: Financial Interests, Personal, Stocks or ownership: Eli Lilly and Company;Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.560

384MO Final overall survival analysis for fulvestrant vs anastrozole in endocrine therapy (ET)-naïve, hormone receptor-positive(HR+) advanced breast cancer (FALCON)

J. Robertson1, Z. Shao2, S. Noguchi3, S. Singh4, S. Subramaniam5, M.J. Ellis6

1Medicine Department, University of Nottingham, School of Medicine, Nottingham,UK; 2Breast Surgery Dept., University Shanghai Cancer Center, Shanghai, China;3Breast Surgery, Hyogo Prefectural Nishinomiya Hospital, Nishinomiya, Japan;4AstraZeneca Netherlands, Zoetermeer, Netherlands; 5AstraZeneca India, Bangalore,India; 6Oncology R&D, AstraZeneca Pharmaceuticals LP, Gaithersburg, MD, USA

Background: The phase 3 international, randomised, double-blind FALCON trial(NCT01602380) met its primary endpoint showing a statistically signiﬁcant improvement in progression-free survival (PFS) with fulvestrant vs anastrozole as a ﬁrst-line treatment for HR+ advanced breast cancer (BC). PFS improvement was conﬁned to non-visceral disease (HR¼0.59 [95% CI 0.42e0.84]) vs visceral disease (HR¼0.99 [95%CI 0.74e1.33]). At the primary analysis, interim overall survival (OS) data were immature (31%). Here we report the prespeciﬁed ﬁnal analysis of OS.

Methods: Postmenopausal women with ET-naïve, HR+/HER2e locally advanced or metastatic BC were randomised 1:1 to fulvestrant (500 mg, Days 0, 14 and 28, then monthly thereafter) or anastrozole (1 mg, daily). Secondary endpoints of OS, safety,and quality of life (QoL) are reported. The ﬁnal OS analysis was triggered at a threshold of 65% maturity and 8 years since the last patient was enrolled, with anavailable 1-sided alpha of 0.01845.

Results: In the overall population (462 patients; 68% maturity; cut-off 11 July 2022),median OS was 44.8 months with fulvestrant vs 42.7 months with anastrozole(HR¼0.97 [95% CI 0.77e1.21]; p¼0.7579). Median OS across prespeciﬁed subgroupswas consistent with the overall population. In patients with non-visceral disease, a 15% reduction in the risk of death was observed with fulvestrant vs anastrozole,although statistical signiﬁcance was not reached (Table). No meaningful differences were seen in QoL. No new safety signals emerged.

Table: 384MO Median OS for visceral and non-visceral disease [DCO 11 July 2022]

Median OS, months

HR (95% CI)

Fulvestrant Anastrozole Non-visceral disease n¼95

n¼113

65.2

47.8

0.85 (0.60e1.20)

Visceral disease

n¼135

n¼119

37.2

40.7

1.06 (0.80e1.42)

CI, conﬁdence interval; DCO, data cut-off; HR, hazard ratio; OS, overall survival.

Conclusions: At the ﬁnal analysis of FALCON, no signiﬁcant difference in OS was seen between fulvestrant and anastrozole in ET-naïve postmenopausal women with HR+/HER2e locally advanced or metastatic BC. The positive trend observed in OS for fulvestrant in non-visceral disease compared with visceral disease is consistent with the primary analysis.

Clinical trial identiﬁcation: NCT01602380.

Editorial acknowledgement: Writing assistance was provided by Alison Lovibond PhD of BOLDSCIENCE Inc., funded by AstraZeneca.

Disclosure: J. Robertson: Financial Interests, Personal, Research Grant: AstraZeneca, Novartis;Financial Interests, Personal, Other, Personal fees are reported.: AstraZeneca. S. Noguchi: Financial Interests, Personal and Institutional, Advisory Role: AstraZeneca, Sysmex; Financial Interests, Personal, Invited Speaker: Pﬁzer, Eli Lilly; Financial Interests, Personal and Institutional, Funding: Chugai;Financial Interests, Personal and Institutional, Invited Speaker: Chugai, Sysmex; Financial Interests,Personal and Institutional, Royalties: Sysmex; Financial Interests, Personal and Institutional, Research Grant: Sysmex. S. Singh: Financial Interests, Institutional, Full or part-time Employment: AstraZeneca.

S. Subramaniam, M.J. Ellis: Financial Interests, Personal and Institutional, Full or part-time Employment: AstraZeneca. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.561

385MO

A multicenter, open-label, dose escalation and expansion study of DP303c in patients with HER2-positive pre-treated advanced solid tumors

J. Zhang1, X. Hu2, Y. Du1, Y. Meng1, Y. Liu3, Y. Shi4, J. Wang5, A. Zang6, S. Gu7, T. Liu8,H. Zhou9, H. Guo10, S. Xiang11, X. Zhang12, S. Wu11, M. Li13

1Phase I Clinical Trial Center, Fudan University Shanghai Cancer Center, Shanghai,China; 2Department of Medical Oncology, Fudan University Shanghai Cancer Center,Shanghai, China; 3Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China; 4Department of Breast Medical Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; 5Internal MedicineDigestive Oncology Dept, Henan Cancer Hospital/Afﬁliated Cancer Hospital of Zhengzhou University, Zhengzhou, China; 6Department of Medical Oncology, Afﬁliated Hospital of Hebei University, Baoding, China; 7Department of Radioactive Intervention,Hunan Cancer Hospital & The Afﬁliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; 8Department of Medical Oncology,Zhongshan Hospital Fudan University, Shanghai, China; 9Phase I Clinical Trial Center,The First Afﬁliated Hospital of Bengbu Medical College, Bengbu, China; 10Department of Urology, Nanjing Drum Tower Hospital, Nanjing, China; 11Department of Medicine,CSPC Zhongqi Pharmaceutical Technology Co., Ltd., Beijing, China; 12Department of Medicine, CSPC Zhongqi Pharmaceutical Technology Co., Ltd., Shijiazhuang, China;13Department of Data Science, CSPC Zhongqi Pharmaceutical Technology Co., Ltd.,Shanghai, China

Background: DP303c is a HER2-targeting ADC with a cleavable linker-MMAE payload.

Pre-clinical study demonstrated similar to or better antitumor activity than T-DM1 in xenograft models. Here we present the safety and efﬁcacy of DP303c in patients (pts)with HER2-positive pre-treated advanced solid tumors.

Methods: Adult pts with HER2-positive advanced solid tumors who were not eligible to receive standard of care (SoC) or had no SoC, or failed SoC were recruited. This phase I study consisted of dose escalation with a modiﬁed 3+3 design at DP303c 0.5,

1.0, 2.0, 3.0 and 4.0 mg/kg, and then dose expansion at 3.0 mg/kg, intravenously administered every 3 weeks. The primary endpoints were safety and RP2D.

Results: As of 28 Feb 2023, 94 pts were enrolled in dose escalation (22 pts) and dose expansion (72 pts). The median follow-up was 11.98 months (mo). Median age was

51.5 yrs (range: 28-73). Tumor types were breast cancer (BC, 68 pts), colorectal cancer(10 pts), gastric cancer (9 pts) and others (7 pts). ECOG PS was 0 in 15 pts (16.0%),and 1 in 79 pts (84.0%). All 94 pts received 1 prior line of systemic therapy. 65 pts(95.6%) with BC received 2 prior lines of systemic therapy. One dose limitingtoxicity [Grade (G) 3 eye pain] was observed in 4.0 mg/kg with 3.0 mg/kg selected as expansion dose. Treatment-related adverse events (TRAEs) of any grade occurred in all 94 pts, in which 34 (36.2%) were G 3. The most common G 3 TRAEs were visonblurred (16.0%), xerophthalmia (6.4%), and neuropathy peripheral (3.2%). No treatment-related death occurred. Among 91 efﬁcacy evaluable pts, ORR and DCR were

42.9% (95%CI: 32.5-53.7) and 68.1% (95%CI: 57.5-77.5). The median PFS and DoR

were 4.44 mo (95%CI: 3.35-6.44) and 10.97 mo (95%CI: 3.98-NA) for all 94 pts. The minimal effective dose was 1.0 mg/kg in BC. Among 66 efﬁcacy evaluable pts with BC,ORR and DCR were 51.5% (95%CI: 38.9-64.0) and 77.3% (95%CI: 65.3-86.7). The median PFS and DoR were 6.44 mo (95%CI: 4.14-8.51) and 10.97 mo (95%CI: 3.98-NA)for all 68 pts with BC.

Conclusions: DP303c demonstrated promising anti-tumor activity with acceptable safety in pts with pre-treated advanced solid tumors, especially BC. The pivotal phase II study in pts with BC is ongoing.

Clinical trial identiﬁcation: NCT04146610.

Funding: CSPC Zhongqi Pharmaceutical Technology Co., Ltd.

Disclosure: S. Xiang, X. Zhang, S. Wu, M. Li: Financial Interests, Personal, Full or part-time Employment: CSPC Zhongqi Pharmaceutical Technology Co., Ltd.. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.562

386MO Trastuzumab duocarmazine versus physician’s choice therapy in pre-treated HER2-positive metastatic breast cancer: Final results of the phase III TULIP trial

P.G. Aftimos1, N. Turner2, J. O’Shaughnessy3, E. van den Tweel4, M. Oesterholt4,S. Escrivá-de-Romaní5, N. Quenel Tueux6, T.J.Y. Tan7, J. Lim8, S. Ladoire9,

A.C. Armstronh10, A. Stradella11, G.V. Bianchi12, M.A. Colleoni13, E. Kaczmarek14,K. Punie15, X. Song16, N. Koper4, C. Saura Manich17

1Clinical Trials Conduct Unit, Institute Jules Bordet, Anderlecht, Belgium; 2The Royal Marsden Hospital - Chelsea, London, UK; 3Texas Oncology - Baylor Sammons Cancer Center, Dallas, TX, USA; 4Clinical Development Department, Byondis B.V., Nijmegen,Netherlands; 5Medical Oncology-Breast Cancer Unit, Vall d’Hebron University Hospital,Barcelona, Spain; 6Institute Bergonié, Bordeaux, France; 7Medical Oncology Department, NCCS - National Cancer Centre Singapore, Singapore; 8Medical Oncology, NUHS

- National University Health System, Singapore; 9Oncology Dept., Centre GeorgesFrançois Leclerc (Dijon), Dijon, France; 10The Christie NHS Foundation Trust, Manchester, UK; 11Medical Oncology Department, ICO - Institut Català d’Oncologia l’Hospitalet (Hospital Duran i Reynals), L’Hospitalet De Llobregat, Spain; 12Medical Oncology Department, SC Oncologia Medica 1 Fondazione IRCCS Istituto Nazionale Tumori Milano, Milan, Italy; 13IEO - Istituto Europeo di Oncologia, Milan, Italy;14Centre Oscar Lambret, Lille, France; 15General Medical Oncology and Multidisciplinary Breast Centre, Leuven Cancer Institute, University Hospitals Leuven, Leuven,Belgium; 16Medical Oncology Department, The Ottawa Hospital Regional Cancer Centre, Ottawa, ON, Canada; 17Breast Cancer Program, Vall d’Hebron University Hospital, Barcelona, Spain

Background: Trastuzumab duocarmazine (T-Duo, SYD985) is a HER2-targeting antibody-drug conjugate comprised of trastuzumab bound to the DNA alkylating agent duocarmazine with a drug-antibody ratio of 2.4 to 2.8. TULIP is a randomized, international, multicenter, phase 3 study in patients with pre-treated HER2-positive metastatic breast cancer (MBC). The initial analysis of the primary endpoint progression free survival (PFS) showed a clinically meaningful and statistically signiﬁcant difference in favor of T-Duo versus physician’s choice (PC) (Saura et al., ESMO 2021).

At that time, preliminary overall survival (OS) data were reported. Final OS and updated secondary outcomes are reported here.

Methods: The TULIP trial randomly assigned patients with HER2-positive locally advanced or MBC with 2 previous HER2-targeting MBC regimens or pretreated withT-DM1, in a 2:1 ratio between T-Duo (1.2 mg/kg q3w) and PC. PC could be either trastuzumab combined with capecitabine or vinorelbine or eribulin or lapatinib plus capecitabine. The primary endpoint was PFS by blinded, independent, central review.

Key secondary endpoints are PFS by investigator, OS, overall response rate, QoL,duration of response and safety.

Results: A total of 291 patients were randomized to the T-Duo group and 146 to the PC group. At the data cut off, the median follow-up of the T-Duo and PC groups were

35.6 months and 32.0 months, respectively. Median OS was 21.0 months in the T-Duo group and 19.5 months in the PC group. The hazard ratio was 0.87 (95% CI 0.68, 1.12)p¼0.236. The 1-year survival estimate was 70% in the T-Duo group and 68% in the PCgroup. The primary endpoint PFS (7.0 vs 4.9 months, HR 0.63, p¼0.002) and othersecondary efﬁcacy outcomes did not change in this analysis compared to the initial analysis. No new safety ﬁndings were observed with longer follow-up.

Conclusions: T-Duo showed a meaningful and statistically signiﬁcant improvement in PFS in patients with pre-treated HER2-positive MBC. The ﬁnal OS results conﬁrm a trend towards a numerically prolonged OS (statistically non-signiﬁcant) in the T-Duo group compared with PC group. Safety was aligned with the primary analysis, with no new signals identiﬁed.

Clinical trial identiﬁcation: NCT03262935, Eudract 2017-001994-18.

Legal entity responsible for the study: Byondis B.V.

Funding: Byondis B.V.

AstraZeneca, Lilly, Novartis, Pﬁzer, Roche/Genentech, GSK, Zentalis pharmaceuticals, Repare therapeutics, GSK, Relay therapeutics, Gilead, Inivata, Guardant, Exact Sciences; Financial Interests,Institutional, Funding: AstraZeneca, Pﬁzer, Roche/Genentech, Merck Sharpe and Dohme, Invitae,Inivata, Personalis, Natera; Financial Interests, Institutional, Other, provision of materials: BioRad;Financial Interests, Institutional, Other, Provision of assays: Guardant Health. J. O’Shaughnessy:Financial Interests, Personal, Advisory Board: Abbvie, Agendia, Amgen, Aptitude Health, AstraZeneca, Bristol Myers Squibb, Celgene, Eisai, G1 Therapeutics, Genentech, Immunomedics, Ipsen Biopharmaceuticals, Lilly, Merck, Myriad, Novartis, Ondonate, Pﬁzer, Puma, Prime Oncology, Roche,Seattle Genetics, Syndax, Carrick Therapeutics, Daiichi Sankyo, Gilead Sciences, Ontada, Pierre Fabre Pharmaceuticals, Samsung Bioepis, Sanoﬁ. E. van den Tweel: Financial Interests, Personal, Full or part-time Employment, Clinical Project Leader: Byondis B.V.. M. Oesterholt: Financial Interests,Personal, Full or part-time Employment, Clinical Project leader: Byondis BV. S. Escrivá-de-Romaní:Financial Interests, Personal, Advisory Board: Roche, Daiichi Sankyo/AstraZeneca, Seagen, PierreFabre, COR2ED; Financial Interests, Personal, Invited Speaker: Roche, Daiichi Sankyo/AstraZeneca,Pﬁzer, Seagen, Novartis; Financial Interests, Personal, Other, Travel grants: Pﬁzer, Kern; Financial Interests, Institutional, Local PI: Roche, Synthon, Byondis, Lilly, MedSIR, Zymeworks, Daiichi Sankyo/AstraZeneca, SOLTI. N. Quenel Tueux: Financial Interests, Personal, Advisory Board: Pﬁzer, Astra Zenica, Daiichi; Financial Interests, Personal, Other, Support for congresses: Novartis, Lilly, MSD,Seagen, Gilead, Astra Zenica, Daiichi. T. T.J.Y. Tan: Financial Interests, Personal, Advisory Board:AstraZeneca, MSD, Everest Medicines (Singapore) Pte Ltd, DKSH; Financial Interests, Personal,Invited Speaker: DKSH, AstraZeneca, Novartis, MSD; Financial Interests, Institutional, Research Grant:AstraZeneca; Financial Interests, Institutional, Local PI: Roche, Novartis, AstraZeneca, Daiichi Sankyo,Genentech, Sanoﬁ; Non-Financial Interests, Member: ASCO; Other, Conference sponsorship: DKSH,AstraZeneca, Novartis. J. Lim: Financial Interests, Personal, Advisory Board: Pﬁzer, Novartis, AstraZeneca, DKSH, MSD, Everest Medicine; Financial Interests, Personal, Invited Speaker: AstraZeneca,MSD; Financial Interests, Institutional, Local PI: Synthon pharmaceuticals, Daiichi, Taiho pharmaceuticals; Financial Interests, Institutional, Funding: CTI biopharma. S. Ladoire: Financial Interests,Personal, Advisory Board, advisory board: Pﬁzer, Novartis, AstraZeneca, Sanoﬁ, Daiichi, Gilead,Menarini-Stemline; Financial Interests, Personal, Advisory Board, advisory board, expert testimony:Astellas; Financial Interests, Personal, Advisory Board, expert testimony, invited speaker: Janssen,Ipsen; Financial Interests, Personal, Invited Speaker, invited speaker: BMS, Seagen, Exact Science;Financial Interests, Personal, Invited Speaker, invited speaker, expert testimony: Lilly; Financial Interests, Institutional, Research Grant, research grant: Novartis, Eisai, BMS. A. A.C. Armstronh: Financial Interests, Personal, Advisory Role: AstraZeneca, MSD, Gilead; Financial Interests, Personal, Stocks/Shares, Spousal Shares: AstraZeneca; Financial Interests, Institutional, Research Funding, to institution: AstraZeneca; Non-Financial Interests, Personal, Other, Clinical lead: RCOG Breast Cancer and Pregancy Guideline; Non-Financial Interests, Personal, Other, Clinical Advisor: NICE Menopause Guideline (update). A. Stradella: Financial Interests, Personal, Advisory Board, Advisory about CAPITELLO 291 trial: AstraZeneca; Financial Interests, Personal, Advisory Board, Advisory on new activities for residents: Novartis; Financial Interests, Personal, Invited Speaker, Trastu-Deruxtecan clinical case meeting: Daiichi; Financial Interests, Personal, Invited Speaker, meeting on new data on cyclin inhibitors: Novartis. G.V. Bianchi: Financial Interests, Personal, Advisory Board: Novartis, Lilly,Roche, AstraZenica/Daiichi, MSD, Seagen. M.A. Colleoni: Financial Interests, Institutional, Research Grant: Roche; Non-Financial Interests, Leadership Role, CO-Chair Scientiﬁc Committee: International Breast Cancer Study Group. K. K. Punie: Financial Interests, Institutional, Advisory Board: AstraZeneca,Novartis, Roche, Vifor Pharma, Eli Lilly, Pierre Fabre, McCann Health, Roularta, Teva, Gilead Sciences,Pﬁzer, Gilead, MSD; Financial Interests, Institutional, Invited Speaker: Pﬁzer, Roche, Novartis, Eli Lilly,Mundi Pharma, MSD, Medscape; Financial Interests, Institutional, Other, Consultancy: Roche;Financial Interests, Personal, Other, Consultancy: Gilead, Novartis, MSD, Roche; Financial Interests,Personal, Invited Speaker: Sanoﬁ, AstraZeneca, Exact Sciences, Focus Patient, Pﬁzer, Gilead Sciences;Financial Interests, Personal, Advisory Board: Seagen, AstraZeneca, Pﬁzer; Financial Interests, Personal, Ownership Interest: Need Inc.; Financial Interests, Institutional, Funding: Sanoﬁ; Financial Interests, Institutional, Trial Chair: MSD; Non-Financial Interests, Other, Committee member: ESMO Young Oncologists Committee; Non-Financial Interests, Leadership Role, Vice President: Belgian Society of Medical Oncology BSMO; Non-Financial Interests, Other, Committee Member: ESMO Resilience Task Force; Non-Financial Interests, Leadership Role: EORTC Breast Cancer Task Force Steering Committee Member; Non-Financial Interests, Institutional, Product Samples, Drug provision for academic research: Gilead Sciences; Non-Financial Interests, Advisory Role: Commission personalized medecine Federal Government Belgium; Non-Financial Interests, Advisory Role,External Scientiﬁc Advisor: European Medicine Agency. X. X. Song: Financial Interests, Personal,Advisory Board: EMD, BMS, Novartis, Pﬁzer, merck; Financial Interests, Institutional, Local PI:AstraZeneca, BMS, Gilead, Novartis, Pﬁzer, Roche, Seagen. N. Koper: Financial Interests, Personal,Full or part-time Employment, VP Clinical Development: Byondis B.V.. C. Saura Manich: Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Bristol Meyers Squibb,Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F. Hoffmann - La Roche Ltd, Gilead, Lilly, Merck Sharp & Dohme, Novartis, Pﬁzer, Philips, Piere Fabre, PintPharma, Puma, Roche Farma, SanoﬁAventis, SeaGen, Zymeworks, Genentech, Innoup, Millenium, Pharmalex Spain SLU; Financial Interests, Personal, Other, SC: Byondis B.V., Glaxo, Macrogenics, Menarini, Merus, Synthon Biopharpaceuticals; Financial Interests, Institutional, Research Grant: AstraZeneca, Bayer Pharma,Boehringer Ingelheim, Bristol Myers Squibb (BMS), Cytomx Therapeutics, Daiichi Sankyo, Eli Lilly and Company, F. Hoffmann-La Roche Ltd, Genentech, GSK, Immunomedics, Innoup Farma, Macrogenics,Menarini Ricerche, Merus, Novartis, Pﬁzer, Puma, Roche, Sanoﬁ-Aventis, Seattle Genetics; Financial Interests, Institutional, Coordinating PI: Byondis B.V.; Non-Financial Interests, Member: Spanish Society of Medical Oncology (SEOM), American Society for Clinical Oncology (ASCO), Geicam(Spanish Breast Cancer Research Group), European Society for Medical Oncology (ESMO), Sinology Society of the Ofﬁcial College of Physicians of Barcelona (COMB); Non-Financial Interests, Member,Junta Directiva y Comité Cientíﬁco: SOLTI group (Academic research group in breast cancer). All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.563

387MO First results of the SOLTI-1903 HOPE’s patient-centric molecular screening program in advanced breast cancer

T. Pascual1, E. Segui Solis2, R. Olivera-Salguero3, J.M. Cejalvo4, M. Oliveira5,P. Tolosa Ortega6, M.J. Vidal Losada7, M. Malumbres8, J. Gavilá-Gregori9,C. Saura Manich10, S. Pernas Simon11, M. Margeli Vila12, E.M. Ciruelos13,E. Galve-Calvo14, P. Galván15, E. Sanfeliu Torres16, R. Olmos17, M. Forns18,A. Casas Fernandez Tejerina19, A. Prat20

1Medical Oncology Department, SOLTI/Hospital Clinic y Provincial de Barcelona/IDIBAPS, Barcelona, Spain; 2Medical Oncology, Hospital Clinic y Provincial de Barcelona/SOLTI/IDIBAPS, Barcelona, Spain; 3Scientiﬁc Department, SOLTI Cancer Research Group, Barcelona, Spain; 4Dept. Medical Oncology, Hospital Clinico Universitario de Valencia/INCLIVA/SOLTI, Valencia, Valencia, Spain; 5Medical Oncology Dept., Vall d’Hebron University Hospital, Barcelona, Spain; 6Medical Oncology Dept., Hospital Universitario 12 de Octubre, Madrid, Valencia, Spain; 7Breast Cancer, Hospital Clinic of Barcelona, Barcelona, Spain; 8Cancer Cell Cycle Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; 9Medical Oncology Department, IVO - Fundación Instituto Valenciano de Oncología, Valencia, Spain; 10Head, Breast Cancer Program,Vall d’Hebron University Hospital, Barcelona, Spain; 11Medical Oncology Breast Unit,ICO - Institut Català d’Oncologia l’Hospitalet (Hospital Duran i Reynals), L’Hospitalet De Llobregat, Spain; 12Medical Oncology Dept., ICO - Institut Català d’Oncologia Badalona (Hospital Universitario Germans Trias i Pujol), Badalona, Spain; 13Medical Oncology Dept, Hospital Universitario 12 de Octubre, Madrid, Spain; 14Medical Oncology Dept. , Hospital Universitario de Basurto, Bilbao, Spain; 15Translational genomics and targeted therapies in solid tumors lab, IDIBAPS - Fundació de Recerca Clinic Barcelona - Institut d’Investigacions Biomediques August Pi i Sunyer, Barcelona,Spain; 16Pathology, Hospital Clinic of Barcelona, Barcelona, Spain; 17Patient Advocate,Asociación Española de Cáncer de Mama Metastásico (CMM), Oviedo, Spain; 18Patient Advocacy, Asociación Española de Cáncer de Mama Metastásico, Oviedo, Spain;19Patient Advocacy, Fundación Actitud Frente al Cáncer, Seville, Spain; 20Medical Oncology Department, Hospital Clinic y Provincial de Barcelona, Barcelona, Spain

Background: The SOLTI-1903 HOPE study aims to assess the feasibility of a molecular screening program promoting active participation of patients with Advanced Breast Cancer (ABC) in the management of their disease to better characterize the genomic landscape of ABC and to facilitate pt access to matched-targeted therapies in Spain.

Methods: HOPE (NCT04497285) is a patient-centric study where pts diagnosed with ABC lead their inclusion, participation, and follow-up through a digital tool (DT). They report clinical information and provide archival tumor samples to be analyzed by FoundationOne CDx. At progression disease, patients undergo a liquid biopsy with the Guardant360 panel. Clinical and genomic information is discussed by a Molecular Advisory Board (MAB) that issues a report explaining the alterations and enumerating potentially useful targeted treatments. Then, participants record disease evolution in the DT for 2y. The primary objective is to assess the real-world clinical practice of integrating molecular proﬁling into the Standard of Care management of pts with ABC.

Results: Between Oct 2020 and Feb 2022, 604 patients were included in the study,and the median age was 51 ys (range 27-82y). The most common reported IHC subtype was ER+/HER2- (74%), followed by HER2+ (14%) and triple negative (12%).

512 tumor samples were received from 423 patients, and DNA-seq results with positive results were obtained in 298 (58%) cases. Common alterations were PIK3CA mut (34%), CCND1 amp (27%), and TP53 mut (26%). Blood extractions were obtained from 378 patients, and ctDNA detection was observed in 303 (80%) cases. Frequently mutated genes were PIK3CA (38%), TP53 (38%), and ESR1 (29%). As of April 2023, the MAB reviewed 306 cases, observing at least one ESCAT I-III alteration in 75% of cases.

Of these, only 15% were already known before HOPE. After a mean follow-up of 1.3ys,20% of ABC cases discussed received a targeted treatment.

Conclusions: Patient-centric molecular screening programs implemented on a nationwide level are viable, have the potential to impact treatment decisions in a subgroup of patients and seems more efﬁcient to bring patients to receive treatments targeted to the identiﬁed alterations.

Clinical trial identiﬁcation: NCT04497285.

Legal entity responsible for the study: SOLTI Cancer Research Group.

Funding: Novartis; Roche (Foundation Medicine); Guardant Health; Asociación española de Cáncer de Mama Metastásico; Fundación Actitud Frente al Cáncer; Saray(Asociación Navarra de Cáncer de Mama); Federación Española de Cáncer de Mama(FECMA); Asociación Vive, "Ni una estrella más"; Manualitats Solidàries Cerdanyola.

Disclosure: T. Pascual: Financial Interests, Personal, Invited Speaker: Pﬁzer/ AstraZeneca / Veracyte/ Novartis; Financial Interests, Personal, Advisory Board: Roche/Genentech, Novartis. E. Segui Solis:Financial Interests, Personal, Invited Speaker: Novartis, Veracyte, Pﬁzer; Financial Interests, Personal,Full or part-time Employment: SOLTI; Financial Interests, Personal, Research Grant: Amgen. R. Olivera-Salguero: Financial Interests, Personal, Full or part-time Employment: SOLTI. J.M. Cejalvo:Financial Interests, Personal, Advisory Board: Novartis, Pﬁzer. M. Oliveira: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo / AstraZeneca, Gilead, Pierre Fabre, Roche,SeaGen, iTEOS, Relay Therapeutics; Financial Interests, Personal, Invited Speaker: Gilead, MSD,Novartis, Pﬁzer, Roche, Seattle Genetics; Financial Interests, Personal, Coordinating PI: AstraZeneca;Financial Interests, Institutional, Local PI: AstraZeneca, Boehringer-Ingelheim, GSK, Roche, Seattle Genetics, Zenith Epigenetics, Gilead, Ayala Pharmaceuticals; Financial Interests, Personal, Steering Committee Member: AstraZeneca; Financial Interests, Steering Committee Member: Roche; NonFinancial Interests, Member of Board of Directors: SOLTI Breast Cancer Research; Other, Travel Grant:Pierre Fabre, Eisai, Gilead, AstraZeneca. P. Tolosa Ortega: Financial Interests, Personal, Invited Speaker: Novartis, Pﬁzer, Lilly, Seagen, AstraZeneca, Daiichi Sankyo and MSD; Financial Interests,Personal, Advisory Board: Novartis, Adamed, Seagen and Daiichi Sankyo; Financial Interests, Personal, Full or part-time Employment, Medical Advisor and Medical Monitor: SOLTI; Financial

Interests, Institutional, Funding: Novartis. M.J. Vidal Losada: Financial Interests, Personal, Advisory Board: Novartis/Pﬁzer, Roche, Pﬁzer, AstraZeneca/Daiichi Sankyo; Financial Interests, Personal,Invited Speaker: Novartis/Pﬁzer, Roche/Genentech, AstraZeneca/Daiichi Sankyo, Gilead Sciences;Financial Interests, Personal, Other, Travel, Accommodations, expenses: Pﬁzer; Financial Interests,Personal, Other, Travel, Accommodations, Expenses: Gilead Sciences. M. Malumbres: Financial Interests, Personal, Financially compensated role: Lilly; Financial Interests, Personal, Other: Prosenestar; Financial Interests, Personal and Institutional, Research Funding: Pﬁzer, Lilly, Prosenestar,PharmaMar, Circle Pharma. J. Gavilá-Gregori: Financial Interests, Personal, Advisory Board: Novartis,Pﬁzer, Roche. C. Saura Manich: Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Bristol Meyers Squibb, Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F.

Hoffmann - La Roche Ltd, Gilead, Lilly, Merck Sharp & Dohme, Novartis, Pﬁzer, Philips, Piere Fabre,PintPharma, Puma, Roche Farma, Sanoﬁ-Aventis, SeaGen, Zymeworks, Genentech, Innoup, Millenium, Pharmalex Spain SLU; Financial Interests, Personal, Other, SC: Byondis B.V., Glaxo, Macrogenics,Menarini, Merus, Synthon Biopharpaceuticals; Financial Interests, Institutional, Research Grant:AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Bristol Myers Squibb (BMS), Cytomx Therapeutics, Daiichi Sankyo, Eli Lilly and Company, F. Hoffmann-La RocheLtd, Genentech, GSK, Immunomedics, Innoup Farma, Macrogenics, Menarini Ricerche, Merus, Novartis, Pﬁzer, Puma, Roche,Sanoﬁ-Aventis, Seattle Genetics; Financial Interests, Institutional, Coordinating PI: Byondis B.V.; NonFinancial Interests, Member: Spanish Society of Medical Oncology (SEOM), American Society for Clinical Oncology (ASCO), Geicam (Spanish Breast Cancer Research Group), European Society for Medical Oncology (ESMO), Sinology Society of the Ofﬁcial College of Physicians of Barcelona(COMB); Non-Financial Interests, Member, Junta Directiva y Comité Cientíﬁco: SOLTI group (Academic research group in breast cancer). S. S. Pernas Simon: Financial Interests, Personal, Advisory Board: SeaGen, AstraZeneca- Daiichi Sankyo, Pierre-Fabre, Pﬁzer; Financial Interests, Personal,Invited Speaker: Lilly, Novartis, Eisai, Roche; Financial Interests, Institutional, Local PI: AstraZeneca,Novartis, Daiichi Sankyo; Non-Financial Interests, Member of Board of Directors: SOLTI. M. Margeli Vila: Financial Interests, Personal, Invited Speaker: Pﬁzer; Financial Interests, Personal, Advisory Board: Novartis, MSD, Gylead, Lilly, Pierre Fabre; Financial Interests, Personal, Other, Travel expences: Gylead; Financial Interests, Institutional, Coordinating PI, I have received research funding for my institution from Pﬁzer: Pﬁzer. E.M. Ciruelos: Financial Interests, Personal, Other, Speakers Bureau.nterests, Personal, Advisory Board, Non-permanent advisor:Roche, Lilly, Novartis, Pﬁzer, Daiichi Sankyo, MSD; Financial Interests, Personal, Invited Speaker,Symposia and Education: Lilly; Financial Interests, Personal, Invited Speaker, Educational activities:Pﬁzer; Financial Interests, Personal, Advisory Board, Non-permanent advisor, Travel accommodation:AstraZeneca; Financial Interests, Personal, Other, Advisory Board: Gilead; Financial Interests, Personal, Other, Advisory Board, Invited speaker: Seagen; Financial Interests, Institutional, Funding, PI for Patricia 2 trial (sponsor: SOLTI Group): Pﬁzer; Financial Interests, Institutional, Funding, PI for Prometeo 2 trial (sponsor: SOLTI Group): Pﬁzer; Financial Interests, Institutional, Funding, PI for TATEN trial (sponsor: SOLTI Group): MSD; Financial Interests, Institutional, Funding, PI for ATREZZO trial (sponsor: SOLTI Group): Roche; Non-Financial Interests, Member of Board of Directors, Nonproﬁt organization dedicated to breast cancer research: SOLTI Cooperative Group; Non-Financial Interests, Advisory Role, Scientiﬁc Evaluator at ISCIII (Spanish Government Academic Research Platform): Instituto de Salud Carlos III. Educational activities: Roche; Financial Interests, Personal, Invited Speaker, Symposia and Educational activities: Roche; Financial Interests, Personal, Advisory Board, Non-permanent advisor:Roche, Lilly, Novartis, Pﬁzer, Daiichi Sankyo, MSD; Financial Interests, Personal, Invited Speaker,Symposia and Education: Lilly; Financial Interests, Personal, Invited Speaker, Educational activities:Pﬁzer; Financial Interests, Personal, Advisory Board, Non-permanent advisor, Travel accommodation:AstraZeneca; Financial Interests, Personal, Other, Advisory Board: Gilead; Financial Interests, Personal, Other, Advisory Board, Invited speaker: Seagen; Financial Interests, Institutional, Funding, PI for Patricia 2 trial (sponsor: SOLTI Group): Pﬁzer; Financial Interests, Institutional, Funding, PI for Prometeo 2 trial (sponsor: SOLTI Group): Pﬁzer; Financial Interests, Institutional, Funding, PI for TATEN trial (sponsor: SOLTI Group): MSD; Financial Interests, Institutional, Funding, PI for ATREZZO trial (sponsor: SOLTI Group): Roche; Non-Financial Interests, Member of Board of Directors, Nonproﬁt organization dedicated to breast cancer research: SOLTI Cooperative Group; Non-Financial Interests, Advisory Role, Scientiﬁc Evaluator at ISCIII (Spanish Government Academic Research Platform): Instituto de Salud Carlos III. E. Galve-Calvo: Financial Interests, Personal, Advisory Board:Pﬁzer, Novartis, Roche, Pierre Fabre, Eisai, Daiichi Sankyo, Daiichi Sankyo, AstraZeneca, AstraZeneca,Gilead, Gilead; Financial Interests, Personal, Invited Speaker: Pﬁzer, Daiichi Sankyo, AstraZeneca,Gilead; Other, Travel accommodation: Pﬁzer. A. A. Casas Fernandez Tejerina: Financial Interests, Personal, Invited Speaker: Pﬁzer, Novartis, AstraZeneca. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis, Daiichi Sankyo;Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pﬁzer, Oncolytics Biotech, Guardant Health, Peptomyc; Financial Interests, Institutional, Invited Speaker, Clinical trials:Daiichi Sankyo; Financial Interests, Institutional, Other, Contracted research: Boehringer Ingelheim,Medica Scientia inno. Research; Financial Interests, Personal, Advisory Board: AstraZeneca, 1TRIALSP,S.L.; Financial Interests, Personal, Member of Board of Directors, Leadership role: Reveal Genomics,SL.; Financial Interests, Personal, Stocks/Shares: Reveal Genomics, Oncolytics Biotech; Financial Interests, Personal, Royalties: Reveal Genomics, International Oncology Bureau, S.L.,; Financial Interests, Institutional, Local PI: Roche, AstraZeneca; Financial Interests, Personal and Institutional,Steering Committee Member: Daiichi Sankyo; Financial Interests, Institutional, Coordinating PI:Novartis; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation, Actitud Frente al Cáncer Foundation; Non-Financial Interests, Personal, Other, Asociación Española de Investigación sobre el Cáncer: ASEICA. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.564

Table: 388P Summary of intracranial responses T-DXd n [ 24

TPC n [ 11

Intracranial conﬁrmed ORR(CR + PR), n (%) [95% CI]a

6 (25.0) [9.8-46.7] 0 [0-28.5]

Best overall intracranial response, n (%)

4 (16.7)

2 (8.3)

12 (50.0)

7 (63.6)

1 (9.1)

1 (4.2)

Missingb

5 (20.8)

3 (27.3)

Clinical beneﬁt rate

(CR + PR + (>6 mo) SD),n (%) [95% CI]a

14 (58.3) [36.6-77.9] 2 (18.2) [2.3-51.8]

Disease control rate(CR + PR + SD),n (%) [95% CI]a

18 (75.0) [53.3-90.2] 7 (63.6) [30.8-89.1]

CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease. aBased on Clopper-Pearson method for single proportion. bImaging not performed/available.

388P Subgroup analysis of patients (pts) with HER2-low

metastatic breast cancer (mBC) with brain metastases (BMs)at baseline from DESTINY-Breast04, a randomized phase III study of trastuzumab deruxtecan (T-DXd) vs treatment of physician’s choice (TPC)

J. Tsurutani1, W. Jacot2, T. Yamashita3, F. Riaz4, R. Yerushalmi5, S-A. Im6, N. Niikura7,U. Halser-Strub8, J. Cortés9, A-K. Wennstig10, Y. Chae11, X. Wang12, W. Li13,

H. Simon14, G. Masci15, E. Tamburini16, C. Orbegoso Aguilar17, K. Tecson18, L. Yung19,S. Modi20

1Advanced Cancer Translation Research Institute, Showa University Hospital, Tokyo,Japan; 2Medical Oncology, Institut du Cancer de Montpellier, Montpellier, France;3Breast Surgery and Oncology, Kanagawa Cancer Center, Yokohama, Japan; 4Medicine/Oncology, Stanford School of Medicine, Stanford, CA, USA; 5Oncology Institute,Davidoff Center, Rabin Medical Center, Tel-Aviv University, Petah Tikva, Israel; 6Internal Medicine Dept, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea; 7Breast Oncology, Tokai University School of Medicine, Isehara, Kanagawa, Japan; 8Breast Center, Kantonsspital St.

Gallen, St. Gallen, Switzerland; 9Oncology, International Breast Cancer Center (IBCC),Pangaea Oncology, Quironsalud Group, Madrid & Barcelona, Spain; 10Oncology,Sundsvall Hospital, Sundsvall, Sweden; 11Medical Oncology, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea; 12Medical Oncology, Zhejiang Cancer Hospital - Cancer Research Institute, Hangzhou, China; 13Tumor Center, First Hospital of Jilin University, Changchun, Jilin, China; 14Oncology, CHU Brest-Hôpital Morvan - Institut de Cancerologie et d’Hematologie, Brest, France; 15Medical Oncology, Humanitas Clinical Research Hospital Rozzano, Rozzano, MI, Italy;16Oncology and Palliative Care, "Pia Fondazione Cardinale G. Panico” Hospital, Tricase,Italy; 17Global Oncology R&D, Daiichi Sankyo France SAS, Rueil-Malmaison, France;18Evidence Generation, Daiichi Sankyo, Inc., Basking Ridge, NJ, USA; 19Global Oncology R&D, Daiichi Sankyo, Inc., Basking Ridge, NJ, USA; 20Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

Background: The DESTINY-Breast04 trial (NCT03734029) demonstrated signiﬁcantly improved progression-free survival (PFS) and overall survival (OS) in pts with HER2-low mBC treated with T-DXd vs TPC. Consistent efﬁcacy was also demonstrated in pts with BMs at baseline with T-DXd vs TPC. In this exploratory analysis, we provide additional intracranial (IC) efﬁcacy data in pts with BMs at baseline.

Methods: Pts with centrally conﬁrmed HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization) mBC who were previously treated with 1 or 2 lines ofchemotherapy were randomized (2:1) to T-DXd or TPC. Pts with investigator-assessed clinically stable and treated BMs at baseline were eligible, and exploratory analyses of IC clinical activity were completed. Analysis was based on central review of brain MRI or CT scans. Endpoints included IC objective response rate (ORR) by blinded independent central review (BICR), best overall response, clinical beneﬁt rate, disease control rate, and IC PFS by BICR.

Results: Of 35 pts with BICR-assessed BMs at baseline, 24 pts received T-DXd and 11 received TPC. Like the full dataset, most pts with BMs at baseline had hormone receptor-positive tumors (T-DXd, 75.0%; TPC, 72.7%). Of those pts who received 1dose of trial drug, median treatment duration was 6.6 mo (mo; range, 0.3-24.3 mo)for T-DXd (n ¼ 24) and 1.4 mo (range, 0.4-17.4 mo) for TPC (n ¼ 9); 20.8% and 11.1%of these pts remained on T-DXd and TPC for >12 mo, respectively. IC response data are shown in the table. Median IC PFS by BICR for T-DXd was 9.7 mo (95% CI, 4.4-15.1 mo) vs not evaluable for TPC, due to small pt numbers.

Conclusions: In this exploratory analysis, IC responses favored T-DXd over TPC in pts with clinically stable and treated baseline BMs.While only a small number of pts were included here, the IC efﬁcacy data suggest a clinical beneﬁt of T-DXd over TPC.

Editorial acknowledgement: Under the guidance of authors, assistance in medical writing and editorial support was provided by Lauren Carroll, MS, MPH, Toinette Labuschagne, MS, and Katie Henderson, PhD, of ApotheCom, and was funded by Daiichi Sankyo, Inc.

Disclosure: J. Tsurutani: Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Research Grant: Eisai, Eli Lilly, Ono. T. Yamashita: Financial Interests, Personal, Invited Speaker: Chugai, Eisai,Pﬁzer, Daiichi Sankyo, Astraseneca, Taiho, Novartis Pharma, Nippon Kayaku, Eli Lilly, Kyowa kirin. F.

Riaz: Financial Interests, Institutional, Funding, Site PI for Industry Sponsored Trial: Genentech Roche, Greenwich Sciences, AstraZeneca, Daiichi Sankyo, Novartis. R. Yerushalmi: Financial Interests,Personal, Advisory Board, invited Speaker, Research Grant,: Roche; Financial Interests, Personal,Advisory Board: Pﬁzer; Financial Interests, Personal, Advisory Board, Invited Speaker: Novartis, MSD,AstraZeneca, Eli Lilly, Gilead; Financial Interests, Personal, Invited Speaker: Teva, Medison; Financial Interests, Personal, Advisory Board, Research Grant: Rhenium-Oncotest; Financial Interests, Personal, Funding, (Research Grant): Exact Science. S. Im: Financial Interests, Personal, Advisory Board,no payment: AstraZeneca, Novartis, Eisai, Roche, Hanmi, Pﬁzer, Lilly, MSD, GSK, Daiichi Sankyo;Financial Interests, Institutional, Advisory Board: Bertis; Financial Interests, Personal, Advisory Board:Idience; Financial Interests, Institutional, Research Grant: AstraZeneca, Pﬁzer, Roche, Eisai, Dae Woong; Financial Interests, Institutional, Local PI, Clinical Trial Budget: AstraZeneca, Hanmi, Novartis,Roche, Pﬁzer, Daiichi Sankyo, MSD, Lilly; Financial Interests, Institutional, Coordinating PI, Clinical Trial Budget: Eisai; Financial Interests, Institutional, Research Grant, Clinical Trial Budget: Boryung Pharm. N. Niikura: Financial Interests, Personal, Invited Speaker: AstraZeneca, Pﬁzer, Daiichi Sankyo,Chugai, Eli Lilly, MSD; Financial Interests, Personal and Institutional, Research Grant: Chugai, Eisai,Nippon Kayaku; Financial Interests, Personal and Institutional, Coordinating PI: Daiichi Sankyo. J.

Cortés: Financial Interests, Personal, Advisory Board: Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp & Dohme, GSK, LEUKO,Bioasis, Clovis oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead,Menarini, Zymeworks, Reveal Genomics; Financial Interests, Personal, Invited Speaker: Roche,Novartis, Celgene, Eisai, Pﬁzer, Samsung Bioepis, Lilly, Merck Sharp & Dohme, Daiichi Sankyo;Financial Interests, Personal, Other, Consulting/advisor: Expres2ion Biotechnologies; Financial Interests, Personal, Stocks/Shares: MedSIR, Nektar Therapeutics; Financial Interests, Institutional,Research Grant: Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, Guardant Health, Merck Sharp&Dohme, Pﬁzer, Piqur Therapeutics, Puma B, Queen Mary University of London; Other, Travel cost and expenses: Roche, Novartis, Eisai, Daiichi Sankyo,Pﬁzer, Gilead, AstraZeneca. H. Simon: Financial Interests, Personal, Advisory Board: Daiichi Sankyo;Financial Interests, Personal, Invited Speaker: Viatris, AstraZeneca; Financial Interests, Personal,Invited Speaker, Travel/accomodation: Novartis, Lilly; Financial Interests, Personal, Other, Travel/accomodation: Eisai, Gilead, Pﬁzer; Financial Interests, Personal, Advisory Role: Roche. C. Orbegoso Aguilar, K. Tecson, L. Yung: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. S. S. Modi: Financial Interests, Personal, Advisory Board: Daiichi Sankyo, Genentech, AstraZeneca, Seagen, Macrogenics; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, AstraZeneca; Financial Interests, Personal, Steering Committee Member: daiichi sankyo; Financial Interests, Institutional, Local PI: Daiichi Sankyo, Genentech, AstraZeneca, Seagen. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.565

389P

Efﬁcacy and safety analyses by prior lines of chemotherapy from the phase III TROPiCS-02 study of sacituzumab

govitecan (SG) vs treatment of physician’s choice (TPC) in patients (pts) with HR+/HER2- metastatic breast cancer

(mBC)

J. Cortés1, F. Marmé2, P. Schmid3, H.S. Rugo4, S.M. Tolaney5, W. Verret6, T. Valdez7,Y. Huo8, A. Bardia9

1Department of Medicine, Oncology Department, International Breast Cancer Center(IBCC), Madrid, Spain; 2Department of Obstetrics and Gynaecology, Universitaetsklinikum Mannheim - Medizinische Fakultaet, Mannheim, Germany; 3Medical Oncology, Barts Health NHS Trust, London, UK; 4Department of Medicine,University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; 5Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; 6Department of Clinical Development, Gilead Sciences, Inc., Foster City, CA, USA; 7Department of Patient Safety, Gilead Sciences, Inc., Foster City, CA, USA; 8Department of Biostastistics, Gilead Sciences, Inc., Foster City, CA, USA; 9Medical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA

Background: SG is a Trop-2edirected antibody-drug conjugate approved for pretreated HR+/HER2- (IHC 0, 1+, or 2+/ISH-) mBC in the US. In the TROPiCS-02 study, SG treatment showed statistically signiﬁcant improvement in progression-free survival(PFS; hazard ratio [HR] 0.66; 95% conﬁdence interval [CI] 0.53-0.83) and overall survival (OS; HR 0.79; 95% CI 0.65-0.96) vs TPC with manageable safety in pts with pretreated HR+/HER2- mBC (Rugo et al. ESMO 2022 ). Outcomes worsen with multiple prior lines of chemotherapy (LoT). We present a post-hoc analysis of outcomes with SG vs TPC by prior LoT from TROPiCS-02.

Methods: Pts with HR+/HER2- mBC and 1 endocrine therapy, taxane, and CDK4/6inhibitor, and 2 to 4 prior LoT for mBC, were randomized to SG (10 mg/kg IV Days 1 and 8, Q3W) or TPC. The primary endpoint was PFS; secondary endpoints included OS,objective response rate (ORR), clinical beneﬁt rate (CBR), and safety. This analysis included pts with 2 vs 3 prior LoT in the metastatic setting.

Results: 543 pts were randomized to SG (n ¼ 272; 113 (42%) had 2 prior LoT, 159(58%) had 3) and TPC (n ¼ 271; 120 (44%) had 2 prior LoT, 151 (56%) had 3).Baseline characteristics were similar in pts with 2 and 3 prior LoT and acrosstreatments. Median PFS and OS were improved with SG vs TPC irrespective of prior LoT, with HR of 0.61 and 0.82 in pts with 2 prior LoT and 0.72 and 0.78 in pts with 3prior LoT, respectively (Table). CBR was improved with SG vs TPC in pts with 2 and 3prior LoT, ORR was improved in pts with 2 prior LoT, and the safety proﬁle was similar in both subgroups (Table).

Table: 389P

Efﬁcacy, ITT 2 Prior LoT

‡3 Prior LoT

SG (n¼113) TPC (n[113) SG (n[159) TPC (n[158)

Median PFSa,b

(95% CI), mo

5.7 (4.2-8.5) 4.1 (2.8-5.6) 5.3 (4.0-6.9) 4.0 (2.9-4.4)

HR (95% CI) 0.61 (0.44-0.84)

0.72 (0.54-0.97)

Median OSc

15.3

(12.7-19.8)

12.4

(10.4-14.9)

(12.3-15.5)

(8.7-12.4)

HR (95% CI) 0.82 (0.60-1.12)

0.78 (0.61-1.01)ORRa,c(95% CI), % 30 (22-39) 16 (10-24) 14 (9-21)

13 (8-19)CBRa,c(95% CI), % 41 (32-50) 25 (17-34) 29 (22-37) 20 (14-27)

Safety, all

treated, n (%)

SG (n[112) TPC (n[109) SG (n[156) TPC (n[140)

Any grade TEAEsc 112 (100) 106 (97) 156 (100) 133 (95)

Grade 3/4 79 (71) 58 (53) 113 (72) 92 (66)

aPer independent central review. bData cutoff: Jan 3, 2022; cJul 1, 2022.

Conclusions: Regardless of number of prior LoT, SG demonstrated improved efﬁcacy vs TPC in pts with HR+/HER2- mBC, with manageable safety across subgroups.

Findings are consistent with the ITT population, demonstrating the potential for pts to beneﬁt from SG in earlier LoT. Table

Clinical trial identiﬁcation: NCT03901339.

Editorial acknowledgement: Editorial support was provided by Ben Labbe, PhD, of Parexel and funded by Gilead Sciences, Inc.

Legal entity responsible for the study: Gilead Sciences, Inc.

Funding: Gilead Sciences, Inc.

Disclosure: J. Cortés: Financial Interests, Personal, Advisory Board: Roche, Celgene, Cellestia,AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp &Dohme, GSK, LEUKO, Bioasis, Clovis oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent,Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics; Financial Interests, Personal, Invited Speaker: Roche, Novartis, Celgene, Eisai, Pﬁzer, Samsung Bioepis, Lilly, Merck Sharp & Dohme,Daiichi Sankyo; Financial Interests, Personal, Other, Consulting/advisor: Expres2ion Biotechnologies;Financial Interests, Personal, Stocks/Shares: MedSIR, Nektar Therapeutics; Financial Interests,Institutional, Research Grant: Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, Guardanth health, Merck Sharp&Dohme, Pﬁzer, Piqur Therapeutics,Puma B, Queen Mary University of London; Other, Travel cost and expenses: Roche, Novartis, Eisai,Daiichi Sankyo, Pﬁzer, Gilead, AstraZeneca. F. F. Marmé: Financial Interests, Personal, Invited Speaker:AstraZeneca, GSK/Tesaro, Clovis, Pﬁzer, Lilly; Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, Novartis, Roche, Gilead/immunomedics, EISAI, PharmaMar, GenomicHealth, Myriad,Seagen; Financial Interests, Institutional, Invited Speaker: Seagen, Daiichi Sankyo, GSK, AstraZeneca;Financial Interests, Institutional, Advisory Board: Roche, Immunicom; Financial Interests, Institutional, Local PI: Roche, Novartis, Eisai, MSD, Vaccibody, GSK; Financial Interests, Institutional,Coordinating PI: AstraZeneca, Roche, Gilead/Immunomedics, German Breast Group, AGO Research GmbH; Financial Interests, Institutional, Funding: AstraZeneca, Lilly, Seagen. P. Schmid: Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis,Pﬁzer, Puma, Roche, Gilead, Eisai, MSD, Seagen, Amgen, Celgene, Lilly; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Genentech, Novartis, Oncogenex, Roche, Medivation.

H.S. Rugo: Financial Interests, Personal, Other, Consultancy/advisory support: PUMA, NAPO, Mylan,Daiichi Sankyo, Eisai; Financial Interests, Institutional, Local PI: Novartis, Lilly, Pﬁzer, Daiichi, AstraZeneca, Gilead Sciences, Inc., GSK, Sermonix Pharmaceuticals Ins., Pionyr Immunotherapeutics, Taiho Oncology, Inc., Veru Inc; Financial Interests, Institutional, Coordinating PI: OBI Pharma, Astellas Pharma Inc., F. Hoffmann-La Roche AG/Genentech, Inc., Merck; Financial Interests, Personal, Other,Travel support to academic meetings: Merck, AstraZeneca, Gilead; Non-Financial Interests, Advisory Role, I advise a number of companies without compensation: various. S.M. Consulting: Aadi BioPharma; Financial Interests, Personal, Advisory Board, Ad board participation: Artios, Incyte Corp, BeyondSprings; Financial Interests, Personal, Advisory Board, Ad Board Participant/Consultant: AstraZeneca, Eli Lilly; Financial Interests, Personal, Advisory Board,Advisory Board participation: Bayer, Inﬁnity Therapeutics, Myovant, OncXerna, Umoja Biopharma,Zentalis, Zetagen; Financial Interests, Personal, Other, Consultant: Blueprint Medicines; Financial Interests, Personal, Advisory Board, Ad board participant: Bristol Myers Squibb, Ellipses Pharma,Mersana Therapeutics; Financial Interests, Personal, Other, Steering Committee Member/Consultant: CytomX; Financial Interests, Personal, Advisory Board, Advisory Board participation/consulting:Menarini/Stemline; Financial Interests, Personal, Advisory Board, Ad Board participant/consultant:Merck; Financial Interests, Personal, Advisory Board, Ad board participant/Consultant: Pﬁzer;Financial Interests, Personal, Advisory Board, Advisory board participation: Reveal Genomics;Financial Interests, Personal, Advisory Board, Advisory Board Participation: Zymeworks; Financial Interests, Institutional, Funding: AstraZeneca, Eli Lilly, Pﬁzer, Sanoﬁ, SeaGen, Odonate, Cyclacel,Exelixis, Gilead, Bristol Myers Squibb, Eisai, Merck, Novartis, Nektar, Genentech/Roche; Financial Interests, Personal and Institutional, Steering Committee Member: CytomX. Tolaney: Financial Interests, Personal, Advisory Board, Ad board participant/consultant: 4D Pharma, ARC Therapeutics,Daiichi Sankyo, Eisai, Genentech/Roche, Gilead, Novartis, Sanoﬁ, SeaGen; Financial Interests, Personal, Other, Consulting: Aadi BioPharma; Financial Interests, Personal, Advisory Board, Ad board participation: Artios, Incyte Corp, BeyondSprings; Financial Interests, Personal, Advisory Board, Ad Board Participant/Consultant: AstraZeneca, Eli Lilly; Financial Interests, Personal, Advisory Board,Advisory Board participation: Bayer, Inﬁnity Therapeutics, Myovant, OncXerna, Umoja Biopharma,Zentalis, Zetagen; Financial Interests, Personal, Other, Consultant: Blueprint Medicines; Financial Interests, Personal, Advisory Board, Ad board participant: Bristol Myers Squibb, Ellipses Pharma,Mersana Therapeutics; Financial Interests, Personal, Other, Steering Committee Member/Consultant: CytomX; Financial Interests, Personal, Advisory Board, Advisory Board participation/consulting:Menarini/Stemline; Financial Interests, Personal, Advisory Board, Ad Board participant/consultant:Merck; Financial Interests, Personal, Advisory Board, Ad board participant/Consultant: Pﬁzer;Financial Interests, Personal, Advisory Board, Advisory board participation: Reveal Genomics;Financial Interests, Personal, Advisory Board, Advisory Board Participation: Zymeworks; Financial Interests, Institutional, Funding: AstraZeneca, Eli Lilly, Pﬁzer, Sanoﬁ, SeaGen, Odonate, Cyclacel,Exelixis, Gilead, Bristol Myers Squibb, Eisai, Merck, Novartis, Nektar, Genentech/Roche; Financial Interests, Personal and Institutional, Steering Committee Member: CytomX. W. Verret: Financial Interests, Institutional, Full or part-time Employment, I am a paid employee of Gilead Sciences:Gilead Sciences. T. T. Valdez: Financial Interests, Institutional, Stocks/Shares: Gilead Sciences. A. Bardia:Financial Interests, Personal, Advisory Board: Pﬁzer, Novartis, Genentech, Merck, Sanoﬁ, Eisai, Lilly,Mersana, AstraZeneca/Daiichi, Menarini, Gilead; Financial Interests, Personal, Royalties: UpToDate;Financial Interests, Institutional, Coordinating PI: Genentech, Novartis, Pﬁzer, Merck, Sanoﬁ, Radius

S343

Health, Immunomedics/Gilead, Daiichi Pharma/AstraZeneca, Eli Lilly.; Non-Financial Interests, Principal Investigator: Gilead, Mersana, AstraZeneca/Daiichi, Novartis, Pﬁzer, Genentech, Lilly, Merck,Sanoﬁ. All other authors have declared no conﬂicts of interest.

https://doi.org/10.1016/j.annonc.2023.09.566

390P

Any TR Nause Fatigu Arthra Consti Hot ﬂu

aNo grad headache(n¼1), inpts may event

Vepdegestrant, a proteolysis targeting chimera (PROTAC)estrogen receptor (ER) degrader, in ER+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer:Update of dose escalation results from a phase I/II trial

E.P. Hamilton1, H. Han2, A. Schott3, A. Tan4, R. Nanda5, D. Juric6, N. Hunter7,

P. Munster8, B. Fang9, G. Zahrah10, J. Ranciato11, R. Gedrich12, E. Zhi13, Y. Zhang14,W. Tan15, C. Mather16, J. Perkins17, S. Anderson16, S.A. Hurvitz18

1Drug Development Unit, Sarah Cannon Research Institute, Nashville, TN, USA; 2Breast Oncology, Mofﬁtt Cancer Center, Tampa, FL, USA; 3Department of Internal Medicine,Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA;4Solid Tumor and Investigational Therapeutics, Levine Cancer Institute, Atrium Health,Charlotte, NC, USA; 5Department of Medicine - Section of Hematology/Oncology,University of Chicago, Chicago, IL, USA; 6Hematology/Oncology, Massachusetts General Hospital, Boston, MA, USA; 7Fred Hutchinson Cancer Center, Seattle Cancer Care Alliance, Seattle, WA, USA; 8Medicine Department, University of California San Francisco, San Francisco, CA, USA; 9Medical Oncology, Astera Cancer Care, East Brunswick, NJ, USA; 10Medical Oncology, Norwalk Hospital, Norwalk, CT, USA;11Clinical Operations, Arvinas Operations, Inc., New Haven, CT, USA; 12Translational Medicine, Arvinas Operations, Inc., New Haven, CT, USA; 13Biostatistics, Arvinas Operations, Inc., New Haven, CT, USA; 14Clinical Pharmacology, Arvinas Operations, Inc.,New Haven, CT, USA; 15Clinical Pharmacology, Pﬁzer Inc., San Diego, CA, USA;16Clinical Research, Arvinas Operations, Inc., New Haven, CT, USA; 17Clinical Development, Pﬁzer Inc., New York, NY, USA; 18Medicine/Hematology Oncology Department, UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA

Background: Vepdegestrant (ARV-471), an oral PROTAC ER degrader, was well tolerated and had clinical activity in heavily pretreated patients (pts) with ER+/HER2-advanced breast cancer in the phase 1 dose escalation (data cutoff: Sep 30, 2021) and phase 2 expansion cohort portions of a phase 1/2 study (NCT04072952). We present updated phase 1 dose escalation data after an additional 13 months of follow-up.

Methods: Eligible pts had ER+/HER2- advanced breast cancer, 1 prior cyclin-dependent kinase (CDK)4/6 inhibitor, and 2 prior endocrine therapies. Primaryendpoints were safety, tolerability, and recommended phase 2 dose.

Results: As of Nov 1, 2022, 83 pts (median age: 64 y [range: 36e80]; 99% female)received vepdegestrant (30e700 mg total daily dose). Pts had a median of 4 prior regimens (range: 0e10; 100% prior CDK4/6 inhibitors, 81% prior fulvestrant, and 82%prior chemotherapy [60% in metastatic setting]). There were no dose-limiting toxicities. Treatment-related adverse events were mostly grade 1/2 (Table). Clinical beneﬁt rate (rate of conﬁrmed complete or partial response [PR] or stable disease 24 wks)for evaluable pts (n¼76) was 37% (95% CI: 26e49). Of 64 pts with baselinemeasurable disease, 6 had a conﬁrmed and 4 an unconﬁrmed PR. At data cutoff, 27 pts had treatment for 24 wks (7 for 48 wks) with 10 pts ongoing. Pharmacoki-netics (PK) showed dose-dependent exposure for 30e500 mg daily doses. Substantial on-treatment reductions in mutant ESR1 circulating tumor DNA levels were observed.

390P TRAEs reported in ‡10% of pts overall

30e700 mg total daily dose (n[83)

Any grade

Grade 1/2

Grade 3a

AE, n (%) 58 (70)

53 (64)

5 (6)b

20 (24)

19 (23)

1 (1)

lgia

11 (13)

pation

10 (12)

e 4 TRAEs occurred in any pts bOther grade 3 TRAEs not listed were(n¼1), increased aspartate aminotransferase (n¼1), increased amylasecreased lipase (n¼1), QT prolongation (n¼1), and venous embolism (n¼1);have experienced more than one TRAE TRAE¼treatment-related adverse

Conclusions: Vepdegestrant continued to be well tolerated across all doses and showed clinical activity in heavily pretreated pts with ER+/HER2- advanced breast cancer; PK was dose-dependent up to 500 mg daily. Data support further development of vepdegestrant; the ongoing phase 3 VERITAC-2 study (NCT05654623) is evaluating vepdegestrant 200 mg once daily vs fulvestrant.

Clinical trial identiﬁcation: NCT04072952.

Editorial acknowledgement: Justine Lempart, PhD, of Apollo Medical Communications, and funded by Arvinas Operations, Inc.

Legal entity responsible for the study: Arvinas Operations, Inc.

Funding: Arvinas Estrogen Receptor, Inc.

Disclosure: E.P. Hamilton: Financial Interests, Institutional, Other, Consulting/Advisory Role:Genentech/Roche, Novartis, Lilly, Pﬁzer, Mersana, iTeos, Janssen, Loxo, Relay Therapeutics, Olema Pharmaceuticals, Orum Therapeutics, Stemline Therapeutics, AstraZeneca, Daiichi Sankyo, SeaGen,Ellipses Pharma, Greenwich LifeSciences, Tubulis, Verascity Science, Theratechnologies; Financial Interests, Institutional, Research Grant: Oncomed, Genentech/Roche, Zymeworks, Rgenix, Arqule,Clovis, Millennium, Acerta Pharma, Sermonix Pharmaceuticals, Black Diamond, Karyopharm, Curis,Syndax, Novartis, Boehringer Ingelheim, Immunomedics, FujiFilm, Taiho, Deciphera, Molecular Templates, Onconova Therapeutics, Dana Farber Cancer Inst, Hutchinson MediPharma, MedImmune, SeaGen, Compugen, TapImmune, Lilly, Pﬁzer, H3 Biomedicine, Merus, Regeneron, Arvinas,StemCentRx, Verastem, eFFECTOR Therapeutics, CytomX, InventisBio, Lycera, Mersana, Radius Health, AbbVie, Nucana, Leap Therapeutics, Zenith Epigenetics, Harpoon, Orinove, AstraZeneca,Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, PharmaMar,Olema, Immunogen, Plexxicon, Amgen, Akesobio Australia, Shattuck Labs, ADC Therapeutics, Aravive, Atlas MedX, Ellipses Pharma, Incyte, Jacobio, Mabspace Biosciences, ORIC Pharmaceuticals,Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Repertoire Immune Medicine, Treadwell Therapeutics, Accutar Biotechnology, Artios, BeiGene, Bliss BioPharmaceuticals, Cascadian Therapeutics,Context Therapeutics, Cullinan, Dantari, Duality Biologics, Elucida Oncology, Inﬁnity Pharmaceuticals,K-Group Beta, Kind Pharmaceuticals, Loxo Oncology, Oncothyreon, Orum Therapeutics, Prelude Therapeutics, Profound Bio, Relay Therapeutics, Tolmar, Torque Therapeutics H. Han: Financial Interests, Institutional, Funding: Arvinas; Financial Interests, Institutional, Research Grant: Abbvie, GSK,G1 Therapeutics, Quantum Leap Healthcare Collaborative, Marker, Pﬁzer, Zymeworks; Financial Interests, Personal, Speaker’s Bureau: Eli Lilly; Financial Interests, Personal, Advisory Board: Novartis,AstraZeneca, Gilead. A. Schott: Financial Interests, Personal, Research Grant: Pﬁzer, Takeda, Genentech, Arvinas; Financial Interests, Personal, Other, Receipt of Intellectual Property Rights/Patent Holder: Imbio, LLC. A. Tan: Financial Interests, Personal, Research Grant: Arvinas. R. Nanda: Financial Interests, Personal, Advisory Board: AstraZeneca, BeyondSpring, Cardinal Health, Fujiﬁlm, Immunomedics/Gilead, Inﬁnity, iTeos, Merck, OBI, Oncosec, Seagen; Financial Interests, Funding: Arvinas,AstraZeneca, Celgene, Corcept Therapeutics, Genentech/Roche, Immunomedics, Merck, OBI Pharma, Odonate Therapeutics, OncoSec, Pﬁzer, Seattle Genetics, Taiho. D. Juric: Financial Interests,Personal, Advisory Role: Eisai, EMD Serono, Genentech, Ipsen, MapKure, Novartis, Petra Pharma,Syros Pharmaceuticals, Vibliome Therapeutics; Financial Interests, Institutional, Research Funding:Amgen, Eisai, EMD Serono, Genentech, Inﬁnity Pharmaceuticals, InventisBio, Novartis, Pﬁzer, Placon,Syros Pharmaceuticals, Takeda. N. Hunter: Financial Interests, Funding, Research: Arvinas. P.

Munster: Financial Interests, Institutional, Funding: Cyteir Therapeutics, Inc, InventisBio Co., Ltd,Amgen, PMV Pharmaceuticals, Inc, Genentech, Inc, Revolution Medicines, Inc, Hoffman-La Roche, JS InnoPharm, LLC, Seagen Inc, Tempest Therapeutics, Janssen, Deciphera Pharmaceuticals LLC, Clovis Oncology, Inc, ORIC Pharmaceuticals, Merck Sharp & Dohme LLC, Pﬁzer, Novartis; Financial Interests,Personal, Royalties: Alessa, RasCal, AtlasMedx; Financial Interests, Personal, Other, Consulting Fees:Alessa, RasCal, AtlasMedx. B. Fang: Financial Interests, Personal, Full or part-time Employment:Astera Cancer Care; Financial Interests, Personal, Leadership Role: Astera Cancer Care; Financial Interests, Institutional, Research Funding: Abbvie, Arvinas, Bristol Myers Squibb/Pﬁzer, Daiichi Sankyo/AstraZeneca, Epizyme, Exelixis, Gilead/Forty Seven, ImmunityBio, Janssen Oncology, Mirati Therapeutics, Natera, Novartis, Novocure, POINT Biopharma, Roche/Genentech, Veru, Zymeworks.

G. Zahrah: Financial Interests, Other, Research: Arvinas. J. Ranciato: Financial Interests, Personal, Full or part-time Employment: Arvinas. R. Gedrich: Financial Interests, Personal, Full or part-time Employment: Arvinas, Inc; Financial Interests, Personal, Stocks/Shares: Arvinas, Inc. E. Zhi: Financial Interests, Personal, Full or part-time Employment: Arvinas; Financial Interests, Personal, Project Lead: Arvinas; Financial Interests, Personal, Stocks/Shares: Arvinas. Y. Zhang: Financial Interests,Personal, Full or part-time Employment: Arvinas, Inc; Financial Interests, Personal, Stocks/Shares:Arvinas, Inc. W. Tan: Financial Interests, Personal, Full or part-time Employment: Pﬁzer, Inc; Financial Interests, Personal, Stocks/Shares: Pﬁzer, Inc. C. Mather: Financial Interests, Personal, Full or parttime Employment: Arvinas, Inc; Financial Interests, Personal, Stocks/Shares: Arvinas, Inc. J. Perkins:Financial Interests, Personal, Full or part-time Employment: Pﬁzer; Financial Interests, Personal,Stocks/Shares: Pﬁzer; Financial Interests, Personal, Ownership Interest: Pﬁzer. S. Anderson: Financial Interests, Personal, Full or part-time Employment: Arvinas Operations, Inc; Financial Interests,Personal, Stocks/Shares: Arvinas Operations, Inc. S. S.A. Hurvitz: Financial Interests, Personal, Invited Speaker: Clinical Care Options, axis medical, cancer expert now, ICHE, MJH Associates, PER, Primo,Projects in Knowledge, Prova Education, Research to Practice, Ultimate Medical Academy, Vaniam,WebMD, Peer Education, PrecisCA; Financial Interests, Personal, Stocks/Shares, spouse owns: ROM Tech; Financial Interests, Personal, Ownership Interest, spouse: Ideal Implant; Financial Interests,Personal, Royalties, author medical book: McGraw; Financial Interests, Personal, Royalties: Elsevier,Springer, Sage, Wolters Kluwer, Wiley; Financial Interests, Institutional, Invited Speaker: Ambrx,AstraZeneca, Arvinas, Daiichi Sankyo, Genentech/Roche, Gilead, GSK, Immunomedics, Eli Lilly,Macrogenics, Novartis, Pﬁzer, OBI Pharma, Pieris, PUMA, Radius, sanoﬁ, Seattle Genetics, Dignitana,Zymeworks, Phoenix Molecular Designs, Ltd, Celcuity, cytomx, Dantari, G1 Therapeutics, Greenwich Life Sciences, Loxo Oncology, orinove, Orum; Financial Interests, Institutional, Research Grant:Samumed, Ambrx; Financial Interests, Invited Speaker: Greenwich Life Sciences, Orum; Non-Financial Interests, Advisory Role: Daiichi Sankyo, Novartis, Ambrx, 4DPharma, Dantari, Macrogenics, Lilly,Artios, Roche, Pyxis, Amgen, Pieris, Arvinas, Immunomedics/Gilead; Non-Financial Interests, Principal Investigator: Daiichi Sankyo, Genentech, Seattle Genetics; Non-Financial Interests, Member:ASCO, AACR; Non-Financial Interests, Other, speaker: National Breast Cancer Coalition; Non-Financial Interests, Member, site representative for breast cancer guidelines: National Comprehensive Cancer Network.

https://doi.org/10.1016/j.annonc.2023.09.567

391P Detrimental effect on overall survival of CDK4/6 inhibitor dose reduction if immortal time bias is considered

A. Bjerrum1, A.F. Henriksen1, A.S. Knop1, T. Berg1, I.E.V. Tuxen2, U.N. Lassen1,T.S. Petersen3

1Department of Oncology, Rigshospitalet, Copenhagen, Denmark; 2Department of Oncology, Nordsjællands Hospital, Hillerød, Denmark; 3Department of Clinical Pharmacology, Bispebjerg Hospital, Copenhagen, Denmark

Background: Since 2017, the combination of CDK4/6 inhibitors and endocrine therapy has been the standard ﬁrst-line treatment for patients diagnosed with hormonepositive/HER2-negative metastatic breast cancer (mBC) in Denmark. Previous analyses, based on randomized phase III studies, have shown that the clinical beneﬁt

remains after CDK4/6i dose reduction, but analyses may have been susceptible to immortal time bias.

Methods: This real-world cohort study is based on electronic health records from 695 patients from the capitol region of Denmark who initiated ﬁrst-line treatment for mBC with CDK4/6i between May 2017 and October 2022. We used landmark Kaplan-Meier estimates and Cox regression to examine the association of dose reduction with treatment duration and overall survival. Patients were categorized based on dose reduction from the recommended dose prior to the landmark, deﬁned at 3 months after initiation of treatment. Hazard ratios were adjusted for CDK4/6i agent, age,comorbidity, BMI, LDH > ULN, ECOG performance status and visceral metastases.

Results: A total of 530 patients were eligible for inclusion in the landmark analysis and 198 (37%) were categorized into the dose reduction group. Patients with dose reduction were signiﬁcantly older and more had received prior endocrine therapy.

Dose reduction was signiﬁcantly associated with overall survival and shorter treatment duration, 39.6 vs 55.6 months (95%CI: 35.5-NE vs 49.9-NE) and 19.6 vs. 30.3 months, respectively. Adjusted hazard ratio for death was 1.49 for patients with dose reduction (95% CI: 1.01-2.22).

Table: 391P

Characteristic

Dose reduction,N [ 1981

Full dose,N [ 3321

CDK4/6i

0.14

Abemaciclib

48 (24%)

99 (30%)

Palbociclib

104 (53%)

145 (44%)

Ribociclib

引用 / 出处

2023 ESMO 摘要集 (LBA+O+MO+POSTER). 2023.

2023 ESMO 摘要集 (LBA+O+MO+POSTER)

European Society for Medical Oncology (ESMO)

ESMO Executive Board

相关指南

引用 / 出处