（2025.V5）NCCN临床实践指南：乳腺癌

指南肿瘤内科· 乳腺癌 · 2025

NCCN Guidelines Version 5.2025

*William J. Gradishar, MD/Chair † 2018 Robert H. Lurie Comprehensive Cancer Center of Northwestern University

*Meena S. Moran, MD/Vice-Chair §Yale Cancer Center/Smillow Cancer Hospital

Jame Abraham,MD‡↑ Case Comprehensive Cancer Center/University Hospitals Seldman Cancer Center and Cleveland Clinic Taussig Cancer Institute

Vandana Abramson, MD † Vanderbilt-Ingram Cancer Center

*Rebecca Aft, MD, PhD 9 Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Doreen Agnese, MD 1 The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute

Kimberly H. Allison, MD $\neq$ Stanford Cancer Institute

Bethany Anderson,MD §University of Wisconsin Carbone Cancer Center

Janet Bailey,MD §University of Michigan Rogel Cancer Center

Harold J. Burstein, MD, PhD\d Dana-Farber/Brigham and Women's Cancer Center

Nan Chen,MD‡The UChicago Medicine Comprehensive Cancer Center

*Helen Chew, MD+TCudavis Comprehensive Cancer Center

NCCN

Rashmi Kumar,PhD Ryan Schonfeld,BA NCCN Guidelines Panel Disclosures

Chau Dang,MD† Memorial Sloan Kettering Cancer Center

*Anthony D. Elias, MD t+ University of Colorado Cancer Center

Sharon H. Giordano, MD, MPH t The University of Texas MD Anderson Cancer Center

Matthew P. Goetz, MD#†+Mayo Clinic Comprehensive Center

*Rachel C. Jankowitz, MD t Abramson Cancer Center at the University of Pennsylvania

Sara H. Javid, MD T Fred Hutchinson Cancer Center

Jairam Krishnamurthy,MD t Fred& Pamela Buffett Cancer Center

A. Marilyn Leitch, MD 11 UT Southwestern Simmons Comprehensive Cancer Center

Janice Lyons, MD §Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute

Susie McCloskey, MD, MSHS §UCLA Jonsson Comprehensive Cancer Center

Melissa McShane, MD t Fox Chase Cancer Center

Joanne Mortimer,MD t+City of Hope National Medical Center

Sameer A. Patel, MD Y ①Fox Chase Cancer Center

Laura H. Rosenberger, MD, MS 9 Duke Cancer Institute

![Continue\n](2/aj0YEe4oUhYkBdfpda0fYP/figure13d35ae744ba4f5685c73ccfc3561d04_0_32.png) Hope S. Rugo, MD $\underline{+}$ UCSF Helen Diller Family Comprehensive Cancer Center

*Cesar A. Santa-Maria, MD, MSCI+ Johns Hopkins Kimmel Cancer Center

Bryan P. Schneider, MD $\dagger$ Indiana University Melvin and Bren Simon Comprehensive Cancer Center

Mary Lou Smith, JD, MBA ¥Research Advocacy Network

Hatem Soliman, MD t Moffitt Cancer Center

Corey Speers, MD, PhD §O'Neal Comprehensive Cancer Center at UAB

Erica M. Stringer-Reasor, MD t\ddot{t}N O'Alcomprehensive Cancer Center at UAB

Melinda L. Telli, MD t p Stanford Cancer Institute

Mei Wei,MD† Huntsman Cancer Institute at the University of Utah

Kari B. Wisinski, MD $\dagger$ University of Wisconsin Carbone Cancer Center

Amulya Yellala, MBBS‡ Fred & Pamela Buffett Cancer Center

Kay T.Yeung,MD,PhD b+UC San Diego Moores Cancer Center

Jessica S. Young, MD 1$\pi$ Roswell Park Comprehensive Cancer Center

‡ Hematology/Hematology oncology

P Internal medicine

+Medical oncology

≠ Pathology

S Radiation oncology/Radiotherapy

Y Reconstructive surgery

1 Surgery/Surgical oncology* Discussion Section Writing Committee

NCCN Guidelines Index Table of Contents Discussion

National Comprehensive Cancer Network®

Find an NCCN Member Institution: https://www.nccn.org/home/member-institutions.NCCN Categories of Evidence and Consensus: All recommendations to Breast-Conserving Approaches 2A unless otherwise indicated.See NCCN Categories of Evidence and Consensus.See NCCN Categories of NCCN Categories of Preference:All recommendations are considered appropriate.See NCCN Categories of Preference.

NCCN Breast Cancer Panel Members Summary of Guidelines Updates

Recommendations for Lobular Carcinoma In Situ were removed from the NCCN Guidelines for Breast Cancer. See NCCN Guidelines for Breast Cancer Screening and Diagnosis

Noninvasive Breast Cancer

Ductal Carcinoma In Situ (DCS) Workup and Primary Treatment(DCIS-1)

DISC Postursurgical Treatment and Surveillance/Follow-up(DCIS-2)

Invasive Breast Cancer

Clinical Stage, Workup (BIN-1)

Locoregional Treatment of cT1-3,cN0 or N+,M0 Disease

●BCS+ Whole Breast RT(BINV-2)

●Mastectomy± PMRT(BINV-3)

Systemic Adjuvant Treatment

●HR-Positive-HER2-Positive Disease(BINV-5)

●HR-Positive-HER2-Negative Disease:

Postmenopausal Patients(BINV-6)

Premenopausal Patients with pT1-3, pN0 (BINV-7)

Premenopausal Patients with pT1-3, pN+(BINV-8)

●HR-Negative-HER2-Positive Disease(BINV-9)

●HR-Negative-HER2-Negative Disease(BINV-10)

●Favorable Histologies(BINV-11)

Workup Prior to Preoperative Systemic Therapy (BINV-12)

Adjuvant Systemic Therapy After Preoperative Systemic Therapy(BINV-16)

Surveillance/Follow-up(BINV-17)

Recurrent/Stage IV(M1) Disease (BINV-18)

Treatment of Local and Regional Recurrence(BINV-19)

Systemic Treatment of Recurrent Unresectable(Local or

Regional) or Stage IV (M1) Disease (BINV-21)

Principles of Survivorship for Those Living with Advanced or

Metastatic Breast Cancer (BINV-28)

Special Considerations

Phylodes Tumor(PHYLL-1)

Paget Disease(PAGET-1)

Breast Cancer During Pregnancy

(PREG-1)

Inflammatory Breast Cancer

(IBC-1)

Staging(ST-1)

Abbreviations(ABBR-1)

The NCCN Guidelines are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network®(NCCN®) makes no representations or warranties of any regard including their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without their content, use or application of NCCN.©2025.

BINV-Q 2 of 15 and BINV-A:

BINV-Q 3 of 15

Abstract

• Second line: HER2 IHC 0+ moved to new row and fam-trastuzumab deruxtecan-nxki was changed from a category 1, preferred recommendation to a category 2A, other recommended regimen. • Footnote verbiage was updated to align with FDA approved scoring and CAP reporting: The distinction between HER2 test results of IHC 0/absent membrane staining, IHC 0+/with membrane staining (faint, partial membrane staining in ≤10%), IHC 1+ or 2+/ISH negative is currently clinically relevant for therapy selection. • Footnote f revised: Fam-trastuzumab deruxtecan-nxki may be used for HER2 IHC 0+ 1+ or 2+/ISH negative, in those previously treated with at least one line of endocrine-based therapy in the metastatic setting...

Abstract

• Second Line, row 3 revised: No germline BRCA1/2 mutation and HER2 IHC 0+, 1+ , or 2+/ISH negative.

Abstract

• Second Line, row 3, column 2: Fam-trastuzumab deruxtecan-nxki changed from a category 1, preferred to a category 2A, other recommended regimen.

Abstract

• Footnote k revised: Fam-trastuzumab deruxtecan may be considered in a later line for HER2 IHC 0+, 1+ or 2+/ISH negative, if not used in second line or may be considered first line therapy when disease has progressed during or within 6 months after completing adjuvant chemotherapy...

Updates in Version 3.2025 of the NCCN Guidelines for Breast Cancer from Version 2.2025 include:

Erratum: BINV-M 3 of 10 • Regimen revised: AC (doxorubicin/cyclophosphamide) followed or preceded by carboplatin + taxane (paclitaxel or docetaxel). BINV-M 6 of 10 • Added dosing for AC followed or preceded by carboplatin + taxane (paclitaxel).

BINV-Q 2 of 15

• Erratum: "Datopotamab deruxtecan-dlnk is indicated as second-or subsequent-line therapy for those who have received a prior endocrine-based therapy and chemotherapy for unresectable or metastatic disease." was added to the beginning of footnote h to clarify that the recommendation aligns with the FDA indication and panel vote. • For Breast Cancer Version 1.2025, BINV-M 6 of 10: Dosing correction for AC followed or preceded by carboplatin + docetaxel. BINV-M 3 of 10 • Regimen clarified: TC followed by or preceded by AC was replaced with AC (doxorubicin/cyclophosphamide) followed or preceded by carboplatin + docetaxel.

BINV-M 4 of 10

• Erratum: Paclitaxel + trastuzumab + pertuzumab was inadvertently listed under "Adjuvant setting only". This has been corrected and this regimen is listed under "Preoperative or adjuvant setting".

Updates in Version 2.2025 of the NCCN Guidelines for Breast Cancer from Version 1.2025 include:

Updates in Version 5.2025 of the NCCN Guidelines for Breast Cancer from Version 4.2025 include:

BINV-P (2 of 3)

• Other Recommended Regimens for first and/or subsequent lines of therapy Bullet 1 revised: For HER2-negative disease and ESR1 mutated tumors after a prior line of aromatase inhibitor ± CDK 4/6 inhibitor therapy (in adjuvant or metastatic setting), and after progression on one or two prior lines of endocrine therapy, including one line containing a CDK4/6 inhibitor, see BINV-Q (6) for options. BINV-Q 6 of 15 • Imlunestrant was added as a category 2A, other recommended regimen recommendation for first-line or subsequent line therapy.

• Footnote y added: For disease progression during or after prior line of aromatase inhibitor plus CDK 4/6 inhibitor therapy in the adjuvant or metastatic setting.

• Footnote z added: For disease progression during or after a prior line of aromatase inhibitor with or without CDK 4/6 inhibitor therapy in the adjuvant or metastatic setting.

• Footnote aa added: The combination of imlunestrant + abemaciclib is not FDA approved but has been studied in phase III EMBER-3 trial (Jhaveri KL, et

References

NCCN Guidelines Version 5.2025 Breast Cancer

Version 5.2025, 10/16/25 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index Table of Contents Discussion

Continued UPDATES DCIS-1• Footnote g revised: Surgical axillary staging should not be performed for preoperative (biopsy-determined) pure DCIS unless there is some clinical-pathologic

suggestion of invasion or axillary metastasis. A SLNB should also can be considered in the setting of 1) mastectomy for DCIS, where there is a small risk of

detecting invasive disease in the mastectomy specimen or 2) excision in an anatomic location compromising the performance of a future SLNB procedure.

• Footnote h added: A SLNB may be considered in the setting of 1) mastectomy for DCIS, 2) excision in an anatomic location compromising the performance of a future SLNB procedure 3) oncoplastic breast conserving surgery (see BINV-D for appropriate candidates for SLNB).

• Footnote m, last sentence revised: Select patients with "low" risk DCIS may be considered suitable for APBI/PBI or omission of RT (endocrine therapy alone, if all RTOG 9804 criteria are met: screen-detected, grade 1–2, size ≤2.5 cm, margins ≥3 mm).

DCIS-2• Surveillance/Follow-up, 2nd bullet revised: First mammogram 6–12 mo, after end of RT, if given, or after BCS therapy (category 2B) if no RT is given

and annually thereafter

• Footnote q revised: The standard dose of tamoxifen is 20 mg/day for 5 years. Low-dose tamoxifen (5 mg/day or 10 mg/every other day, for 3 years) is an option in patients who are symptomatic or unwilling to take standard 20-mg dosing. Low-dose tamoxifen (5 mg per day or 10 mg every other day for 3–5 years) is an option if patient is symptomatic on the 20-mg dose or if patient is unwilling or unable to take standard-dose 20 mg per day tamoxifen

[10 mg every other day since 5-mg dose is not available in the United States]. This low dosage needs further investigation in premenopausal individuals(DeCensi A, et al. J Clin Oncol 2019;37:1629-1637).

BINV-1• Workup

Last bullet added: Consider baseline lymphedema screening, as per NCCN Guidelines for Survivorship

• Clinical Stage

Bottom pathway, last column middle node, bullet 1 revised: BCS + surgical axillary staging ± whole breast RT Followed by RT

Bottom pathway, last column middle node, bullet 2 revised: Mastectomy + surgical axillary staging ± PMRT Followed by RT

BINV-2• Column headers added: Surgery, Adjuvant Systemic Therapy, Nodal Status, RT

• Column 2

Last sentence added: RT is typically given after systemic therapy (Also for BINV-3)

• pN1a pathway, bullet 1 revised: cT1–T3 2, cN0

• pN1a pathway, "No" node, last column revised: Whole breast RT with inclusion of any portion of the undissected axilla at risk ± boost to tumor bed

(category 1). Strongly consider comprehensive RNI, including any portion of the undissected axilla.

• Footnote o revised: Sentinel node biopsy may be omitted based on the SSO Choosing Wisely recommendation in patients ≥70 years of age with HR+/

HER2-negative and pT1, cN0 tumors (Hughes KS, et al. J Clin Oncol 2013;31:2382-2387. Kunkler IH, et al. N Engl J Med 2023:388:585-594).

• Footnote p added: Determined by surgery, clinical findings, or radiographic imaging.

• Footnote q added: Based on emerging data from the SOUND trial, patients with HR+/HER2-negative tumors, pT1, N0 (node negative by axillary

ultrasound), may be considered for omission of SLN biopsy. Gentilini OD, et al. JAMA Oncol 2023;9:1557-1564.

BINV-3• Header revised: Locoregional Treatment of cT–3, cN0 or cN+, M0 Disease: Mastectomy ± PMRT

• Column headers added: Surgery, Adjuvant Systemic Therapy, Pathologic Nodal Status, RT

• Column 1 revised: Nipple-sparing, skin-sparing, or total mastectomy with surgical axillary staging (category 1) ± reconstruction

BINV-4• Header added: Adjuvant Systemic Therapy Considerations Based on Histology and Receptor Status after Upfront Surgery

Updates in Version 1.2025 of the NCCN Guidelines for Breast Cancer from Version 6.2024 include:

NCCN Guidelines Version 5.2025 Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

Continued UPDATES

BINV-5• pT1c-pT3 pathway revised: Adjuvant chemotherapy with trastuzumab (category 1) (± pertuzumab for pT2-T3) and endocrine therapy

• Footnote hh revised: The prognosis of benefit of HER2-targeted therapy is uncertain in patients with HER2-positive breast cancer with pT1a–b, N0

tumors, pT1a and pT1b tumors that are pN0 is uncertain even when HER2 is amplified or overexpressed. This is a population of patients with breast

cancer that was not studied in available randomized trials. The decision for use of trastuzumab therapy in this cohort of patients must balance with the known toxicities of trastuzumab, such as cardiac toxicity, and the uncertain, absolute benefits that may exist with trastuzumab therapy.

• Footnote ii revised: Adjuvant chemotherapy with weekly paclitaxel and trastuzumab can be considered for pT1,N0,M0, HER2-positive cancers,

particularly if the primary cancer is HR-negative. The absolute benefit of HER2-based systemic chemotherapy is likely negligible in patients with HRpositive cancers and tumor size bordering on T1mic (<1 mm), when the estimated recurrence risk is less than 5% and endocrine therapy remains a

viable option for systemic treatment. (Also for subsequent pages)

BINV-6• Middle pathway, column 3, new node added: Determine if candidate for chemotherapy (Also for BINV-7)

New branch point added: Not a candidate for chemotherapy (Also for BINV-7)

• Footnote removed: Addition of 1 year of adjuvant olaparib is an option for select patients with germline BRCA1/2 mutation after completion of adjuvant chemotherapy. See BINV-L. In patients eligible for adjuvant olaparib and abemaciclib or ribociclib the optimal sequence is not known. (Also for BINV-8 and 10)

BINV-7• Not a candidate for chemotherapy, last column, new node added: Adjuvant endocrine therapy ± ovarian suppression/ablation. Consider adjuvant

ribociclib for eligible patients. See BINV-K 2 of 3 for eligibility criteria.

BINV-8• Bottom pathway revised: Adjuvant chemotherapy followed by endocrine therapy ± ovarian suppression/ablation (category 1). Consider adjuvant

abemaciclib or ribociclib and/or adjuvant olaparib if germline BRCA1/2 mutation for eligible patients. See BINV-K 2 of 3 and BINV-M for eligibility criteria.

BINV-9• pT1c-pT3 pathway revised: Adjuvant chemotherapy with trastuzumab (category 1) (± pertuzumab for pT2-T3)

BINV-10• Last column, middle pathway revised: Consider adjuvant chemotherapy and adjuvant olaparib if germline BRCA1/2 mutation, see BINV-M for eligibility criteria.

• Last column, bottom pathway revised: Adjuvant chemotherapy (category 1) and adjuvant olaparib if germline BRCA1/2 mutation, see BINV-M for

eligibility criteria.

BINV-14• Footnote t added: Special Considerations for Breast Cancer in Males (Sex Assigned at Birth) (BINV-J). (Also for BINV-15 and BINV-16)

BINV-16• Footnote removed: High-risk criteria include stage II–III TNBC. The use of adjuvant pembrolizumab (category 2A) may be individualized.

BINV-17• Endocrine therapy

Psychosocial support added: Survivors are at elevated risk for fear of recurrence, distress, anxiety, and depression that may persist for many years

after diagnosis. Periodic screening and referral to mental health professionals if needed are recommended. See NCCN Guidelines for Survivorship.

Updates in Version 1.2025 of the NCCN Guidelines for Breast Cancer from Version 6.2024 include:

NCCN Guidelines Version 5.2025 Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

UPDATES Continued

BINV-18• Workup, Imaging for systemic staging

Bullet 6, sub-bullet revised: FDG-PET/CT (consider FES-PET/CT for ER-positive disease and lobular histology)

• Footnote iii revised: Tumor tissue or plasma-based circulating tumor DNA (ctDNA) assays may be used and each of these have benefits and limitations for diagnosis

and disease progression. Tissue-based assays have greater sensitivity for some alterations, but ctDNA may reflect tumor heterogeneity more accurately. If one

specimen is negative for actionable biomarkers, testing on the alternative specimen can be considered.

• Footnote kkk added: In the setting of oligometastatic breast cancer, the currently available data do not support ablative metastasis-directed RT (ie, stereotactic body

radiation therapy [SBRT]) for extending overall survival (OS) or progression-free survival (PFS). (Also for BINV-21)

BINV-19• Column 3

1st row revised: Repeat BCS or mastectomy + consider surgical axillary staging if no prior ALND + RT after BCS and if indicated after mastectomy

2nd row revised: Total mastectomy + consider surgical axillary staging if no prior ALND + repeat RT if feasible and indicated

3rd row revised: Surgical resection if feasible + consider surgical axillary staging + postmastectomy radiotherapy (PMRT)

4th row revised: Surgical resection if feasible + consider surgical axillary staging if no prior ALND + repeat RT, if feasible and indicated

• Footnote mmm revised: In patients with a local breast recurrence after BCS who had a prior SLNB, a repeat SLNB may be considered although the accuracy of repeat SLNB is unproven. After mastectomy, repeat SLNB may be considered although there are limited data in this setting. In patients who had a prior ALND or mastectomy,repeat SLNB with lymphoscintigraphy may be considered rather than ALND (Poodt IGM, et al. Ann Surg Oncol 2019;26:2417-2427).

BINV-22• Footnote removed: If progression on initial endocrine therapy, switch to a different endocrine therapy option.

BINV-25• Top pathway, column 4 revised: Systemic therapy + ± HER2-targeted therapy until progression

• Footnote cccc revised: Continue HER2-targeted therapy following progression on first-line HER2-targeted chemotherapy for metastatic breast cancer. The optimal

duration of trastuzumab in patients with long-term control of disease is unknown. (Also for BINV-26)

BINV-26• Column 4 revised: Alternate systemic therapy + HER2-targeted therapy until progression

BINV-27• Footnote removed: Targeted Therapies and Associated Biomarker Testing for Recurrent Unresectable (Local or Regional) or Stage IV (M1) Disease BINV-Q (6).

BINV-28• New section: Principles of Survivorship for Those Living with Advanced or Metastatic Breast Cancer

BINV-A (1 of 2)• Footnote d revised: The distinction between HER2 IHC 0 with no membrane staining from IHC 0+ with faint, partial membrane staining in ≤10%, 1+, or 2+/ISH negative results (on primary or metastatic samples) and 1+ is currently clinically relevant in the since patients with metastatic disease setting since with HER2 1+ or 2+/ISH

negative results (on primary or metastatic samples) may be eligible for treatment targeting non-amplified levels of HER2 expression.

BINV-C• New paragraph added: The general considerations for fertility and sexual health/function outlined for specific populations in NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology and NCCN Guidelines for Survivorship are applicable to all patients diagnosed with breast cancer. See NCCN Guidelines for Adolescent and

Young Adult (AYA) Oncology and NCCN Guidelines for Survivorship.

BINV-D• Section significantly revised.

BINV-E• Paragraph 2 revised: In the absence of definitive data demonstrating superior survival, the performance of axillary staging may be considered optional in patients who have particularly favorable tumors, patients for whom the selection of adjuvant systemic and/or RT is unlikely to be affected, those ≥70 years of age, or those with

serious comorbid conditions.

• Footnote a revised: Sentinel node biopsy may be omitted based on the SSO Choosing Wisely recommendation in patients ≥70 years of age with HR+/HER2-negative and pT1, cN0 tumors (Hughes KS, et al. J Clin Oncol 2013;31:2382-2387. Kunkler IH, et al. N Engl J Med 2023:388:585-594).

• Footnote b added: Based on emerging data from the SOUND trial, patients with HR+/HER2-negative tumors, pT1, N0 (node negative by axillary ultrasound), may be

considered for omission of SLN biopsy. Gentilini OD, et al. JAMA Oncol 2023;9:1557-1564.

Updates in Version 1.2025 of the NCCN Guidelines for Breast Cancer from Version 6.2024 include:

NCCN Guidelines Version 5.2025 Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

Continued UPDATES

Updates in Version 1.2025 of the NCCN Guidelines for Breast Cancer from Version 6.2024 include:

BINV-F (1 of 2)• Bullet 1 added: Pathology report should include:

Sub-bullet 3 added: Quantification of the extent of disease that is approximating the inked margin.

BINV-F (2 of 2)• Row 7, column 1 revised: Pure Classic LCIS at surgical margin

BINV-G• Title revised: Contraindications to breast-conserving approaches Special Considerations to Breast-Conservation Therapy Requiring RT

BINV-H (2 of 7)• Footnote g revised: Common donor sites for autologous tissue include the abdomen (ie, DIEP, MS-TRAM, SIEA, free TRAM, pedicled TRAM), gluteal region (ie, SGAP,IGAP), thigh (ie, TUG, VUG, DUG, PAP), or the back (ie, LD, TDAP, LAP).

BINV-H (3 of 7)• Footnote n revised: Addition of latissimus or other regional or free flap to prosthetics in the patient who has previously had irradiation mitigates many of the effects

specified in the previous footnote.

BINV-H (5 of 7)• Bullet 3, first sentence revised: Selection of reconstructive option and timing of reconstruction option is based on an assessment of cancer treatment, body habits of

patients, obesity, smoking history, comorbidities, and patient concerns.

BINV-H (6 of 7)• Last bullet revised: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) and other rare implant-associated malignancies

Sub-bullet 1 added: BIA-ALCL commonly presents with delayed periprosthetic effusion and breast asymmetry occurring >1 year after implantation.

Sub-bullet 2 added: Rarely, BIA-ALCL can present with a mass, regional lymphadenopathy, overlying skin rash, and/or capsular contracture.

Sub-bullet 3 added: Similar symptoms can also be seen in breast implant-associated squamous cell carcinoma (BIA-SCC), another rare implant associated

malignancy. Individuals with breast implants have a very small risk of developing BIA-ALCL (average 7–9 years after implantation) and BIA-SCC (average 22 years

after implantation).

Sub-bullet 4 revised:The majority of cases of BIA-ALCL have been seen in textured implants, while BIA-SCC is associated with either smooth or textured implants.

Rare cases of implant associated diffuse large B-cell lymphomas have also been reported. There exists an association between certain types of textured breast

implants and BIA-ALCL. The risk appears to vary based on the method of texturing. Patients with a past or current history of textured implants should follow up with

their reconstructive surgeon.

BINV-I (1 of 3)• Optimizing Delivery of Individual Therapy, bullet 3 added: In the setting of oligometastatic breast cancer, the currently available data do not support ablative metastasisdirected RT (ie, SBRT) for extending overall survival OS or PFS to provide more durable local control and pain relief.

• Whole Breast Radiation, bullet 2, sub-bullet 2 revised: A boost to the tumor bed is recommended in patients at higher risk for recurrence. Typical boost doses are 10–16 Gy in 4–8 fractions. The boost can be given sequentially after whole breast RT or as a simultaneous integrated boost. Typical boost doses when given sequentially are 10–16 Gy in 4–8 fractions. When given concurrently, the whole breast should receive 40 Gy in 15 fractions and the lumpectomy site should receive 48 Gy in 15

fractions.

• Footnote a added: Vicini FA, Winter K, Freedman GM, et al. NRG RTOG 1005: A phase III trial of hypo fractionated whole breast irradiation with concurrent boost vs.

conventional whole breast irradiation plus sequential boost following lumpectomy for high risk early-stage breast cancer. Int J Radiation Oncol 2022;114;S1.

• Footnote b added: Coles CE, Haviland JS, Kirby AM, et al. Dose-escalated simultaneous integrated boost radiotherapy in early breast cancer (IMPORT HIGH): a

multicentre, phase 3, non-inferiority, open-label, randomised controlled trial. Lancet 2023;401:2124-2137.

NCCN Guidelines Version 5.2025 Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

UPDATES Continued

Updates in Version 1.2025 of the NCCN Guidelines for Breast Cancer from Version 6.2024 include:

BINV-I (2 of 3)• PMRT (including breast reconstruction)

Bullet 1 revised: The target includes the ipsilateral chest wall and the entire clinically relevant mastectomy scar ± drain sites.

Bullet 4, sub-bullet 1 revised: The routine use of bolus is not recommended. Bolus should be considered in the use of used for inflammatory breast cancer or and

considered in clinical-pathologic clinically relevant situations with the dose delivered to the skin is not adequate.

Bullet 4, sub-bullet 2 revised: Chest wall RT dose is may be delivered in conventional dosing of 45–50.4 Gy at 1.8–2 Gy/fx in 25–28 fractions or moderately

hypofractionated dosing of 40 –Gy at 2.67 Gy/fx or 42.5 Gy at 2.66 Gy/fx in 15–16 fractions.

Bullet 4, sub-bullet 3 revised: In patients who are at high risk for local recurrence, a chest wall scar boost of approximately 10 16 Gy/fx delivered in at 1.8 to 2.0 Gy/fx

total 5 4–5 fractions may be delivered with or without bolus using electrons or photons.

Regional Nodal Radiation

Bullet 3, sub-bullet 1 revised: Regional node dose RT doses to the regional nodes of 46-50 Gy (conventional fractionation) or 39-42 Gy (moderately fractionated)

dosing schedules similar to PMRT and whole breast may be considered is 45–50.4 Gy at 1.8–2 Gy/fx.

BINV-I (3 of 3)• Section significantly revised.

BINV-K (1 of 3)• General Principles

Bullet 2 revised: Considering that majority of all HR+ breast cancers are ER+ or ER+/PR+ and ER-negative/PR+ tumors are relatively uncommon, ER and/or

PR+ tumors are referred to as HR+ throughout the guidelines. The majority of hormone sensitive tumors are ER+/PR+ or ER+/PR-negative. Considering that ER

-negative/PR+ tumors are relatively uncommon, in these guidelines, ER and/or PR+ tumors are referred to as HR+.

• Methods for OFS

Sub-bullet 2 revised: Leuprolide 3.75–7.5 mg IM or SC every 4 weeks or 11.25–22.5 mg IM or SC every 12 weeks

Sub-bullet 3 added: Triptorelin: 3.75 mg IM every 4 weeks.

• Initiation of OFS

Bullet 1 revised: Prior to or with start of chemotherapy (neoadjuvant preoperative or adjuvant)

• Duration of OFS

Bullet 1 revised: 5 years of OFS is optimal based on SOFT and TEXT trials. The 8-year DFS was 85.4% with OFS + tamoxifen versus 80.2% with tamoxifen alone.

A minimum 2 years of OFS is encouraged. There are no data on efficacy or safety to support prolonging of OFS > 5 years. 5 years optimal according to SOFT and

TEXT trial. No efficacy or safety date to support prolonged OFS. It is encouraged to complete a minimum 2 years of OFS. The 8-year DFS was 85.4% with OFS +

tamoxifen versus 80.2% with tamoxifen alone.

BINV-L (1 of 2)• Known Benefits of Preoperative Systemic Therapy

Bullets moved to Opportunities:

◊ May allow time for genetic testing

◊ May allow time to plan breast reconstruction in patients electing mastectomy

◊ May allow time for delayed decision-making for definitive surgery

BINV-M• Section significantly revised.

BINV-P (1 of 3)• New page added: General Considerations

BINV-P (2 of 3)• Other Recommended Regimens for first and/or subsequent lines of therapy

Bullet 1 revised: For HER2-negative disease and ESR1 mutated tumors and after progression on one or two prior lines of endocrine therapy, including one line

containing a CDK4/6 inhibitor, see BINV-Q (6)

NCCN Guidelines Version 5.2025 Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

UPDATES

Updates in Version 1.2025 of the NCCN Guidelines for Breast Cancer from Version 6.2024 include:

Continued

BINV-P (3 of 3)• Row 1, sentence added: If treatment was initiated with chemotherapy and trastuzumab + pertuzumab, and the chemotherapy was stopped, endocrine therapy may be added to

trastuzumab + pertuzumab.

• Abemaciclib in combination with fulvestrant and trastuzumab was added as a category 2B recommendation.

• Footnote m added: See BINV-Q (1) for Considerations for those receiving systemic HER2-targeted therapy.

• Footnote removed: An FDA-approved biosimilar is an appropriate substitute for trastuzumab. Trastuzumab and hyaluronidase-oysk injection for subcutaneous use may be substituted

for trastuzumab. It has different dosage and administration instructions compared to intravenous trastuzumab. Do not substitute trastuzumab and hyaluronidase-oysk for or with adotrastuzumab emtansine or fam-trastuzumab deruxtecan-nxki.

BINV-Q (1 of 15)• General considerations, bullets added:

An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.

Screen for and manage immunotherapy-related toxicities and endocrine dysfunctions (eg, hypothyroidism, adrenal insufficiency) in patients treated with immune checkpoint inhibitors.

See NCCN Guidelines for Management of Immunotherapy-Related Toxicities.

Regular cardiac monitoring for patients with current or prior use of anthracyclines or HER2-targeted therapy. See NCCN Guidelines for Survivorship: Cardiovascular Disease Risk

Assessment.

Consider scalp cooling to reduce incidence of chemotherapy-induced alopecia for patients receiving chemotherapy. Results may be less effective with anthracycline.

BINV-Q (2 of 15)• First Line

Subtype/Biomarker column revised: No germline BRCA1/2 mutation and/or IHC HER2 0+, 1+, or 2+/ISH negative

Regimen column revised: Systemic chemotherapy (category 1, preferred) BINV-Q (5), or fam-trastuzumab deruxtecan-nxki (other recommended regimen)

• Second Line

For HER2 IHC 0, 1+, or 2+/ISH negative: Datopotamab deruxtecan-dlnk was added as a category 2A other recommended regimen.

Subtype/Biomarker column revised: HER2 IHC 0+, 1+, or 2+/ISH negative (Also for BINV-Q 3)

• Footnote d revised: Principles of HER2 Testing (BINV-A). The distinction between HER2 test results of IHC 0 with no membrane staining, IHC 0+ with faint, partial membrane staining in≤10%, IHC 1+, or 2+/ISH negative is currently clinically relevant for therapy selection. (Also for BINV-Q 3)

• Footnote e added: Systemic chemotherapy (eg, oral chemotherapy) is generally preferred in the first-line setting. Selection of systemic therapy versus fam-trastuzumab-nxki for first-line therapy should be individualized based on clinical features and patient preference.

• Footnote f revised: Fam-trastuzumab deruxtecan-nxki may be considered used for in a later line for HER2 IHC 0+ 1+ or 2+/ISH negative, previously treated with at least one line of

endocrine-based therapy in the metastatic setting. if not used in second–line. Fam-trastuzumab deruxtecan-nxki is associated with interstitial lung disease (ILD)/pneumonitis. Regular

monitoring for this serious side effect is recommended. For patients with a history of ILD/pneumonitis, there are no data on managing safety or toxicity of this drug in a trial.

• Footnote h added: Datopotamab deruxtecan-dlnk did not meet the OS endpoint in the TROPION-Breast01 trial. Whereas the previously approved antibody drug conjugates (ADC), famtrastuzumab deruxtecan-nxki and sacituzumab govitecan have shown a benefit in OS in randomized phase III trials. The benefit of using datopotamab deruxtecan-dlnk in patients with

prior ADC treatment are not known as the TROPION-Breast01 trial did not include patients with prior ADC treatment.

BINV-Q (3 of 15)• Footnote j revised: Sacituzumab govitecan-hziy may be used in patients who have received at least 1 prior regimen in the metastatic setting. it may be considered for later line if not used as second line therapy.

• Footnote k added: Fam-trastuzumab deruxtecan may be considered in a later line for HER2 IHC 0+, 1+ or 2+/ISH negative, if not used in second line or may be considered first line

therapy when disease has progressed during or within 6 months after completing adjuvant chemotherapy. Fam-trastuzumab deruxtecan-nxki is associated with interstitial lung disease

(ILD)/pneumonitis. Regular monitoring for this serious side effect is recommended. For patients with a history of ILD/pneumonitis, there are no data on managing safety or toxicity of this drug in a trial.

BINV-Q (4 of 15)

• Abemaciclib in combination with fulvestrant and trastuzumab (for HR+ only) was added as a category 2B recommendation.

BINV-Q (5 of 15)• Footnote removed and added to table: Sequential single agents are preferred, but chemotherapy combinations may be used in select patients with high tumor burden, rapidly progressing disease, and visceral crisis.

• Footnote removed: Alternative taxanes (ie, docetaxel, paclitaxel, albumin-bound paclitaxel) may be substituted for select patients due to medical necessity (ie, hypersensitivity reaction). If substituted for weekly paclitaxel or docetaxel, then the weekly dose of albumin-bound paclitaxel should not exceed 125 mg/m2.

• Footnote removed: Consider scalp cooling to reduce incidence of chemotherapy-induced alopecia for patients receiving chemotherapy. Results may be less effective with anthracycline containing regimens.

• Footnote removed: Consider cryotherapy of hands and feet to decrease the risk of peripheral neuropathy when receiving taxane therapies.

BINV-Q (6 of 15)

BINV-Q (8 of 15)

Abstract

• Targeted Therapies and Associated Biomarker Testing for Recurrent Unresectable (Local or Regional) or Stage IV (M1) Disease Detection column significantly revised (Also for BINV-Q 7 and 8) Last row, NCCN Category of Preference column revised: Other recommended regimen subsequent-line therapy • Footnote t added: Some plasma-based ctDNA assays include a measure of tumor fraction (TF), which can aid in identification of low ctDNA content. Samples with low TF, especially < 1%, should be interpreted with caution. Tests have varying sensitivities at low TF. Additional sampling from current tumor sample or future plasma can be considered. (Also for BINV-Q 7 and 8) • Footnote x revised: For postmenopausal or premenopausal patients receiving ovarian ablation or suppression or adult males with ER-positive, HER2-negative, ESR1-mutated disease after progression on one or two prior lines of endocrine therapy, including one line containing a CDK4/6 inhibitor. Assess for ESR1 mutations at progression following prior lines of endocrine therapy (ctDNA preferred). BINV-Q (7 of 15) • Germline PALB2 row moved from subsequent page.

Abstract

• Footnote y added: This regimen is not FDA approved for this indication. Tung NM, Robson ME, Ventz S, et al. TBCRC 048: phase II study of olaparib for metastatic breast cancer and mutations in homologous recombination-related genes. J Clin Oncol 2020;38:4274-4282. • Footnote dd added: Tissue biopsy is more sensitive than ctDNA (liquid biopsy) at detecting homozygous copy loss of PTEN or TMB-H. (Also for BINV-Q 7) • Footnote removed: NCCN Guidelines for Management of Immunotherapy-Related Toxicities.

Abstract

• Row 1 column 4 revised: Neratinib + ± trastuzumab/ fulvestrant was added as a category 2A, useful in certain circumstances recommendation.

Abstract

• Row 3 added: Erdafitinib was added as a category 2B, useful in certain circumstances recommendation.

Abstract

• Footnote hh revised: Jhaveri KL, Goldman JW, Hurvitz SA, et al. Neratinib plus fulvestrant plus trastuzumab (N+F+T) for hormone receptor-positive (HR+), HER2-negative, HER2-mutant metastatic breast cancer (MBC): Outcomes and biomarker analysis from the SUMMIT trial.

References

National Comprehensive Cancer Network®

NCCN Guidelines Version 5.2025 Ductal Carcinoma In Situ (DCIS)

NCCN Guidelines Index Table of Contents Discussion

![DIAGNOSIS WORKUP\nPRIMARY TREATMENT\nWhole breast RT(category 1) with or without boost to tumor bedj,k,l,m or accelerated partial breast irradiation/partial breast radiation(APBI/PBI)j,k,l or No RTj,k,m(category 2B)\nDCIS Tis,N0,M0, Encapsulated or solid papillary carcinoma (SPC)a\n● Diagnostic bilateral mammogram\n● Pathology reviewb\n● Determination of tumor estrogen receptor (ER) status\n● Determination of tumor estrogen receptor (ER) status\n● Genetic counseling for patients at riskc of hereditary breast cancer\n● Breast MRId,e as indicated\nTotal mastectomy with sentinel lymph node biopsy\nSpectralal treatment(DCIS-2)\nor irradiation/partial breast radiation(APBI/PBI)j,k,l or No RTj,k,m(category 2B)\nPostsurgical treatment(DCIS-2) Treatment(DCIS)2)\n](2/aj0YEe4oUhYkBdfpda0fYP/figure2cee26ee2ca54595a88483e7bfec2e25_0_4.png) a Encapsulated papillary carcinoma (EPC) without associated conventional invasion is staged as pTis because behavior is similar to DCIS (per AJCC). SPC should be specified as in situ or invasive based on WHO criteria but both forms have favorable outcomes.

bThe Panel endorses the College of American Pathologists Protocol for pathology reporting for all invasive and noninvasive carcinomas of the breast. http://www.cap.org.

c For risk criteria, see NCCN Guidelines for Genetic/Familial High-Risk Assessment:Breast,Ovarian, Pancreatic, and Prostate.

d Principles of Dedicated Breast MRI Testing(BINV-B).

e The use of MRI has not been shown to increase likelihood of negative margins or decrease conversion to mastectomy. Data to support improved long-term outcomes are lacking.

f Re-resection(s) may be performed in an effort to obtain negative margins in patients desiring breast-conservation therapy. Patients in whom adequate surgical margins cannot be achieved with BCS should undergo a total mastectomy. For definition of adequate surgical margins, see Margin Status Recommendations After BCS for Invasive Cancers and DCIS(BINV-F).

9 Surgical axillary staging should not be performed for preoperative (biopsy-determined)pure DCIS unless there is some clinical-pathologic suggestion of invasion or axillary metastasis.

h A SLNB may be considered in the setting of 1) mastectomy for DCIS,2)excision in an anatomic location compromising the performance of a future SLNB procedure 3) oncoplastic breast conserving surgery(see BINV-D for appropriate candidates for SLNB).

iPrinciples of Breast Reconstruction Following Surgery(BINV-H).

${}^{i}$ Invasive disease at total mastectomy or re-excision should be managed as clinical stage I or stage II disease (BINV-1).

k Principles of Radiation Therapy(BINV-I).

l Contraindications to Breast-Conserving Approaches Requiring RT(BINV-G).

m Whole breast RT following BCS reduces ipsilateral breast tumor recurrence rates in DCIS by 50%-70%. Approximately half of the recurrences are invasive and half are DCIS. The risk of local relapse increases with larger DCIS, palpable mass, grade III disease, margins ≤2 mm,ER-negative tumors, and age<50. Select patients with "low" risk DCIS may be considered suitable for omission of RT (endocrine therapy alone, if all RTOG 9804 criteria are met: screen-detected, grade 1-2, size≤2.5 cm, margins ≥3 mm).

Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines Version 5.2025 Ductal Carcinoma In Situ (DCIS)

NCCN Guidelines Index Table of Contents Discussion

DCIS POSTSURGICAL TREATMENT

SURVEILLANCE/FOLLOW-UP

Risk reduction therapy for ipsilateral breast following BCS:

●Consider endocrine therapy for 5 years for patients with ER-positive DCIS, if:

▶Treated with BCS and RTn (category 1)

▶Treated with excision aloneo

•Endocrine therapyP:

● Tamoxifen ${}^{n,q}$ for premenopausal patients

●Tamoxifen ${ }^{n,q}$ or aromatase inhibitor for postmenopausal patients with some advantage for aromatase inhibitor therapy in patients<60 years or with concerns for thromboembolism

Risk reduction therapy for contralateral breast:

●Counseling regarding risk reduction

•Interval history and physical exam every 6-12 mo for 5 y,then annually

●First mammogram 6-12 mo, after end of RT, if given, or after BCS(category 2B) if no RT is given and annually thereafter

nCYP2D6 genotype testing is not recommended for patients considering tamoxifen.

Available data suggest endocrine therapy provides risk reduction in the ipsilateral breast treated with breast conservation and in the contralateral breast in patients with mastectomy or breast conservation with ER-positive primary tumors. Since a survival advantage has not been demonstrated, individual consideration of risks and benefits is important.

P The use of a bisphosphonate (PO/IV) or denosumab is acceptable to maintain or improve bone mineral density and reduce risk of fractures in postmenopausal (natural or induced) patients receiving adjuvant aromatase inhibitor therapy. Optimal duration of either therapy has not been established. Benefits from duration beyond 3 years or optimal duration beyond 3 years is not known. Factors to consider for duration of anti-osteoporosis therapy include bone mineral density, response to therapy, and risk factors for continued bone loss or fracture. There are case reports of spontaneous fractures after denosumab discontinuation. Patients treated with a bisphosphonate or denosumab should undergo a dental examination with preventive dentistry prior to the initiation of therapy, and should take supplemental calcium and vitamin D.

9Low-dose tamoxifen (5 mg per day or 10 mg every other day for 3-5 years) is an option if patient is symptomatic on the 20-mg dose or if patient is unwilling or unable to take standard-dose 20 mg per day tamoxifen [10 mg every other day since 5-mg dose is not available in the United States]. This low dosage needs further investigation in premenopausal individuals (DeCensi A, et al. J Clin Oncol 2019;37:1629-1637).

Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

![DIAGNOSIS (CLINICAL)\nWORKUPa\nCLINICAL STAGE\n● History and physical exam\n● Diagnostic bilateral mammogram Ultrasound as necessary Breast MRlb (optional), with special consideration for mammographically occult tumors\n● Estrogen/progesterone receptor (ER/PR) status and HER2 status dTM) ● Genetic counseling and testing if patient is at riské for hereditary breast cancer, has triple-negative breast cancer (TNBC) (at any age), or is a candidate for adjuvant olaparib ● Address fertility and sexual health concerns as appropriate! ● Pregnancy test in all patients of childbearing potential (lf pregnant), see PREG-1) ● Assess for distress9 ● Consider additional imaging studies only in the presence of signs and symptoms of metastatic disease and for patients who are clinically high risk (BINV-18) h ● Consider baseline lymphedema screening, as per NCCN Guidelines for Survivorship\nINflammatory breast cancer (IBC) ● Estrogen/progesterone receptor (ER/PR) status and HER2 status dTM) ● Genetic counseling and testing if patient is at riské for hereditary breast cancer, has triple-negative breast cancer (TNBC) (at any age), or is a candidate for adjuvant olaparib ● Address fertility and sexual health concerns as appropriate! ● Pregnancy test in all patients of childbearing potential (lf pregnant), see PREG-1) ● Assess for distress9 ● Consider additional imaging studies only in the presence of signs and symptoms of metastatic disease and for patients who are clinically high risk (BINV-18) h ● Consider baseline lymphedema screening, as per NCCN Guidelines for Survivorship\nINflammatory breast cancer (IBC) ● Estrogen/progesterone receptor (ER/PR) status and HER2 status dTM) ● Genetic counseling and testing if patient is at riské for hereditary breast cancer, has triple- and/or internal mammary nodal disease. See Principles of Dedicated Breast MRI Testing (BINV-B) and NCCN. # Guidelines for Breast Cancer Screening and Diagnosis. # The panel endorses the College of American Pathologists The panel endorses the College of American Pathologists for pathology reporting for all invasive and noninvasive carcinomas of the breast. http://www.cap.org. # Principles of Biomarker Testing (BINV-A). # The panel endoers the College of American Pathologists for disease and disease is suspected, see Workup on BINV-18. # Principles of Biomarker Testing (BINV-A). # The panel endoers the College of American Pathologists for disease and disease is suspected, see Workup on BINV-18.\n](2/aj0YEe4oUhYkBdfpda0fYP/figure55a1c4aa1bca41019b891b0ed239df19_0_4.png) Inflammatory breast cancer (IBC)Workup for IBC (IBC-1)Metastatic (M1) invasive breast cancer - Stage IV (M1) or $\rightarrow$ Workup for Recurrent or Recurrent disease Stage IV (M1) Disease (BINV-18)

a For tools to aid optimal assessment and management of older adults, see NCCN Guidelines for Older Adult Oncology.

b Breast MRI may be useful for characterizing axillary and/or internal mammary nodal disease. See Principles of Dedicated Breast MRI Testing(BINV-B) and NCCN Guidelines for Breast Cancer Screening and Diagnosis.

c The panel endorses the College of American Pathologists Protocol for pathology reporting for all invasive and noninvasive carcinomas of the breast. http://www.cap.org.}^#Principles of Biomarker Testing(BINV-A).

e For risk criteria, see NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast,Ovarian, Pancreatic, and Prostate.F For Fertility and Birth Control, see BINV-C. The general considerations for fertility and sexual health/function outlined for specific populations in NCCN Guidelines for Adolescent and Young Adult(AYA) Oncology and NCCN Guidelines for Survivorship are applicable to all patients diagnosed with breast cancer.

g NCCN Guidelines for Distress Management.

h Routine systemic staging is not indicated for non-metastatic(M0) cancer in the absence of systemic symptoms. If metastatic disease is suspected, see Workup on BINV-18.

i Patients with a known genetic predisposition to breast cancer may have an increased risk of contralateral or ipsilateral breast cancers for breast-conservation therapy. Risk reduction strategies including prophylactic mastectomies should be discussed.See NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast,Ovarian, Pancreatic, and Prostate.

NCCN Guidelines Index

Table of Contents Discussion

National Comprehensive Cancer Network®

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

LOCOREGIONAL TREATMENT OF cT1-3, cN0 or cN+, M0 DISEASEa: BREAST-CONSERVING SURGERY(BCS)+ WHOLE BREAST RT

![SURGERY ADJUVANT SYSTEMIC THERAPY\nNODAL STATUS\nRT\nnodal irradiation(RNI) in patients with central/medial tumors, pT3 tumors, or pT2 tumors and one of the following high-risk features: grade 3, extensive lymphovascular invasion (LVI), or hormone-receptor (HR)-negative.1\nor Consider APBI/PBI in selected patients who are low risk (category 1)s,u\nConsider omitting breast irradiation if adjuvant endocrine therapy is planned and following criteria are met (category 1):1)≥70 y, HR+, HER2-negative, cN0, pT1 (≤2cm)0,t\nASCTAN 2)≥65 y, HR+, HER2-negative, pN0, pT≤3 cm\nBCSi,j±surgical systemic RT is typically given after systemic therapy. See BINV-I for sequencing of systemic and systemic therapy and RT.\nSee BINV-4 to determine whether adjuvant systemic study. 2)≥65 y, HR+, HER2-negative, cN0, PNT1 (≤2cm)0,t\nASCTAN 3)≥1.4°.4°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5\n](2/aj0YEe4oUhYkBdfpda0fYP/figuree86bb0def41e4a299fcc92a72d69144c_0_6.png) aFor tools to aid optimal assessment and management of older adults, see NCCN Guidelines for Older Adult Oncology.

Patients with a known genetic predisposition to breast cancer may have an increased risk of contralateral or ipsilateral breast cancers after breast-conservation therapy. Risk reduction strategies including prophylactic mastectomy should be discussed. See NCCN Guidelines for Genetic/Familial High-Risk Assessment:Breast,Ovarian, Pancreatic, and Prostate.

For patients>40 years of age with 2 biopsy proven cTis-cT2 lesions(with at least one invasive site) after MRI evaluation, intending on adjuvant whole breast radiation+ boost, breast-conservation therapy may be considered (Boughly JC, et al. J Clin Oncol 2023;41:3184-3193). See BIN-V.

k Considerations for Surgical Axillary Staging (BINV-D).

l See Axillary Lymph Node Staging (BIN-VE) and Margin Status Recommendations After BCS for Invasive Cancers and DCIS (BIN-VF).

m Containdications to Breast-Conserving Approaches Requiring RT(BINV-G).

n Includes techniques such as local tissue rearrangement, local flaps, regional flaps, breast reduction, and mastopexy to allow for greater volumes of resection while optimizing aesthetic outcomes in patients undergoing BCS.

Sentinel node biopsy may be omitted based on the SSO Choosing Wisely recommendation in patients≥70 years of age with HR+/HER2-negative and pT1, cN0 tumors(Hughes KS,et al.J Clin Oncol 2013;31:2382-2387. Kunkler IH,et al.N Engl J Med 2023:388:585-594).

P Determined by surgery, clinical findings, or radiographic imaging.

S based on emerging data from the SOUND trial, patients with HR+/HER2-negative tumors, pT1, N0 (node negative by axillary ultrasound), may be considered for omission of SLN biopsy.Gentilini OD, et al. JAMA Oncol 2023;9:1557-1564.

rCisider imaging for systemic staging, including chest/abdomen± pelvis diagnostic CT with contrast, boneat scan, and optional FDG-PET/CT.

s Principles of Radiation Therapy(BINV-I).

For definition of HR-positive, see Principles of Endocrine Therapy(BINV-K).

u APBI/PBI may be administered prior to chemotherapy.

National Comprehensive Cancer Network®

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

LOCOREGIONAL TREATMENT OF cT1-3, cN0 or cN+, M0 DISEASEa, Y: MASTECTOMY $\pm$ PMRT

![SURGERY ADJUVANT SYSTEMIC THERAPY\nPATHOLOGIC NODAL STATUS\nRT\n0\nNegative axillary nodes and pSt2 (≤5 cm) and margins≥1 mm\nNegative axillary nodes and sT2 (≤5 cm) and negative margins but <1 mm\nNipple.sparing, try the asymptotic therapy is indicated.\nRT\nRT\nRT is\ngiven after systemic therapy. See BINV-I for sequencing therapy and RT.\nNegative axillary nodes and sT2 (≤5 cm and negative margins but <1 mm\nNegative axillary nodes and pSt3 (≤5 cm) and negative margins but <1 mm\nNipple.sparing, try the asymptottic activity for other systemic study. See BINV-I for sequencing therapy and RT.\nNegative axillary nodes\nRight DODAR\nNegative axillary nodes\nNipple.sparing, try the asymptottic and reconstruction\n1-3 positive axillary nodes\nStrongly consider PMRT$ to chest wall + comprehensive RNI(including any portion of the undissected axilla at risk).\nMargins\nRe-excision to negative margins is preferred. If not feasible, then strongly consider PMRT$ to chest wall ± comprehensive RNI(including any portion of the undissected axilla at risk).\n](2/aj0YEe4oUhYkBdfpda0fYP/figure4ff3efd3472e4ac08bdd44b53eafcffa_0_5.png) aFor tools to aid optimal assessment and management of older adults, see NCCN Guidelines for Older Adult Oncology.

k Considerations for Surgical Axillary Staging(BINV-D).

l See Axillary Lymph Node Staging(BINV-E) and Margin Status Recommendations After BCS for Invasive Cancers and DCIS(BINV-F).

Consider imaging for systemic staging, including chest/abdomen± pelvis diagnostic CT with contrast, bone scan, and optional FDG-PET/CT.

s Principles of Radiation Therapy(BINV-I).

vSpecial Considerations for Breast Cancer in Males(Sex Assigned at Birth)(BINV-J).vPrinciples of Breast Reconstruction Following Surgery(BINV-H).

xIn the case of a micrometastasis(>0.2 to ≤2.0 mm), and no axillary dissection, evaluate other patient risk factors when considering RT.

y Postmastectomy RT may be considered for patients with multiple high-risk recurrence factors, including central/medial tumors or tumors≥2 cm and at least one of the following: grade 3, ER-negative, or LVI.

National Comprehensive Cancer Network®

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

ADJUVANT SYSTEMIC THERAPY CONSIDERATIONS BASED ON HISTOLOGY AND RECEPTOR STATUS AFTER UPFRONT SURGERY

![HISTOLOGY\nHR STATUS\nHR STATUS\nHER2 STATUS\nBINV-5\nER2-positivecc dd\nand/or\nPR-positivecc,dd\nHER2-negativecc\nINV-5\nPostmenopausalee\nPIT1-3 AND pN0\nor pN+\nBINV-6\nPrenmenopausalee\nPPT1-3 AND pN0\nBINV-7\nP1-3 AND pN0\nPT1-3 AND pN+\nBINV-8\nPINV-8\nER-negative\nand\nPR-negativecc,dd\nER2-negativecc\nINV-10\nFavorable histologic typebb:\nPure tubular\n●Pure mucinous\nIP, pure cribiformr\n● Adenoid cystic\n● Conventional),secretory\n● Resilaryive\n● Adilary carcinoma\n● Ares low-grade forms of salivary carcinomas\n● Other rare forms\nCC\nER -rate of dly\n● Adil. For the same time and time of the group of health is considered in the context of human cancer,discretation of theoretical results.\nBINV-8\nPIT1-3 AND pN0\nPrenmenopausalee\nPPT1-3 AND pN0\nBINV-8\nPER-negative dek\nINV-9\nHER2-positivecc\nBINV-9\nHER2-negativecc\nBIN-10\nFavorable histologic typebb:\nPure tubular\n● Pure mucinous\nER-positivedd and/or PR-positivedd\nor\nER-negative and PR-negative\nFavorable Histologies\n(BINV-11)\nER-positive and PR-negative\nOR\nPIT1-3 AND pN0\nBINV-7\nPPT1-3 AND pN+\nBINV-8\nSERovicand\nHER2-negative\nBINV-8\nCA Correlation of histology, HR, and HER2 status should always be done with awareness of unusual/discordant or borderline results. See Principles of Biomarker Testing (BINV-A).\n](2/aj0YEe4oUhYkBdfpda0fYP/figuredf22f58fa8d444c2870ffa58709b1f35_0_5.png) ●Rare low-grade forms of metaplastic carcinomas

● Other rare forms

${}^{cc}$ Correlation of histology, HR, and HER2 status should always be done with awareness of unusual/discordant or borderline results. See Principles of Biomarker Testing (BINV-A).

${}^{2}$ According to WHO, carcinoma of no special type (NST) encompasses multiple patterns including medullary pattern, cancers with neuroendocrine expression, and other rare patterns.

<BeginOfPara> dd Although patients with cancers with 1%-100% ER immunohistochemistry (IHC)staining are considered ER-positive and eligible for endocrine therapies, there are more limited data on the subgroup of cancers with ER-low-positive(1%-10%)results. The ER-low-positive group is heterogeneous with reported biologic behavior often similar to ER-negative cancers; thus, individualized consideration of risks versus benefits of endocrine therapy and additional adjuvant therapies should be incorporated into decision-making. See Principles of Biomarker Testing(BINV-A).

aa There are rare subtypes of metaplastic carcinoma(low-grade adenosquamous and low-grade fibromatosis-like carcinoma) that are considered to have a favorable prognosis without adjuvant systemic therapies.

bb To be associated with favorable prognosis, the favorable histologic type should not be high grade, should be pure(>90% as classified on the surgical excision, not core biopsy alone), and should be HER2 negative. If atypical pathologic or clinical features are present, consider treating as ductal/NST.

ee Definition of Menopause(BINV-O).

National Comprehensive Cancer Network®

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

SYSTEMIC ADJUVANT TREATMENT: HR-POSITIVE-HER2-POSITIVE DISEASE$^{\text{d,v,dd}}$

![\nDisERASE\nc\npN0\nr\nn\npT1a(≤0.5cm)\npN1mi\npN1i\ni\npN2-0\npT2-0\nn\npT3-0\nn\npT1b(0.6-1.0 cm)\ni\npN1mi\ni\npT1c(pT3(>1 cm)\nO\npN0\nr\nn\npN+ (≥1 ipsilateral metastases\n>2 mm)\npN+（≥1 ipsilateral metastases\n\n\nn\npN+（≥1 ipsilateral metastases\n\nn\npN+（≥1 200000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000\n](2/aj0YEe4oUhYkBdfpda0fYP/figure1b007d4a27a24ccda1a0ab131f7b4c96_0_5.png) a For tools to aid optimal assessment and management of older adults, see NCCN. Guidelines for Older Adult Oncology.

d Principles of Biomarker Testing (BINV-A).

vSpecial Considerations for Breast Cancer in Males (Sex Assigned at Birth) (BINV-J).

${ }^{2}$ According to WHO, carcinoma of NST encompasses multiple patterns including medullary pattern, cancers with neuroendocrine expression, and other rare patterns.

dd Although patients with cancers with 1%-100% ER IHC staining are considered ER-positive and eligible for endocrine therapies, there are more limited data on the subgroup of cancers with ER-low-positive(1%-10%) results. The ER-low-positive group is heterogeneous with reported biologic behavior often similar to ER-negative cancers; thus, individualized consideration of risks versus benefits of endocrine therapy and additional adjuvant therapies should be incorporated into decision-making. See Principles of Biomarker Testing (BINV-A).

ff Adjuvant Endocrine± CDK/4/6 Inhibitor Therapy and Principles of Adjuvant Endocrine Therapy (BINV-K).

99 Preoperative/Adjuvant Therapy Regimens(BINV-M).

hh The benefit of HER2-targeted therapy is uncertain in HER2-positive breast cancer with pT1a-b, N0 tumors, a population not studied in randomized trials. The decision for use of trastuzumab therapy in this cohort must balance with the known toxicities.

${}^{ii}$ The absolute benefit of HER2-targeted systemic therapy is negligible in patients with HR-positive cancers and tumor size bordering on T1mic(<1 mm), and endocrine therapy remains a viable option for systemic treatment.

ji Consider adjuvant bisphosphonate therapy for risk reduction of distant metastasis for 3-5 years in postmenopausal patients (natural or induced) with high-risk node-negative or node-positive tumors.

kk Consider extended adjuvant neratinib following adjuvant trastuzumab-containing therapy for patients with HR-positive, HER2-positive disease with a perceived high risk of recurrence. The benefit or toxicities associated with extended neratinib in patients who have received pertuzumab or ado-trastuzumab emtansine is unknown.

ll Updated results from the adjuvant APHINITY trial in HER2-positive early breast cancer, with a median follow-up of 8.4 years, have confirmed the benefit of adding pertuzumab to trastuzumab plus chemotherapy in preventing recurrences.

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SYSTEMIC ADJUVANT TREATMENT: HR-POSITIVE-HER2-NEGATIVE DISEASEd,v,dd POSTMENOPAUSALee PATIENTS with pT1-3 AND pN0 or pN+ TUMORS

![\nDuctal/NST$^{2}$\n·Mixed\npT1a(≤0.5 cm)\n|Dual\n·Mixed\n·Micropapillary\npN0\npT1-3 t(>0.5 cm)\nor\npN1 mi(≤2 mm axillary node metastases)\npN1(1-3 positive nodes)\npT1b-T3 (>0.5 cm)\nor\npN1 mi(≤2 mm axillary node metastases)\nDetermine if candidate for chemotherapy\nNot a candidate for chemotherapy\nNot done\n|Adjuvant endocrine therapy.f,jj\nConsider adjuvant abemaciclib or riboclicib for eligible patients.\nSee BINV-K 2 of 3 for eligibility criteria\nAdjuvant whole chemotherapy\nNot done\nAdjuvant endocrine therapy.f,gg followed by endocrine therapy.f,category\n1). Consider adjuvant abemaciclib or riboclicib for eligible patients.\nRecurrence\n1).Consider adjuvant endroduct therapy.f,ij\nScore\n26\nAsult. In the following case\nAdjuvant chemotherapy.f,99\nBINV-K 2 of 3 for EMBIV-N.\nAdjuvant endocrine therapy,f,ij\n1).Consider adjuvant abemaciclib or riboclicib for eligible patients.\nAdjuvant whole therapy.f,ij\n1).Consider adjuvant exedocrine therapy.\nRespeciclet\nSee BINV-K 2 of 3 for EMBIV-N\nAdjuvant whole therapy.f,ii\n1.1\nAschiciblic for eligible patients.\nRecurrence\n1).Consider adjuvant abemaciclib or riboclicib for eligible patients.\nSee BINV-K 2 of 3 for eligibility criteria\nAdjuvant echoine therapy.f,ij\nAdjuvant whole chemotherapy.f,as\n·V8n1-2\nAdjuvant endroduct Oncology.\nPPr準policif\nAdjuvant endocrine\n](2/aj0YEe4oUhYkBdfpda0fYP/figure975f7b5fd5694a7b80d73cb72f6bbc62_0_5.png) a For tools to aid optimal assessment and management of older adults, see NCCN Guidelines for Older Adult Oncology.

d Principles of Biomarker Testing(BINV-A).

v Special Considerations for Breast Cancer in Males (Sex Assigned at Birth)(BINV-J).

${}^{2}$ According to WHO, carcinoma of NST encompasses multiple patterns including medullary pattern, cancers with neuroendocrine expression, and other rare patterns.

dd Although patients with cancers with 1%-100% ER IHC staining are considered ER-positive and eligible for endocrine therapies, there are more limited data on the subgroup of cancers with ER-low-positive(1%-10%) results. The ER-low-positive group is heterogeneous with reported biologic behavior often similar to ER-negative cancers; thus individualized consideration of risks versus benefits of endocrine therapy and additional adjuvant therapies should be incorporated into decision-making. See Principles of Biomarker Testing(BINV-A).

ee Definition of Menopause(BINV-O).

f Adjuvant Endocrine± CDK/4/6 Inhibitor Therapy and Principles of Adjuvant Endocrine Therapy(BINV-K).

gg Preoperative/Adjuvant Therapy Regimens(BINV-M).

ji Consider adjuvant bisphosphonate therapy for risk reduction of distant metastasis for 3-5 years in postmenopausal patients(natural or induced) with high-risk node-negative or node-positive tumors.

mm There are few data regarding the role of gene expression assays in those with 24 ipsilateral axillary lymph nodes. Decisions to administer adjuvant chemotherapy for this group should be based on clinical factors.

nn Other prognostic gene expression assays may be considered to help assess risk of recurrence but have not been validated to predict response to chemotherapy. See Gene Expression Assays for Consideration of Adjuvant Systemic Therapy (BINV-N).

Note: All recommendations are category 2A unless otherwise indicated.

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SYSTEMIC ADJUVANT TREATMENT: HR-POSITIVE-HER2-NEGATIVE DISEASEd,vdd PREMENOPAUSALee PATIENTS with pT1-3 AND pN0 TUMORS

![pT1a (≤0.5 cm) and pN0\nDuctal/NSTZ\n·Ductal/NSTZ\n·Mided\n·Micropapillary\nDetermine if candidate for chemotherapy\n·Ductal/NSTZ\n·Mixed\n·Micropapillary\nDetermine if candidate for chemotherapy\n·Determine if candidate for chemotherapy\n·Mancend for chemotherapy\n·Not a candidate for chemotherapy\n·Ductal/NSTZ\n·Mancend for chemotherapy\n·Mancend\n·Mancend\n·Mancend\n·Mancend\n·Mancend\n·Mancend\n·Mancend\n·Mancend\n·Mancend\n·Mancend\n·Mancend\n·Mancend\n·Mancend\n·Mancend\n·Mancend\n·Mancend\n](2/aj0YEe4oUhYkBdfpda0fYP/figure8d10ca6c14b749ca931e1f0cc48fa4eb_0_5.png) d Principles of Biomarker Testing(BINV-A).

v Special Considerations for Breast Cancer in Males(Sex Assigned at Birth)(BINV-J).

z According to WHO, carcinoma of NST encompasses multiple patterns including medullary pattern, cancers with neuroendocrine expression, and other rare patterns.

dd Although patients with cancers with 1%-100% ER IHC staining are considered ER-positive and eligible for endocrine therapies, there are more limited data on the subgroup of cancers with ER-low-positive(1%-10%) results. The ER-low-positive group is heterogeneous with reported biologic behavior often similar to ER-negative cancers; thus individualized consideration of risks versus benefits of endocrine therapy and additional adjuvant therapies of either incorporated into decision-making. See Principles of Biomarker Testing(BINV-A).

Adjuvant Endocrine+CDK/4/6 Inhibitor Therapy and Principles of Adjuvant Endocrine Therapy(BINV-K).

gg Preoperative/Adjuvant Therapy Regimens(BINV-M).

ij Consider adjuvant bisphosphonate therapy for risk reduction of distant metastasis for 3-5 years in postmenopausal patients(natural or induced) with high-risk node-negative or node-positive tumors.

$\dots$ Of patients with T1b tumors with low-grade histology and no LVI should be treated with endocrine monotherapy as the TAILORx trial did not include patients with such tumors.PP In premenopausal patients with recurrence score<26, the addition of chemotherapy to endocrine therapy was associated with a lower rate of distant recurrence compared with endocrine monotherapy, but it is unclear if the benefit was due to the ovarian suppression effects promoted by chemotherapy.

Note: All recommendations are category 2A unless otherwise indicated.

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SYSTEMIC ADJUVANT TREATMENT: HR-POSITIVE - HER2-NEGATIVE DISEASE ${}^{d}$,v,dd PREMENOPAUSAL${}^{ee}$ PATIENTS with pT1-3 AND pN+ TUMORS

![\nDetermine if candidate for chemotherapy\nP1N1 mi (≤2 mm axillary node metastasis) or pN1 (1-3 positive nodes)\nNot a candidate for chemotherapy\n|lib|ly by end of chemotherapy\n|fl consider adjuvant abemacic lib or adjuvant abemacic liboriblic for eligible patients. See BINV-K 2 of 3 for eligibility criteria.\nAdjuvant endocrine therapy\n| 2\nAdjuvant adjuvant ademacic liboriblic adjuvant abemacic liborib by endocrine therapy\n| 2\nAdjuvant endocrine therapy\nAdjuvant chemotherapy\n| Adjuvant endocrine therapy\n| Adjuvant adjuvant ademic lorty by endocrine therapy\n| 2\nAdjuvant adjuvant echoprial by endocrine therapy:emother gene expression\n| 2\nAdjuvant endocrine therapy\n| 2\nAdjuvant adjuvant ademic lorty by 2\nAdjuvant adjuvant echoprial by 2\nAdjuvant adjuvant ech by end erner and end erner's\nAdjuvant end erner3\nAdjuvant end erner3\nAdjuvant end erner3\nAdjuvant end erner3\nAdjuvant end erner3\nAdjuvant end erner3\nAdjuvant end erner3\nAdjuvant end erner3\nAdjuvant end erner3\nAdjuvant end erner3\nAdjuvant end erner3\nAdjuvant end erner3\nAdjuvant end erner3\nAdjuvant end erner3\nAdjuvant end erner3\nAdjuvant end erner3\nAdjuvant end erner3\nAdjuvant end erner3\nAdjuvant end erner3\nAdjuvant end erner3\nAdjuvant end erner3\nAdjuvant end erner3\nAdjuvant end erner3\nAdjuvant end erner3\nAdjuvant end erner3\nAdjuvant end erner3\nAdjuvant end erner3\nAdjuvant end \n](2/aj0YEe4oUhYkBdfpda0fYP/figured9d9ca7c67664d99afda0d9f5c90f3c6_0_5.png) d Principles of Biomarker Testing(BINV-A).

vSpecial Considerations for Breast Cancer in Males(Sex Assigned at Birth)(BINV-J).

z According to WHO, carcinoma of NST encompasses multiple patterns including medullary pattern, cancers with neuroendocrine expression, and other rare patterns.

dd Although patients with cancers with 1%-100% ER IHC staining are considered ER-positive and eligible for endocrine therapies, there are more limited data on the subgroup of cancers with ER-low-positive(1%-10%) results. The ER-low-positive group is heterogeneous with reported biologic behavior often similar to ER-negative cancers; thus individualized consideration of risks versus benefits of endocrine therapy and additional adjuvant therapies should be incorporated into decision-making. See Principles of Biomarker Testing(BINV-A).

ee Definition of Menopause(BINV-O).

ff Adjuvant Endocrine± CDK/4/6 Inhibitor Therapy and Principles of Adjuvant Endocrine Therapy (BINV-K).

99 Preoperative/Adjuvant Therapy Regimens(BINV-M).

j Consider adjuvant bisphosphonate therapy for risk reduction of distant metastasis for 3-5 years in postmenopausal patients (natural or induced)with high-risk node-negative or node-positive tumors.

PP In premenopausal patients with RS<26, the addition of chemotherapy to endocrine therapy was associated with a lower rate of distant recurrence compared with endocrine monotherapy, but it is unclear if the benefit was due to the ovarian suppression effects promoted by chemotherapy.

qq There are few data regarding the role of gene expression assays in those with $\geq 4$ ipsilateral axillary lymph nodes. Decisions to administer adjuvant chemotherapy for this group should be based on clinical factors.

"Gene Expression Assays for Consideration of Adjuvant Systemic Therapy(BINV-N).

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SYSTEMIC ADJUVANT TREATMENT: HR-NEGATIVE -HER2-POSITIVE DISEASE$^{\text{dV}}$

![pT1a(≤0.5 cm)\npN1mi\npT1b(0.6-1.0 cm)\nConsider adjuvant chemotherapy^a,gg with trastuzumabhh(category 2B)\nConsider adjuvant chemotherapy^a,gg with trastuzumabhh(cc) 0\npN1mi\nwith trastuzumabhh(cc)5.253\nNCCN\nNCCN\nNCCN\nNCCN\nNational Guidelines Version 5.2025\npT1, pT2, or pT3; and pN0 or pN1mi(≤2 mm axillary node metastasis)\npT1b(0.6-1.0 cm)\nPt1b(0.6-1.0 cm\nnich\nis with trastuzumabhh.jj\nAdjuvant chemotherapy^a,gg with trastuzumabhhjj\nPertuzumab] (category 1)\nAdjuvant chemotherapy^a,gg with trastuzumabhh(cc) 1\nAdjuvant chemotherapy^a,gg with trastuzumabhhii\nAdjuvant chemotherapy^a,gg with trastuzumabhhii\nPertuzumab] (category 1,\nor and RT\nAdjuvant chemotherapy^a,gg with trastuzumabhhii\nAdjuvant chemotherapy^a,gg with trastuzumabhhii\nAdjuvant chemotherapy^a,gg with trastuzumabhhii\nPertuzum|6:95\nACCN|SCCN|Ond11 Oncology\n\n](2/aj0YEe4oUhYkBdfpda0fYP/figure8172b9d5fee54898a28543a87240a0c8_0_5.png) a For tools to aid optimal assessment and management of older adults, see NCCN Guidelines for Older Adult Oncology.

d Principles of Biomarker Testing(BINV-A).

vSpecial Considerations for Breast Cancer in Males(Sex Assigned at Birth)(BINV-J).

z According to WHO, carcinoma of NST encompasses multiple patterns including medullary pattern, cancers with neuroendocrine expression, and other rare patterns.

99 Preoperative/Adjuvant Therapy Regimens(BINV-M).

hh The benefit of HER2-targeted therapy is uncertain in HER2-positive breast cancer with pT1a-b, N0 tumors, a population not studied in randomized trials. The decision for negative or node-positive tumors.

j Consider adjuvant bisphosphonate therapy for risk reduction of distant metastasis for 3-5 years in postmenopausal patients(natural or induced) with high-risk node-negative or node-positive tumors.

I"Updated results from the adjuvant APHINITY trial in HER2-positive early breast cancer, with a median follow-up of 8.4 years, have confirmed the benefit of adding pertuzumab to trastuzumab plus chemotherapy in preventing recurrences.

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SYSTEMIC ADJUVANT TREATMENT: HR-NEGATIVE -HER2-NEGATIVE DISEASED,v

![pT1, pT2, or pT3; and pN0 or pN1mi(≤2 mm axillary node metastasis)\npT1b(0.6-1.0 cm)\nOlaparib should be given after completion\nDuctal/NSTZ\nLobular\nMixed\no(Mixedapillary\nMetaplastica\nMetaplastica\npN+(21 ipsilateral metastases>2 mm)\npN+（≥1 ipsilateral metastases）\nAdjuvant chemotherapy\nPn1ci\nOaparib\nAdjuvant chemotherapy ya,gg.jj\n1) and adjuvant olaparib if germline BRCA1/2 mutation, see BINV-M for eligibility by different completion\npN1mi\nAdjuvant chemotherapy ya,gg.ij\nAdujuant chemotherapya,gg.gg\n2) and adjuvant olaparib if germline BRCA1/2 mutation, see BINV-M for eligibility by different completion\nPnM1ni\nOaparib should be given after completion\nAdjuvant chemotherapy ya,gg.ij\nAdujant chemotherapy ya,gg.ij\n(category 1) and adjuvant olaparib if germline BRCA1/2 mutation, see BINV-M for eligibility by different completion\nAdjuvant chemotherapy ya,gg.ij\nOaparib or DINV-I.}\nAdjuvant chemotherapy ya,gg.ij\nD2) and adjuvant odaroparib if germline BRCA1/2 mutation, see BINV-M for different completion\nPnN+(21 ipsilateral metastases>2 mm)\nAdjuvant chemotherapy ya,gg.ij\nA2) and adjuvant chemotherapy ya,gg.ij\n\nPnN+(21 ipsilateral metal metastases>2 mm)\nAdjuvant chemotherapy ya,gg.ij\nD2) and adjuvant odaroparib if germline BRCA1/2 mutation, see BINV-M\nAlduovant\nPnN+(21 1ipsilateral metal metalstase\nGenv1-1\nemphas\n](2/aj0YEe4oUhYkBdfpda0fYP/figured5276a603dca42678c670b58e2ec72d7_0_5.png) a For tools to aid optimal assessment and management of older adults, see NCCN Guidelines for Older Adult Oncology.

d Principles of Biomarker Testing(BINV-A).

vSpecial Considerations for Breast Cancer in Males (Sex Assigned at Birth) (BINV-J).

${}^{2}$ According to WHO, carcinoma of NST encompasses multiple patterns including medullary pattern, cancers with neuroendocrine expression, and other rare patterns.

aa There are rare subtypes of metaplastic carcinoma(eg, low-grade adenosquamous and low-grade fibromatosis-like carcinoma) that are considered to have a favorable prognosis without adjuvant systemic therapies.

99 Preoperative/Adjuvant Therapy Regimens(BINV-M).

j Consider adjuvant bisphosphonate therapy for risk reduction of distant metastasis for 3-5 years in postmenopausal patients (natural or induced) with high-risk node-negative or node-positive tumors.

SS In select patients with high-risk features(eg, young patients with high-grade histology), adjuvant chemotherapy may be considered(category 2B). See BINV-L.

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SYSTEMIC ADJUVANT TREATMENT: FAVORABLE HISTOLOGIESV,bb

![\n1cm\nConsider adjuvant endocrine therapy of nP1 mi\n1-2.9 cm\n3 Consider adjuvant endocrine therapy of f\n)and node metastasis)\n32 mm axillary therapyff\n1-2.9 cm\n3 Consider aduvent syndrome therapy\n●Pure tubular / .Pure mucinous .\n● Pure mucinous .$$\nER-positive and/or PR-positive,HER2-negative cc\npN+(21 ipsilateral metastases>2 mm)\n1-2.9 cm\n32 cm\n44.4\nAdjuvant endocrine therapy of jjj\n\nADjuvant endocrine therapy of ggg\n23 cm\n1-2.9 cm\n32 cm\nAdjuvant endocrine therapy of jjj\n\nADjuvant end giving 2mm\nAdjuvant endocrine therapy agg\n32 cm\n1-2.9 cm\n32 cm\n52cm\n44.4\nAdjuvant end giving 2mm\nAdjuvant end giving 2mm\nAdjuvant end giving 2mm\nAdjuvant end giving 2mm\nAdjuvant end giving 2mm\nAdjuvant end giving 2mm\nAdjuvant end giving 2mm end\nAdjuvant end giving 2mm end\nAdjuvant end giving 2mm end\nAdjuvant end giving 2mm end\nAdjuvant end giving 2mm end\nAdjuvant end giving 2mm end\nAdjuvant end giving 2mm end\nAdjuvant end giving 2mm end\nAdjuvant end giving 2mm end\nAdjuvant end giving 2mm end\nAdjuvant end giving 2mm end\nAdjuvant end giving 2mm end\nAdjuvant end giving 2mm end\nAdjuvant end giving 2mm end\nAdjuvant end giving 2mm end\nAdjuvant end获得 agg, R.21103745953-233-361149-255-36161526-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-\n](2/aj0YEe4oUhYkBdfpda0fYP/figure8ba202cd95e2400ebc8179a71082db70_0_5.png) ![● Adenoid cystic (conventional),secretory carcinoma, and other salivary carcinoma, and\n and\n PR-negative,HER2-negativecc\n\n Limited available data support local therapy only with consideration for systemic/targeted therapies only in pN+ disease\n● Rare low-grade forms of metaplastic carcinomaaa\n\n](2/aj0YEe4oUhYkBdfpda0fYP/figured5e26d8cc9274dee8b068a4ab2212117_0_6.png) a For tools to aid optimal assessment and management of older adults, see NCCN Guidelines for Older Adult Oncology.

vSpecial Considerations for Breast Cancer in Males(Sex Assigned at Birth)(BINV-J).

bb To be associated with favorable prognosis, the favorable histologic type should not be high grade, should be pure(>90% as classified on the surgical excision,not core biopsy alone), and should be HER2 negative. If atypical pathologic or clinical features are present, consider treating as ductal/NST.

cc Correlation of histology, HR, and HER2 status should always be done with awareness of unusual/discordant or borderline results. See Principles of Biomarker Testing(BINV-A).

ff Adjuvant Endocrine± CDK/4/6 Inhibitor Therapy and Principles of Adjuvant Endocrine Therapy (BINV-K).

99 Preoperative/Adjuvant Therapy Regimens(BINV-M).

${}^{i}$ Consider adjuvant bisphosphonate therapy for risk reduction of distant metastasis for 3-5 years in postmenopausal patients (natural or induced) with high-risk node-negative or node-positive tumors.

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WORKUP PRIOR TO PREOPERATIVE SYSTEMIC THERAPY

CLINICAL STAGE

ADDITIONAL WORKUPa

![c≥T2tt or cN+ and M0 or\nCt71c, cN0 HER2-positive\nor\ncT1c, cN0 HER2-positive\nand NCG\nO percutaneous biopsy of suspicious nodesuu\nO complete blood count (CBC)\nO Comprehensive metabolic panel, including liver function tests and\nalkaline phosphatase\nAdditional tests to consider as clinically indicated\nCt71c, cN0 TNBC\n(For preoperative\nsystemic therapy criteria,\nsee BINV-L 1)\n● FDG-PET/CTV\n● Breast MRIb (optional), with special consideration for\nmammographically occult tumors, if not previously done\nFor inoperable\nBraest cancer: see Preoperative Systemic\nTherapy (BINV-15)\n● FDG-PET/CTV\n● Cancer's: see Breast and Axillary Evaluation Prior\nTo Preoperative Systemic\nTherapy (BINV-13)\n● 03.333.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.3\n](2/aj0YEe4oUhYkBdfpda0fYP/figure417ba256076b404799584601993b54f1_0_7.png) aFor tools to aid optimal assessment and management of older adults, see NCCN Guidelines for Older Adult Oncology.

b Breast MRI may be useful for characterizing axillary and/or internal mammary nodal disease. See Principles of Dedicated Breast MRI Testing(BINV-B) and NCCNN Guidelines for Breast Cancer Screening and Diagnosis.

(If considering preoperative therapy, consider use of a gene expression assay during workup for postmenopausal patients with cN0, operable ER-positive, HER2-negative, for blood A, et al. Breast Cancer Res Treat 2019;173:123-133; Pease AM, et al.Ann Surg Oncol 2019;26:366-371).

$u^{\prime\prime}$ At the time of biopsy of the most suspicious axillary lymph node(s), a marker should be placed to allow for identification and removal at the time of definitive surgery. w^{\prime\prime}\) FDG-PET/CT is most beneficial and accurate for advanced disease(stage III) and invasive ductal(compared to lobular) histology, but may be useful in selected circumstances of earlier stage disease(stage IIA disease: cT1cN1, cT2cN0) such as: equivocal CT+ bone scan results; suspicion of undetected nodal and/or distant disease; and treatment response assessment. An FDG-PET/CT may be utilized as an adjunct to, or in lieu of, initial standard staging and may be performed simultaneously with diagnostic CT. Conversely, a bone scan or sodium fluoride PET/CT may not be needed if an upfront FDG-PET/CT clearly indicates consistent findings on both PET and CT components.

Note: All recommendations are category 2A unless otherwise indicated.

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OPERABLE DISEASE: BREAST AND AXILLARY EVALUATION PRIOR TO PREOPERATIVE SYSTEMIC THERAPY

Prior to preoperative systemic therapy, perform:

●Core biopsy of breast with placement of image-detectable clips or marker(s), if not previously performed, should be performed prior to preoperative therapy to demarcate the tumor bed

● Axillary imaging with ultrasound or MRI (if not previously done)

●Biopsy+ marker placement recommended of the most suspicious and/or clinically positive axillary lymph node, if not previously done; only the most suspicious node should be marked and retrieved along with SLNs

| Preoperative systemic therapy based on HR and Therapy After Preoperative Systemic Therapy (BINV-L 1)

99 Preoperative/Adjuvant Therapy Regimens(BINV-M)

Note: All recommendations are category 2A unless otherwise indicated.

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OPERABLE DISEASE:

SURGICAL TREATMENT AND ADJUVANT THERAPY AFTER PREOPERATIVE SYSTEMIC TREATMENTWW

![BCS possible\nBCS possible\nBCS not possible\nMastectomy and surgical aaxillary staging (BIN-V-1 axillary axillary staging (BINV-D)\n$\bullet$ BCS with surgical staging (BINV-D)\n$\bullet$ BCS with aaxillary staging (BINV-D)\n$\bullet$ OK n+2, Induysant ventioarial ventical ventical\n$\bullet$ axillary staging (BINV-D)\n$\bullet$ BCS not possible $\rightarrow$ 0.25 NCCN Guidelines\n$\bullet$ AC n+2, Induysant ventioarial ventical ventical ventical\n$\bullet$ AC n+2, Induysant ventioarial ventical ventical\n$\bullet$ AC n+2, Induysant ventioarial ventical ventical\n$\bullet$ AC n+2, Induysant ventioarial ventical ventical\n$\bullet$ AC n+2, Induysant ventioarial ventical ventical\n$\bullet$ AC n+2, Induysant ventioarial ventical ventical\n$\bullet$ AC n+2, Induysant ventioarial ventical ventical\n$\bullet$ AC n+2, Induysant ventioarial ventical ventical\n$\bullet$ AC n+2, Induysant ventioarial ventical ventical\n$\bullet$ AC n+2, Induysant ventioarial ventical ventical\n$\bullet$ AC n+2, Induysustnance\n$\bullet$ BCS possible\nBCS possible\nMastectomy and surgical aaxillary staging (BIN-V-1 axillary staging (BINV-D)\n$\bullet$ BC S not possible\n$\pm$ reconstruction\n$\pm$ reconstruction\n$\bullet$ AC n+2, Induysant vorgic 92.6 NCCN\nMastectomy and surgical aaxillary staging (BINV-V-1 axillary axillary axillary axillary stectioarial ventical ventical\n$\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk.\n$\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk.\n$\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk.\n$\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk.\n$\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk.\n$\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk.\n$\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk.\n$\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk.\n$\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk.\n$\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk.\n$\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk.\nAC NCCN\n11.22 NCCN\n12.33 NCCN\n13.33 NCCN\nMastectomy and surgical aaxillary staging (BINV-V-1 axillary axillary axectia or early passage\n$\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk.\n$\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk.\nAC NCCN\n12.33 NCCN\n13.33 NCCN\n$\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk.\nAC NCCN\n13.33 NCCN\n13.33 NCCN\n$\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk.\nAC NCCN\n13.33 NCCN\n13.33 NCCN\n$\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk.\nAC NCCN\n13.33 NCCN\n13.33 NCCN\n$\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk.\nAC NCCN\n13.33 NCCN\n13.33 NCCN\n$\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk.\nAC NCCN\n13.33 NCCN\n13.33 NCCN\n$\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk.\nAC NCCN\n13.33 NCCN\n13.33 NCCN\n13.33 NCCN\n13.33 NCCN\n$\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk.\nAC NCCN\n13.33 NCCN\n13.33 NCCN\n13.33 NCCN\n13.33 NCCN\n$\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk.\nAC NCCN\n13.33 NCCN\n13.33 NCCN\n13.33 NCCN\n13.33 NCCN\n13.33 NCCN\n13.33 NCCN\n13.33 NCCN\n13.33 NCCN\n13.33 NCCN\n13.33 NCCN\n13.33 NCCN\n13.33 NCCN\n13.33 NCCN\n13.33 NCCN\n13.33 NCCN\n13.33 NCCN\n13.33 NCCN\n13.33 NCCN\n13.33 NCCN\n13.33 NCCN\n13.33 NCCN\n13.33 NCCN\n13.33 NCCN\n13.33 NCCN\n](2/aj0YEe4oUhYkBdfpda0fYP/figure4010f06886164f3da49250b4b7d81c34_0_6.png) $^{n}$ Includes techniques such as local tissue rearrangement, local flaps, breast reduction, and mastopexy to allow for greater volumes of resection while optimizing aesthetic outcomes in patients undergoing BCS.

sPrinciples of Radiation Therapy(BINV-I).

t Special Considerations for Breast Cancer in Males(Sex Assigned at Birth)(BINV-J).

wPrinciples of Breast Reconstruction Following Surgery(BINV-H).

ww The accurate assessment of in-breast tumor or regional lymph node response to preoperative systemic therapy is difficult, and should include physical examination and performance of imaging studies (mammogram and/or breast ultrasound and/or breast MRI) that were abnormal at the time of initial tumor staging. Selection of imaging methods prior to surgery should be determined by the multidisciplinary team. MRI is more accurate than mammography for assessing tumor response to preoperative therapy.

$xx$ Complete planned systemic therapy regimen course if not completed preoperative.

yy Strongly consider RT boost for high-risk features (eg, high-grade disease, age < 50 years).

zz Based on emerging data, there may be subsets of patients who achieve pCR in nodes that may not benefit from RNI(in BCS setting) or PMRT+ RNI(in mastectomy setting).(Mamounas E, Bandos H, White J, et al. Loco-regional irradiation in patients with biopsy-proven axillary node Involvement at presentation who become pathologically node-negative after neoadjuvant chemotherapy: Primary outcomes of NRG Oncology/NSABP B-51/RTOG 1304; Abstract GS02-07; SABCS 2023.)

Note: All recommendations are category 2A unless otherwise indicated.

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NCCN Guidelines Version 5.2025 Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

INOPERABLE OR LOCALLY ADVANCED DISEASE (NON-INFLAMMATORY):PREOPERATIVE SYSTEMIC THERAPY AND SUBSEQUENT TREATMENT

![RESPONSEww\n\nADJUVANT TREATMENT AND ADJUVANT THERAPY\nResponse to preoperative\nand tumor is operable\nResponse to other systemic therapy\nand tumor is operable\nMastectomy and surgical axillary staging^{k}^{x} 40 and reconstruction (optional)^{w}\nADJUVN 16)\nADJUVANT STREATNESS\nADjuvant systemic therapy^{xx}^{(BINV-16)}\nand\nADjuvant RTS^{s}$\nADjuvant RTS to the whole breast or chest wall and comprehensive RNI with inclusion of any portion of the undissected axilla at risk.\nResponse to preoperative\ntherapy^{\text{WW-1}}\nADJUVW\nand/or preoperative\nremains inoperable\nConsider additional systemic therapy and/or preoperative\ntherapy/and/or tumor\nradiations\nNo response to preoperative systemic therapy and/or preoperative remains inoperable\nNo response to preoperative systemic therapy w and tumor is inoperable\n](2/aj0YEe4oUhYkBdfpda0fYP/figure6f4f9c76c08e49b99c8db425601dc607_0_5.png) k Considerations for Surgical Axillary Staging (BINV-D).

$^{n}$ Includes techniques such as local tissue rearrangement, local flaps, regional flaps, breast reduction, and mastopexy to allow for greater volumes of resection while optimizing aesthetic outcomes in patients undergoing BCS.

s Principles of Radiation Therapy (BINV-I).

t Special Considerations for Breast Cancer in Males(Sex Assigned at Birth)(BINV-J).

wPrinciples of Breast Reconstruction Following Surgery(BINV-H).

99 Preoperative/Adjuvant Therapy Regimens(BINV-M).

${}^{xx}$ Complete planned systemic therapy regimen course, if not completed preoperatively.

aaa For patients with skin and/or chest wall involvement (T4 non-inflammatory)prior to preoperative systemic therapy, breast conservation may be performed in carefully selected patients based on a multidisciplinary assessment of local recurrence risk. In addition to standard contraindications to breast conservation(BINV-G),exclusion criteria for breast conservation include: inflammatory(T4d)disease before preoperative systemic therapy and incomplete resolution of skin involvement after preoperative systemic therapy.

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NCCN Guidelines Version 5.2025 Invasive Breast Cancer

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ADJUVANT SYSTEMIC THERAPY AFTER PREOPERATIVE SYSTEMIC THERAPY jj

RESPONSE/PATHOLOGIC STAGE AFTER PREOPERATIVE THERAPY

ADJUVANT SYSTEMIC THERAPYt,ff,gg,j

ypT0N0 or pCR→Adjuvant endocrine therapy (category 1)HR-positive/ HER2-negative | |—YpT1-4,N0| Adjuvant endrocrine therapy (category 1) + adjuvant olaparib if germline BRCA1/2 mutation (category 1), see BINV-M 1 of 10 for eligibility criteria. Consider adjuvant abemacilibir or ribociblic for eligible patients, see BINV-K 2 of 3 for eligibility criteria.

> ypT0N0 or pCR→Complete up to 1 year of HER2-targeted therapy with trastuzumab(category 1)± pertuzumab. If node positive at initial staging, trastuzumab+ pertuzumab. category 1).

HR-negative/HER2-positive

HR-positive/HER2-positive

<BeginOfPara>ypT0N0 or pCR\rightarrowEndocrine therapy(category 1)+ complete (up to) 1 year of HER2-directed therapy with trastuzumab ,(category 1) $\pm$ pertuzumab. If node positive at initial staging, trastuzumab + pertuzumab (category 1)

|ypT0N0 or pCR→|For high risk: Adjuvant pembrolizumab(if pembrolizumab-containing regimen was given preoperatively), see BINV-M 3 of 10.| |---|---| |HR-negative/ HER2-negative|Adjuvant pembrolizumab(if pembrolizumab-containing regimen was given preoperatively) cccc and/or Adjuvant capecitabine(6-8 cycles)bbb,ccc and/or Adjuvant olapib for 1 year if germline BRCA1/2 mutationCCC(category 1)|

t Special Considerations for Breast Cancer in Males(Sex Assigned at Birth)(BINV-J).

f Adjuvant Endocrine± CDK/4/6 Inhibitor Therapy and Principles of Adjuvant Endocrine Therapy (BINV-K).

99 Preoperative/Adjuvant Therapy Regimens(BINV-M).

j Consider adjuvant bisphosphonate therapy for risk reduction of distant metastasis for 3-5 years in postmenopausal patients(natural or induced) with high-risk node-negative or node-positive tumors.

"Updated results from the adjuvant APHINITY trial in HER2-positive early breast cancer, with a median follow-up of 8.4 years, have confirmed the benefit of adding pertuzumab to trastuzumab plus chemotherapy in preventing recurrences.

bbb Recommendations do not apply to residual DCIS (ypTis).

ccc There are no data on sequencing or combining adjuvant pembrolizumab with capecitabine or olaparib in patients who meet criteria for treatment with one or more of these agents. However, their sequential/combined use may be considered given high risk of recurrence in patients with residual disease.

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NCCN Guidelines Version 5.2025 Invasive Breast Cancer

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SURVEILLANCE/FOLLOW-UP

Exam:

●History and physical exam 1-4 times per year as clinically appropriate for 5 years, then annually

Genetic screening:

●Periodic screening for changes in family history and genetic testing indications and referral to genetic counseling as indicated, see NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast,Ovarian, Pancreatic,and Prostate

Postsurgical management:

●Educate,monitor, and refer for lymphedema management,see NCCN Guidelines for Survivorship: Lymphedema

Breast imaging:

Mammography every 12 months, beginning 6 months or more after completion of breast-conserving therapy (BCT)ddd

●Routine imaging of reconstructed breast is not indicated

●For patients with germline mutations or family history of breast cancer, please refer to NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast,Ovarian, Pancreatic,and Prostate

Fertility, birth control, and sexual health see BINV-C.

Screening for metastases:

●In the absence of clinical signs and symptoms suggestive of recurrent disease, there is no indication for laboratory or imaging studies for metastases screening.

Post-treatment monitoring:

●Cardioxicity monitoring for patients who received left-sided radiation therapy, anthracyclines, or HER2-targeted therapy. For anthracycline-induced toxicity, see NCCN Guidelines for Survivorship

●Provide guidance on risk of comorbidities

Endocrine therapy:

●Assess and encourage adherence to adjuvant endocrine therapy

●Patients on tamoxifen:

Age-appropriate gynecologic screening

Routine annual pelvis ultrasound is not recommended

●Patients on an aromatase inhibitor or who experience ovarian failure secondary to treatment should have monitoring of bone health with a bone mineral density determination at baseline and periodically thereaftereee

Lifestyle:

●Evidence suggests that active lifestyle, healthy diet, limited alcohol intake, and achieving and maintaining an ideal body weight (20-25 body mass index [BMl]) may lead to optimal breast cancer outcomes. See NCCN Guidelines for Breast Cancer Risk Reduction.

Psychosocial support:

●Survivors are at elevated risk for fear of recurrence, distress,anxiety, and depression that may persist for many years after diagnosis. Periodic screening and referral to mental health professionals if needed are recommended. See NCCN Guidelines for Survivorship.

Communication:

●Coordination of care between the primary care physician(PCP)and specialists is encouraged. Additionally, a personalized survivorship treatment plan including personalized treatment summary of possible long-term toxicity and clear follow-up recommendations is recommended. See NCCN Guidelines for Survivorship

Engagement:

●Patients frequently require follow-up encouragement in order to improve adherence to ongoing screening and medication adherence. See NCCN Guidelines for Patients

ddd Studies indicate that annual mammograms are the appropriate frequency for surveillance of patients with breast cancer who have had BCS and RT with no clear advantage to shorter interval imaging. Patients should wait 6 to 12 months after the completion of RT to begin their annual mammogram surveillance. Suspicious findings on physical examination or surveillance imaging might warrant a shorter interval between mammograms.

eee The use of estrogen, progesterone, or selective ER modulators to treat osteoporosis or osteopenia in patients with breast cancer is discouraged. The use of a bisphosphonate (oral/IV) or denosumab is acceptable to maintain or to improve bone mineral density and reduce risk of fractures in postmenopausal (natural or induced) patients receiving adjuvant aromatase inhibitor therapy. Optimal duration of either therapy has not been established. Benefits of duration beyond 3 years or optimal duration beyond 3 years is not known. Factors to consider for duration of anti-osteoporosis therapy include bone mineral density, response to therapy,and risk factors for continued bone loss or fracture. There are case reports of spontaneous fractures after denosumab discontinuation. Patients treated with a bisphosphonate or denosumab should undergo a dental examination with preventive dentistry prior to the initiation of therapy, and should take supplemental calcium and vitamin D.

Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

RECURRENT/STAGE IV (M1) DISEASE

CLINICAL STAGE

WORKUPa

▶History and physical exam

•Discuss goals of therapy, adopt shared decision-making, and document course of care

·CBC

●Comprehensive metabolic panel, including liver function tests and alkaline phosphatase

●Imaging for systemic staging:

Chest diagnostic CT± contrast

Abdomen± pelvis diagnostic CT with contrast or MRI with contrast

Brain MRI with contrast if suspicious CNS symptoms ff

Spine MRI with contrast if back pain or symptoms of cord compression

Bone scan or sodium fluoride PET/CT(category 2B)

Useful in certain circumstances:

FDG-PET/CT (consider FES-PET/CT for ER-positive disease and lobular histology)

X-rays of symptomatic bones and long and weight-bearing bones abnormal on bone scan

·Biomarker testing:

Biopsy of at least first recurrence of disease (consider re-biopsy if progression)

Evaluation of ER/PR and HER2 status$^{d,ggg,hhh}$

Comprehensive germline and somatic profiling to identify candidates for targeted therapies

●Genetic counseling if patient is at risk® for hereditary breast cancer

●Assess for distress9

hhh In clinical situations where a biopsy cannot safely be obtained but the clinical evidence is strongly supportive of recurrence, treatment may commence based on the ER/PR/HER2 status of the primary tumor. Since ER/PR and HER2 status can change with treatment and metastatic progression, it may be appropriate to consider repeat testing on new samples in these scenarios if management will change.

aFor tools to aid optimal assessment and management of older adults, see NCCN Guidelines for Older Adult Oncology.

d Principles of Biomarker Testing(BINV-A).

e For risk criteria, see NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast,Ovarian.Pancreatic,and Prostate.

9See NCCN Guidelines for Distress Management.

fff For the treatment of brain metastases, see NCCN Guidelines for Central Nervous System Cancers.

999 False-negative ER and/or PR determinations occur, and there may be discordance between the ER and/or PR determination between the primary

iii Tumor tissue or plasma-based circulating tumor DNA (ctDNA) assays may be used and each of these have benefits and limitations for diagnosis and disease progression. Tissue-based assays have greater sensitivity for some alterations,but ctDNA may reflect tumor heterogeneity more accurately.If one specimen is negative for actionable biomarkers, testing on the alternative specimen can be considered.

iJee NCCN Guidelines for Palliative Care and NCCN Guidelines for Supportive Care.

kkk In the setting of oligometastatic breast cancer, the currently available data do not support ablastematised-directed RT (ie, stereotactic body radiation therapy [SBRT]) for extending overall survival (OS) or progression-free survival(PFS). In some cases, SBRT may be preferred over palliative RT to provide more durable local control and pain relief.

an HR-positive tumor(eg, long disease-free interval, limited sites of recurrence,indolent disease, older age).

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

TREATMENT OF LOCAL RECURRENCE: In-breast or Chest wall recurrenceIII (Without clinically overt axillary recurrence)

(For REGIONAL $\pm$ LOCAL RECURRENCE, see BINV-20)

INITIAL (PRIOR SURGERY)

PRIOR RT

![BCS\nNo\nYes\nNo\nBostum\nYes\nBustc\nNo\nSurgical resection if feasiblePPP+consider surgical axillary stagingmm+PMRT$ (BINV-28\naxillary stagingmm+repeat RT,if feasible and indicated 5,000\nMastectomy\nNo\nYes\nSurgical resection if feasiblePPP+consider surgical axillary stagingmm+PARTMS(BINV-3)\n\Consider appropriate systemic therapyqqq\nBinv-K, BINV-M,\nBINV-K, BINV-M,\nand see Principles of Survivorship BINV-28\nSurvivorship BINV-28\n](2/aj0YEe4oUhYkBdfpda0fYP/figure31899f4de9974f26920639c932ca8409_0_9.png) NCCN授权医脉通提供NCCN指南全文下载。wmIsy2025/10/28,21:39在医脉通平台下载，仅供个人使用，严禁分发。2025美国国家综合癌症网络版权所有。

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TREATMENT OF REGIONAL $\pm$ LOCAL RECURRENCEIII

(For LOCAL ONLY RECURRENCE, see BINV-19)

RECURRENCE INITIAL(PRIOR)LOCAL-REGIONAL(CURRENT) TREATMENT

![Axillary\nALND\nSOLNB only\nSurgical resection if feasiblePPP with ALND(for axillary recurrence) + RT if feasibles,000\nNo prior RT\nALND\nRTP<\text{comprehensive on localized}\nSurgical resection of gross diseasePPP\nALND(for axillary recurrence) if feasible+RT if feasibles,000\nSupra/infra-clavicular, Internal mammary\nNo prior RT\nRRT(comprehensive or localized)\nPrior RT\nRepeat RT, if feasibles,000\n](2/aj0YEe4oUhYkBdfpda0fYP/figure4e524fc74f4f4ba8989b0f34edf48ce9_0_7.png) NCCN授权医脉通提供NCCN指南全文下载。wmIsyy于2025/10/28,21:39在医脉通平台下载，仅供个人使用，严禁分发。2025美国国家综合癌症网络版权所有。

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NCCN Guidelines Version 5.2025 Invasive Breast Cancer

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SYSTEMIC TREATMENT OF RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASEV

![ER- and/or PR-positive; HER2-negative^{dd,dd,ttt}\nBINV-22\nER- and/or PR-positive; HER2-positive; HERV-24\nBINV-24\nRecurrent unresectable (local or regional) or stage IV (M1)\nDisease kkk,rrr\nBone disease present\nAdd denosumab zoonedronic acid, or pamidronatesss\nER- and/or PR-positive; HER2-positive; HER2-positive d,dd,ttt\nBINV-24\nER- and/or/or PR-positive; HER2-positive; HER2-positive d,dd,ttt\nBINV-24\nER- and PR-negative; HER2-positive; HER2-positive d,dd,ttt\nBINV-24\nER- and PR-negative; HER2-negative d,dd,ttt\n](2/aj0YEe4oUhYkBdfpda0fYP/figureff72c992944744dc8b01385cb992da48_0_5.png) d Principles of Biomarker Testing(BINV-A).

v Special Considerations for Breast Cancer in Males (Sex Assigned at Birth) (BINV-J).

kkk In the setting of oligometastatic breast cancer, the currently available data do not support ablative metastasis-directed RT(ie, SBRT) for extending overall survival OS or PFS. In some cases, SBRT may be preferred over palliative RT to provide more durable local control and pain relief.

Trt Routine surgical resection of the primary breast tumor is generally not indicated in the management of patients presenting with de novo stage IV (M1) disease. Although there is no survival benefit, it may be considered for local control of the primary tumor. Discussion regarding management of the primary tumor in this setting must be individualized.

sss Denosumab, zoledronic acid, or pamidronate(all with calcium and vitamin D supplementation) should be given(category 1) in addition to systemic therapy or endocrine therapy if bone metastasis is present, expected survival is≥3 months, and renal function is adequate. Patients should undergo a dental examination with preventive dentistry prior to initiation of this therapy. The optimal schedule for zoledronic acid is every 12 weeks.

Baseline assessment of bone density recommended for patients receiving an aromatase inhibitor who are at risk of osteoporosis(eg, age>65, family history, chronic steroids).

Note: All recommendations are category 2A unless otherwise indicated.

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NCCN Guidelines Version 5.2025 Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

SYSTEMIC TREATMENT OF RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE:ER-AND/OR PR-POSITIVE; HER2-NEGATIVE

![Visceral crisisuu$\longrightarrow$Consider initial systemic therapyvvv\nNo visceral crisis and Prior endocrine therapy within 1 y$\_$ $\_$ and therapy within 1 y$\_$ $\_$ Postmenopausalee$\longrightarrow$Systemic therapywww\nor\nContinue systemic therapy until progression\→\nNotain ocrystalline - $\_$ and \(\operatorname{Glyv} \longrightarrow \operatorname{Glyv} \longrightarrow \operatorname{Glyv} \longrightarrow \operatorname{Glyv} \longrightarrow \operatorname{Glyv} \longrightarrow\longrightarrow$\nPostmenopausalee$\longrightarrow$Systemic therapywww\nor\nIsentic therapy therapy\longdots\nNon visceral crisis and cancer to cancel or selective ER modulators//www\nlong 2025\longdots therapy therapy\longdots\\nNo visceral crisis and Therapy within 1 y\nPostmenopausalee$\longrightarrow$Systemic therapywww\nor\nContinue systemic therapy during progression until progression\→\nNotantic therapy\nor Discrular therapy\nProgression and \ngly for Principles\nor/Sivorship\nNo visceral crisis and endocrine therapy within 1 y$\_$ $\_$ $\longrightarrow$\n](2/aj0YEe4oUhYkBdfpda0fYP/figure0c4d9e5599ad4b4f9317d48bff53ef77_0_5.png) d Principles of Biomarker Testing(BINV-A).

ee Definition of Menopause(BINV-O).

uuu According to the 5th ESO-ESMO international consensus guidelines(Cardoso F, et al. Ann Oncol 2020;31:1623-1649) for advanced breast cancer visceral crisis is defined as: “severe organ dysfunction, as assessed by signs and symptoms, laboratory studies and rapid progression of disease. Visceral crisis is not the mere presence of visceral metastases but implies important organ compromise leading to a clinical indication for the most rapidly efficacious therapy."

www Systemic Therapy Regimens for Recurrent Unresectable(Local or Regional) or Stage IV (M1) Disease (BINV-Q).

www Systemic Therapy for ER- and/or PR-Positive Recurrent Unresectable(Local or Regional) or Stage IV (M1) Disease (BINV-P).

yyy Principles of Monitoring Metastatic Disease(BINV-R).

zzz It is acceptable to switch to endocrine-based therapy (BINV-P) after disease stabilizes or response is observed.

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NCCN Guidelines Version 5.2025 Invasive Breast Cancer

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SYSTEMIC TREATMENT OF RECURRENT UNREsectABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE:ER - AND/OR PR-POSITIVE; HER2-NEGATIVE(SEE BINV-28 FOR PRINCIPLES OF SURVIVORSHIP)

![Progressionyy y or unacceptable toxicity on first-line endocrine therapy for other endocrine therapy (see second-line therapy options on BINV-P)\nNoncali ngedinoE 9000-0596-0696-04880\nAlternative endocrine therapy ,Myte oscine therapy (see second-line therapy options on BINV-P)\nNo clinical benefit after up to 3 sequential endocrine therapy may be needed for these 2000 systemic therapy (vvv,Yyyu or Systemic therapy)\nSystemic therapy\nMost patients will be candidates for multiple lines of systemic therapy to palliate advanced breast cancer. At each reassessment clinicians should and ensure that of ongoing treatment, the risks and benefits of an additional line of systemic therapy, patient performance status, and patient preferences through a shared decision-making process .-\nSystemic therapy vvv,yyy\nFor those with visceral crisis:Progressionyy or unacceptable therapy vvv,yyy incersal therapy 0000-06800\nAlternate systemic, and patient performance status, and patient preferences through a shared decision-making process .-\nSystemic therapy vvv,Yyyu or Sonic and NCCN Guidelines for Palliative Care and NCCN Guidelines for Supportive Care)\n](2/aj0YEe4oUhYkBdfpda0fYP/figureac6f00967e63443a9d1cd3cbb6344e1c_0_5.png) d Principles of Biomarker Testing(BINV-A).

999 False-negative ER and/or PR determinations occur, and there may be discordance between the ER and/or PR determination between the primary and metastatic tumor(s). Therefore, endocrine therapy with its low attendant toxicity may be considered in patients with non-visceral or asymptomatic visceral tumors, especially in patients with clinical characteristics predicting for a HR-positive tumor(eg, long disease-free interval, limited sites of recurrence, indolent disease, older age).

$vv$ Systemic Therapy Regimens for Recurrent Unresectable(Local or Regional) or Stage IV (M1) Disease (BINV-Q).

www Systemic Therapy for ER- and/or PR-Positive Recurrent Unresectable(Local or Regional) or Stage IV (M1) Disease (BINV-P).

yyy Principles of Monitoring Metastatic Disease(BINV-R).

aaaa The potential side effects of additional lines of therapy may outweigh any clinical benefit in a patient who has a compromised performance status. Patient preference must be taken into account.

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NCCN Guidelines Version 5.2025 Invasive Breast Cancer

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SYSTEMIC TREATMENT OF RECURRENT UNREsectABLE(LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE:ER - and/or PR-POSITIVE; HER2-POSITIVE(SEE BIN-28 FOR PRINCIPLES OF SURVIVORSHIP)

![Systemic therapy + HER2-targeted therapy\v,www\nend\nor endocrine therapy + HERb$\pm$ HER2-targeted therapy\nif premenopausal,ee consider ovarian ablation or suppression)ww,ccccc\nContinue therapy until progressiony\nOK\n\nProgression\nand\nSee BINV-28 for Principles\nof Survivorship\n](2/aj0YEe4oUhYkBdfpda0fYP/figure10aa0fa31d924f2aa246486ddfd6ab79_0_5.png) d Principles of Biomarker Testing(BINV-A).

ee Definition of Menopause(BINV-O).

www Systemic Therapy Regimens for Recurrent Unresectable(Local or Regional) or Stage IV (M1) Disease (BINV-Q).

www Systemic Therapy for ER- and/or PR-Positive Recurrent Unresectable(Local or Regional) or Stage IV (M1) Disease (BINV-Q).

yyy Principles of Monitoring Metastatic Disease(BINV-R).

bbbb If prior endocrine therapy within 1 y, consider a different endocrine therapy.

ccc For premenopausal patients, tamoxifen alone (without ovarian ablation/suppression) + HER2-targeted therapy is also an option.

National Comprehensive Cancer Network®

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

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SYSTEMIC TREATMENT OF RECURRENT UNREsectABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE:ER - and/or PR-POSITIVE; HER2-POSITIVE* (SEE BINV-28 FOR PRINCIPLES OF SURVIVORSHIP)

![Progressionyyy\nConsider alternate endocrine therapy,\n$ \nendocrine therapy\nof not endocrine\nrefractory 100,28,21:39在中医脉通平台下载，仅供个人使用，严禁分发。2025美国国家综合癌症网络版权所有。\nProgressionyyy\n on first-line endocrine\n $\rightarrow$ $\leftarrow$ for other RER2-targeted therapy of ER2-targeted\n\ntherapy ± 更换成RER2-targeted therapy of ER2-targeted therapy\n to 3 sequential endocrine therapy endocrine therapy\n $\rightarrow$ $\pm$ HER2-targeted therapy until progression vv,yyy,dddd and higher assessment of the systemic therapy.\n$ \nMost patients will be considered in the 29th 20th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30t\n](2/aj0YEe4oUhYkBdfpda0fYP/figurea5c2b22c67594ab98d0442cd150dbb5b_0_5.png) ![Progressionyy y\n on systemic time\n HER2-targeted\n therapy\n HER2-targeted\n + HER2-targeted\n therapy vvv\n HER2-targeted\n 999-False-negative ER and/or PR determinations occur, and there may be discordance between the ER and/or PR determination between the primary and metastatic tumor(s). Therefore, endocrine therapy with its low attendant toxicity may be considered in patients with non-visceral or asymptomatic visceral tumors, especially in patients with clinical characteristics predicting for a HR-positive tumor(eg), long disease-free interval, limited sites of recurrence, indolent disease, older age).\n\n YR2-Plincples of Monitoring Metastatic Disease(BINV-R).\n aaaa The potential side effects of additional lines of therapy may outweigh any clinical benefit in a patient who has a compromised performance status. Patient preference must be taken into account.\n](2/aj0YEe4oUhYkBdfpda0fYP/figured0cbfe630e1646da8a0a51d8d6e80f57_0_6.png) d Principles of Biomarker Testing(BINV-A).

999 False-negative ER and/or PR determinations occur, and there may be discordance between the ER and/or PR determination between the primary and metastatic tumor(s). Therefore, endocrine therapy with its low attendant toxicity may be considered in patients with non-visceral or asymptomatic visceral tumors, especially in patients with clinical characteristics predicting for a HR-positive tumor(eg),long disease-free interval, limited sites of recurrence, indolent disease, older age).

vw Systemic Therapy Regimens for Recurrent Unresectable(Local or Regional) or Stage IV (M1) Disease (BINV-Q).

www Systemic Therapy for ER- and/or PR-Positive Recurrent Unresectable(Local or Regional) or Stage IV (M1) Disease (BINV-P).

yyy Principles of Monitoring Metastatic Disease(BINV-R).

aaaa The potential side effects of additional lines of therapy may outweigh any clinical benefit in a patient who has a compromised performance status. Patient preference must be taken into account.

dddd The optimal duration of trastuzumab in patients with long-term control of disease is unknown.

National Comprehensive Cancer Network®

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

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SYSTEMIC TREATMENT OF RECURRENT UNREsectABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE:ER - and/or PR-NEGATIVE; HER2-POSITIVEd (SEE BINV-28 FOR PRINCIPLES OF SURVIVORSHIP)

![\nContinue therapy until progressiony\nor unacceptable or unacceptable toxicity dddd and See BINV-28 for Principles of Survivorship\nMost patients will be candidates for multiple lines of systemic therapy to palliate advanced breast cancer. At each reassessment clinicians should assess value of ongoing treatment, the risks targeted therapy until and some other patients as the future of the future of the research > 2\nNCCN\nHer2-rotated to toxicity dddd\nngressionxy therapy + HER2-targeted therapy until progressionv v, yyy,dddd\nMainpleative systemic therapy and service\ng pregression vv, v, y,y,dddd\nNCCN Guidelines for Palliative Care and nCCN\nSupportive Care\n2\n3\nNCCN Guidelines for NCCN Guidelines for Supportive Care\n](2/aj0YEe4oUhYkBdfpda0fYP/figurefcf9078f1be142c680741a87c7c7907f_0_5.png) d Principles of Biomarker Testing(BINV-A).

WWSystemic Therapy Regimens for Recurrent Unresectable (Local or Regional) or Stage IV (M1) Disease (BINV-Q).

yyy Principles of Monitoring Metastatic Disease (BINV-R).

aaaa The potential side effects of additional lines of therapy may outweigh any clinical benefit in a patient who has a compromised performance status. Patient preference must be taken into account.

National Comprehensive Cancer Network®

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

SYSTEMIC TREATMENT OF RECURRENT UNREsectABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE:ER - AND/OR PR-NEGATIVE; HER2-NEGATIVE(SEE BINV-28 FOR PRINCIPLES OF SURVIVORSHIP)

![\nContinue therapy until progressionary\nor unacceptable to toxicity and See BINV-28 for Survivorship\n\n Most patients will be candidates for multiple lines of systemic therapy to palliate advanced breast cancer. At each reassessment clinicians\nshould assess value of ongoing treatment, the risks and benefits of an additional line of systemic therapy, patient performance status, and patient preferences through a shared decision-making process.\n](2/aj0YEe4oUhYkBdfpda0fYP/figuref907eeddd2fc49cdb56dffd438fdcdf8_0_5.png) d Principles of Biomarker Testing(BINV-A).

aaa The potential side effects of additional lines of therapy may outweigh any clinical benefit in a patient who has a compromised performance status. Patient preference must be taken into account.

NCCN

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF SURVIVORSHIP FOR THOSE LIVING WITH ADVANCED OR METASTATIC BREAST CANCER

General Principles

●The management of patients with unresectable, Stage IV (M1) or metastatic disease requires a multifaceted approach, encompassing treatment and a comprehensive survivorship plan.

●For principles of monitoring metastatic disease, see BINV-R.

●Encourage patients to promptly report any new or worsening symptoms. A comprehensive evaluation is essential, as these symptoms could indicate disease progression, treatment effects, or other unrelated medical issues.

●Additional health monitoring,management, and immunizations should be performed as appropriate to the prognosis under the care of a PCP.

●Patients are encouraged to maintain a therapeutic relationship with a PCP throughout their lifetime.

Treatment Management and Supportive Care

●Regular follow-up discussions about goals of care and care coordination may be necessary to improve both survival and quality of life. Engaging patients in these discussions, including therapy cessation, ensures that care aligns with their values and preferences.

●Surveillance and follow-up plans should be individualized for all patients,particularly older patients, considering comorbidities, functional status, and life expectancy. Personalization of care is key to managing the complexities of older adults or those with multiple medical co-morbidities.

●Patients should receive multidisciplinary and Interprofessional care that seeks to prevent and/or manage morbidities associated with breast cancer or its treatment.

●Patients often experience multiple transitions between different care settings and healthcare providers. Coordination between primary care providers and specialists is essential to ensure continuity of care.

●Address all treatment options at each progression, including the option of supportive care alone or hospice care, is appropriate in patients with stage IV disease

●Early involvement of a palliative care team should be considered to provide advance care planning, goals of care discussions, care transitions,psychosocial support, and management of cancer and therapy-related symptoms.

●Routine screening, evaluation, and assessment for supportive care interventions and referrals are necessary. Some of the symptoms are

Hormone-related symptoms, see NCCN Guidelines for Survivorship.

Cognitive dysfunction, see NCCN Guidelines for Survivorship.

Peripheral neuropathy

Cancer-related pain, see NCCN Guidelines for Adult Cancer Pain.

Cancer-related fatigue, see NCCN Guidelines for Cancer-Related Fatigue.

Cancer-related infections, NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections.

Chemotherapy-induced anemia, neutropenia, and thrombocytopenia, see NCCN Guidelines for Hematopoietic Growth Factors.

Immunotherapy-related toxicities, see NCCN Guidelines for Management of Immunotherapy-Related Toxicities.

Cardiac monitoring for patients treated with anthracyclines or HER2-targeted therapy, see NCCN Guidelines for Survivorship.

Nausea/vomiting, anorexia, cachexia, diarrhea,dyspnea,malignant wounds, sleep-wake disturbances,see NCCN Guidelines for Antemiesis and other NCCN Guidelines under Supportive Care.

Lifestyle, Wellness, and Psychosocial support:

●Patients should be encouraged to maintain a physically active lifestyle and a healthy diet whenever possible, see NCCN Guidelines for Survivorship.

●Consider age- and gender-appropriate cancer and preventive health screenings. These decisions should be individualized according to the patients prognosis.

Screen for anxiety, fear of progression, depression, and post-traumatic stress disorder(PTSD) related to cancer and its treatment, see NCCN Guidelines for Distress Management and NCCN Guidelines for Survivorship.

●Social determinants of health (SDOH) monitoring and referrals Provide resources and assistance through financial navigators,social workers, or other specified personnel to address financial concerns, employment issues, and family support. Ensuring access to these services can alleviate significant stress for patients.

See NCCN Guidelines for Palliative Care: Social Support/Resource Management.

Financial Advocacy Services Guidelines(Association of Cancer Care Centers).

Financial Toxicity and Cancer Treatment(National Cancer Institute).

See NCCN Guidelines for Distress Management.

●Facilitate connections with consumer groups, support networks,and organizations that advocate for accessible and equitable care.Equagement with these groups can empower patients and provide additional support.

●For any patients with sexual health concerns or for fertility and birth control in premenopausal patients, see BINV-C.

Communication

●Consistent and clear communication while acknowledging uncertainties of disease trajectory and prognosis is crucial.

●Treatment goals, survivorship issues, and the specific roles of each provider should be communicated to the patient.

Engagement

●See NCCN Resources for Patients and Caregivers and Guidelines for Patients.

●Address long-term survivorship issues specific to younger patients,such as psychosocial development and educational or vocational support.These patients may face unique challenges that require targeted interventions.

●Living will/end-of-life planning should be discussed.

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NCCN Guidelines Version 5.2025 Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF BIOMARKER TESTING HER2 TESTINGa,b

●HER2 testing should be performed on all new primary or newly metastatic breast cancers using methodology outlined in the ASCO/CAP HER2 testing guideline.

●A re-review of the pathology with consideration for repeat or consultative HER2 testing should be made if a Grade 1 (any histologic type), pure mucinous, pure tubular, or pure cribiformcar carcinoma tests HER2-positive.A

●After a negative HER2 test result on initial biopsy sample, consider retesting on subsequent surgical or other additional sample if the initial sample was suboptimal(eg), minimal invasive cancer was present, cold ischemic time or fixation was suboptimal), testing error is expected, additional samples contain higher grade morphologically distinct cancer from the biopsy, to rule out heterogeneity in a high grade cancer, or if it will otherwise aid in clinical decision-making.

![HER2 testing by validated immunohistochemistry (IHC) assayb,c\nIHC 0,1+d\nIHC 2+ IHC 3+ IHC 3+ IHER 2(+)\nU HER2(-) Must reflex test with ISH (if same specimen), I OFivocal result/or order new test with IHC or dual probe ISH (if new specimen available). \nHER2(+)\nIHC 3+ IHER 2(+)\n](2/aj0YEe4oUhYkBdfpda0fYP/figure89824edf9a88476fa92483b3dc75fc45_0_8.png) ![HER2-Negative:●(Group 5) HER2/CEP17 ratio <2.0 AND average HER2 copy number <4.0 signals/cell HER2-Negative(fetermined by concurrent IHC and ISH results):\nHER2-Negative(Determined by concurrent IHC and ISH results):\n●(Group 2) HER2/CEP17 ratio ≥ 2.0 AND average HER2 copy number ≥ 6.0 signals/cell and concurrent IHC 0-1+ or 2+●(Group 4) HER2/CEP17 ratio \ge 2.0 AND average HER2 copy number ≥ 6.0 signals/cell and concurrent IHC 0-1+ or 2+●(Group 3) HER2/CEP17 ratio \ge 2.0 AND average HER2 copy number \ge 6.0 signals/cell and concurrent IHC 3+●(Group 4) HER2/CEP17 ratio \ge 2.0 AND average HER2 copy number ≥ 6.0 signals/cell and concurrent IHC 3+●(Group 4) HER2/CEP17 ratio \ge 2.0 AND average HER2 copy number ≥ 4.0 and <6.0 signals/cell and concurrent IHC 3+●(Group 1) HER2/CEP17 ratio ≥2.0 AND average HER2 copy number ≥ 4.0 signals/cell and concurrent IHC 3+●(Group 2) HER2/CEP17 ratio \ge 2.0 AND average HER2 copy number ≥ 6.0 signals/cell and concurrent IHC 3+●(Group 4) HER2/CEP17 ratio \ge 2.0 AND average HER2 copy number ≥ 4.0 signals/cell and concurrent IHC 3+●(Group 1) HER2/CEP17 ratio ≥2.0 AND average HER2 copy number ≥ 4.0 signals/cell and concurrent IHC\n](2/aj0YEe4oUhYkBdfpda0fYP/figuree75cbefc9a3c46cb9f57395fa31b23e8_0_9.png) aNCCN endorses the ASC/CAP HER2 testing guideline.“Principles of HER2 Testing modified with permission from Wolff AC, Hammond MEH, Allison KH, et al. Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol 2018;36:2105-2122.

bLaboratory must participate in a quality assurance accreditation program for HER2 testing. Otherwise, tissue specimen should be sent to an accredited laboratory for testing. Health care systems and providers must cooperate to ensure the highest quality testing.

c Evidence from trastuzumab adjuvant trials show that HER2 testing by ISH or IHC have similar utility to predict clinical benefit from HER2-targeted therapy.

d The distinction between HER2 IHC 0/absent membrane staining, IHC 0+/with membrane staining(faint, partial membrane staining in≤10%), IHC 1+, or 2+/ISH negative results(on primary or metastatic samples) is currently clinically relevant since patients with metastatic disease may be eligible for treatment targeting non-amplified levels of HER2 expression.

e Single-probe ISH assays are not preferentially recommended but if used, cases with average HER2 copy number≥4.0 and<6.0 signals/cell should base final results on concurrent IHC and if 2+ reflexed to dual probe ISH testing.

f For ISH Groups 2-4 final ISH results are based on review of concurrent IHC,with recounting of the ISH test by a second reviewer if IHC is 2+(per 2018 CAP/ASCO Update recommendations). Additional report comments are recommended for negative final results in these ISH groups.

NCCN Guidelines Index Table of Contents Discussion

National Comprehensive Cancer Cancer Network®

PRINCIPLES OF BIOMARKER TESTING HR TESTING

●HR testing(ER and PR) by IHC should be performed on any new primary or newly metastatic breast cancer using methodology outlined in the latest ASCO/CAP HR testing guideline.9 DCIS should be tested for ER(PR not required).

● Laboratories should have standard operating procedures to maximize accuracy and reproducibility of results for cases with<10% ER staining or weak intensity staining(to avoid false negatives). The status of controls should be reported for cases with these results.

●ER testing should be used to determine if a patient is a candidate for endocrine therapies.

●PR testing by IHC on invasive cancers can aid in the prognostic classification of cancers and serve as a control for possible false-negative ER results. Patients with ER-negative, PR-positive cancers may be considered for endocrine therapies, but the data on this group are noted to be limited. The same overall interpretation principles apply but PR should be interpreted as either positive(if 1%-100% of cells have nuclear staining) or negative(if<1% or 0% of cells have nuclear staining).

●Cancers with 1%-100% of patients positive for ER expression are considered ER-positive. Patients with these results are considered eligible for endocrine therapies(applies to DCIS and invasive cancers).

Invasive cancers with between $1\%-10\%$ ER positivity are considered ER-low-positive. There are more limited data on the benefit of endocrine therapies in this group, but they suggest possible benefit from endocrine treatment, so patients are considered eligible for this treatment(as above). However, this group is noted to be heterogeneous and the biologic behavior of ER-low-positive cancers may be more similar to ER-negative cancers. This should be considered in decision-making for other adjuvant therapy and overall treatment pathway.

●Interpretation of any ER result by pathology should include evaluation of the concordance with the histologic findings of each case. Clinicians should be aware of when results are unusual and work with pathologists to attempt to resolve(eg, repeat testing, consultative review) or explain atypical reported findings. See table below.

Cancers with<1% staining are considered ER-negative. Patients with cancers with these results have not been shown to benefit from endocrine therapies.

Summary of ER IHC Scoring/Interpretation

|Results (following ER testing by validated IHC assay)|Interpretation/ Report As:| |---|---| |0% to <1% of nuclei stain|ER-negative| |1%-100% of nuclei stain|ER-negative| |1%-100% of nuclei stain|ER-low-positive (with recommended comment)| |>10% of nuclei stain|ER-positive|

Correlation of ER and Histology: Highly Unusual Results

|Highly Unusual ER-Negative Results|Highly Unusual ER-Positive Results| |---|---| |Low-grade carcinomas of no special type (also known as invasive ductal carcinoma)|Metaplastic carcinomas of all subtypes| |Lobular carcinomas (classic type)|Adenoid cystic carcinomas and other salivary gland-like carcinomas of the breast| |Pure tubular,cribiform, or mucinous carcinomas|Secretory carcinoma| |Encapsulated papillary and solid papillary carcinomas|Carcinomas with apocrine differentiation (apocrine carcinoma)|

9Allison KH, Hammond MEH, Dowsett M, et al. Estrogen and Progesterone Receptor Testing in Breast Cancer: ASCO/CAP Guideline Update. J Clin Oncol 2020;38:1346-1366; Arch Pathol Lab Med 2020;144:545-563.

Note: All recommendations are category 2A unless otherwise indicated.

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NCCN Guidelines Version 5.2025

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PRINCIPLES OF DEDICATED BREAST MRI TESTING

See NCCN Guidelines for Breast Cancer Screening and Diagnosis for indications for screening MRI in patients at increased breast cancer risk.

Personnel, Facility, and Equipment

●Breast MRI examinations are performed with IV contrast and should be performed and interpreted by an expert breast imaging team working in concert with the multidisciplinary treatment team.

●Breast MRI examinations require a dedicated breast coil and breast imaging radiologists familiar with the optimal timing sequences and other technical details for image interpretation. The imaging center should have the ability to perform MRI-guided needle sampling and/or image-guided localization of MRI-detected findings.

Clinical Indications and Applications

●May be used for staging evaluation to define extent of cancer or presence of multifocal or multicentric cancer in the ipsilateral breast, or as screening of the contralateral breast cancer at time of initial diagnosis(category 2B). There are no high-level data to demonstrate that the use of MRI to facilitate local therapy decision-making improves local recurrence or survival.1

●May be helpful for breast cancer evaluation before and after preoperative systemic therapy to define extent of disease, response to treatment, and potential for breast-conservation therapy.

●May be useful in identifying otherwise clinically occult disease in patients presenting with axillary nodal metastases(cT0,cN+),with Paget disease, or with invasive lobular carcinoma poorly(or inadequately) defined on mammography, ultrasound, or physical examination.

●False-positive findings on breast MRI are common. Surgical decisions should not be based solely on the MRI findings. Additional tissue sampling of areas of concern identified by breast MRI is recommended.

●The utility of MRI in follow-up screening of most patients with prior breast cancer is undefined and annual MRI is recommended in patients with personal history of breast cancer who:2

1) were diagnosed at age ≤50 or

2) have dense breasts

1 Houssami N, Ciatto S, Macaskill P, et al. Accuracy and surgical impact of magnetic resonance imaging in breast cancer staging: systematic review and meta-analysis in detection of multifocal and multicentric cancer. J Clin Oncol 2008;26:3248-3258.

2 Monticciolo DL, Newell MS, Moy L,et al.Breast cancer screening for women at higher-than-average risk:Updated recommendations from the ACR.J Am Coll Radiol 2023;20:902-914.

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NCCN Guidelines Version 5.2025 Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

FERTILITY, BIRTH CONTROL, AND SEXUAL HEALTH

The general considerations for fertility and sexual health/function outlined for specific populations in NCCN Guidelines for Adolescent and Young Adult(AYA) Oncology and NCCN Guidelines for Survivorship are applicable to all patients diagnosed with breast cancer. See NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology and NCCN Guidelines for Survivorship.

●All premenopausal patients should be informed about the potential impact of chemotherapy on fertility and asked about their desire for potential future pregnancies. Patients who may desire future pregnancies should be referred to fertility specialists before chemotherapy and/or endocrine therapy to discuss the options based on patient specifics, disease stage, and biology(which determine the urgency, type, and sequence of treatment). Timing and duration allowed for fertility preservation, options inclusive of oocyte and embryo cryopreservation as well as evolving technologies, and the probability of successful pregnancies subsequent to completion of breast cancer therapy are also to be discussed.

●Although data are limited, hormone-based birth control is discouraged regardardless of the HR status of the patient's cancer.

●Alternative methods of birth control include intrauterine devices(IUDs),barrier methods, or, for patients with no intent of future pregnancies, tubal ligation or vasectomy for the partner.

●Randomized trials have shown that ovarian suppression with GnRH agonist therapy administered during adjuvant chemotherapy in premenopausal patients with breast tumors(regardless of HR status) may preserve ovarian function and diminish the likelihood of chemotherapy-induced amenorrhea.

●Smaller historical experiences in patients with ER-positive disease have reported conflicting results with regard to the protective effect of GnRH agonist therapy on fertility.

●Although amenorrhea frequently occurs during or after chemotherapy, it appears that the majority of patients<35 years resume menses within 2 years of finishing adjuvant chemotherapy.

●Breastfeeding following breast-conservation cancer treatment is not contraindicated. However, the quantity and quality of breast milk produced by the conserved breast may not be sufficient or may be lacking some of the nutrients needed. Breastfeeding is not recommended during active treatment with chemotherapy and endocrine therapy or within 6 months of completing trastuzumab or pertuzumab.

●Menses and fertility are not necessarily linked. Absence of regular menses, particularly if the patient is taking tamoxifen, does not necessarily imply infertility. Conversely, the presence of menses does not guarantee fertility. There are limited data regarding continued fertility after chemotherapy.

●Patients should be advised not to become pregnant while on any systemic therapy, and specific drug package inserts should be consulted for recommendations.

●A prospective trial(Partridge AH, Niman SM, Ruggeri M, et al.Breast 2021;59:327-338) evaluated premenopausal patients who had completed between 18-30 months of endocrine therapy before temporarily interrupting endocrine therapy for up to 2 years to allow for pregnancy. At short-term follow-up, the risk of recurrence was not increased among those patients who enrolled or those who became pregnant. This approach is an option for patients who desire pregnancy, although long-term safety is still unknown.

Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

CONSIDERATIONS FOR SURGICAL AXILLARY STAGING

![No palpable lymph node at diagnosis or limited axillary lymph node involvement involving needle biopsy and marker placement a in the most suspicious or imaging of manipulation of blood and suspicious solutions as imaging of blood and suspicious solutions as imaging of blood and suspicious solutions as imaging of blood on imaging confirmed by needle biopsy and marker needle biopsy and marker (palpable) lymph nodes or limited axillary lymph node involvement in the most suspicious node in the ollm lymph nodes at diagnosis on exam or imaging of blood or imaging of blood as important information. In 2023-2024-2025-2026. In the following criteria9: Meets ALL of the following criteria9: cT1-T2, T3° cN0 or pN1mic No| 2-2 positive SLNs" 1-2 positive SLNs" 1-3. No preoperative chemotherapy No further end to all any 2-3. No preoperative The most suspicious cancer and risk and suspicious on exam or imaging of blood as suspicious node in the ollm lymph nodes at diagnosis on exam or imaging of blood as suspicious node in the ollm lymph nodes at diagnosis on exam or imaging of blood as suspicious node in the ollm lymph nodes at disease burden on imaging of blood on marker nucleation. In addition, this message and risk and suspicious on exam or imaging of blood as suspicious node in the ollm lymph nodes at diagnosis on exam or imaging of blood as suspicious node in the ollm lymph node in the ollm lymph nodes at diagnosis on exam or imaging of blood as suspicious node in the ollm lymph node in the ollm lymph node at diagnosis on exam or imaging of blood as suspicious node in the ollm lymph nodes at diagnosis on exam or imaging of blood as suspicious node in the ollm lymph node. In the ollm lymph node at the time of surgery. Only the most suspicious node should be marked and retrieved on the post-19:79-GS4-01-GS04-01-SENOMAC: de Boniface J,et al.N Engl J Med 2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SIN\n](2/aj0YEe4oUhYkBdfpda0fYP/figurec243ec201b1141f3b7f9cf27a6d37a26_0_5.png) a If a positive lymph node is clipped or tattooed during biopsy, every effort should be made to remove the clipped or tattooed node at the time of surgery. Only the most suspicious node should be marked and retrieved along with SLNs to reduce the false negative rate.

b SLN mapping injections may be peritumoral, subareolar, or subdermal.Sentinel node involvement is defined by multilevel node sectioning with hematoxylin and eosin(H&E) staining. Cytokeratin IHC may be used

hematoxylin and eosin(H&E) staining. Cytokeratin IHC may be used for equivocal cases on H&E. Routine cytokeratin IHC to define node involvement is not recommended in clinical decision-making.

d If clinically negative axilla before chemotherapy and then have a positive sentinel node after chemotherapy, consider completion axillary lymph node dissection or multidisciplinary tumor board discussion on appropriateness of radiation of axilla without further surgery.

e Limited data exist for T3 tumors.

f Axillary Lymph Node Staging(BINV-E).

9.ACOSOG Z0011: Giuliano AE, et al. JAMA 2017:318:918-926.EORTC AMAROS:Donker M, et al. Lancet Oncol 2014:15:1303-1310; Ruters E,et al.Cancer Res 2019;79-GS4-01-GS04-01.SENOMAC: de Boniface J,et al.N Engl J Med 2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-OFF: Treinteri C,et al.Br J Surg 2023;110:1143-1152. Galimberti V,et al. Lancet Oncol 2013;14:297-305.

h Limited data exist for ≥3 positive SLNs.

In the mastectomy setting, in patients who were initially cNO, who have positive nodes on SLNB, and have no axillary dissection, RT to the chest wall should include undissected axilla at risk± RNI.

1Among patients shown to be N+ prior to preoperative systemic therapy, SLNB has a large% false-negative rate when performed after preoperative systemic therapy,which can be improved by marking and removing the most suspicious biopsied node,disusing dual tracers, and by obtaining $\ge$ 3 sentinel nodes(targeted axillary lymph node dissection).(Caudle AS, et al. J Clin Oncol 2016;34:1072-1078.)

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

BINV-E

AXILLARY LYMPH NODE STAGING

SLNB should be performed and is the preferred method of axillary lymph node staging if the patient is an appropriate SLNB candidate (BINV-D).

In the absence of definitive data demonstrating superior survival, the performance of axillary staging may be considered optional in patients who have particularly favorable tumors, patients for whom the selection of adjuvant systemic and/or RT is unlikely to be affected, or those

with serious comorbid conditions.a,b

Level III dissection to the thoracic inlet should be performed only in cases with gross disease in level II and/or lll.

In the absence of gross disease in level II nodes, lymph node dissection should include tissue inferior to the axillary vein from the latissimus dorsi muscle laterally to the medial border of the pectoralis minor muscle (level I/II).

Lymphedema is a potential side effect after the treatment of axillary lymph node surgery resulting from damage to the lymphatic system.

Early detection/diagnosis of lymphedema is key for optimal management. Consider pretreatment measurement of both arms as a baseline for patients with risk factors for lymphedema. See NCCN Guidelines for Survivorship: Lymphedema (SLYMPH-1).

a Sentinel node biopsy may be omitted based on the SSO Choosing Wisely recommendation in patients ≥70 years of age with HR+/HER2-negative and pT1, cN0 tumors (Hughes KS, et al. J Clin Oncol 2013;31:2382-2387. Kunkler IH, et al. N Engl J Med 2023:388:585-594).

b Based on emerging data from the SOUND trial, patients with HR+/HER2-negative tumors, pT1, N0 (node negative by axillary ultrasound), may be considered for omission of SLN biopsy. Gentilini OD, et al. JAMA Oncol 2023;9:1557-1564.

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BINV-F 1 OF 2

• Margins should be evaluated on all surgical specimens from BCS. Accurate orientation of the surgical specimens is required for optimal

margin evaluation.

• Pathology report should include:

Description of the gross and microscopic margin status.

Reporting of the distance, orientation, and type of tumor (invasive or DCIS) in relation to the closest margin.

Quantification of the extent of disease that is approximating the inked margin.

• For mammographically detected DCIS with microcalcifications, complete resection should be documented by analysis of margins and

specimen radiography. Post-excision mammography can be considered if there is uncertainty.

• The NCCN Panel accepts the definitions of negative margins after breast-conservation therapy from the 2014 SSO/ASTRO Margins

Guideline1 for Stage I/II Invasive Cancers and the 2016 SSO/ASTRO/ASCO Guideline for DCIS.2 For patients with stage I or II invasive cancers after BCS, a positive margin is defined as “ink on tumor” (any invasive cancer or DCIS cells on ink). These patients generally require further surgery—either a re-excision to achieve a negative margin or a mastectomy. If re-excision is technically feasible to allow for BCS to achieve“no ink on tumor,” this can be done with resection of the involved margin guided by the orientation of the initial resection specimen or reexcision of the entire original excision cavity. There may be select patients with stage III invasive cancers who may be eligible for BCS. For

these patients, the margins status would be accessed with similar definitions.

DCIS

• For patients with pure DCIS treated by BCS and whole breast RT, a quantitative description of any tumor close to margin resection width

of at least 2 mm is associated with a reduced risk of ipsilateral breast tumor recurrence (IBTR) relative to narrower negative margin widths,while the routine practice of obtaining margins >2 mm to further improve outcomes is not supported by the evidence. When there is only

minimal or focal DCIS involvement near the margin, clinical judgment should be utilized to weigh the risks of re-excision with risk of

recurrence for an individual patient.

• For patients with DCIS treated with excision alone (no whole breast RT), regardless of margin width, there is a substantially higher rate of

IBTR than treatment with excision and whole breast RT, even in predefined, patients who are low risk. Although the optimal margin width

for treatment with excision alone is unknown, it should be at least 2 mm, with some evidence suggesting improved IBTR rates with margin

widths wider than 2 mm.

• DCIS with microinvasion (DCIS-M), defined as an invasive focus ≤1 mm in size, should refer to the DCIS margin definition when considering the optimal margin width (>2 mm), given that the majority of DCIS-M is comprised of DCIS and systemic therapy utilization for this lesion

more closely reflects the treatment pattern for DCIS than for invasive carcinoma.

Continued MARGIN STATUS RECOMMENDATIONS AFTER BREAST-CONSERVING SURGERY (BCS) FOR INVASIVE CANCERS AND DCIS

1 Moran MS, Schnitt SJ, Giuliano AE, et al. Society of Surgical Oncology-American Society for Radiation Oncology consensus guideline on margins for breastconserving surgery with whole-breast irradiation in stages I and II invasive breast cancer. J Clin Oncol 2014;32:1507-1515.

2 Morrow M, Van Zee KJ, Solin LJ, et al. Society of Surgical Oncology-American Society for Radiation Oncology-American Society of Clinical Oncology Consensus

Guideline on Margins for Breast-Conserving Surgery With Whole-Breast Irradiation in Ductal Carcinoma In Situ. J Clin Oncol 2016;34:4040-4046.

NCCN

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MARGIN STATUS RECOMMENDATIONS AFTER BCS FOR INVASIVE CANCERS AND DCIS

Invasive Breast Cancer

●For invasive breast cancers that have a component of DCIS, regardless of the extent of DCIS, the negative margin definition of"no ink on tumor" should be based on the invasive margin guideline. In this setting, "no ink on tumor" is recommended for either DCIS or invasive cancer cells, primarily because the natural history, treatment, and outcomes of these lesions are more similar to invasive cancer than DCIS.For specifically challenging cases, clinical judgment and discussion with the patient should precede routine re-excision.

●These margin recommendations cannot be applied directly to patients undergoing APBI/PBI,1 where data regarding local recurrence are more limited. Furthermore, individualized clinical judgment should be utilized on a case-by-case basis, using postoperative mammography to identify residual calcifications and clinical-pathologic factors such as quantitative extent of disease near margin, presence of extensive intraductal component (EIC),3 young age, or multiple close margins to assist in identifying patients who may have an increased risk of IBTR and therefore may be selected to benefit from re-excision.

●For patients with invasive breast cancer after BCS, with microscopically focally positive margins (in the absence of an EIC),3 the use of a higher radiation boost dose to the tumor bed may be considered, since generally a boost to the tumor bed is recommended for patients at higher risk of recurrence. See BINV-I.

||No ink on tumor|2-mm margin|No margin necessary| |---|---|---|---| |Invasive breast cancer|X|X|| |Invasive breast cancer + DCIS|X|X|| |Invasive breast cancer + extensive DCIS|X|X|| |Invasive breast cancer (treated with neoadjuvant chemotherapy followed by breast-conservation therapy),4,5|X||| |Pure DCIS||X|| |DCIS with microinvasion||X|| |Classic LCIS* at surgical margin||X|X| |Atypia at surgical margin|||X|

*For pleomorphic lobular carcinoma in situ(LCIS), the optimal width of margins is not known.

1 Moran MS,Schnitt SJ,Giuliano AE,et al.Society of Surgical Oncology-American Society for Radiation Oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in stages I and II invasive breast cancer. J Clin Oncol 2014;32:1507-1515.

${}^{3}$ EIC is defined as an infiltrating ductal cancer where $>25\%$ of the tumor volume is DCIS and DCIS extends beyond the invasive cancer into surrounding normal breast parenchyma.

4 Choi J, Laws A, Hu J, et al. Margins in breast-conserving surgery after neoadjuvant therapy. Ann Surg Oncol 2018;25:3541-3547.

5 Wimmer K, Bolliger M, Bago-Horvath Z,et al. Impact of surgical margins in breast cancer after preoperative systemic chemotherapy on local recurrence and survival.Ann Surg Oncol 2020;27:1700-1707.

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BINV-G

1 Boughey JC, Rosenkranz KM, Ballman KV, et al. Local recurrence after breast-conserving therapy in patients with multiple ipsilateral breast cancer: Results from

ACOSOG Z11102 (Alliance). J Clin Oncol 2023;41:3184-3193.

2 Arthur DW, Winter KA, Kuerer HM, et al. Effectiveness of breast-conserving surgery and 3-dimensional conformal partial breast reirradiation for recurrence of breast

cancer in the ipsilateral breast: The NRG Oncology/RTOG 1014 Phase 2 Clinical Trial. JAMA Oncol 2020;6:75-82.

a Contraindications to radiation delivery where toxicity may be increased.b Patients with a known genetic predisposition to breast cancer may have an increased risk of contralateral or ipsilateral breast cancers after breast-conservation

therapy. Risk reduction strategies including prophylactic mastectomies should be discussed. See NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate.

c For patients >40 years of age with 2 biopsy proven cTis-cT2 lesions (with at least one site invasive) after MRI evaluation, intending on adjuvant whole breast radiation with boost, breast-conservation therapy may be considered. See Boughey JC, et al. J Clin Oncol 2023;41:3184-3193.

Note: All recommendations are category 2A unless otherwise indicated.

CONTRAINDICATIONS TO BREAST-CONSERVING APPROACHES REQUIRING RT

Absolute contraindications (mastectomy is recommended)

• Inflammatory breast cancer or invasive breast cancer with extensive skin or dermal lymphatic involvement

• Diffuse suspicious or malignant-appearing microcalcifications

• Inability to clear multiple positive pathologic margins after one or more re-excision attempts, see BINV-F

• Homozygous ATM mutation (often leads to ataxia-telangiectasia syndrome) (category 2B)a

• Multicentric disease with any of the following criteria1,b:

Receipt of neoadjuvant chemotherapy or endocrine therapy

Age ≤ 40

Triple negative breast cancer (ER-, PR-, and HER2-negative)

More than 2 lesions involving more than 2 quadrants by MRI evaluation

Any individual lesion ≥5 cm

BRCA mutation carrier

Multicentric pure DCIS

Inability to achieve negative margins (defined as no ink on tumor for invasive cancers ± DCIS), see BINV-F cN2–N3

Any reason for precluding the delivery of adjuvant whole breast RT + boost

• Patients diagnosed with gestational breast cancer who cannot receive RT within 12–16 weeks.a See PREG-1.

Relative contraindications (mastectomy should be considered, but breast-conserving therapy may be appropriate)

• Patients with a known genetic predisposition to breast cancerb

• Pathologic p53 mutation (Li-Fraumeni syndrome) (category 2B)a,b

(See NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate)

• Active connective tissue disease involving the skin (eg, scleroderma or lupus)a

• A history of prior radiation therapy to the affected area; knowledge of doses and volumes prescribed is importanta,c,2

National Comprehensive Cancer Network®

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF BREAST RECONSTRUCTION AFTER SURGERY

![BCSC (mark cavity with clips for subsequent RT planning, particularly in cases of oncoplastic tissue rearrangement/ reduction)d\nCarcinoma\nin situa,b\nor Invasive bepaned\nBCSC (mark block with clips for subsequent RT planning, particularly in cases of oncoplastic tissue rearrangement/ reduction)d\nNo reconstruction required if ratio of tumor to breast volume is small and minimal cosmetic deformity will result or Consider oncoplastic reduction or mastopexy and simultaneous or delayed contralateral matching procedure or Consider bilateral breast reduction if symptoms warrant breast reduction or Local tissue rearrangement, regional flap (LD, partial LD, TDAP)\nRT red ondo F 4\nNo history of RT no adjuvant RT needed\nDelayed flap for correction of contour defects performed≥6 months after RT for symmetry\nCarcinoma in situa,b or Invasive carcinoma</n\nMastectomy\nIBC\nNo history of RT no adjuvant RT needed\nReconstruction Based on Planning Adjuvant RT (BINV-H 2)\n$No history of RT/no adjuvant RT needed\nImplant, autologous, or combination reconstruction\nUnknown RT history or need for RT\nReconstruction Based on Unknown History of RT or Unknown Need for Postmastectomy (BINV-H 7)\n](2/aj0YEe4oUhYkBdfpda0fYP/figure03caefcdc7aa48f8b43335c1ae47e8ef_0_5.png) a General Principles of Breast Reconstruction(BINV-H 5).

b Patient Factors Affecting Choice of Reconstruction (BINV-H 6).

c An evaluation of the likely cosmetic outcome of BCS should be performed prior to surgery.Oncoplastic techniques for breast conservation can extend breast-conserving surgical options in situations where the resection by itself would likely yield an unacceptable cosmetic outcome.Application of these oncoplastic techniques may reduce the need for mastectomy and decrease the need for a secondary surgery to minimize breast deformity. Patients should be informed of the possibility of margins and potential need for secondary surgery, which could include either segmental re-excision, or mastectomy with or without loss of the nipple. Systematic oncoplastic reduction specimen orientation as well as highly specific operative documentation regarding tissue rearrangement should be conducted. Enhanced communication between the radiation oncology team and reconstructive team will be necessary for boost cavity localization for RT treatment planning(Shah C, et al. Ann Surg Oncol 2018;25:2509-2511).

d Consider staged partial mastectomy reconstruction(oncoplastic approaches) if preoperative margin status is unclear(lobular,multifocal/centric).

eAs with any mastectomy, there is a risk of locoregional cancer recurrence, and evidence suggests skin-sparing or skin- and nipple-sparing mastectomy is probably equivalent to standard mastectomy in this regard. Indications for PMRT following skin-sparing mastectomy should not differ from standard mastectomy.

National Comprehensive Cancer Network®

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF BREAST RECONSTRUCTION AFTER SURGERY

RECONSTRUCTION BASED ON PLANNED ADJUVANT RT^{a,b}

![Intersspace expansion followed by exchange to implant prior to the initiation of RT$^{k,k}_{1}$ implant- implant (prepectoral, partial submuscular, or total submuscular tissue expander)\n2 stage: tissue expander followed by permanent implant (prepectoral, partial submuscular, or total submuscular tissue expander)\nImplant-based reconstruction plannedef\n1 stage: direct to implant${}^{h}$ \n26 months after completion of RT$^{h}$ \nI\ng\nImmediate autologous reconstruction ${}^{1}$ \nDelayed reconstruction ${}^{2}$ 6 months after the completion of RT\nPlace tissue expander at the time of surgery, followed by expansion, RT, and delayed autologous reconstruction ${}^{1}$ \n26 months after completion of RT$^{6}$ \n](2/aj0YEe4oUhYkBdfpda0fYP/figure6456c279a6b541dc987fe537976089d8_0_6.png) a General Principles of Breast Reconstruction(BINV-H 5).

b Patient Factors Affecting Choice of Reconstruction(BINV-H 6).

f The use of RT significantly increases the baseline risk of capsular contracture,aesthetic deformity,malposition,implant exposure,infection, and reconstructive failure.

g Common donor sites for autologous tissue include the abdomen(ie, DIEP, MS-TRAM, SIEA, free TRAM, pedicled TRAM), gluteal region(ie, SGAP, IGAP), thigh

h Determined by preoperative size and ptosis, patient desire of postoperative size,and assessment intraoperatively of skin and soft-tissue quality and perfusion, with consideration for patient-specific relative contraindications(eg, smoking, obesity)to single-stage versus two-stage approaches. Healing issues may occur and delay initiation of RT.

Consider delaying autologous reconstruction until after RT is completed, as RT to a flap may cause loss of cosmesis and/or fat necrosis.

k Exchange of tissue expander to implant should be timed to avoid any delay in adjuvant RT.

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NCCN Guidelines Version 5.2025 Invasive Breast Cancer

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PRINCIPLES OF BREAST RECONSTRUCTION AFTER SURGERY

RECONSTRUCTION BASED ON PRIOR HISTORY OF RTa,b

![Recurrent carcinoma after breast conservation including RT\nAssess soft tissue preoperatively and intraoperatively!\nInadequate\nAdequatem\n2 stage: tissue expander followed by implant\nInadequate\n00\n2 stage: tissue expander followed by implant\n0\n](2/aj0YEe4oUhYkBdfpda0fYP/figureaacf5cb68a684179af648f9ef4322c67_0_6.png) ![Delayed reconstruction after mastectomy and RT\nAssess soft tissue preoperatively and intraoperatively\nAdequate\n2 stage: tissue expander followed by implant or autologous tissue\nInadequate\nInadequateem\n8\nAutologous(preferred) or combination,no\n](2/aj0YEe4oUhYkBdfpda0fYP/figure7004f101fedd4110a36fc2a4f6427f7c_0_7.png) a General Principles of Breast Reconstruction(BINV-H 5).

b Patient Factors Affecting Choice of Reconstruction(BINV-H 6).

|Assessment includes clinical examination and may also include intraoperative technologies to assess perfusion.

m In patients with a history of RT to the breast, implant-based reconstruction carries a significantly increased risk of capsular contracture, aesthetic deformity,malposition, implant exposure, infection, and reconstructive failure.

` n Addition of latissimus or other regional or free flap to prosthetics in the patient who has previously had irradiation mitigates many of the effects specified in the previous footnote.`

°In the patient with delayed reconstruction, there is often limited soft tissue even with the addition of a latissimus flap. Therefore, latissimus flap+ tissue expander placement may be required if a permanent implant cannot be accommodated under the latissimus flap.

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NCCN Guidelines Version 5.2025 Invasive Breast Cancer

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PRINCIPLES OF BREAST RECONSTRUCTION AFTER SURGERY

RECONSTRUCTION BASED ON NO OR UNKNOWN HISTORY OF RT OR UNKNOWN NEED FOR POSTMASTECTOMY RTa,b

![No RT planned\n:Convert to autologous tissue reconstruction\nAdjuvant chemotherapy\nplanned\nTissue expansion during chemotherapy\nRT planned\nPrior to initiation of RT, if no delay to initiation of RT or6 months after RT)\nImmediate placement of tissue expander at the time of mastectomy (prepectoral, partial submuscular, total submuscular tissue expander placement)^{f}\nNo adjuvant chemotherapy planning\nRT planned\nR RT planned\n1 stage:direct to implant ${^{\varepsilon}}$ or the ipsalateral or contralateral breast after RT if needed\ned autologous tissue reconstruction\n8\nConversion to autologous tissue reconstruction\n6 months after RT\nRT planned\nTissue expansion followed by exchange to permanent implant or autologous tissue reconstruction\n1 stage:direct to implant ${^{\varepsilon}}$ or immediate autologous tissue ${\varepsilon}$ and delay initiation of RT\nConsider revisional surgeries to the ipsilateral or contralateral breast after RT if needed\ndeformation or mastectomy\nLayed reconstruction\nRT not required\nReconstruction with implant, autologous tissue, or a combination\nDelayed reconstruction\nR RT required\nReconstruction Based on History of RT (BINV-H 3)\n](2/aj0YEe4oUhYkBdfpda0fYP/figureaebc481e34394c578b811dada045eabe_0_6.png) ![1 stage: direct to implant\nor\nConsider reversal surgeries or leptital or contralateral reconstruction or latissimus dorsi\nwith implant at time of mastectomy i\nor RT not required→Reconstruction with implant, autologous tissue, or a combination\n](2/aj0YEe4oUhYkBdfpda0fYP/figure8ebe2d8a9f19461989fb6eacb1389104_0_7.png) ![Tissue expansion followed by RT; conversion to permanent implant or autologous tissue≥6 months after completion of RT (category 2B)j or\nTissue expansion followed by exchange to permanent implant before RT (if no delay to initiation of RT)\n](2/aj0YEe4oUhYkBdfpda0fYP/figure516807c556d646ca85d5fa485c661a0d_0_8.png) ![Delayed reconstruction\nRT not required→Reconstruction with implant, autologous tissue, or a combination\nRedelayed reconstruction\nRT required→Reconstruction Based on History of RT(BINV-H 3)\n](2/aj0YEe4oUhYkBdfpda0fYP/figure0cd0687b91274432948cb4e291d68734_0_9.png) a General Principles of Breast Reconstruction(BINV-H 5).

Consider delaying autologous reconstruction until after RT is completed, as RT to a flap may cause loss of cosmesis and/or fat necrosis.

b Patient Factors Affecting Choice of Reconstruction(BINV-H 6).

f The use of RT significantly increases the baseline risk of capsular contracture,aesthetic deformity,malposition,implant exposure, infection, and reconstructive failure.

Consultation with radiation oncologists may be necessary to determine if volume of contralateral tissue expander will affect RT treatment planning. In some cases, contralateral deflation may be required prior to CT simulation. Radiation oncology consultation should also be requested in cases of an anticipated close or positive deep margin, as this may impact the optimal placement of the expander(pre- vs.subpectoral). Clips to identify the close/positive margins should be placed to assist in delineating the tumor bed boost.

h Determined by preoperative size and ptosis, patient desire of postoperative size, and assessment intraoperatively of skin and soft-tissue quality and perfusion,with consideration for patient-specific relative contraindications (eg, smoking,obesity) to single-stage versus two-stage approaches. Healing issues may occur and delay initiation of RT.

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Note: All recommendations are category 2A unless otherwise indicated.

BINV-H 5 OF 7

General Principles of Breast Reconstruction

• Breast reconstruction may be an option for any patient receiving surgical treatment for breast cancer. All patients undergoing breast

cancer treatment should be educated about breast reconstructive options as adapted to their individual clinical situation. However,

breast reconstruction should not interfere with the appropriate surgical, medical, and radiation management of the cancer or the scope of appropriate surgical treatment for this disease. Coordinating consultation and surgical treatment with a reconstructive surgeon should be executed within a reasonable time frame. The process of breast reconstruction should not govern the timing or the scope of appropriate

surgical treatment for this disease. The availability of or the practicality of breast reconstruction should not result in the delay or refusal of appropriate surgical, medical, and radiation intervention.

• Some patients may choose not to have reconstruction after mastectomy. The option to undergo mastectomy alone with a surgically

optimized closure should be offered to all patients as part of a comprehensive discussion of reconstructive options. Achieving the optimal

result in this scenario may require additional procedures beyond the initial mastectomy. See BINV-H (6) for patient factors influencing choice of reconstruction.

• Selection of reconstructive option and timing of reconstruction option is based on an assessment of cancer treatment, body habits of

patients, obesity, smoking history, comorbidities, and patient concerns. Smoking and obesity (WHO Class 2 and 3) increase the risk of

perioperative complications for all types of breast reconstruction. Patients with these high-risk factors should be counseled about their

increased risk for complications following breast reconstruction, including donor site complications/hernias and bulges of the abdominal

wall, delayed healing, mastectomy skin flap necrosis, total flap failure (obesity), and implant failure (smoking).

• Nipple areolar reconstruction should be offered to patients if the nipple-areolar complex (NAC) has been removed as part of their cancer

treatment. Various techniques are available for nipple reconstruction. Three-dimensional (3-D) tattooing can be offered to patients as an

option for NAC reconstruction.

• Additionally, patients who are not satisfied with the cosmetic outcome following completion of breast cancer treatment should be offered

reconstructive surgery consultation.

• Patients known to harbor genetic mutations that increase the risk of breast cancer may opt to undergo bilateral prophylactic mastectomies with reconstruction. Reconstruction can be performed with prosthetic, autologous tissue, or a combination of implant with autologous

tissue.

• Skin-sparing mastectomy should be performed by an experienced breast surgery team that works in a coordinated, multidisciplinary fashion to guide proper patient selection for skin-sparing mastectomy, determine optimal sequencing of the reconstructive procedure(s) in relation to adjuvant therapies, and perform a resection that achieves appropriate surgical margins.

• Revisional surgery may be necessary after breast reconstruction. This may include procedures such as fat grafting, mastopexy, direct

excision/suction-assisted lipectomy, contralateral procedures (in cases of unilateral reconstruction), and others. Patients should be informed before reconstruction that revision surgery may be necessary.

PRINCIPLES OF BREAST RECONSTRUCTION AFTER SURGERY

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BINV-H 6 OF 7

Patient Factors Influencing Breast Reconstruction

• Breast reconstruction is elective and patients may choose to not have breast reconstruction. Individual patients present preoperatively witha variety of factors that may impact the choice of reconstruction, the risk of complications, donor site morbidity, and aesthetic result. Eachof these factors must be taken into account, along with patient desire, to choose the optimal method of reconstruction.

• Patient desire

The patient may have a strong feeling towards one form of reconstruction after being given the options. Breast reconstruction should be ashared decision.

• Medical comorbidities

Medical comorbidities may preclude longer reconstructive procedures such as autologous tissue reconstruction in some patients.

The selection of the reconstructive method of choice should take into consideration patient comorbidities.

Poorly controlled diabetes is a risk factor for postoperative complications in both implant and autologous tissue reconstruction.

Patients should be screened for personal or familial thrombophilia. Thrombophilia may result in reconstructive failure of microsurgical reconstruction or thromboembolic events.

• Tobacco use

Smoking has been associated with increased risk of delayed wound healing, mastectomy flap necrosis, NAC necrosis in the setting ofnipple-sparing mastectomy, infection, and failure of implant-based reconstruction. In free flap reconstruction, smoking increases the risk of donor complications. Patients should be encouraged to stop smoking prior to reconstruction.

Smoking has not definitively been shown to increase the risk of microvascular thrombosis in free flap breast reconstruction.

• Breast size/shape

If patient has significant macromastia or ptosis, consideration can be given to a reduction pattern mastectomy with either implant-based orautologous tissue reconstruction, or oncoplastic reduction techniques. The volume limitations of implants may preclude an acceptable reconstruction in patients with macromastia if preservation of volume is a priority.

• BMI

Patients with a markedly elevated BMI may be at increased risk of infectious complications and seromas as well as donor sitecomplications from autologous reconstruction, including delayed healing and hernia formation. Immediate reconstruction can be performed, but delayed reconstruction can be considered if the patient is motivated to lose weight. Oncoplastic reduction techniques can be considered if the breast is large/ptotic.

• Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) and other rare implant-associated malignancies

BIA-ALCL commonly presents with delayed periprosthetic effusion and breast asymmetry occurring >1 year after implantation.

Rarely, BIA-ALCL can present with a mass, regional lymphadenopathy, overlying skin rash, and/or capsular contracture.

Similar symptoms can also be seen in breast implant associated squamous cell carcinoma (BIA-SCC), another rare implant associated malignancy. Individuals with breast implants have a very small risk of developing BIA-ALCL (average 7–9 years after implantation) and BIA-SCC (average 22 years after implantation). The majority of cases of BIA-ALCL have been seen in textured implants, while BIA-SCC is associated with either smooth or textured implants. Rare cases of implant associated diffuse large B-cell lymphomas have also been reported. See NCCN Guidelines for T-Cell Lymphomas.

PRINCIPLES OF BREAST RECONSTRUCTION AFTER SURGERY

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PRINCIPLES OF BREAST RECONSTRUCTION AFTER SURGERY

Special Cases

• Nipple-sparing mastectomy

NAC-sparing procedures may be an option in patients with cancer who are carefully selected by experienced multidisciplinary teams.

Retrospective data support the use of NAC-sparing procedures for early-stage breast cancer, DCIS, risk-reduction procedures, and in

some locally advanced invasive cancers (ie, with complete clinical response to preoperative chemotherapy and no nipple involvement with

cancer).

Contraindications to NAC include: Preoperative clinical or radiographic evidence of nipple involvement, including Paget disease, bloody

nipple discharge associated with malignancy, IBC, and/or imaging findings suggesting malignant involvement of the nipple or subareolar

tissues.

Nipple margin assessment is mandatory and should be clearly designated on the specimen.

Preoperative breast size, shape, and nipple position should also be considered in the decision to perform NAC-sparing mastectomy.

Patients with small to moderate breast volume with good nipple position are ideal candidates. In patients with large or significantly ptotic breasts, NAC-sparing mastectomies may be offered in select cases by using various reduction patterns or delay techniques to augment

the NAC perfusion, either in an immediate or delayed fashion, as long as it does not delay oncologic care. Intraoperative assessment of the

NAC perfusion should also guide the decision to preserve the NAC or remove it.

Patients should be counseled on the risk of delayed healing, nipple necrosis, loss of pigmentation, loss of sensation, loss of projection,

and need for subsequent removal of the NAC.

Topical 2% nitroglycerine (45 mg total dose) used prophylactically has been shown to reduce mastectomy skin flap necrosis in both skinsparing mastectomy and nipple sparing mastectomy in one randomized control trial.

• Inflammatory breast cancer

Delayed reconstruction after mastectomy for IBC remains the clinical standard for several reasons. The need to resect involved skin

negates the benefit of skin-sparing mastectomy for immediate reconstruction, and high rates of local and distant recurrence warrant

comprehensive RNI in a timely fashion, which may be technically more challenging or subject to delay after immediate reconstruction.

Advances in multimodal therapy have improved 5-year survival in patients with IBC, justifying clinical studies to see if immediate

reconstruction may be appropriate for certain patients with IBC, but neither the outcomes nor the clinical features to predict such

outcomes are known at this time.

In the uncommon clinical circumstance that the extent of skin excision at the time of mastectomy precludes primary or local closure,

reconstruction of the chest wall defect with autologous tissue is necessary, and concomitant immediate reconstruction may be

accomplished.

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Optimizing Delivery of Individual Therapy• It is important to individualize RT planning and delivery.

3-D CT-based treatment planning should routinely be utilized to delineate target volumes & organs at risk, and assess dose distributionacross the entire treatment volume.

Radiation is generally delivered with single or mixed energy photons ± electrons.

Treatment planning should be optimized to maximally improve homogeneity across the target volume while minimizing dose to organs atrisk.

Additional techniques such as respiratory control (deep inspiration breath-hold), prone positioning, and cardiac blocks may also be usedto try to further reduce dose to heart, lung, and adjacent normal tissue.

At a minimum, weekly imaging to verify treatment setup should be utilized. More frequent imaging may be needed for selected cases withinconsistent reproducibility. Image-guided radiation therapy (IGRT) may be utilized with deep inspiration breath-hold (DIBH) technique toreduce normal tissue exposure of the heart, lung or liver.

Dose-volume histograms (DVHs) should be used to evaluate dose, normal tissue constraints (ie, heart, lung), and planning target volumes(PTVs).• It is common for RT to follow chemotherapy when chemotherapy is indicated. See BINV-I 2 of 3.• In the setting of oligometastatic breast cancer, the currently available data do not support ablative metastasis-directed RT (ie, SBRT) forextending overall survival OS or PFS. In some cases, SBRT may be preferred over palliative radiotherapy to provide more durable localcontrol and pain relief.

Whole Breast RT• Target definition is the breast tissue at risk.• RT dosing:

The whole breast should receive a hypofractionated dose of 40–42.5 Gy in 15–16 fractions; in selected cases 45–50.4 Gy in 25–28 fractions may be considered. A boost to the tumor bed is recommended in patients at higher risk for recurrence. The boost can be given sequentially after whole breast RT or as a simultaneous integrated boost. Typical boost doses when given sequentially are 10–16 Gy in 4–8 fractions. When given concurrently, the whole breast should receive 40 Gy in 15 fractions and the lumpectomy site should receive 48 Gy in 15 fractions.a,b Ultra-hypofractionated whole breast RT of 28.5 Gy in 5 (once-a-week) fractions may be considered for selected patients over 50 years following BCS with early-stage, node-negative disease, particularly those in whom a boost is not intended.c,d• Lumpectomy cavity boost can be delivered using enface electrons, photons, or brachytherapy.

Note: All recommendations are category 2A unless otherwise indicated.

BINV-I 1 OF 3

PRINCIPLES OF RADIATION THERAPY

a Vicini FA, Winter K, Freedman GM, et al. NRG RTOG 1005: A phase III trial of hypo fractionated whole breast irradiation with concurrent boost vs. conventional whole

breast irradiation plus sequential boost following lumpectomy for high risk early-stage breast cancer. Int J Radiation Oncol 2022;114;S1.

b Coles CE, Haviland JS, Kirby AM, et al. Dose-escalated simultaneous integrated boost radiotherapy in early breast cancer (IMPORT HIGH): a multicentre, phase 3, non-inferiority, open-label, randomised controlled trial. Lancet 2023;401:2124-2137.

c Alternatively, 26 Gy in 5 daily fractions over one week may be considered, though data beyond 5 years for local relapse or toxicity are not yet available for this

regimen. (Murray Brunt A, Haviland JS, Wheatley DA, et al. Hypofractionated breast radiotherapy for 1 week versus 3 weeks [FAST-Forward]: 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial. Lancet 2020;395:1613-1626.)

d Brunt AM, Haviland JS, Sydenham M, et al. Ten-year results of FAST: A randomized controlled trial of 5-fraction whole-breast radiotherapy for early breast cancer. J

Clin Oncol 2020;38:3261-3272.

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NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

BINV-I 2 OF 3

PRINCIPLES OF RADIATION THERAPY

PMRT (including breast reconstruction)

• The target includes the ipsilateral chest wall and the clinically relevant mastectomy scar ± drain sites.

Regional nodal RT is typically delivered with the chest wall. See below.

• In the case of cT3N0, high-risk features for considering PMRT include, but are not limited to, young age and/or LVI.

• Based on anatomic considerations and presence of reconstruction, various 3-D-, intensity modulated radiation therapy [IMRT], or volumetric modulated arc therapy (VMAT) techniques using photons and/or electrons are appropriate.

• PMRT details and dosing:

The routine use of bolus is not recommended. Bolus should be used for inflammatory breast cancer and considered in clinically relevant situations

where the dose to the skin may not be adequate.

Chest wall RT dose may be delivered in conventional dosing of 45–50.4 Gy in 25–28 fractions or moderately hypofractionated dosing of 40–42.5 Gy in

15–16 fractions.

In patients who are at high risk for local recurrence, a chest wall scar boost may be considered of approximately 10 Gy delivered in 4-5 fractions with or

without bolus.

Regional Nodal Radiation

• For supra/infra-clavicular and axillary nodes, prescription depth varies based on the patient anatomy.

• Regional nodes should be contoured when when RNI is indicated. Refer to breast atlases for contouring guidelines.e,f

• RT dosing:

RT doses to the regional nodes of 46–50 Gy (conventional fractionation) or 39–42 Gy (moderately fractionated) dosing schedules similar to PMRT and

whole breast may be considered.

A supplemental boost of RT can be delivered to grossly involved or enlarged lymph nodes (ie, internal mammary, supra/infra-clavicular) that have not

been surgically removed.

RT with Preoperative or Adjuvant Systemic Therapy

• In patients treated with preoperative systemic therapy, adjuvant RT is based on the maximal disease stage (ie, clinical stage, pathologic stage, tumor

characteristics) at diagnosis (before preoperative systemic therapy) and pathology results after preoperative systemic therapy.

• Sequencing of RT with systemic therapy:

It is common for RT to follow chemotherapy when chemotherapy is indicated. However,

– CMF (cyclophosphamide/methotrexate/fluorouracil) is the only standard regimen that can be given concurrently with RT.

– Capecitabine is typically given after completion of RT.

– Olaparib should be given after completion of RT.

Available data suggest that sequential or concurrent endocrine therapy with RT is acceptable. Due to compounding side effects, initiating endocrine

therapy at the completion of RT may be preferred.

◊ Abemaciclib or ribociclib should be initiated after completion of surgery/RT/chemotherapy, concurrently with endocrine therapy.

Adjuvant HER2-targeted therapy ± endocrine therapy may be delivered concurrently with RT.

e Offersen BV, Boersma LJ, Kirkove C, et al. ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer.

Radiother Oncol 2015;114:3-10.

f Gentile MS, Usman AA, Neuschler EI, et al. Contouring guidelines for the axillary lymph nodes for the delivery of radiation therapy in breast cancer: Evaluation of the

RTOG Breast Cancer Atlas. Int J Radiat Oncol Biol Phys 2015;93:257-265.

NCCN

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF RADIATION THERAPY

Accelerated Partial Breast Irradiation(APBI)/Partial Breast Irradiation(PBI)

●The NCCN Panel endorses API/PBI for any patient without germline BRCA 1/2 mutations who meets the criteria outlined in the 2023 ASTRO guidelines. Patients aged≥40 years are recommended"suitable" for APBI/PBI if they have:

Invasive ER-positive ductal carcinoma measuring≤2 cm(pT1 disease),grade 1-2,with negative margin widths,no LVSI,and negative nodes Or

▶DCIS measuring size ≤2cm with low-intermediate grade with negative margins

●APBI offers comparable local control and comparable or improved cosmesis to whole breast RT when delivered with the following dose regimens. The APBI regimens have not been compared directly but 30 Gy/5 fractions is preferred based on the highest rated cosmesis outcomes.

●RT dosing:

|Dose|Regimen| |---|---| |EBRT APBI|EBRT APBI| |30 Gy/5 fractions QOD (preferred); IMRT/VMAT protocol mandated|-Livi L,Meattini,Imrazzo L,et al.Accelerated partial breast irradiation using intensity-modulated radiotherapy versus whole breast irradiation: 5-year survival analysis of a phase 3 randomised controlled trial. Eur J Cancer 2015;51:451-463. ● Meattini,Imrazzo L,Saieve Ca,et al.Accelerated partial-breast irradiation compared with whole-breast irradiation for early breast cancer: Long-term results of the randomized phase III APBI-IMRT-Florence Trial. J Clin Oncol 2020;38:4175-4183. ● Franceschini D, Loi M, Chiola I, et al. Preliminary results of a randomized study on postmenopausal women with early stage breast cancer: Adjuvant hypofractionated whole breast irradiation versus accelerated partial breast irradiation (HYPAB Trial). Clin Breast Cancer 2021;21:231-238. ● Lo Faro L, Fogliata A, Franceschini D, et al. Adjuvant hypofractionated whole breast irradiation (WBI) vs. accelerated partial breast irradiation (APBI) in postmenopausal women with early stage breast cancer: 5 years update of the HYPAB trial. Clin Breast Cancer 2024;24:253-260. ● Coles CE,Griffin CL, Kirby AM, et al. Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomised, controlled, phase 3, non-inferiority trial. Lancet 2017;390:1048-1060. ●Brachytherapy APBI (including balloon/interstitial) ● Vicini FA, Cecchini RS, White JR, et al. Long-term primary results of accelerated partial breast irradiation after breast-conserving surgery for early-stage breast cancer: a randomised, phase 3, equivalence trial. Lancet 2019;394:2155-2164. ●Strnad V, Ott OJ, Hildebrandt G, et al. 5-year results of accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy versus whole- breast irradiation with boost after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: a randomised, phase 3, non-inferiority trial. Lancet 2016;387:229-238. ●Polgár C, Ott OJ, Hildebrandt G, et al. Late side-effects and cosmetic results of accelerated partial breast irradiation with interstitial brachytherapy versus whole-reliobreast irradiation after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: 5-year results of a randomised, controlled, phase 3 trial. Lancet Oncol 2017;18:259-268.|

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NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

BINV-J 1 OF 2

SPECIAL CONSIDERATIONS FOR BREAST CANCER IN MALES (SEX ASSIGNED AT BIRTH)

NCCN recommendations have been developed to be inclusive of individuals of all sexual and gender identities to the greatest extent possible. On this page, the terms males and females refer to sex assigned at birth.

• Few males have been included in breast cancer trials.1 Therefore, recommendations regarding management of breast cancer in males aregenerally extrapolated from findings of clinical trials focusing on breast cancer in females.

• Although there are some biologic and clinical differences between breast cancer in males and females, management of breast cancer inmales is similar overall to management of breast cancer in females, with the following special considerations pertinent to male patients2:

Genetics: The NCCN Panel recommends consideration of genetic testing for all males with breast cancer (See NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate).

Breast surgery: Historically, males with breast cancer have undergone mastectomy more often than BCS. However, breast-conservation therapy is increasingly being performed in males and evolving data indicate that breast conservation in males is associated with equivalent outcomes to mastectomy and that it is safe and feasible. Decisions about breast conservation versus mastectomy in males should be made according to similar criteria as for females.2-9 Axillary lymph node surgery: As in females, SLNB should be performed in the setting of male breast cancer with a clinically node-negative axilla.2,4 RT: Indications for radiation after breast surgery in males with breast cancer are the same as for females with breast cancer.2,5,10,11 Use of molecular assays: Data are limited regarding the use of molecular assays to assess prognosis and to predict benefit from chemotherapy in males with breast cancer.2 Available data suggest the 21-gene assay recurrence score provides prognostic information in males with breast cancer.12,13 Preoperative/adjuvant systemic therapy: Chemotherapy with/without HER2-targeted therapy should be recommended for males with breast cancer according to guidelines for females with breast cancer.2 Options for adjuvant endocrine therapy for males with breast cancer include tamoxifen for 5–10 years or, if tamoxifen is contraindicated, a GnRH analog plus an aromatase inhibitor. In males, single-agent adjuvant treatment with an aromatase inhibitor has been associated with inferior outcomes compared to tamoxifen alone, likely due to inadequate estradiol suppression, and is not recommended.2,14-17 Follow-up after treatment for early-stage disease: There are only limited data to support screening for breast cancer in males.2 The NCCN Panel recommends that bone density be assessed at baseline and every 2 years in males with breast cancer who receive adjuvant GnRH analog therapy. Low bone density should be managed according to standard guidelines.18 Systemic therapy for advanced disease: Management of advanced breast cancer in males is similar to that in females; however, it is preferred that when an aromatase inhibitor is used, a GnRH analog should be given concurrently.2 Available data suggest single-agent fulvestrant has similar efficacy in males as in females.19 CDK4/6 inhibitors in combination with an aromatase inhibitor or fulvestrant, mTOR inhibitors, and PIK3CA inhibitors have not been systematically evaluated in clinical trials in males with breast cancer. However, available real-world data suggest comparable efficacy and safety profiles and it is reasonable to recommend these agents to males based on extrapolation of data from studies comprised largely of female participants with advanced breast cancer. Indications for and recommendations regarding chemotherapy, HER2-targeted therapy, immunotherapy, and PARP inhibitors for advanced breast cancer in males are similar to those for advanced breast cancer in females.1 References on BINV-J 2 of 2

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NCCN Guidelines Index Table of Contents Discussion

BINV-J 2 OF 2 SPECIAL CONSIDERATIONS FOR BREAST CANCER IN MALES (SEX ASSIGNED AT BIRTH)

Abstract

Note: All recommendations are category 2A unless otherwise indicated.

References

NCCN Guidelines Index

National NCCN Comprehensive NCCN Guidelines Version 5.2025 Cancer Cancer Invasive Breast Cancer

Contents Discussion

PRINCIPLES OF ADJUVANT ENDOCRINE THERAPY

(for pT1-3,pN+,M0)

General Principles

Ovarian function assessment

●Hormone receptor-positive(HR+)tumors:Breast tumors may be positive for estrogen receptors(ER+),progesterone receptors(PR+) or both(ER+/PR+).See Principles of Biomarker Testing(BINV-A).

●Menopausal status cannot be determined while receiving OFS.a

●Monitor estradiol and follicle-stromating hormone(FSH)/luteinizing hormone(LH) levels:

ER+ tumors: ER testing should be used to determine if a patient is a candidate for endocrine therapies. a Patients with cancers with 1%-100% ER IHC staining are considered ER+ and eligible for endocrine therapies, there are limited efficacy data on the subgroup of cancers with ER-low-positive(1%-10%) results.The ER-low-positive group is heterogeneous with reported biologic behavior often similar to ER-negative cancers; thus, individualized consideration of risks versus benefits of endocrine therapy and additional adjuvant therapies should be incorporated into decision-making.

If under 60 years and amenorheic for≤12 months prior to treatment with adjuvant endocrine therapy

Amenorheic after chemotherapy or after tamoxifen +/- ovarian function suppression (OFS).

After switching from tamoxifen to an Al, or if taken off OFS

Prior to next dose of GNRH agonist, particularly in women under 45 years. Frequency of testing of estradiol and FSH/LH levels should be individualized.

PR+ tumors: Patients with ER-negative, PR+ cancers may be considered for endocrine therapies, but the data on this group are noted to be limited. The same overall interpretation principles apply but PR should be interpreted as either positive(if 1%-100% of cells have nuclear staining) or negative(if<1% or 0% of cells have nuclear staining).

●Al can stimulate ovarian function. If vaginal bleeding occurs while on Al, contact physician immediately.

Methods for OFS

●GNRH agonists

Goserelin 3.6 mg SC every 4 weeks or 10.8 mg SC every 12 weeks

●The majority of hormone sensitive tumors are ER+/PR+ or ER+/PR-negative.Considering that ER-negative/PR+ tumors are relatively uncommon, in these guidelines, ER and/or PR+ tumors are referred to as HR+.

Leuprolide 3.75-7.5 mg IM or SC every 4 weeks or 11.25-22.5 mg IM or SC every 12 weeks

Triptorelin:3.75 mg IM every 4 weeks.

●The magnitude of risk reduction from adjuvant endocrine therapy is dependent on:

●Radiation therapy

Level of ER expression: Low ER+ expression is less likely to benefit from endocrine therapy.

●Bilateral oophorectomy

Initiation of OFS

Recurrence score(RS) on gene expression assay test results: Patients with high RS will gain relatively less benefit from adjuvant endocrine alone compared to those with RS.

●Prior to or with start of chemotherapy (preoperative or adjuvant)

●If no chemotherapy planned, then OFS should be started alone for at least 1-2 cycles or concurrently with tamoxifen elistradiol level in postmenopausal range at which time an aromatase inhibitor could considered.

Candidates for Ovarian Suppression + Endocrine Therapy

●Premenopausal patients

●Endocrine sensitive tumors with high enough recurrence risk where the additional absolute decrease in recurrence compared with tamoxifen alone is worth the additional toxicity(young age, high-grade tumor, lymph node involvement).b

Concurrently with RT or upon completion Duration of OFS

●5 years of OFS is optimal based on SOFT and TEXT trials.The 8-year DFS was 85.4% with OFS+ tamoxifen versus 80.2% with tamoxifen alone. A minimum 2 years of OFS is encouraged. There are no data on efficacy or safety to support prolonging of OFS> 5 years.c

a Definition of Menopause(BINV-O).

●Premenopausal patients wishing to continue adjuvant endocrine therapy after OFS stopped should use tamoxifen.

b A balanced discussion of the risks and benefits associated with ovarian suppression therapy is critical, including the potential side effects of premature menopause.Aromatase inhibitor or tamoxifen for 5 years plus ovarian suppression should be considered, based on SOFT and TEXT clinical trial outcomes, for premenopausal patients at higher risk of recurrence(ie, young age, high-grade tumor, lymph node involvement).

cBaek SY,Noh WC,Ahn SH,et al.Adding ovarian suppression to tamoxifen for premenopausal women with hormone receptor-positive breast cancer after chemotherapy: An 8-year follow-up of the ASTRRA Trial. J Clin Oncol 2023;41:4864-4871.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

ADJUVANT ENDOCRINE ± CDK4/6 INHIBITOR THERAPY

![\nAromatase inhibitor for 5 y (category 1)\nPostmenopausala\nor\nConsider tamoxifen h for a additional 5 y to complete 10 y\nasymptosis, and, e,f,g\nor eligible\nor\nAromatase inhibitor for 5 y\nor\nConsider tamoxifen h for a additional 5 y to complete 10 y\nasymptosis, and, e,f,g\nor\nAromatase inhibitor for 5 y\nor ablationb,f (category 1).\nConsider adjuvant abemaciclib\nor ribociblc in eligible patientsi\nor\nAromatase inhibitor for 5 y\nor ablationb,f (category 1).\nConsider adjuvant abemaciclib\nor ribociblc in eligible patientsi\n](2/aj0YEe4oUhYkBdfpda0fYP/figurec87d0f85bc884f85aca1d46b131ab888_0_6.png) a Definition of Menopause (BINV-O).

b A balanced discussion of the risks and benefits associated with ovarian suppression therapy is critical, including the potential side effects of premature menopause. Aromatase inhibitor or tamoxifen for 5 years plus ovarian suppression should be considered, based on SOFT and TEXT clinical trial outcomes, for premenopausal patients at higher risk of recurrence(ie, young age, high-grade tumor, lymph node involvement).

d Baseline assessment of bone density recommended for patients receiving an aromatase inhibitor who are at risk of osteoporosis(eg, age≥65, family history, chronic steroids).

e The use of a bisphosphonate (oral/IV) or denosumab is acceptable to maintain or to improve bone mineral density and reduce risk of fractures in postmenopausal(natural or induced) patients receiving adjuvant aromatase inhibitor therapy.

f Evidence suggests that the magnitude of benefit from surgical or radiation ovarian ablation in premenopausal patients with HR-positive breast cancer is similar to that achieved with CMF alone.

9 Safety data support administration of GnRH agonists before or with chemotherapy,especially if there is a goal to enhance fertility preservation. They can also be initiated after chemotherapy in patients who remain premenopausal.

h Some SSRIs like fluoxetine and paroxeline decrease the formation of endoxifen, 4-OH tamoxifen, and active metabolites of tamoxifen, and may impact its efficacy. Caution is advised about coadminstration of these drugs with tamoxifen. However, SNRs(citalopram and venlafaxine) appear to have minimal impact on tamoxifen metabolism. At this time, based on current data the panel recommends against CYP2D6 gene testing for patients being considered for tamoxifen therapy.

In patients with HR-positive/HER2-negative breast cancer,1) for those with high-risk breast cancer(ie, those with ≥4 positive lymph nodes(confirmed preoperatively and/or at surgery), or 1-3 positive lymph nodes with either grade 3 disease or tumor size≥5 cm (on pre-operative imaging and/or at surgery), 2 years of adjuvant abemaciclib can be considered in combination with endocrine therapy(category 1, preferred).VTE risk should be considered when combining abemaciclib with tamoxifen. 2) For those with any lymph node involvement (excluding microscopic nodal involvement),or if no nodal involvement either tumor size >5 cm, or if tumor size 2-5 cm, either Grade 2 (and high genomic risk or Ki-67 ≥20%), or Grade 3, 3 years of ribociclib with aromatase inhibitor may be considered (Category 1, preferred). Notably adjuvant CDK4/6 inhibitors have been studied in patients at high risk who mostly received adjuvant/neadjuvant chemotherapy; there are limited data in those who did not receive chemotherapy. In patients eligible for adjuvant olaparib (see BINV-L)and abemaciclib or ribociclib, the benefit and optimal sequence is not known.

National Comprehensive Cancer Network®

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

ADJUVANT ENDOCRINE ± CDK4/6 INHIBITOR THERAPY

![Aromatase inhibitor for 5 y (category 1). Consider arombe inhibitor for an additional 3-5 yj in eligible patientsi\nAromatase inhibitork for 2-3 y (category 1).\nTamoxifen\ to complete 5 y of endocrine therapy (category 1)\nPostmenopausalat diagnosis a,d,e,k\nat diagnosis\nTamoxifen\ to for 4.5-6 y\nPatients with a contraindication to aromatase inhibitors, or inhibitors, who decline aromatase inhibitors, or who are intolerant to aromatase inhibitors\nToamixenfh\nAromatase inhibitor to complete 5 yj of endocrine therapy in eligible patients\nAromatase inhibitor to complete 5 yj of endocrine therapy in\nor\nThamoxifen\nAromatase inhibitor to complete 5 yj of endocrine therapy in\nor\nThamoxifen\nAromatase inhibitor for yj of endino echnology therapy (category 1)\nUp to 5 y of an aromatase inhibitor (category 2B)\nAromatase inhibitor for 5 yj (category 1)\nStemaseartol.considerabaseartchol.24\nAnatomase inhibitors in an eneckal therapy can\nAromatase inhibitor for 5 yj (category 1)\nAtomoxifen hj\ncalacturak.25\nBimberseartol.26\nAromataseolin.26\nAromatase inhibitor for aromatase inhibitors\nAromatase inhibitor for 5 yj (category 1)\nStemaseartol.26\nAromatase inhibitor for 6 yj (category 2B)\nAtomaseartol.26\nAromataseolin hchentabach.3\nAromatasebiol.26\nAromatasebiol chchentabach.4\nAromatasebiol chchentabach.5\nAromatasebiol chchentabach.6\nAnatomaseartol.26\nAromatasebiol chchentabach.5\nAromatasebiol chchentabach.5\nAromatasebiol chchentabach.6\nAnatomaseartol.26\nAromatasebiol chchentabach.5\nAromatasebiol chchentabach.5\nAromatasebiol chchentabach.5\nAromatasebiol chchentabach.5\nAromatasebiol chchentabach.5\nAromatasebiol chchentabach.5\nAromatasebiol chchentabach.5\nAromatasebiol chchentabach.5\nAromatasebiol chchentabach.5\nAromatasebiol chchentabach.5\nAromatasebiol chchentabach.5\nAromatasebiol chchentabach.5\nAromatasebiol chchentabach.5\nAromatasebiol chchentabach.5\nAromatasebiol chchentabach.5\nAromatasebiol chchentabach.5\nAromatasebiol chchentabach.\n](2/aj0YEe4oUhYkBdfpda0fYP/figured235534535044a8c9b6d73508deeacd3_0_5.png) a Definition of Menopause (BINV-O).

b A balanced discussion of the risks and benefits associated with ovarian suppression therapy is critical, including the potential side effects of premature menopause. Aromatase inhibitor or tamixenfor 5 years plus ovarian suppression should be considered, based on SOFT and TEXT clinical trial outcomes, for premenopausal patients at higher risk of recurrence(ie, young age, high-grade tumor, lymph node involvement).

d Baseline assessment of bone density recommended for patients receiving an aromatase inhibitor who are at risk of osteoporosis(eg, age>65, family history, chronic steroids).

e The use of a bisphosphonate(oral/IV) or denosumab is acceptable to maintain or to improve bone mineral density and reduce risk of fractures in postmenopausal(natural or induced) patients receiving adjuvant aromatase inhibitor therapy.

h Some SSRIs like fluoxetine and paroxeline decrease the formation of endoxifen, 4-OH tamoxifen, and active metabolites of tamoxifen, and may impact its efficacy. Caution is advised about coadministration of these drugs with tamoxifen. However, SNRIs(citalopram and venlafaxine) appear to have minimal impact on tamoxifen metabolism. At this time, based on current data the panel recommends against CYP2D6 gene testing for patients being considered for tamoxifen therapy.

in patients with HR-positive/HER2-negative breast cancer,1) for those with high-risk breast cancer (ie, those with ≥4 positive lymph nodes (confirmed preoperatively and/or at surgery), or 1-3 positive lymph nodes with either grade 3 disease or tumor size ≥5 cm (on pre-operative imaging and/or at surgery), 2 years of adjuvant abemacilib can be considered in combination with endocrine therapy (category 1, preferred).VTE risk should be considered when combining abemacilib with tamoxifen. 2) For those with any lymph node involvement (excluding microscopic nodal involvement),or if no nodal involvement either tumor size >5 cm, or if tumor size 2-5 cm, either Grade 2 (and high genomic risk or Ki-67 ≥20%), or Grade 3, 3 years of ribocilib with aromatase inhibitor may be considered (Category 1, preferred). Notably adjuvant CDK4/6 inhibitors have been studied in high-risk patients who mostly received adjuvant/neadjuvant chemotherapy; there are limited data in those who did not receive chemotherapy. In patients eligible for adjuvant aloparib (see BINV-L)and abemacilib or ribocicibl, the benefit and optimal sequence is not known.

7.The three selective aromatase inhibitors(ie, anastrozole,letrozole,exemstane)have shown similar anti-tumor efficacy and toxicity profiles in randomized studies in the adjuvant and preoperative settings. The optimal duration of aromatase inhibitors in adjuvant therapy is uncertain. Patients with lymph node involvement may benefit from extended aromatase inhibitor duration(7.5-10 years total).

k If patient is not postmenopausal, sequential evaluation of hormonal status is recommended to consider an alternative endocrine agent.

NCCN Guidelines Index Table of Contents Discussion

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

PRINCIPLES OF PREOPERATIVE SYSTEMIC THERAPY

Known Benefits of Preoperative Systemic Therapy

●Facilitates breast conservation

●Can render inoperable tumors operable

●Treatment response provides important prognostic information at an individual patient level, particularly in patients with TNBC or HER2-positive breast cancer

●Identifies patients with residual disease at higher risk for relapse to allow for the addition of supplemental adjuvant regimens, particularly in patients with TNBC or HER2-positive breast cancer.

Opportunities

●May allow SLNB alone if initial cN+ becomes cN0 after preoperative therapy

●May provide an opportunity to modify systemic treatment if no preoperative therapy response or progression of disease

●May allow for more limited radiation fields in patients with cN+ who become cN0/pN0 after preoperative therapy

●Provides excellent research platform to test novel therapies and predictive biomarkers

●May allow time for genetic testing

●May allow time to plan breast reconstruction in patients electing mastectomy

●May allow time for delayed decision-making for definitive surgery

Cautions

●Possible overtreatment with systemic therapy if clinical stage is overestimated

●Possible undertreatment locoregionally with radiotherapy if clinical stage is underestimated

●Possibility of disease progression during preoperative systemic therapy

Candidates for Preoperative Systemic Therapy

●Patients with inoperable breast cancer:

IBC

Bulky or matted cN2 axillary nodes

cN3 nodal disease

cT4 tumors

●In select patients with operable breast cancer

Preoperative systemic therapy is preferred for:

◆HER2-positive disease and TNBC, if≥cT2 or≥cN1

◆ Large primary tumor relative to breast size in a patient who desires breast conservation

◆ cN+ disease likely to become cN0 with preoperative systemic therapy

Preoperative systemic therapy can be considered for cT1c,cN0 HER2-positive disease and TNBC

●Patients in whom definitive surgery may be delayed.

Non-candidates for Preoperative Systemic Therapy

●Patients with extensive in situ disease when extent of invasive carcinoma is not well-defined

●Patients with a poorly delineated extent of tumor

●Patients whose tumors are not palpable or clinically assessable

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF PREOPERATIVE SYSTEMIC THERAPY

●Pathology evaluation of surgical resection specimens following preoperative systemic therapy should include the standardized tissue sampling and reporting elements of the Residual Cancer Burden(RCB)(category 2B).a

●Randomized trials of chemotherapy demonstrate similar long-term outcomes when patients are given the same treatment preoperatively compared with postoperatively.b

●Pathologic complete response (pCR) to preoperative systemic therapy is associated with an extremely favorable disease-free and overall survival (OS), particularly in situations in which all treatment is given preoperatively. The correlation between pathologic response and long-term outcome is strongest for TNBC, somewhat less so for HER2-positive disease, and least for ER-positive disease.c,d

●A number of chemotherapy regimens have activity in the preoperative setting. In general, those chemotherapy regimens recommended in the adjuvant setting may be considered in the preoperative setting. See Preoperative/Adjuvant Therapy Regimens(BINV-M).

●Preoperative endocrine therapy alone may be considered for patients with ER-positive disease based on comorbidities or low-risk luminal biology based on clinical characteristics and/or genomic signatures(until desired effect is achieved). Data shows that optimal duration for response if achieved between 4-6 months.e

●Patients with HER-2 positive,≥cT2 and/or cN+ should be considered for HER2-directed therapy preoperatively. See Preoperative/Adjuvant Therapy Regimens. Thayr Regimens(BINV-M).

●Some studies suggest an increased risk of locoregional recurrence following use of preoperative chemotherapy.f These trials delivered chemotherapy regimens that are no longer standard, did not include targeted therapies, did not use modern imaging techniques, and/or used non-standard locoregional management. Care should be taken to follow the procedures outlined in BINV-12 and BINV-14 to assure appropriate locoregional management. Not all patients are appropriate candidates for preoperative systemic therapy. Accurate clinical staging at baseline prior to initiation of preoperative systemic therapy is critical. See Potentially Operable Disease: Breast and Axillary Evaluation Prior to Preoperative Systemic Therapy (BINV-12).

●Tumor response should be routinely assessed by clinical exam and imaging studies(see footnote uu on BINV-13) during delivery of preoperative therapy. It is preferred that the standard regimen is completed prior to surgery. If all intended treatment is not completed prior to surgery, the remainder may be given in the adjuvant setting. Patients with operable breast cancer experiencing progression of disease during preoperative systemic therapy may be given an alternate systemic regimen or proceed to surgery if deemed resectable. Locoregional therapy principles should be applied in the same manner as in patients treated with adjuvant systemic therapy.

d Cortazar P, Zhang L, Untch M,et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014;384:164-172.

a Yau C, Osdoit M, van der Noorda M, et al. Residual cancer burden after neoadjuvant chemotherapy and long-term survival outcomes in breast cancer: a multicentre pooled analysis of 5161 patients. Lancet Oncol 2022;23:149-160.

e Hunt KK, Suman VJ, Wingate HF,et al. Local-regional recurrence after neoadjuvant endocrine therapy: Data from ACOSOG Z1031 (Alliance), a Randomized Phase 2 neoadjuvant comparison between letrozole, anastrozole,and exemestame for postmenopausal women with estrogen receptor-positive clinical stage 2 or 3 breast cancer. Ann Surg Oncol 2023;30:2111-2118.

b Rastogi P,Anderson SJ,Bear HD,et al.Preoperative chemotherapy: Updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27.J Clin Oncol 2008;26:778-785.

f Early Breast Cancer Trialists' Collaborative Group (EBTCG). Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer:metaanalysis of individual patient data from ten randomised trials. Lancet Oncol 2018;19:27-39.

cvon Minckwitz G, Untch M,Blohmer JU,et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 2012;30:1796-1804.

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NCCN Guidelines Index Table of Contents Discussion

Considerations for Those Receiving Preoperative/Adjuvant Systemic Therapy

General Considerations:

• An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.

• Screen for and manage immunotherapy-related toxicities and endocrine dysfunctions (eg, hypothyroidism, adrenal insufficiency) in patients treated with immune checkpoint inhibitors, see NCCN Guidelines for Management of Immunotherapy-Related Toxicities.

• Regular cardiac monitoring for patients on anthracyclines or HER2-targeted therapys, see NCCN Guidelines for Survivorship: Cardiovascular Disease Risk Assessment.

For Those Receiving Preoperative/Adjuvant Chemotherapy:

• Patients at a higher risk of taxane-induced peripheral neuropathy (TIPN) (eg, African descent, diabetes) may consider docetaxel as the

preferred taxane based on data supporting less TIPN and less dose reductions (Schneider BP, Zhao F, Ballinger TJ, et al. ECOG-ACRIN

EAZ171: prospective validation trial of germline predictors of taxane-induced peripheral neuropathy in Black women with early-stage breast cancer. J Clin Oncol 2024;42:2899-2907).

• Consider cryotherapy of hands and feet to decrease the risk of peripheral neuropathy when receiving taxane therapies.

• Consider scalp cooling to reduce incidence of chemotherapy-induced alopecia for patients receiving neoadjuvant/adjuvant chemotherapy.

Results may be less effective with anthracycline-containing regimens.

• Alternative taxanes (ie, docetaxel, paclitaxel, albumin-bound paclitaxel) may be substituted for select patients due to medical necessity (ie,

hypersensitivity reaction). If substituted for weekly paclitaxel or docetaxel, then the weekly dose of albumin-bound paclitaxel should not

exceed 125 mg/m2.

• Sequence of therapies in the adjuvant setting:

Chemotherapy and endocrine therapy should be given sequentially, with endocrine therapy given after chemotherapy.

Adjuvant olaparib can be given concurrently with endocrine therapy.

For sequencing of RT with systemic therapy, see BINV-I (2).

For those receiving HER2-targeted therapy:

Trastuzumab and hyaluronidase-oysk subcutaneous injection may be substituted for trastuzumab IV; however, dosing and administration

instruction differ. Do not substitute trastuzumab and hyaluronidase-oysk for or with ado-trastuzumab emtansine.

Pertuzumab, trastuzumab, and hyaluronidase-zzxf subcutaneous injection may be substituted for IV pertuzumab and trastuzumab;

however, the dosing and administration instruction may differ.

PREOPERATIVE/ADJUVANT THERAPY REGIMENS

Note: All recommendations are category 2A unless otherwise indicated.

BINV-M 1 OF 10

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

BINV-M 2 OF 10

PREOPERATIVE/ADJUVANT THERAPYa,b

HR-Positive, HER2-Negative

Patients with HR-positive disease are recommended to receive adjuvant endocrine therapy ± CDK4/6 inhibitor therapy (see BINV-K).

Preferred Regimens:

Preoperative or adjuvant setting:

• Dose-dense AC (doxorubicin/cyclophosphamide) followed or preceded by paclitaxel every 2 weeksc

• Dose-dense AC (doxorubicin/cyclophosphamide) followed or preceded by weekly paclitaxelc

• TC (docetaxel and cyclophosphamide)

Adjuvant setting only:

• If germline BRCA1/2 mutationsd: Olaparib

Useful in Certain Circumstances:

Preoperative or adjuvant setting:

• Dose-dense AC (doxorubicin/cyclophosphamide)

• AC (doxorubicin/cyclophosphamide) every 3 weeks (category 2B)

• CMF (cyclophosphamide/methotrexate/fluorouracil)

• AC followed by weekly paclitaxelc

Other Recommended Regimens:

Preoperative or adjuvant setting:

• AC followed by docetaxel every 3 weeksc

• EC (epirubicin/cyclophosphamide)

• TAC (docetaxel/doxorubicin/cyclophosphamide)

b Principles of Preoperative Systemic Therapy (BINV-L).c It is acceptable to change the administration sequence to taxane followed by AC.d Patients in the OlympiA trial did not receive capecitabine; thus, there are no data on sequencing or to guide selection of one agent over the other. In patients eligible for both adjuvant olaparib and abemaciclib, the optimal sequence is not known. See BINV-K, 2.

The regimens listed in the table are all category 1 (except where indicated) when used in the adjuvant setting. See BINV-M, 1 for Considerations for Those Receiving Preoperative/Adjuvant Systemic Therapy.

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Note: All recommendations are category 2A unless otherwise indicated.

BINV-M 3 OF 10

PREOPERATIVE/ADJUVANT THERAPYa,b

HR-Negative, HER2-Negative

Preferred Regimens:Stage 1Preoperative or adjuvant setting:• Dose-dense AC (doxorubicin/cyclophosphamide) followed or preceded by paclitaxel every 2 weeksc,e• Dose-dense AC (doxorubicin/cyclophosphamide) followed or preceded by weekly paclitaxelc,e• TC (docetaxel and cyclophosphamide)e

Stage II–IIIPreoperative followed by adjuvant:• Preoperative pembrolizumab + carboplatin + paclitaxel, followed by preoperative pembrolizumab + cyclophosphamide + doxorubicin orepirubicin, followed by adjuvant pembrolizumab (category 1)

Stages I–IIIAdjuvant setting only:

• If residual disease after preoperative therapy with taxane-, alkylator-, and anthracycline-based chemotherapyd,e: Capecitabine

• Germline BRCA1/2 mutationsd: Olaparib

Useful in Certain Circumstances:

Preoperative only:• Docetaxel/carboplatin/pembrolizumabPreoperative or adjuvant:• Dose-dense AC (doxorubicin/cyclophosphamide)• AC (doxorubicin/cyclophosphamide) every 3 weeks (category 2B)• CMF (cyclophosphamide/methotrexate/fluorouracil)• AC followed by weekly paclitaxelc• AC (doxorubicin/cyclophosphamide) followed or preceded bycarboplatin + taxane (paclitaxel or docetaxel)cMaintenance therapy after adjuvant chemotherapy:• Capecitabine

Other Recommended Regimens: Preoperative or adjuvant setting:• AC followed by docetaxel every 3 weeksc• EC (epirubicin/cyclophosphamide)• TAC (docetaxel/doxorubicin/cyclophosphamide)• Paclitaxel + carboplatin (various schedules) (category 2A)• Docetaxel + carboplatin1 (category 2A)• Regimens listed as “Preferred” for stage I, may be consideredfor patients with Stage II–III disease who are not eligible forpembrolizumab.

a Alternative taxanes (ie, docetaxel, paclitaxel, albumin-bound paclitaxel) may be substituted for select patients due to medical necessity (ie, hypersensitivity reaction). If substituted for weekly paclitaxel or docetaxel, then the weekly dose of albumin-bound paclitaxel should not exceed 125 mg/m2.b Principles of Preoperative Systemic Therapy (BINV-L).c It is acceptable to change the administration sequence to taxane followed by AC.d Patients in the OlympiA trial did not receive capecitabine; thus, there are no data on sequencing or to guide selection of one agent over the other. In patients eligible for both adjuvant olaparib and abemaciclib, the optimal sequence is not known. See BINV-K, 2.e For patients with stage II–III disease who are not eligible for pembrolizumab, the regimens listed as "preferred" for stage 1 could be considered as other recommended options.

The regimens listed in the table are all category 1 (except where indicated) when used in the adjuvant setting. See BINV-M, 1 for

Considerations for Those Receiving Preoperative/Adjuvant Systemic Therapy.

References on BINV-M 10 of 10

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PREOPERATIVE/ADJUVANT THERAPYa

See BINV-M,1 for Considerations for Those Receiving Preoperative/Adjuvant Systemic Therapy.

|HR-positive or negative and HER2-Positive|| |---|---| |Patients with HR-positive disease are recommended to receive adjuvant endocrine therapy ± CDK4/6 inhibitor therapy(see BINV-K).|| |Preferred Regimens: Preoperative or adjuvant setting:|| |●Paclitaxel+trastuzumabf ●TCHD(docetaxel/carboplatin/trastuzumab) ●TCHP(docetaxel/carboplatin/trastuzumab/pertuzumab) Adjuvant setting only:|| |●If no residual disease after preoperative therapy or no preoperative therapy: Complete up to 1 year of HER2-targeted therapy with trastuzumabh,(category 1)±pertuzumab.If node positive at initial staging,trastuzumab(category 1)^9 ●If residual disease after preoperative therapy: Ado-trastuzumab emansine(category 1) alone. If ado-trastuzumab emansine discontinued for toxicity, then trastuzumab(category 1)±pertuzumab to complete 1 year of therapy.n If node positive at initial staging,trastuzumab+ pertuzumab(category 1)^9|| |Useful in Certain Circumstances: Preoperative or adjuvant setting:|Other Recommendeded Regimens: Preoperative or adjuvant setting:| |●AC followed by Tc+ trastuzumab,h (doxorubicin/cyclophosphamide followed by paclitaxel plus trastuzumab, various schedules)|●AC followed by docetaxelc+ trastuzumab,i (doxorubicin/cyclophosphamide followed by docetaxel+ trastuzumab)| |●AC followed by Tc+ trastuzumab+pertozubam[h (doxorubicin/cyclophosphamide followed by paclitaxel plus trastuzumab plus pertuzumab, various schedules)|●AC followed by docetaxelc+ trastuzumab+pertuzumab+(doxorubicin/cyclophosphamide followed by docetaxel+ trastuzumab+pertuzumab)| |●Paclitaxel+ trastuzumab+ pertuzumab pHertuzumab, various schedules)|●Paclitaxel/cyclophosphamide followed by docetaxel+ pertuzumab| |●Paclitaxel+trastuzumab pertuzumab|| |●Adu-trastuzumab emansine(TDM-1)||

9 Updated results from the adjuvant APHINITY trial in HER2-positive early breast cancer,with a median follow-up of 8.4 years, have confirmed the benefit of adding pertuzumab to trastuzumab plus chemotherapy in preventing recurrences in those with node positive disease.

h Trastuzumab given in combination with an anthracycline is associated with significant cardiac toxicity. Concurrent use of trastuzumab and pertuzumab with an anthracycline should be avoided.

c It is acceptable to change the administration sequence to taxane(with or without HER2-targeted therapy) followed by AC.

f Paclitaxel+ trastuzumab may be considered for patients with low-risk T1,N0,M0,HER2-positive disease, particularly those not eligible for other standard adjuvant regimens due to comorbidities.

Consider extended adjuvant neratinib following adjuvant trastuzumab-containing therapy for patients with HR-positive,HER2-positive disease with a perceived high risk of recurrence.The benefit or toxicities associated with extended neratinib in patients who have received pertuzumab or ado-trastuzumab emansine is unknown.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

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DOSING: PREOPERATIVE/ADJUVANT THERAPY REGIMENS

|HER2-Negative|• Preoperative pembrolizumab + chemotherapy followed by adjuvant pembrolizumab4,j,k| |---|---| |Doxorubicin 60 mg/m2 IV day 1|Pemrolizumab 200 mg IV or 2mg/kg day 1| |Cyclophosphamide 600 mg/m2 IV day 1|Pooperative:| |$\bigcirc$ Cycled every 14 days for 4 cycles|Pemblizumab 200 mg IV or 2mg/kg day 1| |$\bigcirc$ Followed by:|$\bigcirc$ Paclitaxel 80 mg/m2 IV days 1,8,15| |Paclitaxel 175 mg/m2 by 3 h IV infusion day 1|$\bigcirc$ Carboplatin AUC 5 IV day 1| |$\bigcirc$ Cycled every 14 days for 4 cycles|Or| |Dose-dense AC followed by weekly paclitaxel2|$\bigcirc$ Carboplatin AUC 1.5 IV days 1,8,15| |Doxorubicin 60 mg/m2 IV day 1|- Cycled every 21 days x 4 cycles (cycles 1-4)| |Cyclophosphamide 600 mg/m2 IV day 1|Followed by:| |$\bigcirc$ Cycled every 14 days for 4 cycles|Pemblizumab 200 mg IV or 2mg/kg day 1| |$\bigcirc$ Followed by:|Doxorubicin 60 mg/m2 IV day 1 or Epirubicin 90 mg/m2 IV day 1| |Paclitaxel 80 mg/m2 by 1 h IV infusion weekly for 12 weeks|$\bigcirc$ Cycledphosphamide 600 mg/m2 IV day 1| |$\cdot$ TC3|- Cycled every 21 days x 4 cycles (cycles 5-8)| |Docetaxel 75 mg/m2 IV day 1|Followed by:| |Cyclophosphamide 600 mg/m2 IV day 1|Adjuvant pembrolizumab 200 mg IV or 2mg/kg day 1| |$\bigcirc$ Cycled every 21 days for 4 -6 cycles|$\bigcirc$ Cycled every 21 days x 9 cycles| |$\bullet$ Riboclicun (in combination with an aromatase inhibitor)|$\bullet$ Capecitabine 5| |400 mg PO once daily|1000-1250 mg/m2 PO twice daily on days 1-14| |21 days on/7 days off for 3 years|$\bigcirc$ Cycled every 21 days for 6-8 cycles| ||$\bullet$ Olaparib6| ||300 mg PO twice daily| ||Cycled every 28 days for 1 year|

References on BINV-M 10 of 10

All cycles are with myeloid growth factor support. See NCCN Guidelines for Hematopoietic Growth Factors.

k Pembrolizumab 400 mg or 4mg/kg every 42 days may be given instead of pembrolizumab 200 mg every 21 days in this regimen.

The selection, dosing, and administration of anti-cancer agents and the management of associated toxicities are complex. Modifications of drug dose and schedule and initiation of supportive care interventions are often necessary because of expected toxicities and individual patient variability, prior treatment, and comorbidity. The optimal delivery of anti-cancer agents therefore requires a health care delivery team experienced in the use of anti-cancer agents and the management of associated toxicities in patients with cancer.

Abstract

Note: All recommendations are category 2A unless otherwise indicated. NCCN Guidelines Version 5.2025 Invasive Breast Cancer NCCN Guidelines Index Table of Contents Discussion 6 OF 10 DOSING: PREOPERATIVE/ADJUVANT THERAPY REGIMENS j All cycles are with myeloid growth factor support. See NCCN Guidelines for Hematopoietic Growth Factors. k Pembrolizumab 400 mg or 4mg/kg every 42 days may be given instead of pembrolizumab 200 mg every 21 days in this regimen.

• Dose-dense AC 2 Doxorubicin 60 mg/m² IV day 1 Cyclophosphamide 600 mg/m² IV day 1 ◊ Cycled every 14 days for 4 cycles j

• AC 15 Doxorubicin 60 mg/m² IV on day 1 Cyclophosphamide 600 mg/m² IV day 1 ◊ Cycled every 21 days for 4 cycles The selection, dosing, and administration of anti-cancer agents and the management of associated toxicities are complex. Modifications of drug dose and schedule and initiation of supportive care interventions are often necessary because of expected toxicities and individual patient variability, prior treatment, and comorbidity. The optimal delivery of anti-cancer agents therefore requires a health care delivery team experienced in the use of anti-cancer agents and the management of associated toxicities in patients with cancer.

References

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

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DOSING: PREOPERATIVE/ADJUVANT THERAPY REGIMENS

|HER2-Positive${}^{1,m}$|||| |---|---|---|---| |TCH+pertuzumab23|TCH+pertuzumab23|TCH+pertuzumab23|TCH+pertuzumab23| |Paclitaxel+trastuzumab21|TCH22|TCH+pertuzumab23|TDM-1| |Paclitaxel 80 mg/m2 IV weekly for 12 weeks|Docetaxel 75 mg/m2 IV day 1|Docetaxel 75 mg/m2 IV day 1|3.6 mg/kg day 1| |With:|Carboplatin AUC 6 IV day 1|Carboplatin AUC 6 IV day 1|$\diamond$ Cycled every 21 days for 6 cycles| |Trastuzumab 4 mg/kg IV with first dose of paclitaxel|O Cycled every 21 days for 6 cycles|$\diamond$ Cycled every 21 days for 6 cycles|14 cycles| |Followed by:|Followed by:|With:|| |Trastuzumab 2 mg/kg IV weekly to complete 1 year of treatment. As an|Trastuzumab 2 mg/kg IV for 17 weeks|Trastuzumab 8 mg/kg IV for 17 weeks|| |alternative, trastuzumab 6 mg/kg IV every 21 days may be used following|Followed by:|Trastuzumab 6 mg/kg IV on day 1|▶ Followed by:| |every 21 days may be used following the completion of paclitaxel,|Cycled every 21 days to complete|Pertuzumab 420 mg IV day 1|| |and given to complete 1 year of|OR|$\diamond$ Cycled every 21 days to complete|1 year of therapyn| |trastuzumab treatment.|Followed by:|of therapyn|| ||Trastuzumab 8 mg/kg IV week 1||| ||Followed by:||| ||Trastuzumab 6 mg/kg IV||| ||1 year of therapyn|||

${}^{n}$ Evaluate left ventricular ejection fraction (LVEF) prior to and during treatment.The optimal frequency of LVEF assessment during adjuvant trastuzumab therapy is not known. The FDA label recommends LVEF measurements prior to initiation of trastuzumab and every 3 months during therapy.

NCCN Guidelines Index

National Comprehensive Cancer Network®

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

DOSING: PREOPERATIVE/ADJUVANT THERAPY REGIMENS

HER2-Positivel,m

AC followed by T+ trastuzumab24

Doxorubicin 60 mg/m2 IV day 1

●Cyclophosphamide 600 mg/m2 IV day 1

◇Cycled every 21 days for 4 cycles.

◆ Followed by:

●Paclitaxel 80 mg/m2 by 1 h IV weekly for 12 weeks.

◇With:

Trastuzumab 4 mg/kg IV with first dose of paclitaxel ▶ Followed by:

Trastuzumab 2 mg/kg IV weekly to complete 1 year of treatment.As an alternative, trastuzumab 6 mg/kg IV every 21 days may be used following the completion of paclitaxel, and given to complete 1 year of trastuzumab treatment.n

Dose-dense AC followed by paclitaxel+trastuzumab26

Doxorubicin 60 mg/m2 IV day 1

●Cyclophosphamide 600 mg/m2 IV day 1

Cycled every 14 days for 4 cycles ▼ Followed by:

●Paclitaxel 175 mg/m2 by 3 h IV infusion day 1

Cycled every 14 days for 4 cycles With:

Trastuzumab 4 mg/kg IV with first dose of paclitaxel Followed by:

Trastuzumab 2 mg/kg IV weekly at complete 1 year of treatment. As an alternative, trastuzumab alternative, trastuzumab 6 mg/kg IV every 21 days may be used following the completion of paclitaxel, and given to complete 1 year of trastuzumab treatment.n

AC or Dose-Dense AC followed by T+trastuzumab+ pertuzumab26

Doxorubicin 60 mg/m2 IV day 1

●Cyclophosphamide 600 mg/m2 IV day 1

Cycled every 21 days for 4 cycles or

For dose-dense: Cycle every 14 days for 4 cycles

▶Followed by:

Pertuzumab 840 mg IV day 1 followed by 420 mg IV

Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg IV

Paclitaxel 80 mg/m2 IV weekly to complete 1 year of treatment. As an

<BeginOfPara>Paclitaxel 80 mg/m2 IV days 1,8;and 15

Trastuzumab 6 mg/kg IV day 1

Pertuzumab 420 mg IV day 1

Cycled every 21 days to complete 1 year of therapy

m Pertuzumab,trastuzumab,and hyaluronidase-zzxf injection for subcutaneous use may be substituted anywhere that the combination of intravenous pertuzumab and intravenous trastuzumab are given as part of systemic therapy. Pertuzumab,astuzumab,and hyaluronidase-zzxf injection for subcutaneous use has different dosing and administration instructions compared to the intravenous products. ${ }^{n}$ Evaluate LVEF prior to and during treatment. The optimal frequency of LVEF assessment during adjuvant trastuzumab therapy is not known. The FDA label recommends LVEF measurements prior to initiation of trastuzumab and every 3 months during therapy.

NCCN Guidelines Index

National Comprehensive Cancer Cancer Network®

Table of Contents Discussion

DOSING: PREOPERATIVE/ADJUVANT THERAPY REGIMENS

HER2-Positive,m

AC followed by docetaxel+ trastuzumab21,28

Doxorubicin 60 mg/m2 IV day 1

Cyclophosphamide 600 $mg/m^{2}$ IV day 1

Cycled every 21 days for 4 cycles

▶Followed by:

Docetaxel 100 mg/m2 IV day 1

Cycled every 21 days for 4 cycles

With:

Trastuzumab

4 mg/kg IV week 1; Followed by:

2 mg/kg IV weekly for 11 weeks; Followed by:

◇$6 mg/kg IV

Cycled every 21 days to complete 1 year of trastuzumab therapy $^{n}$

Paclitaxel/carbogplatin+trastuzumab

+ pertuzumab29

Paclitaxel 80 mg/m2 IV day 1 and 8

Carboplatin A C 6 V day 1

Cycled every 21 days for 9 cycles

Trastuzumab 8 mg/kg IV day 1

Pertuzumab 840 mg IV day 1

▶Followed by:

Trastuzumab 6 mg/kg IV day 1

Pertuzumab 420 mg IV day 1

Cycled every 21 days to complete 1 year

complete 1 year of therapy

AC followed by docetaxel+ trastuzumab+ pertuzumab30

Doxorubicin 60 mg/m2 IV day 1

Cyclophosphamide 600 $m^{2}$ IV day 1

◇Cycled every 21 days for 4 cycles

◆ Followed by:

Pertuzumab 840 mg IV day 1 followed by 420 mg IV

Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg IV

Docetaxel 75-100 mg/m2 IV day 1

Cycled every 21 days for 4 cycles

◆ Followed by:

Trastuzumab 6 mg/kg IV

Pertuzumab 420 mg IV day 1

Cycled every 21 days to complete 1 year of therapy

Neratinib31

<BeginOfPara>120 mg PO daily on days 1-7; Followed by:

160 mg PO daily on days 8-14; Followed by:

<240 mg PO daily on days 15-28

Cycled every 28 days x1 cycle

<BeginOfPara>Followed by:

240 mg PO daily on days 1-28

Cycled every 28 days x 12 cycles beginning with cycle 2

Paclitaxel+trastuzumab+ pertuzumab32

Paclitaxel 80 mg/m2 IV day 1

▶Cycled every 7 days x 12 cycles

Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg IV

Pertuzumab 840 mg IV day 1 followed by 420 mg IV

Cycled every 21 days x 4 cycles

▶Followed by:

▶Trastuzumab $6 mg/kg$ IV;

Pertuzumab 420 mg IV day 1;

▶Cycled every 21 days to complete 1 year of therapy

Ado-trastuzumab emtansine (T-DM1)33

3.6 mg/kg IV day 1

Cycled every 21 days for 17 cycles

BINV-M 9 OF 10

|Trastuzumab,brastuzumab, and hyaluronidase-zzxf injection for subcutaneous use may be substituted anywhere that the combination of intravenous pertuzumab and intravenous trastuzumab are given as part of systemic therapy. Pertuzumab, trastuzumab, and hyaluronidase-zzxf injection for subcutaneous use has different dosing

${}^{n}$ Evaluate LVEF prior to and during treatment. The optimal frequency of LVEF assessment during adjuvant trastuzumab therapy is not known. The FDA label recommends LVEF measurements prior to initiation of trastuzumab and every 3 months during therapy.

National Comprehensive Cancer Network®

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PREOPERATIVE/ADJUVANT THERAPY REGIMENS- REFERENCES

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23 Chehneweiss A, Chia Sichish T,et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 2013;24:2278-2284.

7 von Minkwitz G, Raab G, Caputo A, et al. Doxorubicor with cyclophosphamide followed by docetaxel every 21 days compared with doxorubic and docetaxel every 14 days as preoperative treatment in operable breast cancer: the GEPARDU study of the German Breast Group. J. Clin Oncol 2005;23:2676-2885.

24 Remonh EH, Perez EZ, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2 positive breast cancer. N Engl J Med 2005;353:1673-1684.

8 Pichart M,Di Leo A, Beaudun M, et al. Phase III trial comparing two dose levels of epirubic combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in-node positive breast cancer. J Clin Oncol 2001;29:1310:3110.

Cang F, Cormier M, Sugarman S, et al. The safety of dose-dense doxorubic and cyclophosphamide followed by paclitaxel with trastuzumab in HER-2/neu over-expressed/amplified breast cancer. J Clin Oncol 2008:26:12-1262.

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12 von Minkowitz G, Schneweissens A, Loibl S, et al. Neoadjuvant carboplatin in patients with triple-negative and HER2-pertensive breast cancer.(Genarix-SGG). a randomised phase 2013. Lancet Oncol 2014;15:747-756.

Aun.Samhorst MS. van der Oarter, Avan Werkhoven ED,et al. Anovadjuvant chemotherapy with or without antiferucit, open-label, randomised, phase 3 trial. Lancet Oncol 2018;19:1630-1640.

13 Sharma P, Lopez-Tarruella S, Garcia-Saenz J,et al. Efficacy of neoadjuvant carboplatin plus docetaxel in triple-negative breast cancer: Combined analysis of two cohorts. Clin Cancer Res 2017;23:649-657.

30 Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant temportuzum aband trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer(NoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 2018;19:1630-1640.

14 Zhang L, Wu ZY, Li J, et al. Neoadvjuant docetaxel plus carboplatin versus epirubicin plus cyclophosphamide followed by docetaxel in triple-negative, early-stage breast cancer(NeoCART):Results from a multicenter, randomized controlled, open-label phase II trial. Int J Cancer 2022;150:654-662.

31 Chan A, Delaogle S, Holmes FA,et al. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer(ExteNet): a multicentre, randomised, double-blind, placebo-controlled, phase trial. Lancet Oncol 2016;17:367-377.

15 Fisher B, Brown AM, Dimitrov NV,et al. Two months of doxorubicin-vapor than 33.11.19.80011990;8:1483-1496.16 Goldhirsch A, Colleoni M, Coates AS, et al: Adding adjuvant CMF chemotherapy to either radiotherapy or tamoxifen: are all CMFs alike? The International Breast Cancer Study Group(ICBSG).Ann Oncol 1998;9:489-493.

32 Nitz UA, Gluz O, Christgen M, et al. De-escalation strategies in HER2-positive early breast cancer(EBC):final analysis of the WSG-ADAPTER HER2+/HR- phase III: efficacy, safety, and predictive markers for 12 weeks of neoadjuvant dual blockade with trastuzumab and pertuzumab± weekly placitaxel. Ann Oncol 2011;39:2786-2772.

16 Goldhirsch A, Colleoni M, Coates AS, et al: Adding adjuvant CMF chemotherapy to either radiotherapy or tamoxifen: are all CMFs alike? The International Breast Cancer Study Group(ICBSG).Ann Oncol 1998;9:489-493.

35 Toplaney SM, Tayob N, Dang C, et al. Adjuvant trastuzumab emansine versus paclitaxel. Ann Oncol with trastuzumab for stage I HER2-positive breast cancer(ATEPT): A randomized clinical trial. J Clin Oncol 3021;39:2375-2385.

30219;39:2375-2385.34 John J,Kim GM,Jung KH,et al.A randomized, multicenter, open-label, phase III trial comparing anthracyclines followed by taxane versus anthracyclines followed by taxane plus carboplatin as(neo)antaburry therapy in patients with early triple-negative breast cancer: Korean Cancer Study Group BR 15-1 PEARLY trial. J Clin Oncol 2024;42: LBA502.

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NCCN Guidelines Version 5.2025 Invasive Breast Cancer

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GENE EXPRESSION ASSAYS FOR CONSIDERATION OF ADJUVANT SYSTEMIC THERAPYa,b

|Assay|Predictive|Prognostic|NCCN Category of Preference|NCCN Category of Evidence and Consensus|Recurrence Risk and Treatment Implications| |---|---|---|---|---|---| |21-gene (Oncotype Dx) (for pN0)|Yes|Yes|Preferred|1|BINV-N (2)| |21-gene (Oncotype Dx) for pN1 (1-3 positive nodes)c|Yes|Yes|Postmenopausal: Preferred|1|BINV-N (2)| |21-gene (Oncotype Dx) for pN1 (1-3 positive nodes)c|Yes|Yes|Premenopausal: Other|2A|BINV-N (2)| |70-gene (MammaPrint) for pN0 and pN1 (1-3 positive nodes)|Not determined|Yes|Other|1|BINV-N (3)| |50-gene (Prosigna) for pN0 and pN1 (1-3 positive nodes)|Not determined|Yes|Other|2A|BINV-N (3)| |12-gene (EndoPredict) for pN0 and pN1 (1-3 positive nodes)|Not determined|Yes|Other|2A|BINV-N (3)| |Breast Cancer Index (BCI)|Predictive of benefit of extended adjuvant endocrine therapy|Yes|Other|2A|BINV-N (4)|

a Gene expression assays provide prognostic and therapy-predictive information that complements T,N,M and biomarker information. Use of these assays is not required for staging. The 21-gene assay(Oncotype Dx) is preferred by the NCCN Breast Cancer Panel for prognosis and prediction of chemotherapy benefit. Other prognostic gene expression assays can provide prognostic information but the ability to predict chemotherapy benefit is unknown.

bSpecial Considerations for Breast Cancer in Males(Sex Assigned at Birth)(BINV-J).

cIn the overall study population of the RxPONDER trial, 10.3% had high-grade disease and 9.2% had 3 involved nodes.

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GENE EXPRESSION ASSAYS FOR CONSIDERATION OF ADJUVANT SYSTEMIC THERAPYa,b

|Assay|Recurrence Risk|Treatment Implications| |---|---|---| |21-gene (Oncotype Dx) (for postmenopausal patients with pN0 and pN1 [1-3 positive nodes])^c|<26|Patients with T1b/c-2, pN0, HR-positive, HER2-negative tumors, with recurrence scores (RS) between 0-10 have a risk of distant recurrence of <4% and those with RS 11-25 derived no benefit from the addition of chemotherapy to endocrine therapy in the prospective TAILORx study.1 Postmenopausal patients with pT1-3, pN1, HR-positive, HER2-negative, with RS <26 derived no benefit from the addition of chemotherapy to endocrine therapy in the prospective RxONDER study.2| |21-gene (Oncotype Dx) (for postmenopausal patients with pN0 and pN1 [1-3 positive nodes])^c|≥26|In postmenopausal patients with pT1-3, HR-positive, HER2-negative, and pN0 and pN1 (1-3 positive nodes) tumors and an RS ≥ 26, the addition of chemotherapy to endocrine therapy is recommended.1,2| |21-gene (Oncotype Dx) (for premenopausalpatients):pN0)|≤15|Premenopausal patients with T1b/c -2, pN0, HR-positive, HER2-negative, HER2-negative tumors with RS <16 derived no benefit from the addition of chemotherapy to endocrine therapy in the prospective TAILORx study.1| |21-gene (Oncotype Dx) (for premenopausalpatients):pN0)|16-25|In premenopausal patients with RS between 16-25, a small benefit from the addition of chemotherapy to endocrine therapy in the prospective TAILORx study.1| |21-gene (Oncotype Dx) (for premenopausalpatients):pN0)|≥26|In premenopausal patients with HR-positive, HER2-negative, and pN0 tumors and an RS ≥ 26, the addition of chemotherapy to endocrine therapy is recommended.1| |21-gene (Oncotype Dx) (for premenopausalpatients with 1-3 positive nodes)c|<26|In premenopausal patients with pT1-3 and pN1 (1-3 positive nodes) tumors and an RS ≥ 26, the addition of chemotherapy to endocrine therapy in the prospective RxONDER study.2| |21-gene (Oncotype Dx) (for premenopausalpatients with 1-3 positive nodes)c|≥26|In premenopausal patients with HR-positive, HER2-negative, and pN0 and pN1 (1-3 positive nodes) tumors and an RS ≥ 26, the addition of chemotherapy to endocrine therapy is recommended.|

b Special Considerations for Breast Cancer in Males(Sex Assigned at Birth)(BINV-J).

cIn the overall study population of the RxPONDER trial, 10.3% had high-grade disease and 9.2% had 3 involved nodes.

Note: All recommendations are category 2A unless otherwise indicated.

References on BINV-N 5 of 5

BINV-N 2 OF 5

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GENE EXPRESSION ASSAYS FOR CONSIDERATION OF ADJUVANT SYSTEMIC THERAPYa,b

|Assay|Recurrence Risk|Treatment Implications| |---|---|---| |70-gene (MammaPrint) (for pNO and 1-3 positive nodes)|High|Patients with high clinical risk and low genomic risk were randomly assigned to receive chemotherapy (n=749) or not (n=748); this was the intention-to-treat population. The 8-year estimates for distant metastasis-free survival in the intention-to-treat population were 92.0% (95% CI, 89.6-93.8) for chemotherapy versus 89.4% (86.8-91.5) for no chemotherapy (HR, 0.66; 95% CI, 0.48-0.92). An exploratory analysis confined to the subset of patients with HR-positive, HER2-negative disease (1358 [90.7%] of 1497 randomly assigned patients, of whom 676 received chemotherapy and 682 did not) shows different effects of chemotherapy administration on 8-year distant metastasis-free survival according to age:93.6% (95% CI, 89.3-96.3) with chemotherapy versus 88.6% (83.5-92.3) without chemotherapy in 464 patients aged ≤50 years (absolute difference 5.0 percentage points [SE, 2.8; 95% CI ,-0.5 to 10.4]) and 90.2% (86.8-92.7) versus 90.0% (86.6-92.6) in 894 females >50 years (absolute difference 0.2 percentage points [2.1,-4.0 to 4.4]). The 8-year distant metastasis-free survival in the exploratory analysis by nodal status in these patients was 91.7% (95% CI, 88.1-94.3) with chemotherapy and 89.2% (85.2-92.2) without chemotherapy in 699 patients who are node-negative (absolute difference 2.5 percentage points [SE, 2.3; 95% CI, -2.1 to 7.2]) and 91.2% (87.2-94.0) versus 89.9% (85.8-92.8) for 658 patients with 1-3 positive nodes (absolute difference 1.3 percentage points [2.4,-3.5 to 6.1]). ${}^{3}$| |70-gene (MammaPrint) (for pNO and 1-3 positive nodes)|50-gene (Prosigna) (for pNO and 1-3 positive nodes)|Patients with high clinical risk and low genomic risk were randomly assigned to receive chemotherapy (n=749) or not (n=748); this was the intention-to-treat population. The 8-year estimates for distant metastasis-free survival in the intention-to-treat population were 92.0% (95% CI, 89.6-93.8) for chemotherapy versus 89.4% (86.8-91.5) for no chemotherapy (HR, 0.66; 95% CI, 0.48-0.92). An exploratory analysis confined to the subset of patients with HR-positive, HER2-negative disease (1358 [90.7%] of 1497 randomly assigned patients, of whom 676 received chemotherapy and 682 did not) shows different effects of chemotherapy administration on 8-year distant metastasis-free survival according to age:93.6% (95% CI, 89.3-96.3) with chemotherapy versus 88.6% (83.5-92.3) without chemotherapy in 464 patients aged ≤50 years (absolute difference 5.0 percentage points [SE, 2.8; 95% CI ,-0.5 to 10.4]) and 90.2% (86.8-92.7) versus 90.0% (86.6-92.6) in 894 females >50 years (absolute difference 0.2 percentage points [2.1,-4.0 to 4.4]). The 8-year distant metastasis-free survival in the exploratory analysis by nodal status in these patients was 91.7% (95% CI, 88.1-94.3) with chemotherapy and 89.2% (85.2-92.2) without chemotherapy in 699 patients who are node-negative (absolute difference 2.5 percentage points [SE, 2.3; 95% CI, -2.1 to 7.2]) and 91.2% (87.2-94.0) versus 89.9% (85.8-92.8) for 658 patients with 1-3 positive nodes (absolute difference 1.3 percentage points [2.4,-3.5 to 6.1]). ${}^{3}$| |Node positive: Low (0-40)|50-gene (Prosigna) (for pNO and 1-3 positive nodes)|In patients with HR-positive, HER2-negative, pN+ tumors (3-1 positive lymph nodes) with low risk of recurrence score, treated with endocrine therapy alone, the distant recurrence risk was less than 3.5% at 10 years and no distant recurrence was seen at 10 years in the TransATAC study in a similar group. ${}^{5}$| |Node positive: High (41-100)||In patients with HR-positive, HER2-negative, pN+ tumors (3-1 positive lymph nodes) with low risk of recurrence score, treated with endocrine therapy alone, the distant recurrence risk was less than 3.5% at 10 years and no distant recurrence was seen at 10 years in the TransATAC study in a similar group. ${}^{5}$| |12-gene (EndoPredict) (pNO and 1-3 positive nodes)|Low (≤3.3)|For patients with T1 and T2 HR-positive, HER2-negative, and pN0 tumors, a 12-gene low-risk score, regardless of T size, places the tumor into the same prognostic category as T1a-T1b,N0,M0.6 In ABCSG 6/8, patients in the low-risk group had risk of distant recurrence of 4% at 10 years and in the TransATAC study, patients with 1-3 positive nodes in the low-risk group had a 5.6% risk of distant recurrence at 10 years. ${}^{6,7}$ The assay is prognostic in patients treated with endocrine and chemo-endocrine.| |12-gene (EndoPredict) (pNO and 1-3 positive nodes)|High (>3.3)|For patients with T1 and T2 HR-positive, HER2-negative, and pN0 tumors, a 12-gene low-risk score, regardless of T size, places the tumor into the same prognostic category as T1a-T1b,N0,M0.6 In ABCSG 6/8, patients in the low-risk group had risk of distant recurrence of 4% at 10 years and in the TransATAC study, patients with 1-3 positive nodes in the low-risk group had a 5.6% risk of distant recurrence at 10 years. ${}^{6,7}$ The assay is prognostic in patients treated with endocrine and chemo-endocrine.|

b Special Considerations for Breast Cancer in Males(Sex Assigned at Birth)(BINV-J).

d Postmenopausal patients with UltraLow risk in the Stockholm Tamoxifen trial had a 20-year breast cancer specific survival of 97% with 2-5 years of Tamoxifen(Esserman LJ,et al.JAMA Oncology 2017;3:1503-1510). Patients with an ultralow-risk risk in the MINDACT trial have shown 8-year breast cancer specific survival above 95.6%.(Lopes Cardozo JMn, et al. J Clin Oncol 2022;40:1335-1345).

Note: All recommendations are category 2A unless otherwise indicated.

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GENE EXPRESSION ASSAYS FOR CONSIDERATION OF EXTENDED ADJUVANT SYSTEMIC THERAPYa,b

|Assay|Recurrence Risk/ Predictive Result|Treatment Implications| |---|---|---| |Breast Cancer Index (BCI)e|BCI (H/I) Low|●For patients with T1 and T2 HR-positive,HER2-negative, and pN0 tumors, a BCI (H/I) in the low-risk range (0-5),regardless of T size, places the tumor into the same prognostic category as T1a-T1b, N0, M0. ●Patients with BCI (H/I) low demonstrated a lower risk of distant recurrence (compared to BCI [H/I] high) and no significant improvement in disease-free survival (DFS) or OS compared to the control arm in terms of extending endocrine therapy duration.8| |Breast Cancer Index (BCI)e|BCI (H/I) High|●For patients with T1 HR-positive,HER2-negative, and pN0 tumors, a BCI (H/I) high (5.1-10) demonstrated significant rates of late distant recurrence. ●In secondary analyses of the MA.17, Trans-aTTom, and IDEAL trials, patients with HR-positive, T1-T3, pN0 or pN+ who had a BCI (H/I) high demonstrated significant improvements in DFS when adjuvant endocrine therapy was extended, compared to the control arm.8-11|

b Special Considerations for Breast Cancer in Males(Sex Assigned at Birth)(BINV-J).

e The benefit of testing BCI(H/l) for extended adjuvant endocrine therapy is unknown in patients who had ovarian function suppression, CDK4/6 inhibitors, or oparib in addition to adjuvant endocrine therapy.

Note: All recommendations are category 2A unless otherwise indicated.

BINV-N 4 OF 5

GENE EXPRESSION ASSAYS FOR CONSIDERATION OF ADJUVANT SYSTEMIC THERAPY REFERENCES

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

NCCN Guidelines Index

Abstract

Note: All recommendations are category 2A unless otherwise indicated.

Abstract

Table of Contents Discussion BINV-N 5 OF 5 1 Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med 2018;379:111-121. 2 Kalinsky K, Barlow WE, Meric-Bernstam F, et al. First results from a phase III randomized clinical trial of standard adjuvant endocrine therapy (ET) +/-chemotherapy (CT) in patients (pts) with 1-3 positive nodes, hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer (BC) with recurrence score (RS) < 25: SWOG S1007 (RxPonder). Cancer Res 2021;81:Abstract GS3-00. 3 Piccart M, van 't Veer LJ, Poncet C, et al. 70-gene signature as an aid for treatment decisions in early breast cancer: updated results of the phase 3 randomised MINDACT trial with an exploratory analysis by age. Lancet Oncol 2021;22:476-488. 4 Laenkholm AV, Jensen MB, Eriksen JO, et al. PAM50 risk of recurrence score predicts 10-year distant recurrence in a comprehensive Danish cohort of postmenopausal women allocated to 5 years of endocrine therapy for hormone receptor-positive early breast cancer.

References

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

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Note: All recommendations are category 2A unless otherwise indicated.

BINV-O

DEFINITION OF MENOPAUSE

• Menopause is the permanent cessation of menses and includes a profound and permanent decrease in ovarian estrogen synthesis.

• Determination of menopausal status may be required to guide selection of endocrine therapy for breast cancer.

• Menopause is usually a clinical diagnosis made after ≥12 months of amenorrhea. Natural menopause is experienced between ages 42–58

years.

• Breast cancer treatments may affect ovarian function and menses.

In those who are premenopausal at the beginning of chemotherapy and who develop chemotherapy-induced amenorrhea, ovarian function

may still be intact despite amenorrhea or may resume over time. The likelihood of ovarian function resuming after chemotherapy is higher

among those aged <40 years.

Tamoxifen may cause amenorrhea without inducing menopause in premenopausal individuals.

Ovarian function suppression induces amenorrhea and reduces ovarian estrogen synthesis without causing permanent menopause.

• Twelve months of amenorrhea alone is insufficient to diagnose menopause with chemotherapy-induced amenorrhea or with tamoxifen

± ovarian suppression. FSH and estradiol levels are used to support the diagnosis of menopause; however, clear criteria to guide

interpretation of FSH and estradiol in this population is lacking.

Tamoxifen may alter FSH levels, limiting its utility in determination of menopausal status.

FSH and estradiol should be repeated serially to ensure menopausal status in patients with breast cancer with chemotherapy-induced

amenorrhea.

• Evidence-based criteria for the diagnosis of menopause in patients with breast cancer are lacking. Clinical trials in breast cancer have

utilized a variety of definitions of menopause. Reasonable criteria for determining menopause in patients with breast cancer include any of the following:

Prior bilateral oophorectomy

Age ≥60 years

Age <60 with amenorrhea for ≥12 months in the absence of prior chemotherapy, receipt of tamoxifen, toremifene, or ovarian suppression

and estradiol and FSH in the postmenopausal range

Age <60 years: chemotherapy-induced amenorrhea for ≥12 months with FSH and estradiol in post-menopausal range on serial

assessments

Age <60 years: on tamoxifen with FSH and estradiol level in postmenopausal range

• Menopausal status cannot be determined in those receiving ovarian function suppression

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SYSTEMIC THERAPY FOR ER- AND/OR PR-POSITIVE

RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE General Considerations for therapy selection for HR-positive disease

Ovarian function assessment: (see BINV-O and BINV-K 1 of 2)

• Assess serum estradiol prior to therapy initiation.

• If premenopausal or perimenopausal,

Ovarian suppression/ablation/resection plus anti-estrogen therapy is more effective than endocrine therapy alone.

Start OFS with or prior to initiation of endocrine therapy

Choice of endocrine therapy:

• Depends on prior adjuvant endocrine agent and disease-free interval (see BINV-P 2 of 3)

• Must balance benefit with additional side effects.

Endocrine + CDK4/6 inhibitor therapy:

• Endocrine therapy + CDK4/6 inhibitor is preferred over chemotherapy, even for extensive visceral involvement

• Chemotherapy recommended only if true visceral crisis

• If frail or extensive comorbidity, consider single agent aromatase inhibitor (AI).

Management of toxicity (particularly early in initiation of these therapies) is essential.

Duration of initial response to endocrine therapy can guide likelihood of benefit of continued endocrine therapy as later line therapy.

Note: All recommendations are category 2A unless otherwise indicated.

BINV-P 1 OF 3

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BINV-P 2 OF 3

SYSTEMIC THERAPY FOR ER- AND/OR PR-POSITIVE

RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASEa

HER2-Negative and Postmenopausal or

Premenopausal Receiving Ovarian Ablation or Suppression

See BINV-P 1 of 3 for general considerations for therapy selection for HR-positive, HER2-negative disease.

First-Line Therapy

Second- and/or Subsequent-Line Therapy

Preferred Regimens

• Aromatase inhibitor + CDK4/6 inhibitorb

Aromatase inhibitor + ribociclib (category 1)c

Aromatase inhibitor + abemaciclib

Aromatase inhibitor + palbociclib

If disease progression on adjuvant endocrine therapy or relapse within 12 months of adjuvant endocrine therapy completion consider:

• Fulvestrantd + CDK4/6 inhibitorb

Fulvestrant + ribociclib (category 1)e

Fulvestrant + abemaciclib (category 1)e

Fulvestrant + palbociclib

Preferred Regimens

• Fulvestrant + CDK4/6 inhibitor (abemaciclib, palbociclib, or ribociclib) if CKD4/6 inhibitor not previously used (category 1)f,g

• For HER2-negative tumors with PIK3CA or AKT1 activating mutations or PTEN alterations, see BINV-Q (6)h

• Everolimus + endocrine therapy (exemestane, fulvestrant, tamoxifen)i,j

• Targeted therapy, see BINV-Q (6) and BINV-Q (7), and emerging biomarker

options, see BINV-Q (8)

Useful in Certain Circumstances

• For HER2-negative tumors with PIK3CA activating mutations and

disease progression on adjuvant endocrine therapy or relapse within 12 months of adjuvant endocrine therapy completion, see BINV-Q (6)

Useful in Certain Circumstances

• Megestrol acetate

• Estradiol

• Abemaciclibl

• Targeted therapy, see BINV-Q (6) and BINV-Q (7), and emerging biomarker options,see BINV-Q (8)

Other Recommended Regimens for first and/or subsequent lines of therapy

• For HER2-negative and ESR1 mutated tumors after a prior line of aromatase inhibitor ± CDK 4/6 inhibitor therapy (in adjuvant or metastatic setting), see BINV-Q (6) for options.

• Fulvestrant) + aromatase inhibitor (anastrozole, letrozole) (category 1)k

• Fulvestrant

• Anastrozole

• Letrozole

• Tamoxifen

• Exemestane

Footnotes on BINV-P 3 of 3

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SYSTEMIC THERAPY FOR ER- AND/OR PR-POSITIVE RECURRENT UNRESELECTABLE(LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASEA

|HER2-Positive and Postmenopausal or Premenopausal Receiving Ovarian Ablation or Suppression| |---| |See BINV-Q (1) for Considerations for Systemic Therapy.| |If treatment was initiated with chemotherapy and trastuzumab+ pertuzumab, and the chemotherapy was stopped, endocrine therapy may be added to trastuzumab+ pertuzumab.| |● Aromatase inhibitor ± trastuzumab| |● Aromatase inhibitor ± lapatinib| |● Fulvestant ± trastuzumab| |● Fulvestant ± trastuzumab| |● Tamoxifen ± trastuzumab| |● Abemaciblin in combination with fulvestant and trastuzumab(category 2B)| |● Targeted therapy see BINV-Q (7) and emerging biomarker options see BINV-Q (8)|

a Baseline assessment of bone density recommended for patients receiving an aromatase inhibitor who are at risk of osteoporosis(eg, age $>65$, family history, chronic steroids).

b There is controversy on the choice of CDK4/6 inhibitor as there are no head to head comparisons between the agents and there are some differences in the study populations in the phase 3 randomized studies.

cIn phase 3 randomized controlled trials, ribocibil+ endocrine therapy have shown OS benefit in the first-line setting.

d Consider for disease progression on adjuvant endocrine therapy or with early disease relapse within 12 months of adjuvant endocrine therapy completion e In phase 3 randomized controlled trials, fulvestrant+ ribocibil or abemaciclib has shown OS benefit in the first-line setting

f In phase 3 randomized controlled trials, fulvestant in combination with a CDK4/6 inhibitor (abemaciclib, palocibiclib, and ribociclib) has shown OS benefit in the second-line setting.

9f there is disease progression while on palociblic, there are limited phase II data to support the use of ribociclib in the second line setting.

If there is progression while on a Pl3K inhibitor, there are limited data to support another line of therapy with a Pl3K-pathway inhibitor-containing regimen.

If there is disease progression while on an everolimus-containing regimen, there are no data to support an additional line of therapy with another everolimus regimen.J A combination of exemestane with everolimus can be considered for patients who meet the eligibility criteria for BOLERO-2(progressed within 12 mo or on non-steroidal aromatase inhibitor).

kA single study(S0226) in patients with HR-positive breast cancer and no prior chemotherapy, biological therapy, or endocrine therapy for metastatic disease demonstrated that the addition of fulvestrant to anastrozole resulted in prolongation of time to progression and OS. Subset analysis suggested that patients without prior adjuvant tamoxifen and more than 10 years since diagnosis experienced the greatest benefit. Two studies with similar design(FACT and SOFEA) demonstrated no advantage in time to progression with the addition of fulvestrant to anastrozole.

Indicated after progression on prior endocrine therapy and prior chemotherapy in the metastatic setting.

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BINV-Q 1 OF 15

• For treatment of brain metastases, see NCCN Guidelines for Central Nervous System Cancers.

General considerations:

• An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines.

• Screen for and manage immunotherapy-related toxicities and endocrine dysfunctions (eg, hypothyroidism, adrenal insufficiency) in patients treated with immune checkpoint inhibitors. See NCCN Guidelines for Management of Immunotherapy-Related Toxicities.

• Regular cardiac monitoring for patients with current or prior use of anthracyclines or HER2-targeted therapy. See NCCN Guidelines for

Survivorship: Cardiovascular Disease Risk Assessment.

• Consider scalp cooling to reduce incidence of chemotherapy-induced alopecia for patients receiving chemotherapy. Results may be less

effective with anthracycline.

• When receiving taxane-containing regimen:

Alternative taxanes (ie, docetaxel, paclitaxel, albumin-bound paclitaxel) may be substituted for select patients due to medical necessity (ie,

hypersensitivity reaction). If substituted for weekly paclitaxel or docetaxel, then the weekly dose of albumin-bound paclitaxel should not

exceed 125 mg/m2.

Consider cryotherapy of hands and feet to decrease the risk of peripheral neuropathy.1,2

For Those Receiving HER2-targeted Therapy

• Trastuzumab and hyaluronidase-oysk subcutaneous injection may be substituted for trastuzumab IV; however, dosing and administration

instruction differ. Do not substitute trastuzumab and hyaluronidase-oysk for or with ado-trastuzumab emtansine or fam-trastuzumab

deruxtecan-nxki.

• Pertuzumab, trastuzumab, and hyaluronidase-zzxf subcutaneous injection may be substituted for IV pertuzumab and trastuzumab; however,the dosing and administration instruction may differ.

• Patients previously treated with chemotherapy plus trastuzumab in the absence of pertuzumab in the metastatic setting may be consideredfor one line of therapy including both trastuzumab plus pertuzumab in combination with or without cytotoxic therapy (such as vinorelbine ortaxane). Further research is needed to determine the ideal sequencing strategy for anti-HER2 therapy.

1 Sphar BG, Bowe C, Dains JE. The impact of peripheral cooling on chemotherapy-induced peripheral neuropathy: An integrative review. J Adv Pract Oncol

2020;11:845-857.

2 Hanai A, Ishiguro H, Sozu T, et al. Effects of cryotherapy on objective and subjective symptoms of paclitaxel-induced neuropathy: Prospective self-controlled trial. J

Natl Cancer Inst 2018;110:141-148.

SYSTEMIC THERAPY FOR RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE

NCCN

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SYSTEMIC THERAPY FOR RECURRENT UNREsectABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASEa

|HR-Positive and HER2-Negative with Visceral Crisis ${}^{+}$ or Endocrine Refractory||| |---|---|---| |See BINV-Q(1) for Considerations for Systemic Therapy.||| |Setting|Subtype/Biomarker|Regimen| |First Line|No germline BRCA1/2 mutationb and/or HER2 IHC 0+, 1+, or 2+/ISH negative|Systemic chemotherapy (category 1, preferred) BINV-Q(5), or fam-trastuzumab deruxtecan-nxki${}^{f}$ (other recommended regimen)| |First Line|Germline BRCA1/2 mutationb|PARPi (olaparib, talazoparib) ${}^{c}$ (category 1, preferred)| |Second Line|HER2 IHC 1+ or 2+/ISH negative|Fam-trastuzumab deruxtecan-nxki${}^{f}$ (category 1, preferred)| |Second Line|HER2 IHC 0+d|Fam-trastuzumab deruxtecan-nxki${}^{f}$ (other recommended regimen)| |Second Line|Not a candidate for fam-trastuzumab deruxtecan-nxki|Sacituzumab govitecan9(category 1, preferred)| |Second Line|Not a candidate for fam-trastuzumab deruxtecan-nxki|Systemic chemotherapy BINV-Q (5)| |Targeted therapy BINV-Q (6) and BINV-Q(7)|Not a candidate for fam-trastuzumab deruxtecan-nxki|| |For HER2 IHC 0, 1+, or 2+/ISH negative:d Datopotamab deruxtecan-dlnk${}^{h}$ (other recommended regimen)||| |Third Line and beyond|Any|Systemic chemotherapy BINV-Q(5)| |Third Line and beyond|Biomarker positive(ie,MSI-H,NTRK,RET, TMB-H)|Targeted agents and emerging biomarker options BINV-Q(6). BINV-Q(7), and BINV-Q(8)|

${}^{+}$ According to the 5th ESO-ESMO international consensus guidelines(Cardoso F, et al. Ann Oncol 2020;31:1623-1649) for advanced breast cancer visceral crisis is defined as:“severe organ dysfunction, as assessed by signs and symptoms, laboratory studies and rapid progression of disease. Visceral crisis is not the mere presence of visceral metastases but implies important organ compromise leading to a clinical indication for the most rapidly efficacious therapy."

a For treatment of brain metastases, see NCCN Guidelines for Central Nervous System Cancers.

bAssess for germline BRCA1/2 mutations in all patients with recurrent or metastatic breast cancer to identify candidates for PARPi therapy.

c PARPi can be considered for a later line for those with germline BRCA1/2 mutation, however available evidence suggests it is more effective if used earlier.

d Principles of HER2 Testing(BINV-A). The distinction between HER2 test results of IHC 0/absent membrane staining, IHC 0+/with membrane staining(faint, partial membrane staining in≤10%), IHC 1+, or 2+/ISH negative is currently clinically relevant for therapy selection.

e Systemic chemotherapy(eg, oral chemotherapy) is generally preferred in the first-line setting. Selection of systemic therapy versus fam-trastuzumab-nxki for first-line therapy should be individualized based on clinical features and patient preference.

Fam-trastuzumab deruxecan-nxki may be used in those previously treated with at least one line of endocrine-based therapy in the metastatic setting. Fam-trastuzumab deruxecan-nxki is associated with interstitial lung disease(ILD)/pneummonitis. Regular monitoring for this serious side effect is recommended. For patients with a history of ILD/pneumonitis, there are no data on managing safety or toxicity of this drug in a trial.

9 Sacituzumab deruxecan-nxki may be used after prior treatment including endocrine therapy, a CDK4/6 inhibitor, and at least two lines of chemotherapy, one of which was a taxane, and at least one of which was in the metastatic setting. If may be considered for later line if not used as second line therapy.

h Datopatomab deruxecan-dlnk is indicated as second- or subsequent-line therapy for those who have received a prior endocrine-based therapy and chemotherapy for unresectable or metastatic disease. Datopatomab deruxecan-dlnk did not meet the OS endpoint in the TROPION-Breast01 trial. Whereas the previously approved antibody drug conjugates(ADC), fam-trastuzumab deruxecan-nxki and sacituxumab gotivecan have shown a benefit in OS in randomized phase III trials. The benefit treatment of using datotopamab deruxecan-dlnk in patients with prior ADC treatment are not known as the TROPION-Breast01 trial did not include patients with prior ADC treatment.

![NCCN\nNational Comprehensive Cancer\nCancer\nNetwork®\n](2/aj0YEe4oUhYkBdfpda0fYP/figure62a6b90163ae432b8ac2dc2385167b34_0_1.png) National Comprehensive Cancer

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

SYSTEMIC THERAPY FOR RECURRENT UNREsectABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE$a

|HR-Negative and HER2-Negative (Triple-Negative Breast Cancer; TNBC)||| |---|---|---| |See BINV-Q(1) for Considerations for systemic therapy.||| |Setting|Subtype/Biomarker|Regimen| |First Line|PD-L1 CPS ≥109 regardless of germline BRCA mutation statusb|Pembrolizumab + chemotherapy (albumin-bound paclitaxel, paclitaxel, or gemcitabine and carboplatin)（category 1, preferred）| |First Line|PD-L1 CPS <109 and no germline BRCA1/2 mutationb|Systemic chemotherapy BINV-Q (5)| |First Line|PD-L1 CPS <109 and germline BRCA1/2 mutationb|● PARPi (olaparib, talazoparib) (category 1, preferred) ● Platinum (cisplatin or carboplatin)（category 1, preferred）| |Second Line|Germline BRCA1/2 mutationb|PARPi (olaparib, talazoparib) (category 1, preferred)| |Second Line|Any|Sacituzumab govitecanj (category 1,preferred)| |Second Line|No germline BRCA1/2 mutationb and HER2 IHC 1+ or 2+/ISH negatively|Fam-trastuzumab deruxecan-nxkik (other recommended regimen)| |Third Line and beyond|Biomarker positive (ie, MSI-H, NTRK, RET, TMB-H)|Targeted agents and emerging biomarker options BINV-Q(7) and BINV-Q(8)| |Third Line and beyond|Any|Systemic chemotherapy BINV-Q (5)|

a For treatment of brain metastases, see NCCN Guidelines for Central Nervous System Cancers.

b Assess for germline BRCA1/2 mutations in all patients with recurrent or metastatic breast cancer to identify candidates for PARPi therapy.

9PD-L1 expression is assessed using 22C3 antibody. Threshold for positivity combined positive score 10.

While available data are in the first-line setting, this regimen can be used for second and subsequent lines of therapy if PD-1/PD-L1 inhibitor therapy has not been previously used. If there is disease progression while on a PD-1/PD-L1 inhibitor, there are no data to support an additional line of therapy with another PD-1/PD-L1 inhibitor.

J Sacituzumab govitecan-hziy may be considered for later line if not used as second line therapy.

k Fam-trastuzumab deruxecan may be considered in a later line for HER2 IHC+ 1+ or 2+/ISH negative, if not used in second line or may be considered first line therapy when disease has progressed during or within 6 months after completing adjuvant chemotherapy. Fam-trastuzumab deruxecan-nxki is associated with ILD/pneumonitis. Regular monitoring for this serious side effect is recommended. For patients with a history of ILD/pneumonitis, there are no data on managing safety or toxicity of this drug in a trial.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

SYSTEMIC THERAPY FOR RECURRENT UNREsectABLE(LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE$\underline{a}$,

|HR-Positive or -Negative and HER2-Positive|| |---|---| |See BINV-Q(1) for Considerations for systemic HER2-targeted therapy.|| |Setting|Regimen| |First Line|Pertuzumab+ trastuzumab+ docetaxel(category 1, preferred)| |First Line|Pertuzumab+ trastuzumab+ paclitaxel(preferred)| |Second Line°|Fam-trastuzumab deruxtecan-nxki^n(category 1, preferred)| |Third Line|Tucatinib+ trastuzumab+ capecitabine (category 1, preferred)| |Third Line|Ado-trastuzumab emtansine(T-DM1)p| |Fourth Line and Beyond (optimal sequence is not known)q|Trastuzumab+ docetaxel or vinorelbine| |Fourth Line and Beyond (optimal sequence is not known)q|Trastuzumab+ paclitaxel± carboplatin| |Fourth Line and Beyond (optimal sequence is not known)q|Capecitabine+ trastuzumab or lapatinib| |Fourth Line and Beyond (optimal sequence is not known)q|Trastuzumab+ lapatinib(without cytotoxic therapy)| |Fourth Line and Beyond (optimal sequence is not known)q|Trastuzumab+ other chemotherapy agents$r,s| |Fourth Line and Beyond (optimal sequence is not known)q|Neratinib+ capecitabine| |Fourth Line and Beyond (optimal sequence is not known)q|Margetuximab-cmkb + chemotherapy| |Abemaciblin in combination with fulvestant and trastuzumab (for HR+ only)(category 2B)|| |Targeted Therapy and emerging biomarker Options BINV-Q(7) and BINV-Q(8)||

a For treatment of brain metastases, see NCCN Guidelines for Central Nervous System Cancers.

AAssess for germline BRCA1/2 mutations in all patients with recurrent or metastatic breast cancer to identify candidates for PARPi therapy. While olarapib and talazoparib are FDA-indicated in HER2-negative disease, the panel supports use in any breast cancer subtype associated with a germline mutation. There is lower-level evidence for HER2-positive tumors, therefore category 2A for this setting.

mMaintenance trastuzumab/pertuzumab after response(with concurrent endocrine therapy if ER+ and HER2+ metastatic breast cancer).

n Fam-trastuzumab deruxetcan-nki may be considered in the first-line setting as an option for select patients(ie, those with rapid progression within 6 months of neoadjuvant or adjuvant therapy[12 months for pertuzumab-containing regimens]). Fam-trastuzumab deruxetcan-nki is associated with ILD/pneumonitis. Regular monitoring for this serious side effect is recommended. For patients with a history of ILD/pneumonitis, there are no data on managing safety or toxicity of this drug in a trial.

Tucatinib+ trastuzumab+ capecitabine is preferred in patients with both systemic and CNS progression in the third-line setting and beyond; and it may be given in the second-line setting.

P May be used as an option for third-line and beyond; the optimal sequence for third-line therapy and beyond is not known. If not a candidate fam-trastuzumab T-DM1 could be considered in the second-line.

9 Multiple lines of concurrent chemotherapy with anti-HER2 therapy (trastuzumab or a TKI) offer clinical benefit for recurrent unresectable HER2+ metastatic breast cancer and have been studied in phase 2 or 3 trials. Clinical experience suggests frequent clinical benefit for such treatment. However, there are no meaningful data for use of any of these regimens among patients previously treated with perturizumab-based chemotherapy,ado-trastuzumab emtansine, fam-trastuzumab deruxetcan-nxki, or

r Trastuzumab given in combination with an anthracycline is associated with significant cardiac toxicity. Concurrent use of trastuzumab and pertuzumab with an anthracycline should be avoided.

S Trastuzumab may be safely combined with all non-anthracycline-containing preferred and other single agents listed on(BINV-Q 5) for recurrent or metastatic breast cancer.

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

Systemic Chemotherapy for HR-Positive or -Negative and HER2-Negativea

See BINV-Q (1) for Considerations for systemic chemotherapy.

Sequential single agents are preferred, but chemotherapy combinations may be used in select patients with high tumor burden, rapidly progressing disease, and visceral crisis.

Preferred Regimens

Other Recommended Regimens Useful in Certain Circumstances

• Anthracyclines

Doxorubicin

Liposomal doxorubicin

• Taxanes

Paclitaxel

• Anti-metabolites

Capecitabine

Gemcitabine

• Microtubule inhibitors

Vinorelbine

Eribulin

• Cyclophosphamide

• Docetaxel

• Albumin-bound paclitaxel

• Epirubicin

• Ixabepilone

• AC (doxorubicin/cyclophosphamide)

• EC (epirubicin/cyclophosphamide)

• CMF (cyclophosphamide/

methotrexate/fluorouracil)

• Docetaxel/capecitabine

• GT (gemcitabine/paclitaxel)

• Gemcitabine/carboplatin

• Carboplatin + paclitaxel or albumin-bound paclitaxel

Note: All recommendations are category 2A unless otherwise indicated.

BINV-Q 5 OF 15

• For specific lines of systemic therapy options for HR-positive and HER2-negative with visceral crisis or endocrine refractory, see BINV-Q (2).

• For specific lines of systemic therapy options for HR-negative and HER2-negative (TNBC), see BINV-Q (3).

• For specific lines of systemic therapy options for HR-negative or -positive and HER2-positive, see BINV-Q (4).

a For treatment of brain metastases, see NCCN Guidelines for Central Nervous System Cancers.

RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

TARGETED THERAPIES AND ASSOCIATED BIOMARKER TESTING FOR RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE

Biomarkers Associated with FDA-Approved Therapies

|Biomarkers Associated with FDA-Approved Therapies|||||| |---|---|---|---|---|---| |Breast Cancer Subtype|Biomarker|Detectiont|FDA-Approved Agents|NCCN Category of Evidence|NCCN Category of Preference| |HR-positive, HER2-negative|PIK3CA activating mutation|NGS,PCR|Inavolisib + palbociclib + fulvestant|Category 1|Useful in certain circumstances first-line therapy| |HR-positive/ HER2-negative|PIK3CA activating mutation|NGS,PCR|Alpelisib + fulvestant|Category 1|Preferred second- or subsequent-line therapy| |HR-positive/ HER2-negative|PIK3CA or AKT1 activating mutations or PTEN alterations|NGS,PCR|Capivasertib + fulvestantW|Category 1|Preferred second- or subsequent-line therapy in select patientsW| |HR-positive/ HER2-negativex|ESR1 mutationX|NGS,PCR|Elacestranty|Category 2A|Other recommended regimen first-line or subsequent-line therapy| |HR-positive/ HER2-negativex|ESR1 mutationX|NGS,PCR|Imlunestrantz,aa|Category 2A|Other recommended regimen first-line or subsequent-line therapy|

Continued

$^{1}$ Some plasma-based ctDNA assays include a measure of tumor fraction(TF), which can aid in identification of low ctDNA content. Samples with low TF, especially<1%, should be interpreted with caution. Tests have varying sensitivities at low TF. Additional sampling from current tumor sample or future plasma can be considered.

u Consider for disease progression on adjuvant endocrine therapy or with early disease relapse within 12 months of adjuvant endocrine therapy completion.

vThe safety of alpelis in patients with Type 1 or uncontrolled Type 2 diabetes has not been established.

w In adult patients with PIK3CA or AKT1 activating mutations, or for PTEN alterations after disease progression or recurrence after $\geq$ 1 prior lines of endocrine therapy,including one line containing a CDK4/6 inhibitor.

×Assess for ESR1 mutations at progression following prior lines of endocrine therapy (ctDNA preferred).

y For disease progression during or after prior line of aromatase inhibitor plus CDK 4/6 inhibitor therapy in the adjuvant or metastatic setting.

zFor disease progression during or after a prior line of aromatase inhibitor with or without CDK 4/6 inhibitor therapy in the adjuvant or metastatic setting.

aa The combination of imluenstrant+ abemaciclib is not FDA approved but has been studied in phase III EMBER-3 trial (Jhaveri KL, et al. N Engl J Med 2025;392:1189-1202) in those with disease progression during or after a prior line of aromatase inhibitor with or without CDK 4/6 inhibitor therapy in the adjuvant or metastatic setting.

NCCN

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

TARGETED THERAPIES AND ASSOCIATED BIOMARKER TESTING FOR RECURRENT UNREsectABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE

|Biomarkers Associated with FDA-Approved Therapies||||||| |---|---|---|---|---|---|---| |Breast Cancer Subtype|Biomarker|Detectiont|FDA-Approved Agents|NCCN Category of Evidence|NCCN Category of Preference|| |Any|Germline BRCA1 or BRCA2 mutation|Germline sequencing|Olaparib Talazoparib|Category 1|Preferred|| |Any|Germline PALB2|Germline sequencing|Olaparibbb|Category 2A|Other recommended regimen|| |Any|NTRK fusion|FISH,NGS,PCR|Larrotectinibcc Entrectinibcc Repotrectinibdd|Category 2Add|Useful in certain circumstances|| |Any|MSI-H/dMMR|IHC,NGS,PCR|Pembrolizumabe|Category 2A|Useful in certain circumstances|| |Any|TMB-H (≥10 mut/Mb)99|NGS|Pembrolizumabe|Category 2A|Useful in certain circumstances|| |Any|RET-fusion|NGS|Selpercatinibhh|Category 2A|Useful in certain circumstances||

${}^{t}$ Some plasma-based ctDNA assays include a measure of TF, which can aid in identification of low ctDNA content. Samples with low TF, especially <1%, should be interpreted with caution. Tests have varying sensitivities at low TF. Additional sampling from current tumor sample or future plasma can be considered.

bb This regimen is not FDA approved for this indication. Tung NM, Robson ME, Ventz S, et al. TBCRC 048: phase II study of olaparib for metastatic breast cancer and mutations in homologous recombination-related genes. J Clin Oncol 2020;38:4274-4282.

${}^{cc}$ Larotrecinib and entrapinctin and indicated for the treatment of solid tumors that have an NTRK gene fusion without a known acquired resistance mutation and have no satisfactory alternative treatments or that have progressed following treatment.

dd Reprotectinib is indicated for the treatment of solid tumors that have an NTRK gene fusion and are locally advanced or metastatic or where surgical resection is likely to result in severe morbidity and have progressed following treatment or have no satisfactory alternative therapy. The recommendation in the first-line setting is category 2B.

ee Pembrolizumab is indicated for the treatment of patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient(dMMR)solid tumors, or TMB-H tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options.

ff Dostarlimab-gxly is indicated for adult patients with MSI-H/dMMR unresectable or metastatic tumors that have progressed on or following prior treatment and who have no satisfactory alternative treatment options.

99Tissue biopsy is more sensitive than ctDNA(liquid biopsy) at detecting homozygous copy loss of PTEN or TMB-H.

hh Selpercatinib is indicated for adult patients with locally advanced or metastatic solid tumors with a RET gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

EMERGING BIOMARKERS AND NOVEL THERAPIES FOR PATIENTS WITH STAGE IV (M1) DISEASE

|Breast Cancer Subtype|Emerging Biomarkers|Detectiont|Potential Targeted Therapy''|NCCN Category of Evidence|NCCN Category of Preference| |---|---|---|---|---|---| |ER+/HER2-ER-/HER2-|HER2 activating mutations|NGS,PCR|Neratinib $\pm$ fulvestant|Category 2B|Useful in certain circumstances ● If ER+/HER2-, in patients who have already received CDK4/6 inhibitor therapy.| |ER+/HER2-ER-/HER2-|HER2 activating mutations|NGS,PCR|Neratinib $\pm$ fulvestumab/ fulvestan ${}^{kk}$|Category 2A|Useful in certain circumstances ● If ER+/HER2-, in patients who have already received CDK4/6 inhibitor therapy.| |Any|Somatic BRCA1/2 mutations|NGS|Olaparib ${}^{ll}$|Category 2B|Useful in certain circumstances| |Any|FGFR1-3 fusion/ mutation|NGS|Erdafitinib ${}^{ll}$ mm|Category 2B|Useful in certain circumstances|

$^{1}$ Some plasma-based ctDNA assays include a measure of TF, which can aid in identification of low ctDNA content. Samples with low TF, especially<1%, should be interpreted with caution. Tests have varying sensitivities at low TF. Additional sampling from current tumor sample or future plasma can be considered.

ii At the present time, the data for the emerging biomarkers for the potential targeted agents noted in the table are promising but limited.

jj Ma CX, Luo J, Freedman RA, et al. The phase II MutHER study of neratinib alone and in combination with fulvestant in HER2-mutated, non-amplified metastatic breast cancer. Clin Cancer Res 2022;28:1258-1267.

kk Jhaveri K,Eli LD,Wildiers H,et al.Renatinib+ fulvestant+trastuzumab for HR-positive,HER2-negative,HER2-mutant metastatic breast cancer: outcomes and biomarker analysis from the SUMMIT trial. Ann Oncol 2023;34:885-898.

Tung NM, Robson ME, Ventz S, et al. TBCRC 048: phase II study of aloparib for metastatic breast cancer and mutations in homologous recombination-related genes.J Clin Oncol 2020;38:4274-4282.

mm PantS,SchulerM,IyerG,et al.Erdafitinibin in patients with advanced solid tumours with FGFR alterations(RAGNAR): an international, single-arm, phase 2 study.Lancet Oncol 2023;24:925-935.

National NCCN Comprehensive NCCN Guidelines Version 5.2025 NCCN Cancer Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

DOSING: SYSTEMIC THERAPY REGIMENS FOR RECURRENT UNRESECTABLE(LOCAL OR REGIONAL) OR STAGE IV(M1) DISEASE

HER2-Negative Regimens:

●Anthyracyclines:

●Doxorubicin 60-75 mg/m2 IV day 1; cycled every 21 days

Doxorubicin 20 mg/m2 IV day 1 weekly2

Liposomal doxorubicin350 mg/m2 IV day 1; cycled every 28 days

●Taxanes:

Paclitaxel 175 mg/m2 IV day 1; cycled days 4

Paclitaxel 80 mg/m2 IV day 1 weekly 5

●Antimetolabolites:

Capecitabine6 1000-1250 mg/m2 PO twice daily days 1-14; cycled every 21 days

Capecitabine ${ }^{17}$ 500 mg PO twice daily days 1-7 and days 15-21 cycled every 28 days

Gemcitabine8 800-1200 mg/m2 IV days 1,8,and 15; cycled every 28 days

●Microtubule inhibitors:

Vinorelbine9,10

25 mg/m2 IV day 1 weekly; or

20-35 mg/m2 IV days 1 and 8; cycled every 21 days; or

25-30 mg/m2 IV days 1,8, and 15; cycled every 28 days

Eribulin11.4 mg/m2 IV days 1 and 8; cycled every 21 days

●Platinum(for TNBC and germline BRCA1/2 mutation)

●Carboplatin 12 AUC 6 IV on day 1

Cycled every 21-28 days

Cisplatin13 75 mg/m2 IV on day 1

Cycled every 21 days

●Cyclophosphamide14

50 mg PO daily on days 1-21

Cycled every 28 days

●Datotopamab deruxecan-dlnk15

6 mg/kg IV day 1

Cycled every 21 days

●Docetaxel16,17

60-100 mg/m2 IV day 1

Cycled every 21 days

●Docetaxel18

35 mg/m2 IV weekly for 6 weeks followed by a 2-week rest, then repeat

●Albumin-bound paclitaxel19,20

100 mg/m2

or 125 mg/m2 IV days 1,8, and 15

Cycled every 28 days

●Albumin-bound paclitaxel19

>260 mg/m2

Cycled every 21 days

●Epirubicin21

60-90 mg/m2 IV day 1

Cycled every 21 days

●Ixabepilone22

40 mg/m2 IV day 1

Cycled every 21 days

● Sacituzumab govitecan-hziy(for TNBC or HR+/HER2-)23,24

10 mg/kg IV on days 1 and 8

Cycled every 21 days

●Fam-trastuzumab deruxtecan-nxki25

5.4 mg/kg IV day 1

Cycled every 21 days

·AC26

Doxorubicin 60 mg/m2 IV day 1

Cyclophosphamide 600 mg/m2 IV day 1

Cycled every 21 days

·EC27

Epirubicin 75 mg/m2 IV day 1

Cyclophosphamide 600 mg/m2 V day 1

Cycled every 21 days

·CMF28

●Cyclophosphamide 100 mg/m2 PO days 1-14

Methotrexate 40 mg/m2 IV days 1 and 8 and 8

5-fluorouracil 600 mg/m2 IV days 1 and 8

Cycled every 28 days

●Docetaxel/capecitabine29

●Docetaxel 75 mg/m2 IV day 1

Capecitabine 950 mg/m2 PO twice daily days 1-14

◇Cycled every 21 days

●GT30

Paclitaxel 175 mg/m2 IV day 1

Gemcitabine 1250 mg/m2 IV days 1 and 8(following paclitaxel on day 1)

● Gemcitabine/carboplatin31

Gemcitabine 1000 mg/m2 on days 1 and 8

Carboplatin AUC 2 IV on days 1 and 8 Cycled every 21 days

●Carboplatin/albumin-bound paclitaxel32

●Carboplatin AUC 2 IV on days 1 and 8

Albumin-bound paclitaxel 125 mg/m2 IV on days 1 and 8 days 1 and 8

Cycled every 21 days

●Carboplatin/paclitaxel33,34

Paclitaxel 175-200 mg/m2 IV day 1

Carboplatin AUC 6 IV day 1

Cycled every 21 days or

Paclitaxel 100 mg/m2 IV days 1,8, and 15

Carboplatin AUC 2 IV days 1,8, and 15

Cycled every 28 days

See dosing for targeted therapies on BINV-Q(14)

NCCN Guidelines Index Table of Contents Discussion

National NCCN Comprehensive NCCN Guidelines Version 5.2025 Cancer Cancer Invasive Breast Cancer

DOSING: SYSTEMIC THERAPY REGIMENS FOR RECURRENT UNRESECTABLE(LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE

HER2-Positive Regimensnn,00:

●Pertuzumab+trastuzumab+docetaxel35

Pertuzumab 840 mg IV day 1 followed by 420 mg IV day 1

Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg IV day 1 every 21 days

▶Docetaxel 75-100 mg/m2 IV day 1

Cycled every 21 days

●Pertuzumab+trastuzumab+ paclitaxel36,37

●Pertuzumab 840 mg IV day 1 followed by 420 mg IV

Cycled every 21 days

Trastuzumab 4 mg/kg IV day 1 followed by 2 mg/kg IV weekly or

Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg IV day 1 every 21 days38

Paclitaxel 80 mg/m2 IV day 1 weekly 36 or

●Paclitaxel 175 mg/m2 day 1 Cycled every 21 days

●Tucatinib + trastuzumab + capecitabine38

●Tucatinib 300 mg orally twice daily on days 1-21

Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg IV day 1 every 21 days

●Capecitabine 1000 mg/m2 orally twice daily on days 1-14

Cycled every 21 days

●Ado-trastuzumab emtansine (T-DM1)39

3.6 mg/kg IV day 1

Cycled every 21 days

●Fam-trastuzumab deruxecan-nxki40

5.4 mg/kg IV day 1

Cycled every 21 days

●Paclitaxel/carboplatin+ trastuzumab41

●Carboplatin AUC 6V day 1

●Paclitaxel 175 mg/m2 IV day 1

Cycled every 21 days

Trastuzumab 4 mg/kg IV day 1 followed by 2 mg/kg IV weekly or

●Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg IV day 1 every 21 days37

●Weekly paclitaxel/carboplatin+ trastuzumab42

Paclitaxel 80 mg/m2 IV days 1,8, and 15

Carboplatin AUC 2 IV days 1,8, and 15 $\diamond$ Cycled every 28 days

Trastuzumab 4 mg/kg IV day 1 followed by 2 mg/kg IV weekly or

Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg IV day 1 every 21 days37

●Trastuzumab+ paclitaxel43,44

Paclitaxel 175 mg/m2 IV day 1 cycled every 21 days43 or

Paclitaxel 80-90 mg/m2 IV day 1 weekly45

Trastuzumab 4 mg/kg IV day 1 followed by 2 mg/kg IV weekly or

Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg IV day 1 every 21 days37

●Trastuzumab+ docetaxet45,46

Docetaxel 80-100 mg/m2 IV day 1 cycled every 21 days45 or

Docetaxel 35 mg/m2 IV days 1,8, and 15 weekly cycled every 28 days46

Trastuzumab 4 mg/kg IV day 1 followed by 2 mg/kg IV or

▶Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg IV day 1 every 21 days37

See dosing for targeted therapies on BINV-Q(14)

NCCN Guidelines Index Table of Contents Discussion

National NCCN Comprehensive NCCN Guidelines Version 5.2025 NCCN Cancer Invasive Breast Cancer

DOSING: SYSTEMIC THERAPY REGIMENS FOR RECURRENT UNREsectABLE(LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE

HER2-Positive Regimens(continued)n:

●Trastuzumab+ vinorelbine 10,47,48

● Vinorelbine

◆25 mg/m2 IV day 1 weekly; or

◆20-35 mg/m2 IV days 1 and 8; cycled every 21 days; or

25-30 mg/m2 IV days 1,8, and 15; cycled every 28 days

Trastuzumab 4 mg/kg IV day 1 followed by 2 mg/kg IV weekly or

Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg IV day 1 every 21 days 37

●Trastuzumab + capecitabine 49,50,51

●Capecitabine 1000-1250 mg/m2 PO twice daily days 1-14 cycled every 21 days

Trastuzumab 4 mg/kg IV day 1 followed by 2 mg/kg IV weekly43,50 or

Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg IV day 1 every 21 days 35,37

●Lapatinib+ capecitabine52

Lapatinib 1250 mg PO daily days 1-21

●Capecitabine 1000 mg/m2 PO twice daily days 1-14 Cycled every 21 days

●Trastuzumab+ lapatinib53

Lapatinib 1000 mg PO daily for 21 days

●Trastuzumab 4 mg/kg IV day 1 followed by 2 mg/kg IV weekly or

●Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg IV day 1 every 21 days37

● Neratinib + capecitabine54

Neratinib 240 mg PO daily on days 1-21

Capecitabine 750 mg/m2 PO twice daily on days 1-14 Cycled every 21 days or

Neratinib

$ \diamond 120 mg$ PO daily on days 1-7; followed by

160 mg PO daily on days 8-14; followed by

□240mgPO daily on days 15-21

●Capecitabine 750 mg/m² PO twice daily on days 1-14

Cycled every 21 days x 1 cycle

Followed by

Neratinib 240 mg PO daily on days 1-21

●Capecitabine 750 mg/m2 PO twice daily on days 1-14

Cycled every 21 days beginning with cycle 2

●<Margetuximab-cmkb+capecitabine55

Margetuximab 15 mg/kg IV day 1

●Capecitabine 1000 mg/m2 PO twice daily days 1-14

$\diamond$ Cycled every 21 days

● Margetuximab-cmkb+eribulin 55

Margetuximab 15 mg/kg IV day 1

Eribulin 1.4 mg/m2 IV days 1 and 8

$\diamond$ Cycled every 21 days

●Margetuximab-cmkb+gemcitabine55

Margetuximab 15 mg/kg IV day 1

Gemcitabine 1000 mg/m2 IV days 1 and 8

$\diamond$ Cycled every 21 days

●Margetuxim-abcmk+ vinorelbine 55

Margetuximab 15 mg/kg IV day 1

●Vinorelbine 25-30 mg/m2 IV days 1 and 8

◇Cycled every 21 days

See dosing for targeted therapies on BINV-Q(14)

nn Trastuzumab and hyaluronidase-oysk injection for subcutaneous use may be substituted for trastuzumab. It has different dosage and administration instructions compared to intravenous trastuzumab. Do not substitute trastuzumab and hyaluronidase-oysk for or with ado-trastuzumab emtansine or fam-trastuzumab deruxtecan-nxki.

National NCCN Comprehensive NCCN Guidelines Version 5.2025 Cancer Cancer Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

SYSTEMIC THERAPY REGIMENS FOR RECURRENT UNRESECTABLE(LOCAL OR REGIONAL) OR STAGE IV(M1) DISEASE

1Chan S,Friedrichs K,Noel D,et al.Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol 1999;17:2341-2354.

2 Gasparini G, Dal Fior S, Panizoni G, et al. Weekly epirubicin versus doxorubicin as second line therapy in advanced breast cancer. A randomized clinical trial. Am J Clin Oncol 1991;14:38-44.

3O'Brien ME, Wigler N, Inbar M, et al. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl(CAELYX/Doxil) versus conventional doxorubic in first-line treatment of metastatic breast cancer. Ann Oncol 2004;15:440-449.

4 Seidman AD, Tiersten A, Hudis C, et al. Phase II trial of apitclafexel by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer. J Clin Oncol 1995;13:2575-2581.

5 Perez EA, Vogel CL, Irwin DH, et al. Multicenter phase II trial of weekly paclitaxel in women with metastatic breast cancer. J Clin Oncol 2001;19:4216-4223.

6 Bajetta E, Procopio G, Cellio L, et al. Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women. J Clin Oncol 2005;23:2155-2161.

7 Khan QJ,Bohnenkamp C,Monson T,et al.Randomized trial of fixed dose capecitabine compared to standard dose capecitabine in metastatic breast cancer: The X-7/7 trial. J Clin Oncol 2023;41:1007-1007.

8 Seidman AD. Gemlicatine as single-agent therapy in the management of advanced breast cancer. Oncology (Williston Park) 2001;15:11-14.

9 Zelek L, Barthier S, Roifrio M, et al. Weekly voinrelbeine is an effective palliative regimen after failure with anthracyclines and taxanes in metastatic breast carcinoma. Cancer 2001;92:2267-2272.

10 Esfahani K, Ferrario C, Le P, Panasci L. The trastuzumab and vinorebine combination:an alternative to taxane-based chemotherapy for early-stage and locally advanced her2-positive breast cancer. Curr Oncol 2014;21:e723-e727.

11 Cortes J, O'Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer(EMBRACE): a phase 3 open-label randomised study. Lancet 2011;377:914-923.

12 Isakoff SJ, Mayer EL, He L, et al. TBCRC009: A multicenter phase II clinical trial of platinum monotherapy with biomarker assessment in metastatic triple-negative breast cancer.J Clin Oncol 2015;33:1902-1909.

13 Silver DP, Richardson AL, Eklund AC, et al. Efficacy of neoadjuvant cisplatin in triple-negative breast cancer. J Clin Oncol 2010;28:1145-1153.

14 Licchetta A, Correale P, Migali C, et al. Oral metronomic chemo-hormonal-therapy of metastatic breast cancer with cyclophosphamide and megestrol acetate. J Chemother 2010;22:201-204.

15 Bardia A, Jhaveri K, Im SA, et al. Datopotamab deruxtecan versus chemotherapy in previously treated inoperable/metastatic hormone receptor-positive human epidermal growth factor receptor 2-negative breast cancer: Primary Results from TROPION-Breast01.J Clin Oncol 2025;43:285-296.

Note: All recommendations are category 2A unless otherwise indicated.

16 Burris HA, 3rd. Single-agent docetaxel (Taxotere) in randomized phase III trials. Semin Oncol 1999;26:1-6.

17 Harvey V., Mouridsen H, Semiglazov V, et al. Phase III trial comparing doses of docetaxel for second-line treatment of advanced breast cancer. J Clin Oncol 2006;24:4963-4970.

18 Rivera E,Mejia JA, Arun BJ,et al. Phase 3 study comparing the use of docetaxel on an every-3-week versus weekly schedule in the treatment of metastatic breast cancer.Cancer 2008;112:1455-1461.

19 Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III trial of nanoparticle albumin-bound aplacitx compared with polyethylated castor oil-based aplacitx in women with breast cancer. J Clin Oncol 2005;23:7794-7803.

20 Gradishar W, Dimitry K, Sergey C,et al.Significantly longer progression-free survival with nab-pacitlaxet compared with docetaxel as first-line therapy for metastatic breast cancer.J Clin Oncol 2005;23:7794-7803.

21 Bastholt L, Dalmark M, Gjedde SB, et al. Dose-response relationship of epirubicin in the treatment of postmenopausal patients with metastatic breast cancer: a randomized study of epirubicin at four different dose levels performed by the Danish Breast Cancer Cooperative Group. J Clin Oncol 1996;14:1146-1155.

22 Perez E, Lerzo G, Pivot X, et al. Efficacy and safety of ixabepilone(BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol 2007;25:3407-3414.

23 Bardia A, Mayer IA, Vahdat LT, et al. Sacituzumab govitecan-hziy in refractory metastatic triple negative breast cancer. N Engl J Med 2019;380:741-751.

24 Rugo HS, Bardia A, Marme F, et al. Primary Results from TROPiCS-02: A randomized phase 3 study of sacrituzumab devoticance (SG) versus treatment of physician's choice(TPC) in patients with hormone receptor-positive/HER2-negative(HR+/HER2-)advanced breast cancer[abstract]. J Clin Oncol 2022;40:Abstract LB1001.

25 Modi S, Jacot W, Yamashita T, et al. Trastuzumab dercutan in previously treated HER2-low advanced breast cancer. N Engl J Med 2022;7;387:9-20.

26 Nabholtz JM, Falkson C, Campos D, et al. Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: results of a randomized, multicenter, phase III trial. J Clin Oncol 2003;21:968-975.

27 Langley RE, Carmichel J, Jones AL, et al. Phase III trial of epirubicin plus paclitaxel compared with epirubicin plus cyclophosphamide as first-line chemotherapy for metastatic breast cancer: United Kingdom Cancer Research Institute. J Clin Oncol 2005;23:8322-8330.

28 Bonadonna G, Brusamolino E, Valagussa P, et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 1976;294:405-410.

29 Mavroudis D, Papakotoulas P, Ardavanis A, et al. Randomized phase III trial comparing docetaxel plus epirubicin versus docetaxel plus capecitabine as first-line treatment in women with advanced breast cancer. Ann Oncol 2010;21:48-54.

Continued

NCCN Guidelines Index Table of Contents Discussion

National Comprehensive Cancer Cancer Network®

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

SYSTEMIC THERAPY REGIMENS FOR RECURRENT UNREsectABLE(LOCAL OR REGIONAL) OR STAGE IV(M1) DISEASE REFERENCES

30 Albain KS, Nag S, Calderillo-Ruiz G, et al. Gemcitabine plus pacitxel versus paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol 2008;26:3950-3957.

301'Shaughness J, Schwartzberg LS, Danso MA, et al. A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in metastatic triple-negative breast cancer (TNBC). [abstract]. J Clin Oncol 2011;29(Suppl_15):Abstract 1007.

32 Yardley DA, Coleman R, Conte P, et al. nab-Pacitaxel plus carboplatin or gemcitabine versus gemcitabine plus carboplatin as first-line treatment of patients with triple-negative metastatic breast cancer: results from the nT acuity trial. Ann Oncol 2018;29:1763-1770.

33 Perez EA, Hillman DW, Stella PJ, et al. A phase II study of paclitaxel plus carboplatin as first-line chemotherapy for women with metastatic breast carcinoma.Cancer 2000;88:124-131.

34 Loesch D, Robert N. Asmar L, et al. Phase II multicenter trial of a weekly paclitaxel and carboplatin regimen in patients with advanced breast cancer. J Clin Oncol 2002;20:3857-3864.

35 Baselja J,Cortes J, Kim J, Self. A. Periduzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012;366:109-119.

36Dako D,F.Andrea G, Dickler M,et al. Phase II study of pertuzumab,trastuzumab,and weekly pacitval in patients with metastatic HER2-overexpressing metastatic breast cancer [abstract]. Cancer Res 2012;72:Abstract P5-18-20.

37 Leyland-Jones B, Gelmon K, Ayoub JP,et al. Pharmacokinetics, safety, and efficacy of trastuzumab administered every three weeks in combination with paclitaxel.J Clin Oncol 2003;21:3965-3971.

38 Murthy RK, Li Os, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med 2020;382:597-609.

39 Verma S, Miles D, Gianni L, et al. Trastuzumab emansantine for HER2-positive breast cancer [supplementary appendix available online]. N Engl J Med 2012;367:1783-1791.

40 Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med 2020;382:610-621.

41 Robert N, Leyland-Jones B, Asmar L, et al. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 2006;24:2786-2792.

42 Perez EA, Suman VJ, Rowland KM, et al. Two concurrent phase II trials of paclitaxel/carboplatin/trastuzumab(weekly or every-3-week schedule) as first-line therapy in women with HER2-overexpressing metastatic breast cancer: NCCTG study 983252. Clin Breast Cancer 2005;6:425-432.

43 Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783-792.

44 Seidman A, Berry DA, Cirincione C, et al. Randomized phase III trial of weekly compared with every-3-weeks paclitket for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors:final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol 2008;26:1642-1649.

45 Marty M, Cognitti F, Maraninchi D, et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group.J Clin Oncol 2005;23:4265-4274.

46 Esteva FJ, Valero V, Booser D, et al. Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 2002;20:1800-1808.

47 Burstein HJ, Keshaviah A, Baron AD, et al. Trastuzumab plus vinorebline or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and norebline or taxane study. Cancer 2007;110:965-972.

48 Andersson M, Lidbrink E, Bjerre K, et al. Phase III randomized study comparing docetaxel plus trustzumab with neurolineb plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study.J Clin Oncol 2011;29:264-271.

49 von Minckwitz G,du Bois A, Schmidt M, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group 03-05 study. J Clin Oncol 2009;27:1999-2006.

50 Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 1999;17:2639-2648.

51 Bartsch R, Wenzel C, Altorai G, et al. Capecitabine and transutizumab in heavily pretreated metastatic breast cancer. J Clin Oncol 2007;25:3853-3858.

52 Geyer C,Forster J, Lindquist D,et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer.N Engl J Med 2006;355:2733-2743.

53 Blackwell KL, Burstein H, Storniolo A, et al. Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol 2010;28:1124-1130.

54 Saura C, Oliveira M, Feng YH, et al. Neratinib plus capecitabine versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer previously treated with≥2HER2-directed regimens: Findings from the multinational, randomized, phase 3 NALA trial.Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting. May 31-June 4,2019; Chicago, IL.J Clin Oncol 2019;37(suppl): abstract 1002.

55 Rugo HS,Im S,Cardoso F,et al.Efficacy of margetuximab vs trastuzumab in patients with retreated ERBB2-positive advanced breast cancer. JAMA Oncol 2021;573-584.

National NCCN Comprehensive NCCN Guidelines Version 5.2025 Cancer Cancer Invasive Breast Cancer

NCCN Guidelines Index

Table of Contents Discussion

DOSING: TARGETED THERAPIES AND ASSOCIATED BIOMARKER TESTING FOR RECURRENT UNREsectABLE(LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE

●Alpelisib+ fulvestant1

●Larrotectinib8

100 mg PO twice daily on days 1-28

Alpelisib+ 300 mg PO daily on days 1-28; fulvestrant 500 mg IM on days 1 and 15

Cycled every 28 days until disease progression or unacceptable toxicity

28-day cycle for 1 cycle

● Olaparib9 tablet

Followed by alpelisib 300 mg PO daily on days 1-28; fulvestant 500 mg IM on day 1

300 mg PO twice daily

Cycled every 28 days until disease progression or unacceptable toxicity

Cycled every 28 days

●Capivasertib+ fulvestant2

●Pembrolizumab 10-13

Capivasertib 400 mg PO twice daily on days 1-4,8-11,15-18,22-25

●Fulvestant 500 mg IM day 1 and day 15

Cycled every 28 days for 1 cycle

Followed by

Capivertisib 400 mg PO twice daily on days 1-4,8-11,15-18,22-25

●Fulvestrant 500 mg IM day 1 starting with cycle 2

Cycled every 28 days until disease progression or unacceptable toxicity

●Pembrolizumab 10-13

200 mg IV on day 1, every 21 days until disease progression or unacceptable toxicity, or up to 24 months

400 mg IV on day 1, every 6 weeks until disease progression or unacceptable toxicity, or up to 24 months

Cycled every 28 days until disease progression or unacceptable toxicity

●Dostarlimab-glyx3

●Pembrolizumab+ chemotherapy (albumin-bound paclitaxel,aplacitmel,or gemcitabine and carboplatin)14

500 mg IV on day 1

Cycled every 21 days for cycles 1-4

Followed by 1000 mg IV on day 1 of cycle 5

Cycled every 42 days starting with cycle 5

Pembrolizumab 200 mg IV to 20mg/kg day 1(given every 21 days)

Albumin-bound paclitaxel 100 mg/m2 days 1,8,15 (given every 28 days)

OR Paclitaxel 90 mg/m2 IV days 1,8,15 (given every 28 days)OR

●Elacestrant4

Pembrolizumab 200 mg IV or 2mg/kg day 1

345 mg PO daily on days 1-28

Cycled every 28 days until disease progression or unacceptable toxicity

Gemcitabine 1000 mg/m2 IV days 1 and 8

Carboplatin AUC 2 IV days 1 and 8 $\diamond$ Given every 21 days

●Entrectinib5

●Reprotectinib15

600 mg PO daily on days 1-28

Cycled every 28 days until disease progression or unacceptable toxicity

●Imlunestrant6

400mgPO daily on days 1-28

Cycled every 28 days until disease progression or unacceptable toxicity

●Inavolisib+ palbociclib+ fulvestant7

Inavolisib 9 mg PO daily on days 1-28

Palbocici 125 mg PO daily on days 1-21

●Fulvestant 500 mg IM on days 1 and 1528-day cycle for 1 cycle

Followed by

Innavolis 9 mg PO daily on days 1-28

Palbociclib 125 mg PO daily on days 1-21

Fulvestant 500 mg IM on day 1

28-day cycle until disease progression or unacceptable toxicity

●Reprotectinib15

160 mg PO once daily on days 1-14, then 160 mg twice daily until disease progression or unacceptable toxicity

●Selpercatinib16

Patients<50 kg:120 mg PO twice daily until disease progression or unacceptable toxicity

Patients≥50 kg:160 mg PO twice daily until disease progression or unacceptable toxicity

●Talazoparib17 tablet

1mg PO daily

Cycled every 28 days

References on BINV-Q 14 of 15

Note: All recommendations are category 2A unless otherwise indicated. NCCN Guidelines Version 5.2025 Invasive Breast Cancer NCCN Guidelines Index Table of Contents Discussion BINV-Q 15 OF 15 TARGETED THERAPIES AND ASSOCIATED BIOMARKER TESTING FOR RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE REFERENCES

Abstract

V, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: Results from the randomized phase III EMERALD trial.

References

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

BINV-R 1 OF 3

a Rising tumor markers (eg, CEA, CA 15-3, CA 27.29) are concerning for tumor progression, but may also be seen in the setting of responding disease. An isolated

increase in tumor markers should rarely be used to declare progression of disease. Changes in bone lesions are often difficult to assess on plain or cross-sectional radiology or on bone scan. For these reasons, patient symptoms and serum tumor markers may be more helpful in patients with bone-dominant metastatic disease.

PRINCIPLES OF MONITORING METASTATIC DISEASE

Monitoring of patient symptoms and cancer burden during treatment of metastatic breast cancer is important to determine whether the

treatment is providing benefit and that the patient does not have toxicity from an ineffective therapy.

Components of Monitoring

Monitoring includes periodic assessment of varied combinations of symptoms, physical examination, routine laboratory tests, imaging

studies, and blood biomarkers where appropriate. Results of monitoring are classified as response/continued response to treatment, stable disease, uncertainty regarding disease status, or progression of disease. The clinician typically must assess and balance multiple different

forms of information to make a determination regarding whether disease is being controlled and the toxicity of treatment is acceptable.

Sometimes, this information may be contradictory. Clinicians should take into account patient preferences through a shared decision-making process.

Definition of Disease Progression

Unequivocal evidence of progression of disease by one or more of these factors is required to establish progression of disease, either

because of ineffective therapy or acquired resistance of disease to an applied therapy. Progression of disease may be identified through

evidence of growth or worsening of disease at previously known sites of disease and/or of the occurrence of new sites of metastatic disease.

• Findings concerning for progression of disease include:

Worsening symptoms such as pain or dyspnea

Evidence of worsening or new disease on physical examination

Declining performance status

Unexplained weight loss

Increasing alkaline phosphatase, alanine aminotransferase (ALT), aspartate transaminase (AST), or bilirubin

Hypercalcemia

New radiographic abnormality or increase in the size of pre-existing radiographic abnormality

New areas of abnormality on functional imaging (eg, bone scan, PET/CT)

Increasing tumor markers (eg, carcinoembryonic antigen [CEA], CA 15-3, CA 27.29)a

Continued

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

Note: All recommendations are category 2A unless otherwise indicated.

BINV-R 2 OF 3 Continued

PRINCIPLES OF MONITORING METASTATIC DISEASE

Use of Objective Criteria for Response/Stability/Progression

• The most accurate assessments of disease activity typically occur when previously abnormal studies are repeated on a serial and regular

basis. Generally, the same method of assessment should be used over time (eg, an abnormality found on chest CT should generally be

monitored with repeat chest CT).

• Some non-clinically important variation in measurement of abnormalities by all serial studies is common and expected. Therefore, the use

of objective and widely accepted criteria for response, stability, and progression of disease are encouraged. Such systems include the

Response Evaluation Criteria In Solid Tumors (RECIST) guidelines (Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline [version 1.1]. Eur J Cancer 2009;45:228-247) and the WHO criteria (Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981;47:207-214).

• Studies of functional imaging, such as radionuclide bone scans and PET imaging, are particularly challenging when used to assess

response. In the case of bone scans, responding disease may result in a flare or increased activity on the scan that may be misinterpreted as disease progression, especially on the first follow-up bone scan after initiating a new therapy. PET imaging is challenging because of the

absence of a reproducible, validated, and widely accepted set of standards for disease activity assessment.

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 5.2025 Invasive Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

PRINCIPLES OF MONITORING METASTATIC DISEASE

Frequency of Monitoring

The optimal frequency of repeat testing is uncertain, and is primarily based on the monitoring strategies utilized in breast cancer clinical trials. The frequency of monitoring must balance the need to detect progressive disease, avoid unnecessary toxicity of any ineffective therapy,resource utilization, and determine cost. The following table is to provide guidance, and should be modified for the individual patient based on sites of disease, biology of disease, and treatment regimen. Reassessment of disease activity should be performed in patients with new or worsening signs or symptoms of disease, regardless of the time interval from previous studies.

Suggested Intervals of Follow-up for Patients with Metastatic Diseaseb

||Baseline Prior to New Therapy|Chemotherapy or Targeted Therapy|Endocrine Therapy Alone or Combination with CDK 4/6 Inhibitor or Other Targeted Therapy|Restaging if Concern for Progression of Disease| |---|---|---|---|---| |Symptom Assessment|Yes|Prior to each cycle|Every 1-3 months|Yes| |Physical Examination|Yes|Prior to each cycle|Every 1-3 months|Yes| |Performance Status|Yes|Prior to each cycle|Every 1-3 months|Yes| |Weight|Yes|Prior to each cycle|Every 1-3 months|Yes| |LFTs,CBC|Yes|Prior to each cycle, as indicated|Every 1-3 months|Yes| |CT Chest/Abdomen/ Pelvis with Contrast|Yes|Every 2-4 cycles|Every 2-6 months|Yes| |Bone Scan|Yes|Every 4-6 cycles|Every 2-6 months|Yes| |PET/CT|As clinically indicated|As clinically indicated|As clinically indicated|As clinically indicated| |Tumor Markers|As clinically indicated|As clinically indicated|As clinically indicated|As clinically indicated| |Brain MRI with contrast|As clinically indicated|As clinically indicated|As clinically indicated|As clinically indicated|

b In patients who have long-term stable disease, the frequency of monitoring can be reduced.

Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines Version 5.2025 Phyllodes Tumor

NCCN Guidelines Index Table of Contents Discussion

![CLINICAL PRESENTATION\nWORKUP\nCORE BIPSY TREATMENT RESULTS\nFibroadenoma\nObserve\nFibroadenoma\nObserve\nIndeterminate\nBenign phyllodesb,f\nFollow-follow-up for\nfor a benign\nphylodesb\nInfinite phonetsb\nDisyncional\nPhyllodesb\nFibrousologis\nborn a\nbiopsc\nor suspicious\nbiopsc\n\nBenign phylodesb,f\nPhyllodesb\nFollow-up for\nphylodesb\nFollow\nClinical suspicion of phylodesb\nPhyllodesb\nSuspicious\nfor malignant\nPhyllodesb\nin situ cancer\nInvasive or in situ cancer\nSee NCCN Guidelines for Noninvasive Breast Cancer\nfor DCIS (DCIS-1) or Invasive Breast Cancer (BINV-1)\n](2/aj0YEe4oUhYkBdfpda0fYP/figure89eb24fc72ba428c8207efbb4548e0fa_0_4.png) a FNA or core biopsy may not distinguish a fibroadenoma from a phyllodes tumor in some cases. The sensitivity of core biopsy for the diagnosis of phyllodes tumor is greater than that of FNA biopsy, but neither core biopsy nor FNA biopsy can always differentiate phylodes tumors from fibroadenomas. In cases with clinical suspicion for phyllodes tumor,excision of the lesion may be needed for definitive pathologic classification.

b Genetic counseling and testing if patient is at risk for hereditary cancer syndromes, particularly breast, ovarian, and pancreatic cancer.

c Excisional biopsy includes complete mass removal, but without the intent of obtaining surgical margins.

d For borderline or malignant phylodites tumors, wide excision means excision with the intention of obtaining surgical margins $\geq$ 1cm. Narrow surgical margins are associated with heightened local recurrence risk, but are not an absolute indication for mastectomy when partial mastectomy fails to achieve a margin width ≥ 1 cm.

$^{e}$ There are no prospective randomized data supporting the use of RT for phyllodes tumors. However, in the setting where additional recurrence would create significant morbidity (eg, chest wall recurrence following mastectomy), RT may be considered following the same principles that are applied to the treatment of soft-tissue sarcoma.

$^{1}$ The Panel endorses the College of American Pathologists Protocol for standardized pathology reporting for all phylodites tumors(https://documents.cap.org/protocols/Breast.Phyllodes_1.1.0.1.REL_CAPCP.pdf).

9 Borderline and malignant phyllodars tumors are high-risk for local recurrence and heightened imaging should be considered to include ultrasound every 6 months after BCS for 2 years, then annually through 5 years, in addition to annual mammograms(as age appropriate).

National Comprehensive Cancer Network®

NCCN Guidelines Version 5.2025 Phyllodes Tumor

NCCN Guidelines Index Table of Contents Discussion

PHYLLODES TUMOR RECURRENCE

CLINICAL PRESENTATION

WORKUP

FINDINGS

TREATMENT

![Locally recurrent breast of phylodes tumor of phylodes tumor in disease\nNo metastatic disease\nRe-excision with wide margins without axillary \nConsider post-operative radiation (category 2B)${}^{e}$(category 2B)${}^{e}$(Section NCCN Guidelines for Soft Tissue Sarcoma)\n](2/aj0YEe4oUhYkBdfpda0fYP/figuref5751e86934a4e75ac9d077a6a5cf28e_0_9.png) a FNA or core biopsyy may not distinguish a fibroadenoma from a phylodes tumor in some cases. The sensitivity of core biopsy for the diagnosis of phylodes tumor is greater than that of FNA biopsy, but neither core biopsy nor FNA biopsy can always differentiate phylodes tumors from fibroadenomas. In cases with clinical suspicion for phylodes tumor, excision of the lesion may be needed for definitive pathologic classification.

e There are no prospective randomized data supporting the use of RT for phylodes tumors. However, in the setting where additional recurrence would create significant morbidity(eg, chest wall recurrence following mastectomy), RT may be considered following the same principles that are applied to the treatment of soft tissue sarcoma.

Note: All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines Version 5.2025 Paget Disease

NCCN Guidelines Index Table of Contents Discussion

CLINICAL PRESENTATION

WORKUP

![Clinical suspicion of Paget disease\n· Clinical breast exam\n· Diagnostic bilateral mammogram,ultrasound as necessary\nExamination and imaging negative for breast lesion\n](2/aj0YEe4oUhYkBdfpda0fYP/figure1665ab3caf4b48e3814627e29084d09b_0_6.png) a Nipple or areolar eczema, ulceration, bleeding, or itching.

Note:All recommendations are category 2A unless otherwise indicated.

National Comprehensive Cancer Network®

NCCN Guidelines Version 5.2025 Paget Disease

NCCN Guidelines Index Table of Contents Discussion

![WORKUP\nTREATMENT\nBiopsy negative\n[6915]n ncl follow-up Re-biopsy if not healing\nBreast DCIS and NAC Paget\nExamination or imaging positive for breast lesion\n[Core biopsy of breast lesion and full-thickness skin biopsy of involved NAC\nCore biopsy of the full-thickness skin biopsy of involved NAC\nBreast invasive cancer\n[5000]n NAC Paget\nSee NCCN Guidelines for Noninvasive Breast Cancer for DCIS (DCIS-1)\nTREATMENT\nCo biopsy\n[6915]ncl follow-up\n[6000]n NAC Paget\n[6000]n unive AB\n[6000]n unive AB\n[6000]n unive AB\n[6000]nul abive AB\n[6000]nul abive AB\n[6000]nul abive AB\n[6000]nul abive AB\n[6000]nul abive AB\n[6000]nul abive AB\n[6000]nul abive AB\n[6000]nul abive AB\n[6000]nul abive AB\n[6000]nul abive AB\n[6000]nul abive AB\n[6000]nul abive AB\n[6000]nul abive AB\n[6000]nul abive AB\n[6000]nul abive AB\n[6000]nul abive AB\n[6000]nul abive AB\n[6000]nul abive AB\n[6000]nul abive AB\n[6000]nul abive AB\n[6000]nul abive AB\n[6000]nul abive AB\n[6000]nul abive AB\n[6000]nul abive AB\n[6000]nul abive AB\n[6000]nul abive AB\n[6000]nul abive AB\n[6000]nul abive AB\n[6000]nul\n](2/aj0YEe4oUhYkBdfpda0fYP/figure7314c5159244495c9bd82c04385a2d5d_0_4.png) b Principles of Dedicated Breast MRI Testing(BINV-B).

c Mastectomy is always an option with any manifestation of Paget disease(Discussion).

Note: All recommendations are category 2A unless otherwise indicated.

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NCCN Guidelines Version 5.2025 Breast Cancer During Pregnancy

NCCN Guidelines Index Table of Contents Discussion

![WORKUP\nCLINICAL PRESENTATION\nFRARYARY TREATMENT\b\nDiscussion\nprimalary TREATMENT\b\nBeginjuvant chemotherapy in second trimester\ntingerd\nprepanng\nContinuing\nMastectomy\neaxary stagingb,c\nADJUVANT TREATMENTd\nBeginjuatmentov\nmperregnative chemotherapye+adjuvant endocrine\n±± Adjuvant endocrine\ntherapy postpartum\n\nAdjuvant chemotherapyd\n4\n± Adjuvant endocrine and infection\n3\n2\n1\n2\n1 0\n1\n2\n1 0\n1 2\n1 2\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 3\n1 \n](2/aj0YEe4oUhYkBdfpda0fYP/figure806d60106f334ea787965473a42ce0c5_0_4.png) a CT scans and nuclear imaging are contraindicated during pregnancy.

b Considerations and selection of optimal local therapy and systemic therapy are similar to that recommended in non-pregnancy-associated breast cancer; see other sections of this guideline. However, the selection and timing of chemotherapy, endocrine therapy, and RT is different if pregnant. BCS during the first trimester of pregnancy can be considered in those who will require adjuvant chemotherapy and can have adjuvant radiation therapy delayed until after delivery. Chemotherapy should not be administered during the first trimester of pregnancy, and RT should not be administered during any trimester of pregnancy. Coordination is recommended between the oncology and obstetrics teams to plan the optimal timing of systemic therapy administration during pregnancy. Most experience with chemotherapy during pregnancy for breast cancer is from regimens that utilize various combinations of doxorubicin, cyclophosphamide, and fluorourac-tis Considerations for postpartum chemotherapy are the same as for non-pregnancy-associated breast cancer.

c Use of blue dye is contraindicated in pregnancy; radiolabeled sulfur colloid appears to be safe for SLNB in pregnancy. See Considerations for Surgical Axillary Staging (BINV-D).

d There are limited data on the use of taxanes during pregnancy.The optimal schedule is unclear. If used, the NCCN Panel recommends weekly administration of paclitaxel after the first trimester if clinically indicated by disease status. The use of anti-HER2 therapy is contraindicated during pregnancy.

e Survival outcomes of BCT are equivalent to mastectomy in both non-pregnancy and pregnancy-associated BCs. Therapeutic RT is generally avoided during pregnancy due to potential risks to the fetus. Mastectomy may be preferred, particularly for early(1st trimester) gestational diagnosis, as early BCS may preclude timely administration of RT. Generally, intervals of 12-16 weeks between treatment modalities(surgery, RT, and chemotherapy) are considered acceptable.

f If late first trimester, may consider preoperative chemotherapy in the second trimester.

NCCN Guidelines Version 5.2025

Inflammatory Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

IBC-1

CLINICAL

PRESENTATIONa

WORKUP

Clinical

pathologic

diagnosis of IBC

• History and physical exam by multidisciplinary team and

obtain medical photography

• CBC

• Comprehensive metabolic panel, including LFTs and

alkaline phosphatase

• Pathology reviewb

• Determination of tumor ER/PR status and HER2 statusc

• Fertility counseling if premenopausald

• Genetic counseling if patient is at riske for hereditary breast cancer

• Imaging:

Bilateral diagnostic mammogram, ultrasound as necessary Chest diagnostic CT ± contrast

Abdomen ± pelvis diagnostic CT with contrast or MRI with

contrast

Bone scan or FDG-PET/CTf,g

Breast MRI (optional)

Preoperative/Adjuvant Therapy Regimens

(BINV-L)h

a IBC is characterized by: 1) Rapid onset (≤6 months) of erythema, edema, p'eau d'orange occupying ≥1/3 of the breast, with or without a palpable mass.2) Pathologic confirmation of invasive breast cancer.3) Dermal lymphatic involvement may be seen but is not required for the diagnosis.b The panel endorses the College of American Pathologists Protocol for pathology reporting for all invasive and noninvasive carcinomas of the breast.

http://www.cap.org.

c Principles of Biomarker Testing (BINV-A).d Fertility and Birth Control (BINV-C). e For risk criteria, see NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, and Prostate.f If FDG-PET/CT is performed and clearly indicates bone metastasis on both the PET and CT component, bone scan or sodium fluoride PET/CT may not be needed.g FDG-PET/CT can be performed at the same time as diagnostic CT. FDG-PET/CT is most helpful in situations where standard staging studies are equivocal or

suspicious. FDG-PET/CT may also be helpful in identifying unsuspected regional nodal disease and/or distant metastases when used in addition to standard staging studies.

h A pertuzumab-containing regimen may be administered preoperatively to patients with HER2-positive IBC.

Note: All recommendations are category 2A unless otherwise indicated.

See IBC-2

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NCCN Guidelines Version 5.2025 Inflammatory Breast Cancer

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RESPONSE TO PREOPERATIVE THERAPY

![Responsei→\nTotal mastectomy + level l/ll axillary dissection+ RT to chest wall and comprehensive RNI with inclusion of any portion of the undissected axilla at risk±delayed breast reconstruction\nResponsei→\nTotal mastectomy + level l/ll axillary dissection+ RT to chest wall and comprehensive RNI with inclusion of any portion of the undissected axilla at risk±delayed breast reconstruction\nNo response→\nTotal mastectomy + RT to chest wall and comprehensive RNI with inclusion of any portion of the undissected axilla at risk±delayed breast reconstruction\nThis may be candidates for multiple lines of systemic therapy to palliate advanced breast cancer. At each reassessment and clinicians should assess value of ongoing treatment, the risks and benefits of an additional line of systemic therapy, patient performance status, and patient preferences through a shared decision-making process.\n](2/aj0YEe4oUhYkBdfpda0fYP/figure845a0e5c01b24dd4823986db4bcc7a61_0_5.png) ![No response\nConsider additional systemic therapy and chemotherapy\nor preoperative\nradiation.\nPatients may be candidates for multiple lines of systemic therapy to palliate advanced breast cancer.\nAt each reassessment at each reassessment at the risks and benefits of an additional line of systemic therapy, patient performance status, and patient preferences through a shared decision-making process.\nNo response ${}^{i}$ \nNo response ${}^{i}$ \nIndividualized treatment\n'principles of Radiation Therapy(BINV-K)\nSystemic Therapy Regimens for Recurrent Unresectable (Local or Regional) or Stage IV (M1) Disease (BINV-Q)\nResponse ${}^{i}$ \nSee above pathway\nPrinciples of Radiation Therapy(BINV-I)\nNo response ${}^{i}$ \nIndividualized treatment\n](2/aj0YEe4oUhYkBdfpda0fYP/figured042cde88dd046499bd05169e906be4f_0_6.png) iThe accurate assessment of in-breast tumor or regional lymph node response to preoperative systemic therapy is difficult, and should include physical examination and performance of imaging studies (mammogram and/or breast ultrasound and/or breast MRI) that were abnormal at the time of initial tumor staging. Selection of imaging methods prior to surgery should be determined by the multidisciplinary team. MRI is more accurate than mammography for assessing tumor response to preoperative therapy.

Patients with recurrent IBC should be treated according to the guideline for recurrence/stage IV (M1) disease (BINV-19).

k Principles of Breast Reconstruction Following Surgery(BINV-H).

Systemic Therapy Regimens for Recurrent Unresectable (Local or Regional) or Stage IV (M1) Disease (BINV-Q).

m Adjuvant Endocrine Therapy (BINV-K).

n Principles of Radiation Therapy (BINV-I).

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NCCN Guidelines Version 5.2025 Breast Cancer

NCCN Guidelines Index Table of Contents Discussion

American Joint Committee on Cancer (AJCC)

TNM Staging System For Breast Cancer

Primary Tumor (T) The T category of the primary tumor is defined by the same criteria regardless of whether it is based on clinical or pathological criteria, or both. The T category is based primarily on the size of the invasive component of the cancer. The maximum size of a tumor focus is used as an estimate of disease volume. The largest contiguous dimension of a tumor focus is used, and small satellite foci of noncontiguous tumor are not added to the size. The cellular fibrous reaction to invasive tumor cells is generally included in the measurement of a tumor prior to treatment; however, the dense fibrosis observed following neoadjuvant treatment is generally not included in the pathological measurement because its extent may overestimate the residual tumor volume. The clinical size of a primary tumor(T) can be measured based on clinical findings (physical examination and imaging modalities, such as mammography, ultrasound, and MR imaging) and pathological findings (gross and microscopic measurements). Clinical tumor size (cT) should be based on the clinical findings that are judged to be most accurate for a particular case, although it may still be somewhat inaccurate because the intent of some breast cancers is not always apparent with current imaging techniques and because tumors are composed of varying proportions of noninvasive and invasive disease, which these techniques are currently unable to distinguish. Size should be measured to the nearest millimeter.If the tumor size is slightly less than or greater than a cutoff for a given T classification the size should be rounded to the millimeter reading that is closest to the cutoff.For example, a reported size of 4.9 mm is reported as 5 mm, or a size of 2.0 cm (20 mm). The exception to this rounding rule is for a breast tumor sized between 1.0 and 1.4 mm. These sizes are rounded up to 2 mm, because rounding down would result in the cancer's being categorized as microinvasive carcinoma(T1mi) defined as a size of 1.0 mm or less.

Table 1. Definitions for T,N, M

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

Tis Ductal carcinoma in situ

(DCIS)*

Tis Paget disease of the nipple NOT associated with invasive(Paget)carcinoma and/or carcinoma in situ(DCIS) in the underlying breast parenchyma. Carcinomas in the breast parenchyma associated with Paget disease are categorized based on the size and characteristics of the parenchymal disease,although the presence of Paget disease should still be noted

T1 Tumor ≤20 mm in greatest dimension

T1mi Tumor $\leq 1.5$ in greatest dimension

T1a T1b T1a T0.1mm 1 but ≤5 mm in greatest dimension(round any measurement > 1.0 - 1.9 mm to 2 mm)

T1b Tumor >5 mm but ≤10 mm in greatest dimension

T1c Tumor>10 mm but ≤20 mm in greatest dimension

T2 Tumor>20 mm but≤50 mm in greatest dimension

T3 Tumor>50 mm in greatest dimension

T4 Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or macroscopic nodules); invasion of the dermis alone does not qualify as T4

T4a Extension to the chest wall; invasion or adherence to pectoralis muscle in the absence of invasion of chest wall structures does not qualify as T4

T4b Ulceration and/or ipsilateral macroscopic satellite nodules and/or edema(including peau d'orange) of the skin that does not meet the criteria for inflammatory carcinoma

T4c Both T4a and T4b are present

T4d Inflammatory carcinoma

*Note: Lobular carcinoma in situ (LCIS) is a benign entity and is removed from TNM staging in the AJCC Cancer Staging Manual, 8th Edition.

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Table 1. Definitions for T, N, M (continued)

Regional Lymph Nodes (N)

Clinical (cN)

cNX*Regional lymph nodes cannot be assessed (e.g., previously removed)

cN0 No regional lymph node metastases(by imaging or clinical examination)

cN1 Metastases to movable ipsilateral level I, II axillary lymph node(s)

cN1mi** Micrometastases(approximately 200 cells, larger than 0.2 mm, but none larger than 2.0 mm)

cN2C1 Metastases in ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted;

or in ipsilateral internal mammary nodes in the absence of axillary lymph node metastases

cN2a Metastases in ipsilateral level I, II axillary lymph nodes fixed to one another(matted) or to other structures

cN2b Metastases only in ipsilateral internal mammary nodes in the absence of axillary lymph node metastases

cN3N3 Metastases in ipsilateral infraclavicular(level III axillary) lymph node(s) with or without level I, II axillary lymph node involvement;or in ipsilateral internal mammary lymph node(s) with level I, II axillary lymph node metastases;or metastases in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement

cN3a Metastases in ipsilateral infraclavicular lymph node(s)

cN3b Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)

cN3c Metastases in ipsilateral supraclavicular lymph node(s)

Note:(sn) and(f) suffixes should be added to the N category to denote confirmation of metastasis by sentinel node biopsy or fine needle aspiration/core needle biopsy respectively.

*The cNX category is used sparingly in cases where regional lymph nodes have previously been surgically removed or where there is no documentation of physical examination of the axilla.

**cN1mi is rarely used but may be appropriate in cases where sentinel node biopsy is performed before tumor resection, most likely to occur in cases treated with neoadjuvant therapy.

Pathologic (pN)

pNX Regional lymph nodes cannot be assessed (e.g., not removed for pathological study or previously removed)

pN0 No regional lymph node metastasis identified or ITCs only pN0(i+) ITCs only (malignant cells clusters no larger than 0.2 mm) in regional lymph node(s)

pN0(mol+) Positive molecular findings by reverse transcriptase polymerase chain reaction (RT-PCR); no ITCs detected

pN1 Micrometastases; or metastases in 1-3 axillary lymph nodes; and/or in clinically negative internal mammary nodes with micrometastases or macrometastases by sentinel lymph node biopsy

pN1mi Micrometastases(approximately 200 cells, larger than 0.2 mm, but none larger than 2.0 mm)

pN1a Metastases in 1-3 axillary lymph nodes, at least one metastasis larger than 2.0 mm

pN1b Metastases in ipsilateral internal mammary sentinel nodes, excluding ITCs

pN1c pN1a and pN1b combined.

pN2 Metastases in 4-9 axillary lymph nodes; or positive ipsilateral internal mammary lymph nodes by imaging in the absence of axillary lymph node metastases

pN2a Metastases in 4-9 axillary lymph nodes(at least one tumor deposit larger than 2.0 mm)

pN2b Metastases in clinically detected internal mammary lymph nodes with or without microscopic confirmation; with pathologically negative axillary nodes

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Table 1. Definitions for T, N, M (continued)Pathologic (pN)

pN3 Metastases in 10 or more axillary lymph nodes;or in infraclavicular(level III axillary) lymph nodes;or positive ipsilateral internal mammary lymph nodes by imaging in the presence of one or more positive level I, II axillary lymph nodes;or in more than three axillary lymph nodes and micrometastases or macrometastases by sentinel lymph node biopsy in clinically negative ipsilateral internal mammary lymph nodes;

pN3a Metastases in 10 or more axillary lymph nodes (at least one tumor deposit larger than 2.0 mm);

or metastases to the infraclavicular(level III axillary lymph) nodes

pN3b pN1a or pN2a in the presence of cN2b (positive internal mammary nodes by imaging);

pN3c Metastases in ipsilateral supraclavicular lymph nodes

Note: (sn) and (f) suffixes should be added to the N category to denote confirmation of metastasis by sentinel node biopsy or FNA/core needle biopsy respectively, with NO further resection of nodes

Distant Metastasis(M)

MO No clinical or radiographic evidence of distant metastases*

cM0(i+)No clinical or radiographic evidence of distant metastases in the presence of tumor cells or deposits no larger than 0.2 mm detected microscopically or by molecular techniques in circulating blood, bone marrow,or other nonregional nodal tissue in a patient without symptoms or signs of metastases

cM1 Distant metastases detected by clinical and radiographic means

pM1 Any histologically proven metastases in distant organs;or if in non-regional nodes, metastases greater than 0.2 mm

Table 2. AJCC Anatomic Stage Groups

The Anatomic Stage Group table should only be used in global regions where biomarker tests are not routinely available.

Cancer registries in the U.S. must use the Clinical and Pathological Prognostic Stage Group tables for case reporting.

|Stage 0|Tis|NO|M0|Stage IIIA|T0|N2|M0| |---|---|---|---|---|---|---|---| |Stage IA|T1|NO|M0||T1|N2|M0| |Stage IB|T0|N1mi|M0||T2|N2|M0| |Stage IIA|T1|N1mi|M0||T3|N1|M0| |Stage IIA|T1|N1mi|M0||T3|N2|M0| |Stage IIA|T0|N1|M0||T3|N2|M0| |Stage IIA|T1|N1|M0|Stage IIIB|T4|N0|M0| |Stage IIB|T2|N1|M0||T4|N1|M0| |Stage IIB|T2|N1|M0||T4|N2|M0| |Stage IIB|T3|N0|M0|Stage IIIC|Any T|N3|M0| |Stage IIB|Stage IV Any T Any N M1|||||||

Notes:

1. T1 includes T1mi.

2. T0 and T1 tumors with nodal micrometastases (N1mi) are staged as Stage IB.

3.T2,T3, and T4 tumors with nodal micrometastases (N1mi) are staged using the N1 category.

4.M0 includes M0(i+).

5. The designation pM0 is not valid; any M0 is clinical.

6. If a patient presents with M1 disease prior to neoadjuvant systemic therapy, the stage is considered Stage IV and remains Stage IV regardless of response to neoadjuvant therapy.

7. Stage designation may be changed if postsurgical imaging studies reveal the presence of distant metastases, provided the studies are performed within 4 months of diagnosis in the absence of disease progression, and provided the patient has not received neoadjuvant therapy.

8. Staging following neoadjuvant therapy is designated with "yc" or "yp" prefix to the T and N classification. There is no anatomic stage group assigned if there is a complete pathological response(pCR) to neoadjuvant therapy, for example, ypT0ypN0cM0.

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Continued

Used with the permission of the American College of Surgeons, Chicago Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. For complete information and data supporting the staging tables, visit www.springer.com.

Table 2. AJCC Anatomic Stage Groups (continued)Histologic Grade (G)

All invasive breast carcinomas should be assigned a histologic grade. The

Nottingham combined histologic grade (Nottingham modification of the SBR

grading system) is recommended and is stipulated for use by the College of

American Pathologists (see www.cap.org). The grade for a tumor is determined

by assessing morphologic features (tubule formation, nuclear pleomorphism, and calibrated mitotic count), assigning a value from 1 (favorable) to 3 (unfavorable)

for each feature, and totaling the scores for all three categories. A combined score of 3–5 points is designated as grade 1; a combined score of 6–7 points is grade 2; a combined score of 8–9 points is grade 3. The use of subjective grading alone is discouraged.

Invasive Cancer (Scarff-Bloom-Richardson [SBR] Grading System, Nottingham Modification)

GX Grade cannot be assessed

G1 Low combined histologic grade (favorable);

SBR score of 3–5 points

G2 Intermediate combined histologic grade (moderately favorable); SBR

score of 6–7 points

G3 High combined histologic grade (unfavorable);

SBR score of 8–9 points

Ductal Carcinoma in situ: Nuclear Grade

The grade that should be used for ductal carcinoma in situ is nuclear grade (www.cap.org)

GX Grade cannot be assessed

G1 Low nuclear grade

G2 Intermediate nuclear grade

G3 High nuclear grade

ST-4

NCCN Guidelines Version 5.2025 Breast Cancer

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Continued

Favorable Histologic Types

Tubular carcinoma

Cribriform carcinoma

Mucinous carcinoma

Adenoid cystic

Low-grade adenosquamous carcinoma metaplastic carcinoma

Low-grade fibromatosis-like metaplastic carcinoma

Histopathologic Type - WHO Classification 5th Edition (2019)

WHO Classification of Tumors Editorial Board, ed. WHO Classification of Tumors, 5th Edition – Breast Tumors. Lyon: International Agency for Research on Cancer 2019.

ST-5

In situ carcinomas

D uctal carcinoma in situ (DCIS) (low nuclear grade, intermediate nuclear grade, and high nuclear grade)

In situ papillary neoplasms (papillary DCIS, encapsulated papillary carcinoma, solid papillary carcinoma in situ)

Invasive Carcinomas

In vasive breast carcinoma of no special type (ductal and other special patterns)Microinvasive carcinoma

Invasive lobular carcinoma

Tubular carcinoma

Cribriform carcinoma

Mucinous carcinoma

Mucinous cystadenocarcinoma

Invasive micropapillary carcinoma

Invasive papillary carcinoma

Invasive solid papillary carcinoma

Carcinoma with apocrine differentiation

Me taplastic carcinoma (spindle cell, squamous, with heterologous differentiation,

low-grade adenosquamous carcinoma, low-grade fibromatosis-like and mixed

metaplastic)

Neuroendocrine tumor (NET)

Neuroendocrine carcinoma (NEC)

Sa livary gland-type (acinic cell, adenoid cystic, secretory, mucoepidermoid,

polymorphous adenocarcinoma)

Tall cell carcinoma with reversed polarity

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Table 3. Clinical Prognostic Stage

Clinical Prognostic Stage applies to ALL patients with breast cancer for clinical classification and staging. It uses clinical tumor(T), node(N) and metastases(M) information based on history, physical examination, any imaging performed(not necessary for clinical staging) and relevant biopsies.Genomic profile information is not included in Clinical Prognostic Stage as pathologic information from surgery is necessary to ascertain the prognosis

|TNM|Grade|HER2|ER|PR|Stage| |---|---|---|---|---|---| |Tis N0 M0|Any|Any|Any|Any|0| |T1* N0 M0 T0 N1mi M0 T1* N1mi M0|G1|Positive|Positive|Positive|IA| |T1* N0 M0 T0 N1mi M0 T1* N1mi M0|G1|Positive|Positive|Negative|IA| |T1* N0 M0 T0 N1mi M0 T1* N1mi M0|G1|Positive|Negative|Positive|IA| |T1* N0 M0 T0 N1mi M0 T1* N1mi M0|G1|Positive|Negative|Positive|IA| |T1* N0 M0 T0 N1mi M0 T1* N1mi M0|G1|Negative|Negative|Positive|IA| |T1* N0 M0 T0 N1mi M0 T1* N1mi M0|G1|Negative|Negative|Positive|IA| |T1* N0 M0 T0 N1mi M0 T1* N1mi M0|G1|Negative|Negative|Positive|IA| |T1* N0 M0 T0 N1mi M0 T1* N1mi M0|G1|Negative|Negative|Positive|IA| |T1* N0 M0 T0 N1mi M0 T1* N1mi M0|G1|G2|Positive|Positive|IA| |T1* N0 M0 T0 N1mi M0 T1* N1mi M0|G1|G2|Positive|Positive|IA| |T1* N0 M0 T0 N1mi M0 T1* N1mi M0|G1|G2|Positive|Negative|IA| |T1* N0 M0 T0 N1mi M0 T1* N1mi M0|G1|G2|Positive|Negative|IA| |Negative|Positive|G2|Positive|Positive|| |Negative|Positive|G2|Negative|Positive|| |Negative|Negative|G2|IB|||

|TNM|Grade|HER2|ER|PR|Stage| |---|---|---|---|---|---| |T0$N1**$M0 T1*$N1**$M0 T2$N0$M0|G1|Positive|Positive|Positive|IB| |T0$N1**$M0 T1*$N1**$M0 T2$N0$M0|G1|Positive|Positive|Negative|IIA| |T0$N1**$M0 T1*$N1**$M0 T2$N0$M0|G1|Positive|Positive|Negative|IIA| |T0$N1**$M0 T1*$N1**$M0 T2$N0$M0|G1|Positive|Positive|Negative|Negative| |T0$N1**$M0 T1*$N1**$M0 T2$N0$M0|G1|Negative|Positive|Positive|IB| |T0$N1**$M0 T1*$N1**$M0 T2$N0$M0|G1|Negative|Positive|Negative|IIA| |T0$N1**$M0 T1*$N1**$M0 T2$N0$M0|G1|Negative|Positive|Negative|Negative| |T0$N1**$M0 T1*$N1**$M0 T2$N0$M0|G1|Negative|Positive|Negative|Positive| |T0$N1**$M0 T1*$N1**$M0 T2$N0$M0|G1|Negative|Negative|Negative|Positive| |T0$N1**$M0 T1*$N1**$M0 T2$N0$M0|G1|Negative|IIA|Negative|| |T0$N1**$M0 T1*$N1**$M0 T2$N0$M0|G1|G2|Positive|Negative|Positive| |T0$N1**$M0 T1*$N1**$M0 T2$N0$M0|G1|G2|Positive|Negative|Positive| |T0$N1**$M0 T1*$N1**$M0 T2$N0$M0|G1|G2|Positive|Negative|Positive| |T0$N1**$M0 T1*$N1**$M0 T2$N0$M0|G1|G2|Positive|Negative|Negative| |T0$N1**$M0 T1*$N1**$M0 T2$N0$M0|G1|G2|Positive|Negative|Negative| |Negative|Positive|Positive|Positive|IB|| |Negative|Positive|Positive|Negative|Negative|| |Negative|Positive|Negative|Negative|IIA|| |Negative|Positive|Negative|Negative|Negative|IIB| |Negative|Positive|Negative|Positive|Positive|Positive| |Negative|Negative|Negative|Positive|Positive|| |Negative|Negative|Negative|Positive|IIB|| |Negative|Negative|Negative|Positive|Negative|IIB| |Negative|Positive|Negative|Positive|Positive|Positive| |Negative|Positive|Negative|Negative|Positive|| |Negative|Positive|Negative|Negative|Negative|| |Negative|Positive|Negative|IB|IIB||

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NCCN Guidelines Index Table of Contents Discussion

Table 3. Clinical Prognostic Stage(continued)

|TNM|Grade|HER2|ER|PR|Stage| |---|---|---|---|---|---| |T2 N1*** M0 T3 N0 M0|G1|Positive|Positive|Positive|IB| |T2 N1*** M0 T3 N0 M0|G1|Positive|Positive|Negative|IAI| |T2 N1*** M0 T3 N0 M0|G1|Positive|Negative|Negative|IAI| |T2 N1*** M0 T3 N0 M0|G1|Positive|Negative|Positive|Positive| |T2 N1*** M0 T3 N0 M0|G1|Negative|Negative|Positive|IA| |T2 N1*** M0 T3 N0 M0|G1|Negative|Negative|Negative|Positive| |T2 N1*** M0 T3 N0 M0|G1|Negative|Negative|Negative|Negative| |T2 N1*** M0 T3 N0 M0|G1|G2|Positive|Positive|Positive| |T2 N1*** M0 T3 N0 M0|G1|G2|Positive|Positive|Negative| |T2 N1*** M0 T3 N0 M0|G1|G2|Positive|Negative|Negative| |T2 N1*** M0 T3 N0 M0|G1|G2|Positive|Negative|Positive| |T2 N1*** M0 T3 N0 M0|G1|Negative|IB|Negative|Positive| |Negative|Negative|IB||Negative|| |Negative|Positive|Positive|IB|Negative|| |Negative|Positive|Negative|Negative||| |Negative|Negative|IB|||| |Negative|G3|Positive|Positive|Positive|Positive| |Negative|G3|Positive|Positive|Negative|IIIB| |Negative|G3|Positive|Positive|Positive|IB| |Negative|G3|Positive|Positive|Negative|Negative| |Negative|Negative|IIIB|||| |Negative|Negative|Positive||Positive|Positive| |Negative|Negative|Positive|Negative|Negative|| |Negative|Negative|Positive|Positive|Positive|IIIB| |Negative|Negative|Positive|Negative|IIIB|Negative|

|TNM|Grade|HER2|ER|PR|Stage| |---|---|---|---|---|---| |T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $|G1|Positive|Positive|Positive|IIA| |T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $|G1|Positive|Positive|Negative|Positive| |T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $|G1|Positive|Negative|Positive|| |T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $|G1|Positive|Negative|Negative|IIA| |T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $|G1|Positive|G2|Positive|Positive| |T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $|G1|Negative|G2|Positive|Positive| |T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $|G1|Negative|G2|Positive|Positive| |T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $|G1|Negative|G2|Positive|Negative| |T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $|G1|G2|G2|Positive|Positive| |T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $|G1|G2|Negative|IIIA|Positive| |T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $|G1|G2|Negative|Negative|Positive| |T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $|G1|G2|Negative|Negative|Positive| |T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $|G1|G2|G3|Positive|Positive| |T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $|G1|Negative|G3|Positive|Negative| |T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $|G1|Negative|G3|Positive|Negative| |Negative|Negative|IIIB|G3|Positive|| |Negative|G3|Positive|G3|Positive|Positive| |Negative|G3|Positive|Negative|Negative|| |Negative|G3|Positive|Negative|Negative|| |Negative|G3|Positive|Negative|IIIB|| |Negative|G3|Positive|Negative|Negative|IIIC|

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Table 3. Clinical Prognostic Stage(continued)

|TNM|Grade|HER2|ER|PR|Stage| |---|---|---|---|---|---| |T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0|G1|Positive|Positive|Positive|IIIA| |T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0|G1|Positive|Positive|Negative|Positive| |T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0|G1|Positive|Negative|Negative|| |T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0|G1|Positive|Negative|Positive|Positive| |T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0|G1|Negative|Negative|Positive|IIIC| |T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0|G1|G2|Negative|Positive|Positive| |T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0|G1|G2|Negative|Positive|Positive| |T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0|G1|G2|Negative|Positive|Positive| |T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0|G1|G2|Negative|Positive|Positive| |T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0|G1|Negative|Negative|IIIC|Positive| |T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0|G1|G3|Negative|Positive|Positive| |T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0|G1|G3|Negative|Positive|Negative| |T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0|G1|G3|Negative|Positive|Positive| |T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0|G1|G3|Negative|Positive|Positive| |T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0|G1|Any TAny N M1|Negative|Any|Any|

Notes:

1. Because N1mi categorization requires evaluation of the entire node, and cannot be assigned on the basis of an FNA or core biopsy, N1mi can only be used with Clinical Prognostic Staging when clinical staging is based on a resected lymph node in the absence of resection of the primary cancer, such as the situation where sentinel node biopsy is performed prior to receipt of neoadjuvant chemotherapy or endocrine therapy.

2.For cases with lymph node involvement with no evidence of primary tumor(e.g.T0 N1,etc.) or with breast ductal carcinoma in situ(e.g. Tis N1,etc.), the grade,HER2, ER, and PR information from the tumor in the lymph node should be used for assigning stage group.

3. For cases where HER2 is determined to be“equivocal” by ISH(FISH or CISH)testing under the 2013 ASCO/CAP HER2 testing guidelines, the HER2“negative”category should be used for staging in the Clinical Prognostic Stage Group.

4. The prognostic value of these Prognostic Stage Groups is based on populations of persons with breast cancer that have been offered and mostly treated with appropriate endocrine and/or systemic chemotherapy(including anti-HER2 therapy).

***N1 includes N1mi.T2,T3,and T4 cancers and N1mi are included for prognostic staging with T2 N1,T3 N1 and T4 N1, respectively.

Used with the permission of the American College of Surgeons, Chicago Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition(2017) published by Springer International Publishing. For complete information and data supporting the staging tables, visit www.springer.com.

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Table 4. Pathological Prognostic Stage

Pathological Prognostic Stage applies to patients with breast cancer treated with surgery as the initial treatment. It includes all information used for clinical staging plus findings at surgery and pathological findings from surgical resection. Pathological Prognostic Stage does not apply to patients treated with systemic or radiation prior to surgical resection(neoadjuvant therapy).

|TNM|Grade|HER2|ER|PR|Stage| |---|---|---|---|---|---| |Tis N $\text{O}$ M0|Any|Any|Any|Any|0| |T1* N $\text{O}$ M $\text{O}$ T1* N1mi M0 T1* N1mi M0|G1|Positive|Positive|Positive|IA| |T1* N $\text{O}$ M $\text{O}$ T1* N1mi M0 T1* N1mi M0|G1|Positive|Positive|Negative|IA| |T1* N $\text{O}$ M $\text{O}$ T1* N1mi M0 T1* N1mi M0|G1|Negative|Positive|Negative|IA| |T1* N $\text{O}$ M $\text{O}$ T1* N1mi M0 T1* N1mi M0|G1|Negative|Negative|IIA|IA| |T1* N $\text{O}$ M $\text{O}$ T1* N1mi M0 T1* N1mi M0|G1|Negative|Positive|IIA|IA| |T1* N $\text{O}$ M $\text{O}$ T1* N1mi M0 T1* N1mi M0|G1|Negative|Positive|Negative|IA| |T1* N $\text{O}$ M $\text{O}$ T1* N1mi M0 T1* N1mi M0|G1|Negative|G2|Positive|IA| |T1* N $\text{O}$ M $\text{O}$ T1* N1mi M0 T1* N1mi M0|G1|Negative|G2|Positive|IA| |T1* N $\text{O}$ M $\text{O}$ T1* N1mi M0 T1* N1mi M0|G1|Negative|G2|Positive|IA| |T1* N $\text{O}$ M $\text{O}$ T1* N1mi M0 T1* N1mi M0|G1|Negative|G2|Positive|IA| |T1* N $\text{O}$ M $\text{O}$ T1* N1mi M0 T1* N1mi M0|G1|Negative|G3|Positive|IA| |T1* N $\text{O}$ M $\text{O}$ T1* N1mi M0 T1* N1mi M0|G1|Negative|G3|Positive|IA| |Negative|Positive|Positive|G3|IA|| |Negative|Positive|Negative|G3|IA|| |Negative|Negative|Positive|Positive|IA|| |Negative|Negative|Negative|Positive|IA|| |Negative|Negative|Positive|Positive|IIA|| |Negative|Negative|Positive|Negative|IIA|| |Negative|Negative|Positive|Positive|IIA|Positive| |Negative|Negative|Positive|Negative|IIA|Positive| |Negative|Negative|Positive|Positive||| |Negative|Negative|Negative|IB|||

|TNM|Grade|HER2|ER|PR|Stage| |---|---|---|---|---|---| |T0$N1**$M0$ T$1*$N1$M0$ T$2$ N$O$ M0|G1|Positive|Positive|Positive|IA| |T0$N1**$M0$ T$1*$N1$M0$ T$2$ N$O$ M0|G1|Positive|Positive|Negative|IB| |T0$N1**$M0$ T$1*$N1$M0$ T$2$ N$O$ M0|G1|Positive|Negative|Positive|| |T0$N1**$M0$ T$1*$N1$M0$ T$2$ N$O$ M0|G1|Positive|Negative|IA|| |T0$N1**$M0$ T$1*$N1$M0$ T$2$ N$O$ M0|G1|Positive|Negative|Positive|Positive| |T0$N1**$M0$ T$1*$N1$M0$ T$2$ N$O$ M0|G1|Negative|Negative|Positive|IB| |T0$N1**$M0$ T$1*$N1$M0$ T$2$ N$O$ M0|G1|Negative|Negative|Positive|Positive| |T0$N1**$M0$ T$1*$N1$M0$ T$2$ N$O$ M0|G1|Negative|Negative|Positive|IA| |T0$N1**$M0$ T$1*$N1$M0$ T$2$ N$O$ M0|G1|Negative|Negative|IA|| |T0$N1**$M0$ T$1*$N1$M0$ T$2$ N$O$ M0|G1|Negative|Positive|Positive|Positive| |T0$N1**$M0$ T$1*$N1$M0$ T$2$ N$O$ M0|G1|Negative|Positive|Positive|Negative| |T0$N1**$M0$ T$1*$N1$M0$ T$2$ N$O$ M0|G1|Negative|Positive|Negative|Negative| |T0$N1**$M0$ T$1*$N1$M0$ T$2$ N$O$ M0|G1|Negative|Positive|Negative|Positive| |T0$N1**$M0$ T$1*$N1$M0$ T$2$ N$O$ M0|G1|Negative|Positive|Negative|Negative| |T0$N1**$M0$ T$1*$N1$M0$ T$2$ N$O$ M0|G1|Negative|Positive|Positive|IA| |Negative|Negative|Negative|Positive|IA|| |Negative|Negative|Positive|Positive|IA|IIA| |Negative|Negative|Positive|Negative|Negative|IIA| |Negative|Negative|Positive|Negative|Negative|IIA| |Negative|Negative|Positive|Negative|Positive|IIA| |Negative|Negative||Negative|Positive|| |Negative|Negative|Negative|Negative|Positive||

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Table 4. Pathological Prognostic Stage(continued)

|TNM|Grade|HER2|ER|PR|Stage| |---|---|---|---|---|---| |T2 N1*** M0 T3 N0 M0|G1|Positive|Positive|Positive|IA| |T2 N1*** M0 T3 N0 M0|G1|Positive|Positive|Negative|IIB| |T2 N1*** M0 T3 N0 M0|G1|Positive|Negative||IIB| |T2 N1*** M0 T3 N0 M0|G1|Positive|Negative|Positive|Positive| |T2 N1*** M0 T3 N0 M0|G1|Negative|Negative|Positive|I B| |T2 N1*** M0 T3 N0 M0|G1|Negative|Negative|Negative|I B| |T2 N1*** M0 T3 N0 M0|G1|Negative|Negative|Negative|I B| |T2 N1*** M0 T3 N0 M0|G1|G2|Positive|Positive|I B| |T2 N1*** M0 T3 N0 M0|G1|G2|Positive|Positive|Negative| |T2 N1*** M0 T3 N0 M0|G1|G2|Positive|Negative|Negative| |T2 N1*** M0 T3 N0 M0|G1|G2|Positive|Negative|Positive| |T2 N1*** M0 T3 N0 M0|G1|Negative|Negative|Negative|Positive| |Negative|IB||Negative|Negative|| |G3|Positive|Positive|Positive|Negative|IB| |G3|Positive|Negative|Negative|Positive|| |G3|Positive|Negative|Positive|Positive|Positive| |G3|Positive|Negative|Positive|Negative|Negative| |Negative|Positive|Negative|Positive|Positive|| |Negative|Positive|Negative|Negative|Negative|| |Negative|Negative|Positive|Positive|Positive|| |Negative|Negative|Positive|Negative|Negative|| |Negative|Negative|Positive|II A||| |Negative|Negative|Positive|Positive|Positive|II B| |Negative|Negative|Negative|Positive||| |Negative|Negative|Positive|Positive|Positive|| |Negative|Negative|Positive|Negative|Negative|| |Negative|Negative|Positive|IIIA|||

|TNM|Grade|HER2|ER|PR|Stage| |---|---|---|---|---|---| |T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $|G1|Positive|Positive|Positive|IB| |T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $|G1|Positive|Positive|Negative|Positive| |T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $|G1|Positive|Negative|Positive|| |T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $|G1|Positive|Negative|Positive|Negative| |T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $|G1|Positive|G2|Positive|Positive| |T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $|G1|Negative|G2|Positive|Positive| |T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $|G1|Negative|G2|Positive|Negative| |T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $|G1|Negative|G2|Positive|Negative| |T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $|G1|Negative|G2|Positive|Negative| |T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $|G1|G3|Positive|Positive|Positive| |T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $|G1|G3|Positive|Positive|Negative| |T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $|G1|G3|Positive|Negative|Negative| |T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $|G1|G3|Positive|Negative|Negative| |T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $|G1|G3|Positive|||

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Table 4. Pathological Prognostic Stage(continued)

|TNM|Grade|HER2|ER|PR|Stage| |---|---|---|---|---|---| |T4 N0 M0 T4 N1*** M O T4 N2 M0 Any T N3 M0|G1|Positive|Positive|Positive|IIIA| |T4 N0 M0 T4 N1*** M O T4 N2 M0 Any T N3 M0|G1|Positive|Positive|Negative|IIIB| |T4 N0 M0 T4 N1*** M O T4 N2 M0 Any T N3 M0|G1|Positive|Positive|Negative|IIIA| |T4 N0 M0 T4 N1*** M O T4 N2 M0 Any T N3 M0|G1|Negative|Positive|IIIA|| |T4 N0 M0 T4 N1*** M O T4 N2 M0 Any T N3 M0|G1|Negative|Negative|IIIB|| |T4 N0 M0 T4 N1*** M O T4 N2 M0 Any T N3 M0|G1|Negative|Negative|Positive|IIIA| |T4 N0 M0 T4 N1*** M O T4 N2 M0 Any T N3 M0|G1|Negative|Negative|IIIB|| |T4 N0 M0 T4 N1*** M O T4 N2 M0 Any T N3 M0|G1|Negative|Negative|Positive|IIIB| |T4 N0 M0 T4 N1*** M O T4 N2 M0 Any T N3 M0|G1|Negative|Negative|IIIC|| |T4 N0 M0 T4 N1*** M O T4 N2 M0 Any T N3 M0|G1|Negative|G2|Positive|Positive| |T4 N0 M0 T4 N1*** M O T4 N2 M0 Any T N3 M0|G1|Negative|G2|Positive|Positive| |T4 N0 M0 T4 N1*** M O T4 N2 M0 Any T N3 M0|G1|Negative|G2|Positive|Positive| |T4 N0 M0 T4 N1*** M O T4 N2 M0 Any T N3 M0|G1|Negative|G2|Positive|Negative| |T4 N0 M0 T4 N1*** M O T4 N2 M0 Any T N3 M0|G1|Negative|G3|Positive|Positive| |T4 N0 M0 T4 N1*** M O T4 N2 M0 Any T N3 M0|G1|Negative|G3|Positive|IIIB| |Negative|Positive|IIIC|G3|Positive|| |Negative|Negative|IIIB|G3|Positive|| |Negative|Negative|Positive|G3|IIIC|| |Negative|Negative|IIIB|G3||| |Negative|Negative|Positive|G3|IIIB|| |Negative|Negative|IIIC||||

***N1 includes N1mi.T2,T3,and T4 cancers and N1mi are included for prognostic staging with T2 N1,T3 N1 and T4 N1, respectively.

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Discussion

ABBREVIATIONS

|3D-CRT|three dimensional radiation therapy|DMMR| |---|---|---| |AI|aromatase inhibitor|DVH| |APBI|accelerated partial breast irradiation|EIC| |ALND|axillary lymph node dissection|EPC| |ALT|alanine aminotransferase|FDG| |AST|aspartate aminotransferase|FSH| |AST|aspartate aminotransferase|FNA| |AUC|area under the curve|GnRH| |BCs|breast cancers|H&E| |BCI|breast cancer index|IBC| |BCS|breast-conserving surgery|IBTR| |BCT|breast-conservation therapy|IGRT| |BIA-|breast implant-associated|IHC| |ALCL|apanlastic large cell|ILD| |lymphoma||| |BIA-|breast implant-associated|IMRT| |SCC|squamous cell|ISH| |carcinoma||| |BMI|body mass index|LH| |CBC|complete blood count|LVEF| |CEA|carcinoebryonic antigen|LVI| |CPS|combined positive score|MSI-H| |CRF|cancer-related fatigue|NAC| |ctDNA|circulating tumor deoxyribonucleic acid|NGS| |DCIS|ductal carcinoma in situ|NST| |DCIS-M|DCIS with microinvasion|OS| |DFS|disease-free survival|PBI| |DIBH|deep-inspiratory breath hold|pCR|

|dMMR|mismatch repair deficient| |---|---| |DVH|dose-volume histogram| |EBRT|external beam radiation therapy| |EIC|extensive inductal component| |EPC|encapsulated papillary carcinoma| |FDG|fluorodeoxyglucose| |FSH|follicle-stimulating hormone| |FNA|fine-needle aspiration| |GnRH|gonadotropin-releasing hormone| |H&E|hematoxylin and eosin| |IBC|inflammatory breast cancer| |BCS|IBTR| |BCT|breast-conservation therapy| |BIA-|breast implant-associated| |ALCL|anaplastic large cell| |lymphoma|| |BIA-|breast implant-associated| |SCC|IMRT| |SCC|ISH| |carcinoma|LFTs| |BMI|body mass index| |CBC|complete blood count| |CEA|carcinoebryonic antigen| |CPS|combined positive score| |CRF|cancer-related fatigue| |ctDNA|circulating tumor deoxyribonucleic acid| |DCIS|ductal carcinoma in situ| |DCIS-M|DCIS with microinvasion| |DCIS|dcis-free survival| |DIBH|deep-inspiratory breath hold|

|PCP|primary care physician| |---|---| |PD-1|programmed cell death protein 1| |PD-L1|programmed death ligand 1| |PFS|progression-free survival| |PMRT|postmastectomy radiotherapy| |PTSD|post-traumatic stress disorder| |PTV|planning target volume| |RCB|residual cancer burden| |RECIST|response evaluation criteria in solid tumors| |RNI|regional nodal irradiation| |RS|recurrence score| |RT-PCR|reverse transcriptase polymerase chain reaction| |SBRT|stereotactic body radiation therapy| |SE|standard error| |SLN|sentinel lymph node| |SLN|sentinel lymph node biopsy| |SPC|solid papillary carcinoma| |SNRI|serotonin and norepinephrine| |reuptake inhibitors|| |SSRI|selective serotonin reuptake inhibitors| |TF|tumor fraction| |TIPN|taxane-induced peripheral| |neuropathy|neuropathy| |TMB-H|tumor mutational burden-high| |TNBC|triple-negative breast cancer| |VMAT|volumetric modulated arc therapy|

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||NCCN Categories of Evidence and Consensus| |---|---| |Category 1|Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus(≥85% support of the Panel) that the intervention is appropriate.| |Category 2A|Based upon lower-level evidence, there is uniform NCCN consensus(≥85% support of the Panel) that the intervention is appropriate.| |Category 2B|Based upon lower-level evidence, there is NCCN consensus(≥50%, but <85% support of the Panel) that the intervention is appropriate.| |Category 3|Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.|

All recommendations are category 2A unless otherwise indicated.

|NCCN Categories of Preference|| |---|---| |Preferred intervention|Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.| |Other recommended intervention|Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.| |Useful in certain circumstances|Other interventions that may be used for selected patient populations (defined with recommendation).|

All recommendations are considered appropriate.

NCCN

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NCCN Guidelines Version 5.2025 Breast Cancer

Discussion

This Discussion corresponds to the NCCN Guidelines for Breast Cancer. The section for systemic therapies(preoperative and adjuvant) was updated on June 7 ${}^{th}$ , 2024. The update to the rest of the Discussion section is in progress.

Overview $\ldots$ MS-2

Sensitive/Inclusive Language Usage MS-2

Guidelines Update Methodology...MS-2

Literature Search Criteria and Guidelines Update Methodology......MS-2

Ductal Carcinoma in Situ(Tis, N0, M0)..MS-3

Workup for DCIS. MS-3

Primary Treatment for DCIS $\ldots$ MS-4

Management of DCIS After Primary Treatment. MS-8

Invasive Breast Cancer.. .MS-10

Workup for Non-metastatic (M0) Invasive Breast Cancer ..... MS-10

Locoregional Treatment of cT1-3, cN0 or cN+, M0 Disease...... MS-13

Surgery $\ldots$ MS-13

Radiation Therapy .MS-18

Adjuvant Radiation Therapy After BCS $\ldots$ MS-21

Adjuvant Radiation Therapy After Mastectomy $\ldots$ (MS-23

Breast Reconstruction .MS-26

Systemic Therapies (Preoperative and Adjuvant) .. MS-30

Post-Therapy Surveillance and Follow-up for T0-3, N1, M0 and T1-3,N0-1, M0 Tumors..MS-52

Recurrent/Stage IV Breast Cancer.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Special Situations. MS-77

Paget Disease. . . . MS-77

Phyllodes Tumors of the Breast MS-79

Breast Cancer During Pregnancy .MS-80

Inflammatory Breast Cancer. $\ldots$ MS-82

Axillary Breast Cancer..... MS-85

Summary MS-86

References .MS-87

NCCN

National Comprehensive Cancer Network®

NCCN Guidelines Version 5.2025 Breast Cancer

Overview

Breast cancer is the most common malignancy in females in the United States and is second only to lung cancer as a cause of cancer death. The American Cancer Society has estimated that 313,510 Americans will be diagnosed with breast cancer and 42,780 will die of disease in the United States in 2024.1,2 The therapeutic options for patients with noninvasive or invasive breast cancer are complex and varied. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer include guidelines for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, Phylodites tumor, inflammatory breast cancer (IBC), male breast cancer, and breast cancer during pregnancy. These Guidelines have been developed and are updated continuously by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer-focused expertise in the fields of medical oncology, surgical oncology,radiation oncology,pathology,reconstructive surgery, and patient advocacy.

Sensitive/Inclusive Language Usage

NCCN Guidelines strive to use language that advances the goals of equity, inclusion, and representation. NCCN Guidelines endeavor to use language that is person-first; not stigmatizing; anti-racist, anti-classist,anti-misognist, anti-ageist, anti-ableist, and anti-weight-biased; and inclusive of individuals of all sexual orientations and gender identities.NCCN Guidelines incorporate non-gendered language, instead focusing on organ-specific recommendations. This language is both more accurate and more inclusive and can help fully address the needs of individuals of all sexual orientations and gender identities. NCCN Guidelines will continue to use the terms men, women, female, and male when citing statistics, recommendations, or data from organizations or sources that do not use inclusive terms. Most studies do not report how sex and gender data are collected and use these terms interchangeably or inconsistently.

If sources do not differentiate gender from sex assigned at birth or organs present, the information is presumed to predominantly represent cisgender individuals. NCCN encourages researchers to collect more specific data in future studies and organizations to use more inclusive and accurate language in their future analyses.

Guidelines Update Methodology

Literature Search Criteria and Guidelines Update Methodology

Prior to the update of this version of the NCCN Guidelines® for Breast Cancer, an electronic search of the PubMed database was performed to obtain key literature using the following search terms: Breast Cancer,Breast Neoplasms, DCIS, Inflammatory Breast Cancer, OR Phyllodes.The PubMed database was chosen as it remains the most widely used resource for medical literature and indexes peer-reviewed biomedical literature.3

The search results were narrowed by selecting studies in humans published in English. Results were confined to the following article types:Clinical Trial, Phase III; Clinical Trial, Phase IV; Guideline; Randomized Controlled Trial; Meta-Analysis; Systematic Reviews; and Validation Studies.

The potential relevance of the PubMed search was examined. The data from key PubMed articles selected by the Panel for review during the Guidelines update meeting as well as articles from additional sources deemed as relevant to these Guidelines and discussed by the Panel have been included in this version of the Discussion section. Recommendations for which high-level evidence is lacking are based on the Panel's review of lower-level evidence and expert opinion. The complete details of the Development and Update of the NCCN Guidelines are available at www.NCCN.org.

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Ductal Carcinoma in Situ(Tis, N0, M0)

The diagnosis of ductal carcinoma in situ(DCIS) has increased since the introduction and increased utilization of screening mammography.

According to the American Cancer Society, over 50,000 cases of DCIS of the female breast will be diagnosed in the United States in 2022.1

Workup for DCIS

The recommended workup and staging of DCIS includes history and physical examination, bilateral diagnostic mammography, pathology review, determination of tumor estrogen receptor(ER) status, and MRI, as indicated.

For pathology reporting, the NCCN Panel endorses the College of American Pathologists (CAP) Protocol for both invasive and noninvasive carcinomas of the breast.4

The NCCN Panel recommends testing for ER status in order to determine the benefit of adjuvant endocrine therapy or risk reduction. This is in accordance with the American Society for Clinical Oncology(ASCO)/CAP guidelines,5 which recommend that ER testing of newly diagnosed DCIS to determine potential benefit of endocrine therapies for breast cancer risk reduction and progesterone receptor(PR) testing be considered optional.Although the tumor HER2 status is of prognostic significance in invasive cancer, its importance in DCIS has not been established. To date, studies have either found unclear or weak evidence of HER2 status as a prognostic indicator in DCIS,6-9 and no statistically significant benefit to the use of trastuzumab concurrently with radiation in HER2-amplified DCIS.10 The NCCN Panel has concluded that HER2 status for DCIS does not alter the management strategy and therefore is not recommended for DCIS.

Genetic counseling is recommended if the patient is considered to be at high risk for hereditary breast cancer as defined by the NCCN Guidelines

for Genetic/Familial High-Risk Assessment: Breast,Ovarian, and Pancreatic.

The role of MRI in management of DCIS remains unclear. MRI has been prospectively shown to have a sensitivity of up to 98% for high-grade DCIS.11 In a prospective, observational study of 193 patients with pure DCIS who underwent both mammography and MRI imaging preoperatively; 93(56%) patients were diagnosed by mammography and 153(92%) were diagnosed by MRI(P<.0001). Of the 89 patients with high-grade DCIS, 43(48%) who were not diagnosed by mammography were diagnosed by MRI alone.11 However, other studies suggest that MRI can overestimate the extent of disease.12 Therefore, the surgical decisions for performing a mastectomy for DCIS should not be solely based on MRI findings alone. If MRI findings suggest more extensive disease than is seen on mammography such that a markedly larger resection is required for complete excision, the findings should be verified histologically through MRI-guided biopsy of the more extensive enhancement. Studies performed to determine whether the use of MRI reduces re-excision rates and decreases local recurrence in patients with DCIS show conflicting results. While several studies suggest no reduction in re-excision rates in patients with pure DCIS undergoing breast-conserving surgery(BCS)following MRI compared with those who did not undergo preoperative MRI,13,14 some have demonstrated a reduction in re-excision rate with use of preoperative MRI for DCIS.15,16 One study showed an additional cancer detection rate of 6.2% with preoperative MRI.16 Therefore, the use of preoperative MRI remains controversial. The NCCN Panel recommends only performing breast MRI for DCIS in select circumstances where additional information is warranted during the initial workup, noting that the use of MRI has not been shown to increase likelihood of negative margins or decrease conversion to mastectomy for DCIS.

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Primary Treatment for DCIS

The goal of primary therapy for DCIS is to prevent progression to invasive breast carcinoma. Management strategies for DCIS treatment include surgery(mastectomy or BCS), and/or radiation therapy(RT), followed by adjuvant endocrine therapy in eligible patients to reduce risk of recurrence.

The choice of local treatment does not impact overall disease-related survival; therefore, the individual's preferences for risk reduction must be considered.

Several prospective randomized trials of pure DCIS have shown that the addition of whole breast RT(WBRT) after BCS decreases the rate of in-breast disease recurrence,17-24 but not distant metastasis-free survival.25 A meta-analysis of four large multicenter randomized trials confirmed the results of the individual trials, demonstrating that the addition of WBRT after BCS for DCIS provides a statistically and clinically significant reduction in ipsilateral breast events(hazard ratio[HR], 0.49; 95%confidence interval[Cl]; 0.41-0.58, P<.00001).26 However, these trials did not show that the addition of RT has an overall survival(OS) benefit.The long-term follow-up of the NSABP B-17 trial showed that at 15 years,RT resulted in a 52% reduction of ipsilateral invasive recurrence compared with excision alone(HR, 0.48; 95% CI, 0.33-0.69, P<.001).23 The OS and cumulative all-cause mortality rates through 15 years were similar between the two groups(HR for death, 1.08; 95% CI, 0.79-1.48).23 Similar findings were reported by a large observational study of the SEER database that included 108,196 patients with DCIS.27 In a subgroup analysis at 10 years, of 60,000 patients treated with BCS, with or without WBRT, a 50% reduction in the risk of ipsilateral recurrence(adjusted HR,0.47 [95% CI, 0.42-0.53]; P<.001) was associated with the addition of WBRT. However, in this study, breast cancer-specific mortality was found to be similar(HR, 0.86 [95% CI, 0.67-1.10]; P=.22).27

In contrast, several population-based studies suggest beneficial effects of WBRT for DCIS after BCS; for example, the use of WBRT in patients with higher-risk DCIS(eg, higher nuclear grade, younger age, larger tumor size) was demonstrated to be associated with a modest but statistically significant improvement in OS.28 In another observational study of the SEER database including 140,366 patients with DCIS, the 15-year breast cancer mortality rate was 1.7% for those treated with breast-conserving therapy (BCT) versus 2.3% for patients treated with BCS alone (HR, 0.77;95% CI, 0.67-0.88; P<.001), demonstrating a small but significant reduction in breast cancer mortality with BCS and WBRT compared with BCS alone.29

RT Boost: The use of RT boost has been demonstrated to provide a small but statistically significant reduction in ipsilateral breast tumor recurrence(IBTR) risk(4% at 20 years) in all age groups for invasive breast

A pooled analysis of patient-level data from 10 academic institutions evaluated outcomes of pure DCIS patients, all treated with BCS and WBRT (n = 4131) who either received RT boost with a median dose of 14 Gy (n = 2661) or received no boost (n = 1470). The median follow-up of patients was 9 years. A decrease in IBTR was seen in patients who received a boost compared with those who did not at 5 years (97.1% vs.96.3%), 10 years (94.1% vs.92.5%), and 15 years (91.6% vs.88.0%)(P=.0389 for all). The use of RT boost was associated with significantly decreased IBTR across the entire cohort of patients (HR, 0.73; 95% CI,0.57-0.94; P=.01).34 In a multivariate analysis that took into account factors associated with lower IBTR, including grade, ER positive status,use of adjuvant tamoxifen, margin status, and age, the benefit of RT boost still remained statistically significant (HR, 0.69; 95% CI, 0.53-0.91; P<.010).34 Even in patients considered very low risk based on negative margins status (defined as no ink on tumor as per NSABP definition, or margins >2 mm as per Society of Surgical Oncology [SSO]/American

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Society for Radiation Oncology [ASTRO]/ASCO definition),the RT boost remained statistically significant for decreasing the rate of local relapse.

study of 215 patients with DCIS treated with BCS without RT, or systemic risk reduction therapy, the recurrence rates over 8 years were 0%,21.5%,and 32.1% in patients with low-, intermediate-, or high-risk DCIS,respectively.38 The stratification for risk of recurrence in this retrospective study was calculated using the modified Van Nuys Prognostic Index based on tumor grade, size, absence of comedo necrosis, margin width, and age at diagnosis.38

Similar to invasive cancers, though RT boost was beneficial in all age groups studied, the magnitude of the absolute benefit of the boost was greatest in younger patients. Two randomized phase III trials are studying whether an RT boost reduces recurrence in patients with DCIS(ClinicalTrials.gov Identifiers: NCT00470236 and NCT00907868).

These trials have completed accrual and are now in active follow-up. A recent publication on the health-related quality of life (HRQOL) in patients enrolled in the BIG 3-07/TROG 07.01 phase III trial (NCT00470236)showed that after 2 years, the cosmetic status was impacted negatively with the boost versus no boost, suggesting the importance of informed shared decision-making regarding addition of boost until data related to impact on local recurrence and OS are published. ${ }^{35}$ According to the 5-year data from this trial, presented at the 2021 annual San Antonio Breast Cancer Symposium (SABCS) meeting, 93% of patients in the group who did not receive a boost were free from local recurrence compared with 97% in the group who received an RT boost (HR, 0.47; 95% CI, 0.31-0.72; P < .001). ${ }^{36}$ The peer-reviewed publication of these data is awaited.

A multi-institutional, non-randomized, prospective study of selected patients with low-risk DCIS treated without radiation has also provided some support for BCS alone without radiation.41 Patients were enrolled onto one of two low-risk cohorts: 1) low- or intermediate-grade DCIS,tumor size $\leq$ 2.5 cm(n=561); or 2) high-grade DCIS, tumor size $\leq$ 1cm(n=104). Protocol specifications included excision of the DCIS tumor with a minimum negative margin width of $\geq$ 3mm. Only 30% of the patients received tamoxifen. Of note, margins were substantially wider than the3-mm protocol requirement in many patients (ie, the low-/intermediate-risk patient group margins were $\geq$ 5 mm in 62% of patients and>10 mm or no tumor on re-excision in 48% of patients).41 Although the rate of IBTR was acceptably low for the low-/intermediate-grade group at 5 years, at a median follow-up of 12.3 years, the rates of developing an IBTR were 14.4% for low-/intermediate-grade and 24.6% for high-grade DCIS(P=.003).This suggests that IBTR events may be delayed but not prevented in the seemingly low-risk population.

Breast Conserving Surgery Alone Without WBRT: RT adds to treatment cost and is accompanied by adverse effects. Therefore, in an attempt to de-escalate treatment and limit morbidity and preserve quality of life(QOL), several trials have examined omission of RT in carefully selected patients at low risk of disease recurrence.

The RTOG 9804 trial investigated outcomes of RT omission in the setting of low-risk DCIS, randomizing 636 patients with low-risk disease to either RT or observation after surgery.24 In this study, low risk consisted of low-to intermediate-grade DCIS measuring<2.5 cm, with negative margins of≥3 mm. With a median follow-up of 7 years, a reduced risk of local recurrence was seen with use of RT compared with observation(0.9% vs.6.7%; HR,0.11;95% CI,0.03-0.47). No difference was seen in either DFS or OS. With a follow-up of 15 years, local recurrence rates were

There are retrospective series suggesting that selected patients have a low risk of in-breast recurrence when treated with excision alone (without WBRT).37-40 For example, in one retrospective review, 10-year disease-free survival (DFS) rates of 186 patients with DCIS treated with BCS alone were 94% for patients with low-risk DCIS and 83% for patients with both intermediate- and high-risk DCIS.37 In another retrospective

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reduced by 50% with RT versus without RT (7.1% vs. 15.1%; HR, 0.36;95% CI, 0.20-0.66).42

The available evidence from four randomized trials(NSABP B-39/RTOG 0413,43 OCOG-RAPID,44 University of Florence,45 and GEC-ESTRO46) of patients with breast cancer(tumors ≤3 cm) has shown that accelerated partial breast irradiation(APBI) delivered with multi-catheter brachytherapy is noninferior in local control compared with WBRT, with similar toxicity and breast cosmetic outcomes. Patients with DCIS constituted 25%, 18%,8.8%, and 6% of patients in the NSABP B-39/RTOG 0413,OCOG-RAPID,University of Florence, and GEC-ESTRO trials, respectively. Per the ASTRO guideline for APBI, patients with screen-detected DCIS measuring<2.5 cm, with grade I or II disease, and with negative margins of 3 mm or more are“suitable” candidates for APBI.47

Margin Status After Breast-Conserving Therapy: Prospective randomized trials have not been carried out to analyze whether wider margins can replace the need for RT for DCIS. Results from a retrospective study of 445 patients with pure DCIS treated by excision alone indicated that margin width was the most important independent predictor of local recurrence, although the trend for decreasing local recurrence risk with increasing margin width was most apparent with margins<1 mm compared to $\geq 10~mm.^{48}$ In a meta-analysis of 4660 patients with DCIS treated with BCS and radiation, a surgical margin of $^{2}$ mm was associated with increased rates of IBTR compared with margins of 2 mm,although no significant differences were observed when margins of $>2mm$ to 5 mm or $>5mm$ were compared with 2-mm margins.49

A study retrospectively reviewed a database of 2996 patients with DCIS who underwent BCS to investigate the association between margin width and recurrence, controlling all other characteristics. ${ }^{50}$ Wider margins were significantly associated with a lower rate of recurrence only in patients who

did not receive RT(P < .0001), but not in those treated with radiation(P =.95).50

According to the DCIS Consensus Guideline on Margins by SSO/ASTRO/ASCO, the use of at least a 2-mm margin in DCIS treated with WBRT is associated with low rates of IBTR.47 Additional factors to consider in assessing adequacy of excision for DCIS include presence of residual calcifications, which margin is close(anterior against skin or posterior against muscle vs. medial, superior, inferior, or lateral), and life expectancy of the patient. Notably, in situations where DCIS is admixed with invasive carcinoma, the SSO/ASTRO/ASCO Consensus Guideline on Margins for invasive breast cancer should be utilized, which supports “no tumor on ink" as an adequate margin applying to both the invasive and noninvasive components in this mixed tumor scenario.

Mastectomy: Patients with DCIS and evidence of widespread disease(ie,disease involving two or more quadrants) on diagnostic mammography or other imaging, physical examination, or biopsy may require mastectomy.

For DCIS patients undergoing mastectomy, or for local excision in an anatomic location that could compromise the lymphatic drainage pattern to the axilla(eg, tail of the breast), a sentinel lymph node biopsy(SLNB)procedure should strongly be considered at the time of definitive surgery to avoid necessitating a full axillary lymph node dissection(ALND) for evaluation of the axilla.51-54 Since only a small proportion of patients(about 25%) with seemingly pure DCIS on initial biopsy will have invasive breast cancer at the time of the definitive surgical procedure55 and will ultimately require axillary lymph node(ALN) staging, ALND is not recommended unless there is pathologically documented invasive cancer or ALN metastatic disease in patients(by either biopsy or SNLB).

NCCN Recommendations for Primary Treatment of DCI

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Trials are ongoing to determine if there might be a selected favorable biology DCIS subgroup where surgical excision is not required. Until such time that definitive evidence regarding the safety of this non-surgical approach is demonstrated, the NCCN Panel continues to recommend surgical excision for all DCIS.

Contraindications to BCT are listed in the algorithm(see Special Considerations to Breast Conservation Therapy Requiring RT). Patients treated with mastectomy are appropriate candidates for breast reconstruction(see Principles of Breast Reconstruction Following Surgery in the algorithm).

According to the NCCN Panel, primary treatment options for patients with DCIS along with their respective categories of consensus are:

According to the NCCN Panel, complete resection should be documented by analysis of margins and specimen radiography. Post-excision mammography can be considered for any uncertainty about adequacy of the excision remains(eg, the mass and/or microcalcifications are not clearly within the specimen). Clips may be used to delineate the tumor bed and ensure adequate coverage with radiation, provide design of boost and APBI fields, and provide markers should additional surgery be required pending the pathologic margin status review.

1) BCS plus WBRT with or without boost(category 1). While considering RT boost for DCIS, the NCCN Panel recommends an individualized approach based on patient preference and other factors such as longevity.

The NCCN Panel notes that WBRT following BCS reduces IBTR rates in DCIS by about 50% to 70%. For DCIS patients treated with BCS alone(without radiation), irrespective of margin width, the risk of IBTR is substantially higher than treatment with excision followed by WBRT (even for predefined low-risk subsets of DCIS patients).

For patients with pure DCIS treated by BCS and WBRT, a quantitative description of any tumor close to margin is helpful as a resection width of at least 2 mm is associated with a reduced risk of IBTR relative to narrower negative margin widths. The routine practice of obtaining margins >2 mm to further improve outcomes is not supported by the evidence. When there is only minimal or focal DCIS involvement near the margin, clinical judgment should be utilized to weigh the risks of re-excision with risk of recurrence for an individual patient.

2) Total mastectomy, with or without SLNB with optional reconstruction(category 2A).

3) BCS plus APBI in carefully selected patients(category 2A). According to the Panel, select patients with low-risk DCIS may be considered suitable for APBI if they meet all aspects of the definition of RTOG 9804 low-risk DCIS or ASTRO“suitable” DCIS for APBI.

4) BCS alone(category 2B). The option of BCS alone should be considered only in cases where the patient and the physician view the individual as having a low risk of disease recurrence. For patients with low-risk disease that has been fully resected with negative margins and particularly if they are ER-positive and will be receiving endocrine therapy,the absolute reduction of in-breast recurrence may not be large enough to justify the risks associated with RT. Therefore, according to the NCCN Panel, it may be reasonable to omit RT in such cases.

For patients with DCIS treated with excision alone (no WBRT), regardless of margin width, there is a substantially higher rate of IBTR than treatment with excision and WBRT, even in predefined, low-risk patients. Although the optimal margin width for treatment with excision alone is unknown, it should be at least 2 mm, with some evidence suggesting improved IBTR rates with margin widths wider than 2 mm.

For DCIS with microinvasion (DCIS-M), defined as an invasive focus 1 mm or smaller in size, the optimal margin width should refer to the DCIS

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margin definition(≥2 mm), given that the majority of DCIS-M is comprised of DCIS and the natural history and systemic therapy utilization for DCIS-M more closely reflect the treatment pattern for pure DCIS than for invasive carcinoma.

analysis of ER expression in NSABP B-24 suggests that increased levels of ER expression predict for tamoxifen benefit in terms of risk reduction for ipsilateral and contralateral breast cancer development following BCT. ${ }^{60}$

Management of DCIS After Primary Treatment

Tamoxifen: DCIS falls between atypical ductal hyperplasia (ADH) and invasive ductal carcinoma within the spectrum of breast proliferative abnormalities. The Breast Cancer Prevention Trial performed by NSABP showed a 75% reduction in the occurrence of invasive breast cancer in patients with ADH treated with tamoxifen. 56,57 These data also showed that tamoxifen led to a substantial reduction in the risk of developing invasive breast disease.58 The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) overview analysis showed that, with 5 years of tamoxifen therapy, patients with ER-positive or receptor-unknown invasive tumors had a 39% reduction in the annual odds of recurrence of invasive breast cancer.59

A phase III trial randomized patients with excised DCIS to receive WBRT or no WBRT and tamoxifen versus no tamoxifen. ${ }^{22}$ The randomization was independent for each of the two treatments(RT and tamoxifen). With 12.7 years of median follow-up, the use of tamoxifen decreased all new breast events (HR, 0.71; 95% CI, 0.58-0.88; P = .002). The use of tamoxifen decreased ipsilateral and contralateral breast events in the subjects not given WBRT (ipsilateral HR, 0.77; 95% CI, 0.59-0.98; contralateral HR,0.27; 95% CI, 0.12-0.59), but not in those receiving WBRT (ipsilateral HR,0.93; 95% CI, 0.50-1.75; P=.80; contralateral HR, 0.99; 95% CI, 0.39-2.49; P = 1.0).

The standard dose of tamoxifen is 20 mg/day for 5 years. The phase III TAM-01 trial studied a lower dose of tamoxifen(5 mg for 3 years) in 501 patients with breast intraepithelial neoplasia including DCIS, lobular carcinoma in situ(LCIS), and ADH. The rate of recurrence of either intraepithelial neoplasia or invasive breast cancer was 5.7% among those receiving tamoxifen 5 mg daily versus 11.9% for those receiving placebo(HR, 0.48; 95% CI, 0.25-0.89) at a median follow-up of 5.1 years. ${ }^{61}$ The relative risk (RR) reduction with low-dose tamoxifen seen in the TAM-01 trials is consistent with that seen in trials that used a higher dose of tamoxifen, but the rate of severe toxicity compared with placebo was less.

Similarly, the NSABP B-24 trial found a benefit from tamoxifen for patients with DCIS after treatment with breast conservation surgery and RT. In that study, patients with DCIS who were treated with BCT were randomized to receive placebo or tamoxifen. At a median follow-up of 13.6 years,patients who received tamoxifen had a 3.4% absolute reduction in ipsilateral in-breast tumor recurrence risk(HR, 0.30; 95% CI, 0.21-0.42; P<.001) and a 3.2% absolute reduction in contralateral breast cancers(HR,0.68;95% CI,0.48-0.95;P=.023).23 The patients receiving tamoxifen had a 10-year cumulative rate of 4.6% for invasive and 5.6% for noninvasive breast cancers in the ipsilateral breast, compared with 7.3% invasive and 7.2% noninvasive recurrences for those treated with placebo. The cumulative 10-year frequency of invasive and noninvasive breast cancer in the contralateral breast was 6.9% and 4.7% in the placebo and tamoxifen groups, respectively. No differences in OS were noted. A retrospective

Anastrozole: In patients with ER-positive and/or PR-positive DCIS treated by wide local excision with or without RT, a large, randomized,double-blind, placebo-controlled trial(IBIS-II) compared anastrozole (n=1471) with tamoxifen (n = 1509). The results demonstrated non-inferiority of anastrozole to tamoxifen. ${ }^{62}$ After a median follow-up of 7.2 years, 67 recurrences were reported with anastrozole versus 77 for tamoxifen (HR,0.89; 95% CI, 0.64-1.23). A total of 33 deaths were recorded for

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anastrozole and 36 for tamoxifen (HR,0.9393; 95% CI,0.58-1.50;P=.78).62 Although the number of patients reporting any adverse event was similar between anastrozole(n=1323,91%) and tamoxifen (n=1379,93%), the side-effect profiles of the two drugs were different. There were more fractures, musculoskeletal events, hypercholesterolemia, and strokes reported with anastrozole and more muscle spasms, gynecologic cancers and symptoms, vasomotor symptoms, and deep vein thromboses reported with tamoxifen. The NSABP B-35 study randomly assigned 3104 postmenopausal patients with hormone-positive DCIS treated with lumpectomy and radiation to either tamoxifen or anastrozole for 5 years.Prior to being randomly assigned, patients were stratified by age-<60 years or >60 years. The primary endpoint was breast cancer-free interval.63 Anastrozole treatment resulted in an overall statistically significant decrease in breast cancer-free interval events compared with tamoxifen (HR,0.73; 95% CI,0.56-0.96; P=.0234). The significant difference in breast cancer-free interval between the two treatments was apparent in the study only after 5 years of follow-up. The estimated percentage of patients with a 10-year breast cancer-free interval was 89.1% in the tamoxifen group and 93.1% in the anastrozole group.63 In addition, anastrozole resulted in further improvement in breast cancer-free interval in younger postmenopausal patients (<60 years of age). With respect to adverse effects, the overall incidence of thrombosis or embolism was higher in the tamoxifen group while the anastrozole group had slightly more cases of arthralgia and myalgia.63

Results of the IBIS-II and the NSABP-B-35 studies indicate that anastrozole provides at least a comparable benefit as adjuvant treatment for postmenopausal patients with hormone receptor(HR)-positive DCIS treated with BCS and RT, with a different toxicity profile.

Surveillance after treatment for DCIS helps early recognition of disease recurrences(either DCIS or invasive disease) and evaluation and

management of therapy-related complications. The majority of recurrences of DCIS are in-breast recurrences after BCT, and recurrences mostly occur in close proximity to the location of the prior disease. Overall,approximately one-half of the local recurrences after initial treatment for a pure DCIS are invasive in nature, whereas the remainder recur as pure DCIS.

NCCN Recommendations for Management of DCIS After Primary Treatment

According to the NCCN Panel, in patients with ER-positive DCIS treated with BCT, endocrine therapy with tamoxifen(for premenopausal and postmenopausal patients) or an aromatase inhibitor (Al) (for postmenopausal patients, especially those <60 years of age or in those with concerns of embolism) may be considered as a strategy to reduce the risk of ipsilateral breast cancer recurrence(category 1 for those undergoing BCT followed by RT; category 2A for those undergoing excision alone). The benefit of endocrine therapy for ER-negative DCIS is not known. Low-dose tamoxifen (5 mg/day for 3 years) is an option only if the 20-mg standard-dose of tamoxifen is not tolerated (see DCIS-2 in the algorithm).

Follow-up of patients with DCIS includes interval history and physical examination every 6 to 12 months for 5 years and then annually, as well as yearly diagnostic mammography. In patients treated with BCT, the first follow-up mammogram should be performed 6 to 12 months after the completion of RT(category 2B)(see DCIS-2 in the algorithm). Patients receiving endocrine therapy for risk reduction should be monitored as described in the NCCN Guidelines for Breast Cancer Risk Reduction.

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Invasive Breast Cancer

Workup for Non-metastatic (M0) Invasive Breast Cancer

The recommended workup of localized invasive breast cancer(listed on BINV-1 in the algorithm) includes a history and physical examination.Complete blood count(CBC) and liver function tests(LFTs) have no added benefit in the detection of underlying metastatic disease in patients with asymptomatic early-stage breast cancers.64 In addition, monitoring of disease relapse with any tumor markers is not recommended.

Imaging: lmaging with bilateral diagnostic mammography is recommended; breast ultrasonography is recommended only if necessary.

The use of MRI in the workup remains controversial. Breast MRI advocates note its high sensitivity for evaluation of extent of disease,particularly for invasive cancer and in dense breasts where mammographically occult disease is more likely to elude preoperative detection. MRI detractors note that MRI has a high percentage of false-positive findings, resulting in further diagnostic workup-including MRI-guided biopsy-in many circumstances.65-67 MRI findings tend to overestimate extent of disease,68 resulting in increased frequency of mastectomies.69-72

MRI findings alone are not sufficient to determine whether BCT is optimal,as additional tissue sampling is needed to verify true malignant disease warranting excision. MRI use may increase mastectomy rates by identifying areas of mammographically occult disease that may have been adequately treated with radiation after BCS had the disease remained undiscovered without MRI.72

Two prospective randomized studies have examined the utility of preoperative MRI in determining disease extent, and neither demonstrated improvement in rates of re-excision after initial BCS. ${ }^{73,74}$ Retrospective

review of the utility of MRI showed conflicting outcome results-one with benefit75 and another without.76 One systematic review67 documented that breast MRI staging altered surgical treatment in 7.8% to 33.3% of patients;67 however, no differences in local recurrence or survival have been demonstrated. In addition, there is no evidence that use of breast MRI increases rates of margin-negative resection.77,78

Breast MRI may assist with identification and management of clinically occult primary tumors presenting with axillary nodal metastases.79 In patients with Paget disease not identifiable on mammography, breast MRI may help determine the extent of disease.80,81 Breast MRI also has utility in screening patients with higher than average risk based on family history.82

If breast MRI imaging is performed, a dedicated breast coil, an imaging team experienced with reading breast MRI and performing MRI-guided biopsy, and multidisciplinary management are the standard of care.

According to the NCCN Panel, the use of MRI is optional and is not universally recommended by experts in the field. Breast MRI may be used for staging evaluation to define extent of cancer, in the adjuvant or neoadjuvant setting, to detect the presence of multifocal or multicentric cancer in the ipsilateral breast, or as screening of the contralateral breast cancer at time of initial diagnosis. Additional indications for breast MRI include: clinical axillary metastasis with an occult primary cancer; Paget disease of the nipple with breast primary not identified by other breast imaging modalities or physical examination; follow-up screening of patients with prior mammographically undetected breast cancers; and those whose lifetime risk of a second primary breast cancer is>20%(based on models largely dependent on family history).

Pathology Assessment: A central component of the treatment of breast cancer is full knowledge of extent of disease and biologic features. Full

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knowledge of extent of disease and biologic features is central to the treatment of breast cancer.

The specimens should be oriented for the pathologist, and specific requests for determination of biomarkers should be stated(eg, ER, PR,and HER2 status). The Panel also recommends testing for Ki-67 if HR-positive,HER2-negative, and considering adjuvant abemaciclib.

Accurate pathology reporting requires communication between the clinician and the pathologist relating to relevant patient history, prior breast biopsies, prior irradiation to the chest, pregnancy status, characteristics of the abnormality biopsied(eg, palpable, mammographically detected microcalcifications), clinical state of lymph nodes, presence of inflammatory change or other skin abnormality, and any prior treatment administered(eg, chemotherapy, RT). The specimens should be oriented for the pathologist, and specific requests for determination of biomarkers should be stated. The use of consistent, unambiguous standards for reporting is strongly encouraged. Data from both national and local surveys show that as many as 50% of pathology reports for breast cancer are missing some elements critical to disease management.12,13 Significant omissions include failure to orient and report surgical margins and failure to report tumor grade consistently. The CAP has developed pathology reporting protocols to promote complete and standardized reporting of malignant specimens. CAP provides a protocol for each disease site that includes cancer case summaries(checklists) along with background documentation. These checklists form the basis for a synoptic,standardized reporting of pathologic findings. The checklists are available without charge through the CAP website at www.cap.org. Consistent,unambiguous, and complete pathology reporting is a cornerstone of quality breast cancer care. The NCCN Breast Cancer Panel endorses the use of the CAP protocols for reporting the pathologic analysis of all breast cancer specimens.5

Genetic Counseling: For patients considered to be at high risk for hereditary breast cancer as defined by the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast,Ovarian, and Pancreatic,genetic counseling is recommended.

Distress Assessment: Levels of distress may vary in patients and should be addressed individually. Psychological distress can be impacted by body image and other factors. Younger patients have higher rates of psychosocial distress than patients diagnosed at older ages.83-87 The NCCN Breast Cancer Panel recommends assessing for distress in patients newly diagnosed with breast cancer using guidance from NCCN Guidelines for Distress Management.

Fertility and Sexual Health: The general considerations for fertility and sexual health/function outlined for specific populations in NCCN Guidelines for Adolescent and Young Adult(AYA) Oncology and NCCN Guidelines for Survivorship are applicable to all patients diagnosed with breast cancer. The Panel recommends referring to those guidelines for guidance.

Numerous epidemiologic studies have demonstrated that childbearing after treatment for invasive breast cancer does not increase rates of recurrence or death from breast cancer.88 The offspring of pregnancies after treatment for breast cancer do not have an increased rate of birth defects or other serious childhood illness. However, treatment for breast cancer, especially with cytotoxic agents, may impair fertility and fertility may wane during the 5 to 10 years of adjuvant endocrine therapy.

While the potential to regain menstrual function within 2 years of completing chemotherapy is possible, especially for those \<35 years of age, ${}^{89}$ resumption of menses does not correlate with fertility, and conversely, fertility may be preserved without menses. Therefore, all

premenopausal patients should be informed about the potential impact of chemotherapy on fertility and offered the option of fertility preservation if future childbearing is desired.

Considerations for fertility preservation should incorporate patient

preference, tumor stage and biology, age of the patient, risk of premature ovarian failure based on anticipated type and duration of chemotherapy and/or endocrine therapy, as well as the timing and duration allowed for fertility preservation.

Several studies report lower rates of fertility discussion among female

patients with cancer90-92 despite the updated ASCO guidelines stating that patients should not be excluded from consideration for discussion of

fertility preservation for any reason, including parity, prognosis, age, and socioeconomic status.93 The NCCN Panel recommends that all treating

physicians should have a discussion with their patients of childbearing

potential regarding the options for fertility preservation. Patients who

desire to bear children after systemic therapy should be referred to a

fertility specialist prior to initiating systemic (chemotherapy or endocrine) therapy.93-99

Randomized trials have demonstrated that GnRH agonists (such as

goserelin) administered prior to initiating chemotherapy and then

administered concurrently with adjuvant chemotherapy protect against

ovarian failure and reduce the risk of early menopause.100-102 In one trial goserelin improved the probability of pregnancy from 11% to 21% in

patients with HR-negative early-stage breast cancer.103 Smaller historical experiences in patients with HR-positive disease have conflicting results with respect to the protective effects of GnRH agonists in fertility

preservation.

Patients should be informed of all the various modalities available to

minimize gonadal damage and preserve ovarian function and future

fertility. The fertility specialist should discuss specifics of fertility

preservation options including hormonal interventions, ovarian stimulation, embryo or oocyte cryopreservation, and other investigational options, as well as the probability of successful gestation and childbirth.104,105

Combining the various modalities for a specific patient may increase the odds of preservation of future fertility. It is important for fetal safety that

patients actively avoid becoming pregnant during breast cancer treatment.

Additional Diagnostic Workup

The Panel has reiterated that routine systemic imaging is not indicated for patients with early-stage breast cancer in the absence of signs/symptoms of metastatic disease. Recommendations for additional metastatic workup should be performed for those patients with signs or symptoms suspicious for metastatic disease, based on lack of evidence to demonstrate any

benefits with metastatic workup in early-stage disease.106-108 In one study, metastases were identified by bone scan in 5.1%, 5.6%, and 14% of

patients with stage I, II, and III disease, respectively, and no evidence of metastasis was detected by liver ultrasonography or chest radiography in patients with stage I or II disease.106 For patients with stage III breast

cancer, the prevalence of a positive liver ultrasound and positive chest

x-ray was 6% and 7%, respectively.106

CBC, comprehensive metabolic panel, liver function, and alkaline

phosphatase tests should be considered only if the patient is a candidate for preoperative or adjuvant systemic therapy. A bone scan or sodium

fluoride PET/CT is indicated in patients presenting with localized bone

pain or elevated alkaline phosphatase. Bone scan or sodium fluoride

PET/CT may not be needed if FDG-PET/CT is performed and clearly

indicates bone metastasis, on both the PET and CT component.

A diagnostic chest CT is indicated only if pulmonary symptoms (ie, cough or hemoptysis) are present. Likewise, abdominal and pelvic imaging using

diagnostic CT or MRI is indicated if the patient has elevated alkaline

phosphatase, abnormal results on LFTs, abdominal symptoms, or

abnormal physical examination of the abdomen or pelvis.

FDG-PET/CT may be performed at the same time as diagnostic CT, and may be helpful in situations where standard staging studies are equivocal or suspicious. FDG-PET/CT may also be helpful in identifying

unsuspected regional nodal disease and/or distant metastases when used in addition to standard staging studies. The routine use of FDG-PET/CT scanning is not recommended in the staging of clinical stage I, II, or

operable III (T3,N1) breast cancer, due to its high false-negative rate for the detection of lesions that are small (<1 cm) and/or low-grade disease, the high rate of false-positive scans in patients without locally advanced

disease, the low sensitivity for detection of axillary nodal metastases, and the low probability of these patients having detectable metastatic

disease.109-112

Locoregional Treatment of cT1–3, cN0 or cN+, M0 Disease

Surgery

Patients with early-stage operable breast cancer initially undergo upfront definitive surgery (BCS or mastectomy), and adjuvant systemic therapy if indicated, based on primary tumor characteristics, such as tumor size,

grade, lymph node involvement, ER/PR status, expression of HER2

receptor, and tumor genomics. Some patients with early-stage operable HER2-positive or triple-negative disease may be treated with preoperative systemic therapy first, followed by surgery. For NCCN Panel

recommendations and consideration for preoperative systemic therapy,

refer to www.NCCN.org. Radiation is typically sequenced after definitive surgery and after systemic chemotherapy (if delivered).

Several randomized trials document that mastectomy is equivalent to

BCT, which includes BCS with WBRT with respect to OS as primary

treatment for the majority of patients with stage I and stage II breast

cancers (category 1).113-117 The optimal choice of surgery is based on a

shared decision made by the patient and clinician after discussing benefits and risks of mastectomy versus BCT in regards to long-term survival, risk of local recurrence, and the impact on cosmetic outcome and overall QOL.

Breast Conserving Surgery

BCS allows patients to preserve their breast without sacrificing oncologic outcome. BCS is contraindicated for patients who are pregnant and would require radiation during pregnancy; have diffuse suspicious or

malignant-appearing microcalcifications on mammography; have

widespread disease that cannot be incorporated by local excision of a

single region or segment of the breast tissue with a satisfactory cosmetic result; have diffusely positive pathologic margins; or have homozygous

(biallelic) inactivation for ATM mutation (category 2B). Relative

contraindications to lumpectomy include previous RT to the breast or

chest wall; active connective tissue disease involving the skin (especially scleroderma and lupus); persistently positive pathologic margin; or those with a known or suspected genetic predisposition to breast cancer who

may have an increased risk of ipsilateral breast recurrence or contralateral breast cancer with BCT or who may be considered for prophylactic

bilateral mastectomy for risk reduction as per the criteria in the NCCN

Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian,

and Pancreatic or may have known or suspected Li-Fraumeni syndrome

(category 2B).

Several studies of patients with early-stage breast cancer treated with

BCS have identified young age as a significant predictor of an increased likelihood of IBTRs after BCT.118-120 Risk factors, such as a family history of breast cancer or a genetic predisposition for breast cancer (ie, BRCA1/2 or other cancer-predisposing mutation), are more likely to exist in the

population of young patients with breast cancer, thereby confounding the independent contributions of age and treatment to clinical outcome.121

With respect to OS outcomes for young patients with breast cancer, BCT or mastectomy are similar.115,116,122-124 Some studies have shown improved survival125-127 and fewer post-surgical complications128 with BCS.

Mastectomy

Mastectomy is indicated for patients who are not candidates for BCS or

those who choose to undergo this procedure over BCS.

Only limited data are available on the survival impact of risk-reducing

contralateral mastectomy in patients with a unilateral breast cancer.129

Analysis of patients included in the SEER database treated with

mastectomy for a unilateral breast cancer from 1998 to 2003 showed that contralateral risk-reducing mastectomy performed at the time of treatment of a unilateral cancer was associated with a reduction in breast

cancer-specific mortality only in the population of young patients (18–49 years of age) with stage I/II, ER-negative breast cancer (HR, 0.68; 95%

CI, 0.53–0.88; P = .004).130 The 5-year breast cancer survival for this

group was only slightly improved with contralateral risk-reducing

mastectomy versus without (88.5% vs. 83.7%, difference = 4.8%).130

These differences observed in retrospective analysis could be due to

selection bias among patients who chose risk-reducing contralateral

mastectomy.131 A statistical simulation of survival outcomes after riskreducing contralateral mastectomy among patients with stage I or II breast cancer with no BRCA mutation found that the absolute 20-year survival

benefit from risk-reducing contralateral mastectomy was <1% among all age, ER status, and cancer stage groups.132 Data from another

meta-analysis found no absolute reduction in risk of distant metastases

with risk-reducing mastectomy.133 Furthermore, among patients with

unilateral breast cancer who have an increased familial/genetic risk, a

decrease in metastatic contralateral breast cancer incidence was

observed in those who received risk-reducing contralateral mastectomy,

although no improvement was seen in OS of these patients.133

The Panel recommends that patients with breast cancer who are ≤35

years or premenopausal and carriers of a known BRCA1/2 mutation

consider additional risk reduction strategies following appropriate risk

assessment and counseling (see NCCN Guidelines for Breast Cancer

Risk Reduction and NCCN Guidelines for Genetic/Familial High-Risk

Assessment: Breast, Ovarian, and Pancreatic). This process should

involve multidisciplinary consultations prior to surgery, and should include a discussion of the risks associated with development of a contralateral

breast cancer as compared with the risks associated with recurrent

disease from the primary cancer. Except as specifically outlined in the

NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast,

Ovarian, and Pancreatic, risk reduction mastectomy of the contralateral

breast to a known unilateral breast cancer treated with mastectomy or

BCT is discouraged by the Panel.

The NCCN Panel recommends referring to the NCCN Guidelines for Older Adult Oncology for special considerations for this population.

Margin Assessment: After surgical resection, a careful histologic

assessment of resection margins is essential. The NCCN Panel notes that benefit of BCS is predicated on achieving pathologically negative margins after resection. The NCCN Panel accepts the most recent definition

outlined in the guidelines established by the SSO/ASTRO as the standard for negative surgical margins for invasive cancer.134

For patients with stage I or II invasive cancers after BCS, a positive margin is defined as “ink on tumor” (any invasive cancer or DCIS cells on ink).

Patients with positive margins generally require further surgery—either a re-excision to achieve a negative margin or a mastectomy. If re-excision is technically feasible to achieve “no ink on tumor,” this can be done with

resection of the involved margin guided by the orientation of the initial

resection specimen or re-excision of the entire original excision cavity.

There may be select patients with stage III invasive cancers who may be eligible for BCS. For these patients, the margin status would be assessed with similar definitions. If margins remain positive after further surgical

re-excision(s), then mastectomy may be required for optimal local disease control.

In order to adequately assess margins following surgery, the Panel

recommends that the surgical specimens be directionally oriented and that the pathologist provide descriptions of the gross and microscopic margin status and the distance, orientation, and type of tumor (invasive cancer or pure DCIS) in relation to the closest margin. Marking the tumor bed with

clips facilitates accurate planning of the radiation boost field, where

appropriate.

For invasive breast cancers that have a component of DCIS, the negative margin definition of “no ink on tumor” should be utilized based on the

SSO/ASTRO Consensus Guideline on Margins unless it is DCIS-M, which behaves more like pure DCIS and 2-mm margins are recommended. In

this setting, “no ink on tumor” is recommended for either DCIS or invasive cancer cells, primarily because the natural history, treatment, and

outcomes of these lesions are more similar to invasive cancer than DCIS. For specifically challenging cases, clinical judgment and discussion with

the patient should precede routine re-excision.

The same margin recommendations cannot be applied directly to patients undergoing APBI, where data regarding local recurrence are more limited than WBRT. Individualized clinical judgment should be utilized on a caseby-case basis, using postoperative mammography to identify residual

calcifications and clinical-pathologic factors such as quantitative extent of disease near margin, presence of extensive intraductal component (EIC), young age, or multiple close margins to assist in identifying patients who

may have an increased risk of ipsilateral recurrence and therefore may

benefit from re-excision.

Surgical Axillary Staging

Axillary status is important for planning systemic adjuvant treatment and

RT. The lymphatic pathways from the breast go to the ALNs, internal

mammary, infraclavicular, and/or supraclavicular lymph nodes.

Traditional level I and level II ALNDs require that at least 10 lymph nodes be provided for pathologic evaluation to accurately stage the axilla.135,136

ALND should be extended to include level III nodes only if gross disease is apparent in the level II and I nodes. In the absence of gross disease in

level II nodes, lymph node dissection should include tissue inferior to the axillary vein from the latissimus dorsi muscle laterally to the medial border of the pectoralis minor muscle (levels I and II).

Historically, ALND has been the standard of care for axillary staging.137

However, ALND is associated with lymphedema and other significant

morbidities.138-140 This has been largely replaced with SLNB.

SLN mapping injections may be peritumoral, subareolar, or subdermal.

SLNs can be assessed for the presence of metastases by both

hematoxylin and eosin (H&E) staining and cytokeratin

immunohistochemistry (IHC). The clinical significance of a lymph node that is negative by H&E staining but positive by cytokeratin IHC is not clear.

Because the historical and clinical trial data on which treatment decisions are based have relied on H&E staining, the Panel does not recommend

routine cytokeratin IHC to define node involvement and believes that

current treatment decisions should be made based solely on H&E staining. This recommendation is further supported by a randomized clinical trial

(ACOSOG Z0010) for patients with H&E negative nodes where further

examination by cytokeratin IHC was not associated with improved OS over

NCCN Guidelines Version 5.2025 Breast Cancer

MS-16

Abstract

a median of 6.3 years. 141 In the uncommon situation in which H & E staining is equivocal, reliance on the results of cytokeratin IHC is appropriate.

Two randomized trials compared SLNB alone versus ALND. The Milan trial (1998-1999) randomized 516 patients treated with BCS with tumors ≤2 cm to two arms, one receiving immediate axillary dissection and the other receiving the dissection only if the sentinel node was involved. 142 fter 79 months of follow-up, there was no difference in OS and DFS. 143 other similar study, NSABP B-32, conducted between 1999 and 2004, randomized 5611 patients with invasive breast cancer ≤2 cm to either ALND or SLNB alone with ALND performed only if the SLN was positive. 144 After 95.6 months of follow-up, OS and DFS were similar in the two groups. Results of a subgroup analysis of this study showed patients with ALND had significantly higher arm morbidity and significantly more restricted work and social activity and impaired QOL. 145, 146 e ALMANAC trial studied the QOL in patients (n= 1031) with SLNB versus ALND. 147 After 12 months, lymphedema and sensory loss were higher in the ALND group. Operative time, drainage use, hospitalization, and resumption of normal life were much longer in ALND compared to the SLNB group. The SNAC trial 148 and the DBCCG trial 149 also showed less morbidity with SLNB compared with ALND.

Based on the results of the above studies, it was clarified that for negative sentinel nodes, ALND is not needed.

The ACOSOG Z0011 trial addressed the role of ALND in those with a clinically negative axilla but pathologically positive lymph nodes from an SLNB. This trial randomized patients ≥18 years of age with clinical T1/T2 tumors, fewer than 3 positive SLNs, undergoing BCS and WBRT, to SLNB alone (n = 436) or to a completion ALND (n = 420). In this study, there was no difference in local recurrence, DFS, or OS between patients with positive SLN undergoing a completion ALND versus no ALND. Only ER-negative status, age < 50 years, and lack of adjuvant systemic therapy were associated with decreased OS. 150 At a median follow-up of 6.3 years, locoregional recurrences were noted in 4.1% of patients in the ALND group and 2.8% of patients in the SLNB group (P = .11). Median OS was approximately 92% in each group. 151 Long-term follow-up (median 9.25 years) results of the ACOSOG Z0011 study showed no statistically significant difference in local recurrence-free survival (RFS) between trial arms (P = .13). 152 The cumulative incidence of ipsilateral axillary recurrences at 10 years was 0.5% (2 patients) in those who underwent ALND and 1.5% (5 patients) in those who underwent SLNB alone (P = .28). 152 The 10-year cumulative incidence of locoregional recurrences was 6.2% with ALND and 5.3% with SLNB alone (P = .36). 152 e results of the ACOSOG Z0011 trial demonstrate that there is no benefit to ALND in patients with early-stage breast cancer who have only one or two SLN metastases (minimal nodal burden) on SLNB after receiving WBRT as part of BCT. Mastectomy patients were not enrolled in the ACOSOG Z0011 trial since these patients do not routinely receive radiation.

Another randomized trial (IBCSG 23-01) was specifically designed to compare outcomes in patients with sentinel micrometastases (≤2 mm) treated with ALND versus no ALND. 153 While the ACOSOG Z0011 trial was limited to those undergoing BCT, this trial included patients undergoing mastectomy (9%). 153 Between the group treated with SLNB plus ALND versus the group that had SLNB alone, there were no differences in 5-year DFS (84.4%; 95% CI, 80.7%-88.1% vs. 87.8%; 95% CI, 84.4%-91.2%); cumulative incidence of breast cancer events, including local, regional, contralateral breast, and distant recurrence (10.8%; 95% CI, 7.6-14.0 vs. 10.6%; 95% CI, 7.5-13.8); or OS (97.6%; 95% CI, 96.0%-99.2% vs. 97.5%; 95% CI, 95.8%-99.1%). 153 Regional NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/10/28,21:39在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。

References

Abstract

recurrence was < 1% for those who underwent ALND and 1% for those who did not undergo ALND. 153 The results of this trial show that in patients with micrometastases on SLNB, ALND is not needed.

The results of a trial by the European EORTC group (AMAROS) assessed whether axillary RT provides regional control with fewer side effects compared with ALND. 154 This trial included patients (n = 4823) with T1 or T2 breast cancer with positive SLNs randomized to an ALND or axillary RT. One thousand four hundred twenty-five patients had positive SLNs (micrometastatic or macrometastatic), which included a small fraction of patients (n = 248) treated with mastectomy (17%). 154 The results reported no difference in 5-year OS or DFS for patients randomized to ALND versus axillary radiation. 154 The 5-year DFS was 86.9% (95% CI, 84.1-89.3) in the ALND group and 82.7% (79.3-85.5) in the axillary RT group. The 5-year OS was 93.3% (95% CI, 91.0-95.0) in the ALND group and 92.5% (90.0-94.4) in the axillary RT group. 154 At the end of 5 years, lymphedema was less frequent in the group treated with axillary RT versus ALND (11% vs. 23%). 154 The 10-year follow-up results presented at the 2021 SABCS showed no significant differences between the two arms with respect to OS (with ALND, OS was 84.6% vs. 81.4% with axillary RT), distant metastasis-free survival (with ALND was 81.7% vs. 78.2% with axillary RT), or locoregional recurrence rate (3.59% with ALND vs. 4.07% with axillary RT). The axillary recurrence with axillary RT was 1.8% versus 0.93% with ALND. 155 e OTOASAR trial was designed similarly to the AMAROS trial; patients (n = 2100) with tumors ≤3.0 cm who were clinically node negative were randomized to receive either ALND or axillary RT if they had 1 to 2 positive SLNs. 156 The results showed no difference in axillary recurrence with ALND compared with SLNB plus RT to the axilla. 156

In the setting of preoperative chemotherapy, the question that is being explored is whether ALND may be omitted in patients with complete pathologic response after preoperative therapy.

Several prospective studies have evaluated patients with positive lymph nodes before preoperative systemic therapy who had clinical complete response to preoperative therapy and underwent SLNB and ALND. The results of these studies have shown that in those with node-positive disease prior to preoperative systemic therapy, SLNB has a > 10% falsenegative rate when performed after preoperative systemic therapy. In the SENTINA study, 157 the overall false-negative rate was 14.2%. In the ACOSOG-Z1071 trial, 158 the false-negative rate was 12.6% and in the SN FNAC trial, 159 the false-negative rate was 13.3%.

Subgroup analyses from studies have shown that 1) using dual-agent lymphatic mapping (radiotracer and blue dye); 2) identifying three or more SLNs; and 3) marking the metastatic lymph node with a clip before neoadjuvant therapy and then resecting it at the time of surgery reduces false-negative rates to < 10%.

A subgroup analysis of the ACOSOG Z1071 trial showed lower falsenegative rates in patients who had a clip placed in the positive lymph nodes at the time of initial biopsy followed by removal of the clipped node during SLN surgery after preoperative systemic therapy. 160 A another study of selective localization and removal of clipped nodes with SLNB, known as targeted axillary dissection (TAD), showed false-negative rates reduced to approximately 2% compared with 4% with removal of the clipped lymph node alone. 161 veral ongoing clinical trials are examining further de-escalation of axillary surgery in those who have positive nodes after preoperative systemic treatment. The Alliance A011202/MAC19 trial (NCT01901094) is randomly assigning patients who have sentinel node-positive disease NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/10/28,21:39在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。

References

after neoadjuvant chemotherapy to ALND versus no further axillary

surgery. Both arms will receive regional nodal radiation. The SLNB alone arm will include axillary RT to the undissected axilla (levels I–III), whereas the ALND arm will not include RT to levels I or II axillae.

NCCN Recommendations for Surgical Axillary Staging: If ALNs are

clinically negative (no palpable nodes) at the time of diagnosis, ≤2

suspicious lymph nodes are found on imaging, or ≤2 positive lymph nodes are confirmed by needle biopsy, the Panel recommends SLN mapping.

If SLN is negative, no further surgery is needed in these patients. If SLN is positive, based on the ACOSOG Z 0011 data, no further surgery is

recommended only if all of the following criteria are met: the patients have cT1–2, N0 tumors, have not received preoperative systemic therapy, only have 1 or 2 positive SLNs, and will undergo BCT (BCS + WBRT). If any of the above criteria are not met, the Panel recommends level I and II axillary dissection.

Based on the AMAROS and OTASAR trial data, no further surgery is

recommended only if all of the following criteria are met: the patients have cT1–2, N0 tumors, have not received preoperative systemic therapy, have 1 to 2 positive SLNs, and will undergo lumpectomy or mastectomy along with adjuvant RT with intentional inclusion of undissected axilla at risk. If any of the above criteria are not met, the Panel recommends level I and II axillary dissection. In select patients undergoing mastectomy with clinically negative axillae but 1 to 2 positive SLNs, the Panel notes that axillary

radiation may replace ALND for regional control of disease. Based on the results of the IBCSG 23-01 trial, the NCCN Panel recommends no ALND for patients with positive SLNs when that disease is limited to only

micrometastatic. According to the American Joint Committee on Cancer

(AJCC) staging, micrometastatic nodal involvement is defined as a

metastatic deposit or >0.2 mm but ≤2.0 mm.162

In patients with clinically suspicious (palpable) lymph nodes or 3 or more suspicious lymph nodes on imaging, or if preoperative systemic therapy is being considered for patients with suspicious lymph nodes at diagnosis on examination or imaging, the Panel recommends pathologic confirmation of malignancy using ultrasound-guided fine-needle aspiration (FNA)163 or

core biopsy of suspicious nodes with clip placement.

According to the NCCN Panel, the recommendation for ALND of level I

and II nodes is limited to patients with biopsy-proven axillary metastases (in those who did not receive preoperative systemic therapy) or who have residual disease after preoperative chemotherapy. Highly selected

patients with biopsy-proven axillary metastases, who then converted to

clinically node negative after preoperative systemic therapy, may undergo SLNB with removal of the clipped lymph node. This is a currently a

category 2B recommendation as the rate of false negatives is high when SLN is performed after preoperative systemic therapy.

According to the NCCN Panel, based on available data, the false-negative rate can be reduced by marking biopsied lymph nodes to document their removal, using dual tracer, and by removing 3 or more sentinel nodes

(targeted ALND). When sentinel nodes are not successfully identified, the Panel recommends level I and II axillary dissection be performed for

axillary staging.

Radiation Therapy

Principles of Radiation Therapy

It is important to individualize RT planning and delivery. CT-based

treatment planning is encouraged to delineate target volumes and

adjacent organs at risk. Greater target dose homogeneity and sparing of normal tissues can be accomplished using compensators such as

wedges, forward planning using segments, and intensity-modulated RT (IMRT). Respiratory control techniques including deep inspiration

breath-hold and prone positioning may be used to try to further reduce

dose to adjacent normal tissues, particularly the heart and lung.164

Verification of treatment setup consistency is done with weekly imaging. When using certain techniques (ie, prone breast), more frequent imaging may be appropriate. Standard utilization of daily imaging is not

recommended. Radiation to the breast/chest wall and nodal regions is

generally delivered with single-energy or mixed-energy photons with or without electrons. Dose-volume histograms (DVHs) should be used to

evaluate dose constraints, evaluate dose to normal tissues (ie, heart,

lung), and ensure adequate coverage to the intended planning target

volumes (PTVs), including the breast/chest wall, supraclavicular fossa, axillary levels I–III, and internal mammary nodes.

Whole Breast Radiation Therapy

WBRT reduces the risk of local recurrence and has shown to have a

beneficial effect on survival.114,117 Randomized trials have demonstrated decreased in-breast recurrences with an additional boost dose of radiation (by photons, brachytherapy, or electron beam) to the tumor bed.165,166 For greater homogeneity of target dose and to spare normal tissues using

compensators such as tissue wedges, forward planning using segments and IMRT may be used.167,168

Four randomized clinical trials have investigated hypofractionated WBRT schedules (39–42.9 Gy in single fractions of 2.6–3.3 Gy) compared to

standard 50 Gy in single fractions of 2 Gy.169-172 The 10-year follow-up

data from the START trials173 are consistent with the 10-year results of the Canadian trial,172 which reported that local tumor control and breast

cosmesis were similar with a regimen of 42.5 Gy in 16 fractions over 3.2 weeks compared with the standard dose of 50 Gy in 25 fractions over 5

weeks.172 The START trials reported radiation-related effects to normal

breast tissue such as breast shrinkage, telangiectasia, and breast edema as less common with the hypofractionated regimen.173

Another randomized trial showed similar outcomes among patients

receiving a hypofractionated schedule (40 Gy in 15 fractions) compared

with standard fractionation (50 Gy in 25 fractions) in patients (n = 1854)

with node-negative breast cancer (n = 1608) or DCIS (n = 246).174 The 9-year risk of locoregional recurrence was 3.3% in the 50-Gy group and

3.0% in the 40-Gy group. The 9-year OS was 93.4% in the 50-Gy group

and 93.4% in the 40-Gy group. Radiation-associated cardiac and lung

disease were comparable between the groups.

Other shorter schedules of delivering WBRT have also been studied with similar results. The FAST trial compared patients >50 years of age with

low-risk invasive breast carcinoma (pT1–2, pN0) randomly assigned to the standard schedule of 50 Gy in 25 fractions over 5 weeks or 30 Gy or 28.5 Gy in 5 fractions once weekly. After 10-year follow-up, there were no

significant differences reported in normal tissue effects for the standard 50 Gy in 25 fractions schedule versus a once-weekly schedule for 5 weeks

totaling 28.5 Gy, but normal tissue effects were higher with a weekly

schedule for 5 weeks totaling 30 Gy.175

The FAST Forward trial randomized patients with non-metastatic breast

cancer (n = 4096) after BCS or mastectomy to one of the following: 40 Gy in 15 fractions over 3 weeks; 27 Gy in 5 fractions over 1 week; or 26 Gy in 5 fractions over 1 week to either whole beast or chest wall.176 The 5-year incidence of ipsilateral breast tumor relapse was 2.1% with the standard 40 Gy in 15 fractions over 3 weeks versus 1.7% with 27 Gy in 5 fractions over 1 week (5.4 Gy per fraction; HR, 0.86; 95% CI, 0.51–1.44) and 1.4% with 26 Gy in 5 fractions over 1 week (5.2 Gy per fraction; HR, 0.67; 95% CI, 0.38–1.16).176 The moderate or marked tissue effects in the breast or chest wall were 15% with 27 Gy, 12% with 26 Gy, and 10% with 40 Gy,

but differences between the 40 Gy and 26 Gy groups were not statistically different.176

RT Boost to Tumor Bed: In patients with higher risk characteristics (such as age <50 years, high-grade disease, or patients with focally positive

margins) an RT boost has been shown to reduce local

relapse.30,32,166,173,177-179 RT boost treatment in the setting of breast

conservation can be delivered using enface electrons, photons, or

brachytherapy.180

NCCN Recommendations for WBRT: The Panel has defined the target as breast tissue at risk. The NCCN Panel recommends a dose of 40 to 42.5 Gy in 15 to 16 fractions for all patients getting whole breast radiation

without regional nodal radiation, based on its equivalence in efficacy and toxicity demonstrated in the moderately hypofractionated trials.173 While these abbreviated courses of RT of 40 to 42.5 Gy in 15 to 16 fractions are the NCCN Panel’s preferred fractionation schema for whole breast

radiation, the conventionally fractionated regimen of 46 to 50 Gy in 23 to 25 fractions may be utilized in selected patients. The RT boost doses

intended to decrease rate of local recurrence are 10 to 16 Gy in 4 to 8

fractions.

Ultra-hypofractionated WBRT of 28.5 Gy delivered as 5 (once weekly)

fractions may be considered in select patients with pTis/T1/T2/N0 aged

>50 years after BCS, though the optimal fractionation for the boost

delivery is unknown for this regimen. Alternatively, 26 Gy in 5 daily

fractions over one week may be considered, though data beyond 5 years for local relapse or toxicity are not yet available for this regimen and

should be discussed with patients prior to its use. The Panel also notes

that when using ultra-hypofractionated dosing, it is essential to utilize 3D planning to minimize inhomogeneity and exposure to heart and lung.

Chest Wall Radiation

The target includes the ipsilateral chest wall, mastectomy scar, and drain sites when indicated. Depending on whether the patient has had breast

reconstruction, several techniques using photons and/or electrons are

appropriate. Chest wall scar boost may be delivered with or without bolus using electrons or photons.

NCCN Recommendations for Chest Wall Radiation: The NCCN Panel

recommends a dose of 45 to 50.4 Gy in 25 to 28 fractions to the chest

wall. A boost at the scar of 1.8 to 2 Gy per fraction to a total dose of

approximately 60 to 66 Gy may be considered in some cases based on

risk. Special consideration should be given to the use of bolus material to ensure that the skin dose is adequate, particularly in the case of IBC.

Regional Nodal Irradiation

Two studies, MA.20 and EORTC 22922/10925, evaluated the addition of regional nodal irradiation (RNI) to the internal mammary nodes and the

upper axillary nodes including the supraclavicular region, in addition to

WBRT or chest wall irradiation after BCS or mastectomy, respectively. In MA.20, regional recurrences were reduced from 2.7% with breast

irradiation only to 0.7% with the addition of nodal irradiation.181 The distant recurrences were reduced from 17.3% to 13.4%.181 An improvement in

DFS was seen from 77% to 82% at 10 years in those who received RNI

compared to those who did not.181 In EORTC 22922/10925, regional RT reduced the incidence of regional recurrences from 4.2% to 2.7% and

decreased the rate of distant metastases from 19.6% to 15.9% at a

median follow-up of 10.9 years.182 Results of 15.7 years follow-up showed that breast cancer mortality (19.8% vs. 16%; 95% CI, 0.70–0.94) and

breast cancer recurrence (27.1% vs. 24.5%; 95% CI, 0.77%–0.98%) were reduced with internal mammary and medial supraclavicular RT.183

The independent contribution of internal mammary nodal RT as a

component of RNI continues to be debated as it is associated with higher risk of cardiac and lung toxicity, and data regarding its benefits are

conflicting (discussed in detail below).

NCCN Recommendation for RNI: When considering RNI, anatomic

variations across patients result in significant differences in prescription

depth and field design. The NCCN Panel therefore

recommends contouring the individual nodal basins that are at risk using one of the various breast atlases, to ensure adequate RT coverage. 184,185

The recommended dose for RNI is 45 to 50.4 Gy in 25 to 28 fractions to

the regional nodal fields. A supplemental RT boost can be delivered to

grossly involved or enlarged lymph nodes (ie, internal mammary or

clavicular) that have not been surgically addressed.

Accelerated Partial Breast Irradiation

Several large, randomized trials have been published using various forms of APBI rather than WBRT after BCS. Most of these studies have found

that rates of local control in selected patients, with early-stage breast

cancer and low risk of recurrence, are equal to those treated with

WBRT.44,46,186-188 In the NSABP B-39 trial, 10-year cumulative incidence of IBTR with APBI was 4.6% compared with 3.9% with WBRT, yielding an

absolute difference of 0.7% with an HR of 1.22 (90% CI, 0.94–1.58) that

did not meet the prespecified criteria for equivalence.43 However, given the small magnitude in IBTR differences between WBRT and APBI, it is not

likely to be of clinical significance in appropriately selected patients.

QOL, toxicity, and cosmetic outcomes have generally been comparable or slightly favored APBI in randomized trials. For example, the IMPORT-LOW study compared WBRT with partial breast irradiation delivered as 40 Gy in 15 once-daily fractions using reduced-size breast tangents and found less breast firmness, less change in breast appearance, and lower average

number of adverse events per person with partial breast irradiation.186,189 The University of Florence compared WBRT with intensity-modulated

APBI (30 Gy in 5 fractions, delivered every other day), and 10-year results have shown that APBI produced less acute and late toxicity and better

cosmetic outcomes.187 However, the RAPID trial found significantly higher

rates of fair/poor cosmetic outcome with 3D conformal APBI delivered as

38.5 Gy in 10 twice-daily fractions.44,190 The majority of APBI patients on NSABP B-39 were treated with the same external beam regimen, and

treatment-related toxicities were not different for APBI versus WBRT as

currently reported.43 Cosmetic outcome analysis, however, is pending.

NCCN Recommendation for APBI: The Panel accepts the updated

ASTRO APBI consensus statement for guidance on APBI use.191 The

NCCN Panel recommends APBI for any BRCA-negative patient who

meets the ASTRO 2016 “suitable” criteria defined as age >50 years, ERpositive invasive ductal carcinoma measuring ≤2 cm (pT1 disease) with

negative margin widths of ≥2 mm, and no lymphovascular invasion (LVI), and also permits APBI in patients >50 years of age with screen-detected low- or intermediate-grade DCIS measuring ≤2.5 cm, resected with ≥3 mm margins. The Panel prefers the APBI regimen and method followed in the trial by University of Florence (30 Gy/5 fractions every other day delivered using IMRT).187 The Panel encourages participation in clinical trials for

patients who do not meet the above criteria.

Adjuvant Radiation Therapy After BCS

Those who have a positive lymph node have a high risk of recurrence. Therefore, after BCS WBRT is strongly recommended with or without

boost to tumor bed for node-positive disease (category 1 for those with positive nodes; category 2A for those with negative axillary nodes). This recommendation is supported by the results of a meta-analysis by the EBCTCG showing reduction in 10-year risk of recurrence in those who received WBRT versus those who did not (19% vs. 35%; RR, 0.52; 95% CI 0.48–0.56).117 In addition, a significant reduction in 15-year risk of

breast cancer death (21% vs. 25%; RR, 0.82; 95% CI, 0.75–0.90) was also observed.117

For patients with a pathologically confirmed, focally positive margin without EIC, who do not undergo re-excision after BCS, the use of a higher

radiation boost dose to the tumor bed may be considered, since generally a boost to the tumor bed is recommended for patients at higher risk of

recurrence.

Regional Nodal Irradiation After BCS

The reduction in the risk of locoregional and distant recurrence and

improvement in DFS seen in the MA.20 and EORTC 22922/10925

trials,181,182 and the reduction in breast cancer mortality with 15-year followup of the EORTC 22922 patients,183 support the importance of RNI after

BCS.

As mentioned previously, routine inclusion of the internal mammary nodes as a component of RNI remains somewhat controversial due to the

associated cardiac and lung toxicities. A Korean trial KROG 08-06 studied independent effect on DFS of RT to internal mammary nodes after BCS or mastectomy for node-positive disease,192 randomizing patients to RNI with internal mammary RT versus RNI without internal mammary RT. Radiation to the internal mammary nodes did not significantly improve the DFS in

patients with node-positive breast cancer. However, there was a

statistically significant benefit in outcomes with internal mammary nodal

RT for patients with medially or centrally located tumors.192 Conflicting

data have arisen from the Danish Breast Cancer Cooperative Group that recently reported 15-year follow-up of their study on RT to internal

mammary nodes in patients (n = 3089) with positive nodes and earlystage breast cancer.193 In this study, RT to the internal mammary nodes

was delivered to right-sided patients (n = 1,491), while no RT to internal

mammary nodes was delivered to left-sided patients (n = 1,598). The

study reported a 15-year improved OS rate of 60.1% with RT to internal

mammary nodes compared to 55.4% with no RT to internal mammary

nodes. Improvements were also seen with respect to risk of developing

distant recurrence and breast cancer-specific mortality favoring RT to

internal mammary nodes.193

Clinical judgment is needed when determining inclusion of the internal

mammary nodes during RNI. Therefore, the NCCN Panel no longer

specifies the fields that should be included for RNI and refers to it as

comprehensive RNI. According to the Panel, patient selection should

consider risks versus benefits including long-term organ (cardiac and lung) toxicities, comorbidities of the patient, age, and life expectancy. In

including RT to the internal mammary nodes, meticulous treatment

planning with normal tissue dose constraints is mandatory.

RNI After BCS for Node-Negative Disease: The NCCN Panel

recommends consideration of comprehensive RNI in patients with

central/medial tumors (in accordance with EORTC 22922 trial criteria) and in accordance with the MA.20 criteria: 3 tumors, as well as those with T2 tumors who have undergone limited axillary dissection (<10 lymph nodes) and also have other risk factors, including high-grade histology, ERnegative disease, or LVI.181

RNI After BCS for Node-Positive Disease: For those with 1 to 3 positive

nodes, if a patient meets all of the following criteria—has cT1–T2, cN0; did not receive preoperative chemotherapy; and has 1 to 2 positive SLNs—the use of comprehensive RNI with or without the intentional inclusion of the

axilla is at the discretion of the radiation oncologist. If the patients do not

meet all the criteria listed, the NCCN Panel recommends WBRT with

inclusion of any portion of the undissected axilla at risk (category 1) with

strong consideration of comprehensive RNI.

For those with 4 or more positive nodes, the NCCN Panel recommends

comprehensive RNI with inclusion of any portion of the undissected axilla at risk (category 1).

Radiation Therapy After BCS in Older Adults with ER-Positive Tumors

WBRT as a component of BCT does not affect breast cancer-specific

survival in selected patients >70 years of age with more indolent disease. In a study of patients with clinical stage I, ER-positive breast cancer who were ≥70 years of age at diagnosis, patients were randomized to receive BCS with WBRT or BCS alone, both with tamoxifen for 5 years.

Locoregional recurrence rates were 1% in the BCS, radiation, and

tamoxifen arm and 4% in the BCS plus tamoxifen arm. There were no

differences in OS, DFS, or need for mastectomy.194 These results were

confirmed in an updated analysis of this study with a median follow-up of

12.6 years.195 At 10 years, a statistically significant reduction in IBTR was seen with RT with 90% of patients in the BCS and tamoxifen arm

compared with 98% in the BCS plus radiation and tamoxifen arm.195

Concordant results have been demonstrated in other studies of similar

design.196,197 Whether the increase in local relapse without RT is relevant for an individual patient should be individualized after a discussion of the risks and benefits of RT and patient commitment to 5 years of endocrine therapy if RT omission is being considered.

The NCCN Guidelines allow for the use of BCS (pathologically negative

margin required) with 5 years of tamoxifen or an AI, without breast

irradiation, for patients >70 years with clinically negative lymph nodes and ER-positive, T1 breast cancers (category 1).

Adjuvant Radiation Therapy After Mastectomy

Post-Mastectomy RT for Node-Positive Disease

Randomized clinical trials have shown that a DFS and OS advantage is

conferred by the irradiation of chest wall and regional lymph nodes in

patients with positive ALNs after mastectomy and ALND.198-202 In these

trials, the ipsilateral chest wall and the ipsilateral locoregional lymph nodes were irradiated. The results of EBCTCG meta-analyses show that RT after mastectomy and axillary node dissection reduced both recurrence and

breast cancer mortality in the patients with 1 to 3 positive lymph nodes

even when systemic therapy was administered.182,203 According to the

NCCN Panel, post-mastectomy radiation to the chest wall is

recommended in all of these patients (category 1). Data from the EORTC 22922/10925 trial support the inclusion of RNI in patients undergoing postmastectomy radiation. The trial assessed the independent effects of

including RNI versus no RNI when treating the chest wall after

mastectomy. Based on the benefits demonstrated in this trial, the NCCN Panel recommends comprehensive RNI to include any undissected axilla at risk (category 1 for 1 or more positive nodes).

Post-Mastectomy RT for Node-Negative Disease:

In patients with negative nodes, tumor ≤5 cm, and clear margins (≥1 mm), post-mastectomy RT (PMRT) is typically not recommended. However, the Panel has noted that it may be considered in subsets of these patients

with high-risk features. Based on the inclusion criteria of node-negative

patients enrolled onto the RNI trials (MA-20 and EORTC 22922), any

patients with the following high-risk features, including central/medial

tumors, T3 tumors, or tumors ≥2 cm with <10 axillary nodes removed and at least one of the following: grade 3, ER-negative, or LVI, should be

considered for PMRT with RNI to include any undissected axilla at risk.

Features in node-negative tumors that predict a high rate of local

recurrence include primary tumors >5 cm or positive pathologic

margins.204

In patients with positive pathologic margin, if re-resection to negative

margins is not possible, the Panel recommends strongly considering chest wall irradiation with the addition of comprehensive RNI including any

portion of the axilla at risk. Chest wall irradiation should be considered with addition of comprehensive RNI, including any portion of the axilla at risk in those with tumors >5 cm. In patients with tumors ≤5 cm and negative

margins ≤1 mm, chest wall irradiation should be considered with

consideration of comprehensive RNI including any portion of the

undissected axilla at risk only in those with high-risk features.

Considerations for RT in Patients Receiving Preoperative Systemic

Therapy

The Panel recommends that decisions related to administration of

adjuvant RT for patients receiving preoperative systemic chemotherapy

should be made based on maximal stage (ie, clinical/anatomic stage,

tumor characteristics) at diagnosis (before preoperative systemic therapy) and pathologic stage at definitive surgery (after preoperative systemic

therapy). Data from numerous studies in patients with stage III disease

suggest that postoperative RT improves local control even for patients

who have a pathologic complete response (pCR) to neoadjuvant

chemotherapy.205-208

RT After Preoperative Therapy and BCS:

Those who have clinically negative nodes at diagnosis, that remain

pathologically node-negative at definitive surgery (after systemic therapy), should receive adjuvant RT to the whole breast with the addition of boost to the tumor bed after SLNB.

Patients who have clinically/radiographically positive nodes at diagnosis

and convert to clinically/radiographically node-negative after preoperative chemotherapy are candidates for the NSABP B-51 trial assessing the

benefit of RNI. Until the results of this trial become available, the existing data suggest that node-positive disease at presentation is at high risk for locoregional recurrence and should be considered to receive

comprehensive RNI with inclusion of any portion of the undissected axilla at risk.

Patients who have clinically/radiographically positive nodes at diagnosis

who convert to clinically/radiographically negative nodes after preoperative chemotherapy, but are found to have persistent nodal disease on SLNB,

are candidates for the ALLIANCE 11202 trial assessing whether ALND

can be safely replaced with axillary RT. ALND is the standard arm of this trial; however, in the event that a neoadjuvant therapy patient with nodepositive disease (ypN1+) does not undergo a complete axillary dissection, all levels of the undissected axilla should be included with the radiation

treatment.

RT After Preoperative Therapy and Mastectomy:

Those who have clinically positive nodes at diagnosis that respond to

preoperative systemic therapy and become node-negative should be

strongly considered to receive RT to the chest wall and comprehensive

RNI with inclusion of any portion of the undissected axilla at risk based on the discussion above.

For those with positive nodes (ypN1+) after preoperative systemic therapy, axillary dissection is the standard treatment arm of the ongoing Alliance

11202 trial; however, if RT is indicated it should include chest wall along

with comprehensive RNI with inclusion of any portion of the undissected

axilla at risk.

Those who have node-negative disease at diagnosis and after

preoperative systemic therapy and whose axilla was assessed by SLNB or axillary node dissection may forego RT.

Two prospective trials are ongoing and will prospectively evaluate the

benefit of RT in patients treated with neoadjuvant therapy (NSABP B51/RTOG 1304 [NCT01872975] and the Alliance A011202/MAC19 trial

[NCT01901094]).

Sequencing of RT and Systemic Therapy

If chemotherapy and radiation are indicated after surgery, adjuvant

radiation is typically delivered after the completion of chemotherapy.209,210

This recommendation is based on results of the “Upfront-Outback” trial in which patients who had undergone BCS and axillary dissection were

randomly assigned to receive chemotherapy following RT or RT following chemotherapy. The initial results showed an increased rate of local

recurrence in the group with delayed RT at a median follow-up of 58

months;210 however, differences in rates of distant or local recurrence were not statistically significant when the two arms were compared at

135-month follow-up.209 While it is common for RT to follow chemotherapy when chemotherapy is indicated, based on data from prospective and

retrospective studies, CMF (cyclophosphamide/methotrexate/fluorouracil)and RT may be given concurrently.

Data from multiple studies of patients treated with endocrine therapy either before, during, or after RT suggest no difference in outcomes or

toxicity.211-214 Therefore, according to the NCCN Panel, sequential or

concurrent endocrine therapy with RT is acceptable. However, due to

compounding side effects, initiating endocrine therapy at the completion of RT may be preferred.

When adjuvant capecitabine215 is indicated, since it is a known

radiosensitizing agent with potential to increase toxicity to normal tissue, it should be given after completion of adjuvant RT.

When adjuvant olaparib is used, the Panel recommends that olaparib be given after completion of RT. In the OlympiA trial,216 olaparib was not

administered concurrently with RT and there are limited data on safety of concurrent administration.

Adjuvant HER2-targeted therapy may be delivered concurrently with RT. Data from clinical trials in the adjuvant setting do not suggest an increased complication rate with the concurrent administration of HER2-targeted

therapies with adjuvant RT.217

Breast Reconstruction

Breast reconstruction may be an option for anyone receiving surgical

treatment for breast cancer. Therefore, all patients undergoing breast

cancer treatment should be educated about breast reconstructive options as adapted to their individual clinical situation and be offered an

opportunity to consult with a reconstructive plastic surgeon. Breast

reconstruction should not interfere with the appropriate surgical

management. This may increase the risk of overall and cancer-related

death, especially in those with late-stage disease.218 Coordinating

consultation and surgical treatment with a reconstructive surgeon should be executed within a reasonable timeframe.

Several reconstructive approaches are summarized for these patients in the NCCN Guidelines for Breast Cancer under Principles of Breast

Reconstruction Following Surgery.

The decision regarding type of reconstruction includes patient preference, body habitus, smoking history, comorbidities, plans for irradiation, and

expertise and experience of the reconstruction team. Smoking and obesity increase the risk of complications for all types of breast reconstruction

whether with implant or flap.219-223 Smoking and obesity are therefore

considered a relative contraindication to breast reconstruction by the

NCCN Panel. Patients should be informed of increased rates of wound

healing complications and partial or complete flap failure among patients who smoke and have obesity.

Reconstruction is an optional procedure that does not impact the

probability of recurrence or death, but it is associated with an improved

QOL for many patients. It is sometimes necessary to perform surgery on the contralateral breast (ie, breast reduction, implantation) to achieve

optimal symmetry between the ipsilateral reconstructed breast and the

contralateral breast.

Breast Reconstruction After Mastectomy

Mastectomy results in loss of the breast for breastfeeding, loss of

sensation in the skin of the breast and nipple-areolar complex (NAC), and loss of the breast for cosmetic, body image, and psychosocial purposes. The loss of the breast for cosmetic, body image, and psychosocial issues may be partially overcome through the performance of breast

reconstruction with or without reconstruction of the NAC.

Those undergoing mastectomy should be offered consultation regarding options and timing of breast reconstruction.

Many factors must be considered in the decision-making about breast

reconstruction. There are several different types of breast reconstruction that include the use of implants, autogenous tissues, or both.224-226

Reconstruction with implants can be performed either by immediate

placement of a permanent subpectoral implant or initial placement of a

subpectoral expander implant followed by gradual expansion of the

implant envelope with stretching of the pectoralis major muscle and

overlying skin followed by replacement of the expander with a permanent implant. A wide variety of implants are available that contain saline,

silicone gel, or a combination of saline and silicone gel inside a solid

silicone envelope.

Autogenous tissue methods of reconstruction use various combinations of fat, muscle, skin, and vasculature from donor sites (ie, abdomen, buttock, back) that may be brought to the chest wall with their original blood supply (pedicle flap) or as free flaps with microvascular anastomoses to supply

blood from the chest wall/thorax.227 Several procedures using autologous tissue are available including transverse rectus abdominis myocutaneous flap, latissimus dorsi flap, and gluteus maximus myocutaneous flap

reconstruction.

Composite reconstruction techniques use implants in combination with

autogenous tissue reconstruction to provide volume and symmetry.

Patients with underlying diabetes or who smoke tobacco have increased rates of complications following autogenous tissue breast cancer

reconstruction, presumably because of underlying microvascular disease.

Reconstruction can be performed either at the time of the mastectomy

known as “immediate breast reconstruction” and under the same

anesthetic or in a delayed fashion any time, known as “delayed breast

reconstruction.” In many cases, breast reconstruction involves a staged

approach requiring more than one procedure such as surgery on the

contralateral breast to improve symmetry, revision surgery involving the

breast and/or donor site, and/or nipple and areola reconstruction and

tattoo pigmentation.

Plans for post-mastectomy RT can impact decisions related to breast

reconstruction since there is a significantly increased risk of implant

capsular contracture following irradiation of an implant. Furthermore, postmastectomy irradiation may have a negative impact on breast cosmesis

when autologous tissue is used in immediate breast reconstruction, and

may interfere with the targeted delivery of radiation when immediate

reconstruction is performed using either autologous tissue or breast

implants.228,229 Some studies, however, have not found a significant

compromise in reconstruction cosmesis after RT.230 The preferred

approach to breast reconstruction for irradiated patients was a subject of controversy among the Panel. While some experienced breast cancer

teams have employed protocols in which immediate tissue reconstructions are followed by RT, generally RT is preferred to precede autologous

reconstruction due to the reported loss in reconstruction cosmesis

(category 2B). When implant reconstruction is planned in a postmastectomy patient requiring RT, the NCCN Panel prefers a staged

approach with immediate tissue expander placement followed by implant

placement. Immediate placement of an implant in patients requiring

postoperative radiation has an increased rate of capsular contracture,

malposition, poor cosmesis, and implant exposure. Surgery to exchange the tissue expanders with permanent implants can be performed prior to radiation or after completion of RT.

In a previously radiated patient, the use of tissue expanders/implants is

relatively contraindicated.231 Tissue expansion of irradiated skin can result in a significantly increased risk of capsular contracture, malposition, poor cosmesis, implant exposure, and failed reconstruction.232,233

If a patient

has previously received RT to the breast, autologous tissue reconstruction is the preferred method of breast reconstruction.

Skin-Sparing Mastectomy

Skin-sparing mastectomy procedures are appropriate for some patients

and involve removal of the breast parenchyma including the NAC while

preserving the majority of the original skin envelope, and are followed by immediate reconstruction with autogenous tissue, a prosthetic implant, or a composite of autogenous tissue and an implant. Skin-sparing

mastectomy involving preservation of the skin of the NAC has become the subject of increased attention. Possible advantages of this procedure

include improvements in breast cosmesis, body image, and nipple

sensation following mastectomy, although the impact of this procedure on these QOL issues has not been well-studied.234-236 There are limited data from surgical series, with short follow-up, that suggest that performance of NAC-sparing mastectomy in selected patients is associated with low rates of occult involvement of the NAC with breast cancer and local disease

recurrence.235,237,238 NAC-sparing procedures may be an option in patients who are carefully selected by experienced multidisciplinary teams.

According to the NCCN Panel, when considering a NAC-sparing

procedure, assessment of nipple margins is mandatory. Retrospective

data support the use of NAC-sparing procedures for patients with breast

cancer with low rates of nipple involvement and low rates of local

recurrence due to early-stage, biologically favorable (ie, Nottingham grade 1 or 2, node-negative, HER2-negative, no LVI) invasive cancers and/or

DCIS that are peripherally located in the breast (>2 cm from nipple).239,240 Contraindications for nipple preservation include evidence of nipple

involvement such as Paget disease or other nipple discharge associated with malignancy and/or imaging findings suggesting malignant

involvement of nipple and subareolar tissues. Several prospective trials

are underway to evaluate NAC-sparing mastectomy in the setting of

cancer and enrollment in such trials is encouraged.

Advantages of a skin-sparing mastectomy procedure include an improved cosmetic outcome resulting in a reduction in the size of the mastectomy

scar and a more natural breast shape, especially when autologous tissue is used in reconstruction,241 and the ability to perform immediate

reconstruction. Although no randomized studies have been performed,

results of several mostly retrospective studies have indicated that the risk of local recurrence is not increased when patients receiving skin-sparing mastectomies are compared with those undergoing non-skin–sparing

procedures. However, strong selection biases almost certainly exist in the identification of patients appropriate for skin-sparing procedures.242-246

Reconstruction of the NAC may also be performed in a delayed fashion if desired by the patient. Reconstructed nipples are devoid of sensation.

According to the NCCN Panel, skin-sparing mastectomy should be

performed by an experienced breast surgery team that works in a

coordinated, multidisciplinary fashion to guide proper patient selection for skin-sparing mastectomy, determine optimal sequencing of the

reconstructive procedure(s) in relation to adjuvant therapies, and perform a resection that achieves appropriate surgical margins. Post-mastectomy radiation should still be applied for patients treated by skin-sparing

mastectomy following the same selection criteria as for standard

mastectomy.

Breast Reconstruction After Lumpectomy

Issues related to breast reconstruction also pertain to those who undergo or have undergone a lumpectomy, particularly in situations where the

surgical defect is large and/or expected to be cosmetically unsatisfactory. An evaluation of the likely cosmetic outcome of lumpectomy should be

performed prior to surgery. Oncoplastic techniques for breast conservation can extend breast-conserving surgical options in situations where the

resection by itself would likely yield an unacceptable cosmetic outcome.247 The evolving field of oncoplastic surgery includes the use of “volume

displacement” techniques performed in conjunction with a large partial

mastectomy.248 Oncoplastic volume displacement procedures combine the removal of generous regions of breast tissue (typically designed to

conform to the segmentally distributed cancer in the breast) with

“mastopexy” techniques in which remaining breast tissues are shifted

together within the breast envelope to fill the resulting surgical defect and thereby avoid the creation of significant breast deformity. Volume

displacement techniques are generally performed during the same

operative setting as the breast-conserving lumpectomy by the same

surgeon who is performing the cancer resection.248,249

Advantages of oncoplastic volume displacement techniques are that they permit the removal of larger regions of breast tissue, thereby achieving

wider surgical margins around the cancer, and at the same time better

preserve the natural shape and appearance of the breast than do standard breast resections.250

Limitations of oncoplastic volume displacement techniques include lack of standardization among centers, performance at only a limited number of

sites in the United States, and the possible necessity for subsequent

mastectomy if pathologic margins are positive when further

breast-conserving attempts are deemed impractical or unrealistic.

Nevertheless, the Panel consensus is that these issues should be

considered prior to surgery for individuals who are likely to have a surgical defect that is cosmetically unsatisfactory. Those who undergo lumpectomy and are dissatisfied with the cosmetic outcome after treatment should be offered a consultation with a plastic surgeon to address the repair of

resulting breast defects. Patients should be informed of the possibility of positive margins and potential need for secondary surgery, which could

include re-excision segmental resection, or could require mastectomy with or without loss of the nipple. Oncoplastic procedures can be combined

with surgery on the contralateral unaffected breast to minimize long-term asymmetry.

Finally, decisions regarding breast reconstruction should primarily focus

on treatment of the tumor, and such treatment should not be

compromised.

Systemic Therapies (Preoperative and Adjuvant)

Preoperative Systemic Therapy

The NCCN Panel has outlined the rationale, appropriate patient selection, and response assessment for preoperative systemic therapy in a new

section titled, Principles of Preoperative Chemotherapy.

Randomized clinical trials have found no significant differences in

long-term outcomes when systemic chemotherapy is given before or after surgery.251,252 Historically, a primary advantage of administering

preoperative systemic therapy has been to improve surgical outcomes.

Preoperative systemic therapy can convert inoperable tumors to operable and also downstage a significant number of patients with operable breast cancer to allow for more limited breast conservation procedures. 253

Results from large clinical trials and retrospective reviews indicate that

breast conservation rates are improved with preoperative systemic

therapy.252,254 Clinicians need to carefully consider the extent of disease in the breast, tumor biology and likelihood of adequate tumor response

before recommending preoperative systemic therapy to improve the

likelihood of successful breast conservation.

In addition, use of preoperative systemic therapy may provide important prognostic information based on response to therapy. Achieving a

pathologic complete response (pCR) to neoadjuvant therapy is associated with favorable disease-free and OS in early-stage breast cancer. The

correlation between pathologic response and long-term outcomes in

patients with early-stage breast cancer is strongest for patients with

triple-negative breast cancer, less so for HER2-positive disease, and least for hormone-positive disease.255-257

Other benefits of preoperative systemic therapy include allowing time for appropriate genetic testing and for planning potential breast reconstruction in patients proceeding with mastectomy. For those with significant residual disease after standard preoperative systemic therapy, it may provide an

opportunity to identify patients who may benefit from further adjuvant

therapy after surgery. It many allow sentinel lymph node biopsy (SLNB)

alone or allow for limited radiation fields if clinically node positive disease becomes clinically node negative after preoperative systemic therapy. In addition, preoperative systemic therapy also serves as an excellent

research platform to test novel therapies and predictive biomarkers by

providing tumor specimens and blood samples prior to and during

systemic treatment.

Selection of Patients for Preoperative Therapy

Not all patients are appropriate candidates for preoperative systemic

therapy. According to the NCCN Panel, among those with inoperable

breast tumors, preoperative systemic therapy is indicated in patients with locally advanced or inoperable breast cancer including those with

inflammatory breast cancer; those with bulky or matted cN2 axillary nodes; cN3 regional lymph node nodal disease; and cT4 tumors.

In patients with operable tumors, preoperative systemic therapy is the

preferred approach for the following scenarios: for patients with TNBC and HER2+ breast cancer that is clinical stage T2N0 and higher or is clinically node positive; if the patient’s breast cancer subtype is associated with a

high likelihood of response; or if a patient desires BCS and the size of the tumor is large relative to that of the breast.

When preoperative systemic therapy is used to improve the likelihood of

successful breast conservation, the surgical plan should consider the

possibility that clear surgical margins may not always be obtained, and a follow-up mastectomy may be required, with or without breast

reconstruction. This consideration is especially important when oncoplastic

This section for systemic therapies (preoperative and adjuvant) was updated on June 7th, 2024.

breast reduction techniques or contralateral breast symmetry procedures are added to the breast-conserving surgery to achieve optimal cosmetic

outcomes.

The NCCN Panel cautions that preoperative systemic therapy is not

appropriate for certain patients. Preoperative systemic therapy should not be offered in patients with extensive in situ disease when the extent of

invasive disease cannot be defined; in patients where the extent of the

tumor is poorly delineated; or in those whose tumors are not clinically

assessable. The decision to utilize preoperative therapy should be made

in the context of a coordinated and collaborative multi-disciplinary team.

For predicting the response of pre-operative endocrine therapy for

postmenopausal women with ER-positive, HER2-negative, cN0 breast

cancer, data from the TransNEOS study demonstrate a significant

correlation between 21 gene assay Recurrence Score and clinical

response to preoperative letrozole. Those whose tumors had a

Recurrence Score between 0-17 were significantly more likely to respond to preoperative letrozole compared with Recurrence Score of 31-100.258

For predicting the response to pre-operative chemotherapy for postmenopausal, ER-positive, HER2-negative patients with T1/T2, node

negative tumors, another study evaluated the role of the Recurrence

Score with pathologic response rates after pre-operative systemic therapy. Their findings suggest high Recurrence Scores are associated with a

higher likelihood of pCR after preoperative chemotherapy.259

Based on the above two studies that showed the use of 21-gene

Recurrence Score in predicting response to preoperative chemotherapy,

258,259 the NCCN panel has added a footnote for considering the use of a

gene expression assay during workup when contemplating preoperative endocrine or systemic therapy for postmenopausal patients with cN0,

operable ER-positive, HER2-negative disease, to aid in predicting response to preoperative therapy.

Preoperative therapy options:

Chemotherapy: A number of chemotherapy regimens have activity in the preoperative setting. According to the NCCN Panel, those regimens

recommended in the adjuvant setting may be considered in the

preoperative setting. In both settings, the underlying aim remains the

same: eradication or control of undiscovered distant metastases.

Endocrine Therapy: Preoperative endocrine therapy alone may be offered to those with strongly HR-positive tumors based on comorbidities or lowrisk luminal biology based on clinical characteristics and/or genomic

signatures (until desired effect is achieved).260-267 The results of the

ACOSOG Z1031 trial show that preoperative endocrine therapy is

effective in reducing residual disease and enabling BCS for many patients with low rates of local-regional recurrence post-surgery. 268

According to the NCCN Panel, the endocrine therapy options include an aromatase inhibitor (with ovarian function suppression (OFS) for

premenopausal patients) or tamoxifen (with or without OFS for

premenopausal patients). The preferred endocrine therapy option for

postmenopausal patients is an aromatase inhibitor. The panel has added a comment that the optimal response to endocrine therapy, if achieved is anywhere between 4-6 months based on the above trials.

HER2-Targeted Therapy: For patients with HER2-positive breast cancer, that are candidates for preoperative systemic therapy, chemotherapy and trastuzumab-based therapy is recommended.269 Chemotherapy and dual anti-HER2 blockade associated with trastuzumab plus pertuzumab has

shown significant improvements in the pCR rate when compared with

chemotherapy and trastuzumab in the preoperative setting.

In the TRYPHAENA trial, preoperative therapy with pertuzumab and

trastuzumab given along with anthracycline-containing or

anthracycline-free standard chemotherapy regimens to patients with

operable, locally advanced, or inflammatory HER2-positive breast cancer showed pCR rates in all treatment arms ranging from 57% to 66%.270 In

the Neosphere trial, the addition of pertuzumab to trastuzumab and

docetaxel preoperatively led to a statistically significant increase in pCR in the breast which in turn led to improves outcomes in those with nodepositive disease.271,272 The NCCN Panel supports the FDA-approved

indication that a pertuzumab-containing regimen may be administered

preoperatively to patients with greater than or equal to cT2, or greater than or equal to cN1, HER2-positive, early-stage breast cancer.

Immunotherapy: The randomized phase III multicenter, double-blind,

placebo-controlled trial (KEYNOTE-522) compared preoperative

carboplatin and paclitaxel followed by doxorubicin or epirubicin and

cyclophosphamide in combination with either pembrolizumab (n=784) or placebo (n=390), followed by pembrolizumab or placebo administered

every 3 weeks for up to nine cycles after surgery, in patients with

previously untreated stage II-III TNBC.273 After a median follow-up of 39.1 months, a significant improvement in event-free survival was seen with the addition of pembrolizumab compared with placebo plus chemotherapy.

The 3-year event-free survival rates were 84.5% and 76.8%, respectively (HR = 0.63, 95% CI = 0.48–0.82; P < .001).273

The 5-year follow-up of KEYNOTE-522 trial results showed an

improvement in EFS rate in patients treated with chemotherapy plus

pembrolizumab compared with the placebo arm (81.3% vs. 72.3%), with

reduction in risk for recurrence, progression, complications, or death of

37% (HR, 0.63; 95% CI, 0.49-0.81).274 Among patients in the trial who had a pCR and received adjuvant pembrolizumab, the 5-year EFS rate was

92.2% compared with 88.2% in patients who received only

chemotherapy.274 There are no data comparing adjuvant pembrolizumab

with other newer adjuvant therapies such as adjuvant capecitabine and/or olaparib in patients who meet criteria for treatment with one or more of

these agents.

Response Assessment During Preoperative Chemotherapy

The NCCN panel recommends that tumor response should be routinely

assessed by clinical exam during the delivery of preoperative systemic

therapy. Patients with operable breast cancer experiencing progression of disease while undergoing preoperative systemic therapy should be taken promptly to surgery. Imaging during preoperative systemic therapy should not be done routinely but may be considered if tumor progression is

suspected. Imaging prior to surgery should be determined by a

multi-disciplinary team.

In a multicenter analysis of patients (n=5161), the residual cancer burden (RCB) after preoperative chemotherapy was seen to be prognostic within each breast cancer subtype.275 Higher RCB scores were significantly

associated with worse event-free survival, with hazard ratios ranging from

1.55 to 2.16 across different breast cancer subtypes.

This study highlights RCB as a prognostic factor for outcomes in patients with breast cancer patients undergoing preoperative chemotherapy.275

As noted under the “workup” section, in order to have a standardized

method of pathology reporting, the NCCN endorses the CAP protocol for pathology reporting for all invasive and noninvasive carcinomas of the

breast. On the Principles of Preoperative Therapy page, the panel

encourages that the pathology report from definitive surgery after

preoperative systemic therapy include the standardized tissue sampling and reporting elements of the Residual Cancer Burden (RCB). However, since RCB reporting is currently not mandatory given its main purpose for prognostication only, there is inconsistent reporting of RCB across

institutions and no uniform agreement among the panel that RCB is

required in the pathology report, rendering it a category 2B

recommendation.

Adjuvant Systemic Therapy

After surgical treatment, adjuvant systemic therapy should be considered. In patients with early-stage breast cancer, systemic adjuvant therapy is

administered to reduce risk of cancer recurrence. The decision is often

based on individual risk of relapse and predicted sensitivity to a particular treatment (eg, ER/PR and HER2 status). The decision to use systemic

adjuvant therapy requires considering and balancing risk for disease

recurrence with local therapy alone, the magnitude of benefit from

applying adjuvant therapy, toxicity of the therapy, and comorbidity. The

decision-making process requires collaboration between the health care team and patient.

Stratification for Systemic Adjuvant Therapy

The NCCN Guidelines stratify, patients with breast cancer based on their HR- status and HER2 expression. Patients are then further stratified

based on risk of disease recurrence based on anatomic and pathologic characteristics (ie, tumor grade, tumor size, ALN status, angiolymphatic invasion).

Adjuvant Systemic therapy for HR-positive, HER2-negative tumors Patients with HR positive, HER2-negative tumors, receive adjuvant

endocrine therapy to reduce the risk of recurrence and those deemed at high risk for distant recurrence despite adjuvant endocrine therapy,

receive adjuvant chemotherapy. The NCCN Guidelines call for the

determination of ER and PR content in all primary invasive breast

cancers276 to determine whether a patient is a candidate for endocrine

therapies. Patients with cancers with 1%–100% ER IHC staining are

considered ER+ and eligible for endocrine therapies. Given the limited

efficacy data on the ER-low-positive (1%-10%) group, with ER-low-positive patients reported to be a heterogeneous group with a natural

history/biologic behavior often similar to ER-negative cancers,

individualized consideration of risks versus benefits of endocrine therapy and additional adjuvant therapies should be incorporated into decisionmaking. Patients with ER-negative, PR-positive cancers may also be

considered for endocrine therapies, however, the efficacy data on this

group are also limited. The same overall interpretation principles apply but PR should be interpreted as either positive (if 1%–100% of cells have

nuclear staining) or negative (if <1% or 0% of cells have nuclear staining). For the purposes of this guideline, any ER and/or PR-positive tumors is

referred to as ‘hormone receptor (HR)-positive’, given that the majority of all breast cancers are ER-positive or ER and PR-positive and the

subgroup of ER negative/PR-positive tumors are relatively uncommon.

The magnitude of risk reduction from adjuvant endocrine therapy is

dependent on level of ER-expression and on recurrence score (RS) of

gene expression assay test results. Low level of ER expression is less

likely to benefit from endocrine therapy and a high RS will gain less benefit with endocrine therapy alone versus those with low RS.

Patients with invasive breast cancers that are HR- positive should be

considered for adjuvant endocrine therapy regardless of patient age,

lymph node status, or whether adjuvant chemotherapy is to be

administered.277 Selected studies suggest that HER2-positive breast

cancers may be less sensitive to some endocrine therapies, although

other studies have failed to confirm this finding.278-286 A retrospective

analysis of tumor blocks collected in the ATAC trial indicated that HER2

amplification is a marker of relative endocrine resistance independent of

type of endocrine therapy.287 However, given the favorable toxicity profile of the available endocrine therapies, the panel recommends the use of

adjuvant endocrine therapy in the majority of patients with HR-positive

Tamoxifen: The most firmly established adjuvant endocrine therapy is tamoxifen for both premenopausal and postmenopausal patients. 59 In patients with ER-positive breast cancer, adjuvant tamoxifen decreases the annual odds of recurrence by 41% and the annual odds of death by 31% irrespective of the use of chemotherapy, patient age, menopausal status, or ALN status. 59 In patients receiving both tamoxifen and chemotherapy, chemotherapy should be given first, followed by sequential tamoxifen. 288 rospective randomized trials have demonstrated that 5 years of tamoxifen is more effective than 1 to 2 years of tamoxifen. 289, 290 e ATLAS trial randomly allocated pre-and postmenopausal patients to 5 or 10 years (extended therapy) of tamoxifen. The outcome analyses of 6846 patients with ER-positive disease showed that by extending adjuvant treatment to 10 years, the risk of relapse and breast cancer-related mortality was reduced. 291 The risk of recurrence during years 5 to 14 was 21.4% for patients receiving tamoxifen versus 25.1% for controls (absolute recurrence reduction 3.7%). Patients who received tamoxifen for 10 years had a greater reduction in risk of progression, possibly due to a "carryover effect." The reduction in risk of recurrence was 0.90 (95% CI, 0.79-1.02) during 5 to 9 years of tamoxifen treatment and 0.75 (0.62-0.90) after 10 years of treatment. There were decreases in the incidence of contralateral breast cancer as well. Furthermore, reduced mortality was also apparent after completion of 10 years of treatment with tamoxifen. With regards to toxicity, the most important adverse effects noted in all patients in the ATLAS trial after with 10 years of tamoxifen treatment were an increased risk for endometrial cancer and pulmonary embolism. 291 The results of the aTTom trial confirm the significant reduction in recurrence and death from breast cancer seen in the ATLAS trial with 10 versus 5 years of tamoxifen therapy. 292 omatase inhibitors: Several studies have evaluated aromatase inhibitors (AI) in the treatment of postmenopausal patients with early-stage breast cancer. These studies have utilized AI as initial adjuvant therapy, as sequential therapy following 2 to 3 years of tamoxifen, or as extended therapy following 4.5 to 6 years of tamoxifen. The AIs are not active in the treatment of patients with functioning ovaries and should not be used in patients whose ovarian function cannot reliably be assessed owing to treatment-induced amenorrhea.

The results from two prospective, randomized, clinical trials have provided evidence of an OS benefit for patients with early-stage breast cancer receiving initial endocrine therapy with tamoxifen followed sequentially by anastrozole (HR, 0.53; 95% CI, 0.28-0.99; P = .045) or exemestane (HR, 0.83; 95% CI, 0.69-1.00; P = .05 [excluding patients with ER-negative disease]) when compared with tamoxifen as the only endocrine therapy. 293, 294 In addition, the NCIC-CTG MA-17 trial demonstrated a survival advantage with extended therapy with letrozole compared with placebo in patients with ALN-positive (but not lymph node-negative), ER-positive breast cancer. 295 Tamoxifen and aromatase inhibitors have different side effect profiles. Both contribute to hot flashes and night sweats and may cause vaginal dryness. AIs are more commonly associated with musculoskeletal symptoms, osteoporosis, and increased rate of bone fracture, while tamoxifen is associated with an increased risk for uterine cancer and deep venous thrombosis.

Two studies have examined initial adjuvant endocrine treatment with either tamoxifen or an AI. The ATAC trial demonstrated that anastrozole is superior to tamoxifen or the combination of tamoxifen and anastrozole in the adjuvant endocrine therapy of postmenopausal patients with HR-positive breast cancer. 296, 297 With a median of 100 months follow-up, results in 5216 postmenopausal patients with HR-positive, early-stage breast cancer enrolled in the ATAC trial demonstrated fewer recurrences NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/10/28,21:39在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。

References

MS-35

(HR for DFS, 0.85; 95% CI, 0.76-0.94; P = .003) with anastrozole compared with tamoxifen. 298 No difference in survival has been observed (HR, 0.90; 95% CI, 0.75-1.07; P = .2). Patients in the combined tamoxifen and anastrozole group gained no benefit over those in the tamoxifen group, suggesting a possible deleterious effect from the weak estrogenic effect of tamoxifen in patients with near complete elimination of endogenous estrogen levels. 297 ATAC trial sub-protocols show a lesser effect of anastrozole compared with tamoxifen on endometrial tissue; 299 similar effects of anastrozole and tamoxifen on quality of life, with most patients reporting that overall quality of life was not significantly impaired; 300 a greater loss of bone mineral density with anastrozole; 301 a small pharmacokinetic interference of anastrozole in the presence of tamoxifen of unclear significance; 302 and no evidence for an interaction between prior chemotherapy and anastrozole. 303 BIG 1-98 is a randomized trial testing the use of tamoxifen alone for 5 years, letrozole alone for 5 years, or tamoxifen for 2 years followed sequentially by letrozole for 3 years, or letrozole for 2 years followed sequentially by tamoxifen for 3 years. An early analysis compared tamoxifen alone versus letrozole alone, including those patients in the sequential arms during their first 2 years of treatment only. 304 With 8010 patients included in the analysis, DFS was superior in the letrozole-treated patients (HR, 0.81; 95% CI, 0.70-0.93; log rank P = .003). No interaction between PR expression and benefit was observed. No difference in OS was observed. A comparison of the cardiovascular side effects in the tamoxifen and letrozole arms of the BIG 1-98 trial showed that the overall incidence of cardiac adverse events was similar (letrozole, 4.8%; tamoxifen, 4.7%). However, the incidence of grade 3 to 5 cardiac adverse events was significantly higher in the letrozole arm, and both the overall incidence and incidence of grade 3 to 5 thromboembolic events was significantly higher in the tamoxifen arm. 305 In addition, a higher incidence of bone fracture was observed for patients in the letrozole arm compared with those in the tamoxifen arm (9.5% vs. 6.5%). 306 After a longer follow-up (median 71 months) no significant improvement in DFS was noted with either tamoxifen followed by letrozole or the reverse sequence as compared with letrozole alone (HR for tamoxifen followed by letrozole, 1.05; 99% CI, 0.84-1.32; HR for letrozole followed by tamoxifen, 0.96; 99% CI, 0.76-1.21). 307 ve trials have studied the use of tamoxifen for 2 to 3 years followed sequentially by a third-generation AI versus continued tamoxifen in postmenopausal patients. The Italian Tamoxifen Anastrozole (ITA) trial randomized 426 postmenopausal patients with breast cancer who had completed 2 to 3 years of tamoxifen to either continue tamoxifen or to switch to anastrozole to complete a total of 5 years of endocrine therapy. 308 The HR for relapse strongly favored sequential treatment with anastrozole (HR, 0.35; 95% CI, 0.18-0.68; P = .001) with a trend towards fewer deaths (P = .10). 308 Updated results from this study show the HR for relapse-free survival as 0.56 (95% CI, 0.35-0.89; P = .01); P value for OS analysis remained at 0.1. 309 The IES trial randomized 4742 postmenopausal patients with breast cancer who had completed a total of 2 to 3 years of tamoxifen to either continue tamoxifen or to switch to exemestane to complete a total of 5 years of endocrine therapy. 310 The results at a median of 55.7 months of follow-up demonstrated the superiority of sequential exemestane in DFS (HR, 0.76; 95% CI, 0.66-0.88; P = .0001) with a significant difference in OS in only patients with ER-positive tumors (HR, 0.83; 95% CI, 0.69-1.00; log rank P = .05). A prospectively planned, combined analysis of 3224 patients enrolled in the ABCSG 8 trial and the ARNO 95 trial has also been reported. 311 Patients in this combined analysis had been randomized following 2 years of tamoxifen to complete 5 years of adjuvant tamoxifen or 3 years of anastrozole. With 28 months of median follow-up available, event-free survival was superior with crossover to anastrozole (HR, 0.60; 95% CI, 0.44-0.81; P = .0009). No statistically significant difference in survival has NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/10/28,21:39在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。

References

MS-36

been observed. An analysis of the ARNO 95 trial alone after 58 months of median follow-up demonstrated that switching from tamoxifen to anastrozole was associated with significant increases in both DFS (HR, 0.66; 95% CI, 0.44-1.00; P = .049) and OS (HR, 0.53; 95% CI, 0.28-0.99; P = .045). 294 A meta-analysis of ABCSG 8, ARNO 95, and ITA studies showed significant improvement in OS (HR, 0.71; 95% CI, 0.52-0.98; P = .04) with a switch to anastrozole. 312 e TEAM trial compared treatment of exemestane alone versus sequential therapy of tamoxifen for 2.5 to 3.0 years followed by exemestane to complete 5 years of hormone therapy. 313 At the end of 5 years, 85% of patients in the sequential group versus 86% in the exemestane group were disease free (HR, 0.97; 95% CI, 0.88-1.08; P = .60). This is consistent with the data from the BIG 1-98 trial, 307 in which tamoxifen followed by letrozole or the reverse sequence of letrozole followed by tamoxifen was not associated with significant differences in efficacy versus letrozole monotherapy after a median follow-up of 71 months.

The NCCN panel finds no meaningful differences in terms of efficacy or toxicity between the available AIs: anastrozole, letrozole, and exemestane. All three have shown similar anti-tumor efficacy and toxicity profiles in randomized studies in the adjuvant settings.

Ovarian Function Suppression and Endocrine Therapy:

Ovarian function suppression (OFS) is achieved with a gonadotropin-releasing hormone (GnRH) agonist, oophorectomy, or ovarian irradiation. Available GnRH agonists in the United States include goserelin and leuprolide. OFS is generally considered in those who are premenopausal and for tumors with high enough recurrence risk where the additional absolute decrease in recurrence compared with tamoxifen alone is worth the additional toxicity (young age, high-grade tumor, lymph node involvement). A balanced discussion of the risks and benefits associated with OFS is critical, including the potential side effects of premature menopause.

In two randomized trials (TEXT and SOFT), premenopausal patients with HR-positive early-stage breast cancer were assigned to receive AI (exemestane) plus OFS or tamoxifen plus OFS for a period of 5 years. 314 Suppression of ovarian estrogen production was achieved with the use of GnRH agonist triptorelin, oophorectomy, or ovarian irradiation. The DFS was 92.8% in the exemestane plus OFS as compared with 88.8% in the tamoxifen plus OFS (HR for recurrence, 0.66; 95% CI, 0.55-0.80; P < .001). 314 The OS did not differ significantly between the two groups (HR for death in the exemestane plus OFS group, 1.14; 95% CI, 0.86-1.51; P = .37). 314 A 9-year median follow-up analysis of the TEXT-SOFT trials showed sustained improvements in DFS with exemestane plus OFS versus tamoxifen plus OFS (HR-0.77; 95% CI, 0.67 to 0.90) and in distant recurrence-free interval but not OS (HR, 0.98; 95% CI, 0.79 to 1.22). 315 ltimately, with longer follow-up (median = 13 years), an OS was demonstrated for OFS + exemestane in patients with high-risk of recurrence, but not in .exemestane plus OFS in patients with lower risk of relapse not receiving chemotherapy. 316 e benefit of OFS in premenopausal patients with high-risk of recurrence was also seen in the results of the ASTRRA trial. This trial studied premenopausal patients (n= 1483) with HR-positive breast cancer younger than 45 years treated with surgery and who received chemotherapy (as adjuvant or preoperative therapy) and received 5 years of tamoxifen alone or 5 years of tamoxifen with OFS for 2 years. The 8-year DFS with tamoxifen plus OFS was 85.4% versus 80.2% with tamoxifen alone (HR-0.67; 95% CI, 0.51 to 0.87). 317 NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/10/28,21:39在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。

References

The results of the TEXT-SOFT trials suggest an optimal OFS duration of 5 years and data from the ASTRA trial suggests a benefit with a minimum of at least 2 years of OFS. The NCCN Panel has included OFS plus

endocrine therapy for 5 years as an option for premenopausal patients

with HR–positive breast cancer at higher risk of recurrence (eg, young

age, high-grade tumor, lymph-node involvement). Premenopausal patients wishing to continue adjuvant endocrine therapy after ovarian suppression is stopped should continue with tamoxifen versus AI.

Duration of Adjuvant Endocrine Therapy

Adjuvant endocrine therapy is recommended for a minimum of 5 years. A recent retrospective analysis by the Oxford University studied risk of

recurrence for years 5 through 20 after 5 years of endocrine therapy. 318

These data showed a considerable risk of recurrence between years 5

and 20 in these patients treated with initial 5 years of endocrine therapy.318 Data has now emerged showing benefit of extended endocrine therapy in improving DFS.

Data from the ATLAS trial (discussed above)291 and the aTTom trial

confirm greater reduction in recurrence and death from breast cancer with 10 versus 5 years of tamoxifen therapy.292

For those treated initially with adjuvant tamoxifen, there is evidence for

benefit from extended adjuvant endocrine therapy from several

randomized trials. Results of the MA-17 trial in 5187 patients who had

completed 4.5 to 6 years of adjuvant tamoxifen demonstrated that

extended therapy with letrozole provides benefit in postmenopausal

patients with HR-positive, early-stage breast cancer.295,319 With a median follow-up of 64 months, letrozole was associated with improved DFS (HR

0.52, 95% CI 0.45-0.61) and an improved OS (HR 0.61, 95% CI 0.52-0.71) compared with placebo.320

In a separate cohort analysis of the MA-17 trial, the efficacy of letrozole

versus placebo was evaluated after un-blinding of the study in the 1579

patients who had been randomly assigned to placebo after 4.5 to 6 years of tamoxifen.321,322 The median time since completion of tamoxifen was 2.8 years. Both DFS and distant DFS were significantly improved in the group receiving letrozole, thereby providing some evidence for the efficacy of

letrozole in patients who had received 4.5 to 6 years of tamoxifen therapy followed by no endocrine therapy for an extended period. A formal

quality-of-life analysis demonstrated reasonable preservation of quality of life during extended endocrine therapy, although patients may experience ongoing menopausal symptoms and loss of bone mineral density.323,324 No data are available regarding use of aromatase inhibitors for more than 5

years or long-term toxic effects from extended treatment. In addition, the ATLAS trial data do not provide clear direction for treatment of

postmenopausal patients.291 There are no data available to suggest that

an AI for 5 years is better for long-term benefit than 10 years of tamoxifen.

In the extension study of ABCSG trial 6, HR-positive postmenopausal

patients received 5 years of adjuvant tamoxifen and were randomized to 3 years of anastrozole or no further therapy.325 At a median follow-up of 62.3 months, patients who received anastrozole (n = 387) were reported to

have a statistically significantly reduced risk of recurrence compared with patients who received no further treatment (n = 469; HR, 0.62; 95% CI,

0.40–0.96; P = .031).325

The differences in design and patient populations among the studies of the aromatase inhibitors do not allow for the direct comparison of the results of these studies. A meta-analysis of adjuvant trials of aromatase inhibitors

versus tamoxifen alone versus after 2 or 3 years of tamoxifen documented lower recurrence rates with the aromatase inhibitor-containing regimen,

with no clear impact on OS.326 It is not known whether initial, sequential, or extended use of adjuvant aromatase inhibitors is the optimal strategy.

In patients initially treated with an AI, a randomized phase III trial

(MA17.R) evaluated the effects of extending adjuvant AI therapy from 5 to 10 years.327 Postmenopausal patients who had completed 4.5 to 6 years of therapy with an AI (with a median duration of prior tamoxifen of 5

years), were randomized to letrozole or placebo for an additional 5

years.327 Improvement was seen in five-year DFS in those receiving

letrozole compared to those who received placebo (95% [95% CI

93 - 96%] vs. 91% [95% CI 89 -93%]). The annual rate of contralateral

breast cancer reported was lower with letrozole (0.49% vs. 0.21%; HR

0.42, 95% CI 0.22-0.81%). However, longer duration of AI resulted in more frequent bone-related adverse effects compared with those who received placebo and no improvement was observed with respect to OS.

Bone-related adverse effects included bone pain (18% vs. 14%), fractures (14% vs. 9%), and new-onset osteoporosis (11% vs. 6%).327 Patients with high-risk of recurrence (eg. those with lymph node involvement) may

benefit from extended AI duration (7.5–10 years total).328,329

NCCN Recommendations: The decision of whether or not to extend

adjuvant treatment based on the evidence available should be

individualized. When considering endocrine therapy, the Panel

recommends the following adjuvant endocrine therapy options for patients with early-stage breast cancer.

Adjuvant Endocrine Therapy for Postmenopausal Patients: The NCCN

Panel recommends AI as initial adjuvant therapy for 5 years (category 1); and tamoxifen for 2 to 3 years followed by one of the following options: an AI to complete 5 years of adjuvant endocrine therapy (category 1) or 5

years of AI therapy (category 2B); or tamoxifen for 4.5 to 6 years followed by 5 years of AI (category 1) or consideration of tamoxifen for up to 10

years. In postmenopausal patients, the use of tamoxifen alone for 5 years

(category 1) or up to 10 years is limited to those who decline or who have a contraindication to AIs.

Adjuvant Endocrine Therapy for Premenopausal Patients: If

premenopausal at diagnosis, the NCCN Panel recommend 5 years of

tamoxifen alone (category 1) or tamoxifen with OFS (category 1) or OFS plus AI for 5 years (category 1). Patients who are premenopausal at

diagnosis and who become amenorrheic with chemotherapy may have

continued estrogen production from the ovaries without menses.

Menopausal status cannot be determined while receiving OFS. AI can

stimulate ovarian function. To assure a true postmenopausal status, serial assessment of circulating LH, FSH, and estradiol is mandatory when

considering this subset for AI therapy.330,331 Frequency of testing of

estradiol and FSH/LH levels should be individualized.

After 5 years of initial endocrine therapy, for patients who are

postmenopausal at that time (including those who have become

postmenopausal during the 5 years of tamoxifen therapy), the NCCN

Panel recommends considering extended therapy with an AI for up to 5

years (category 1) or based on the data from the ATLAS trial considering tamoxifen for an additional 5 years. For those who remain premenopausal after the initial 5 years of tamoxifen, the panel recommends considering

continuing up to 10 years of tamoxifen therapy.

Additional considerations during Adjuvant Endocrine Therapy: Symptom management for patients on adjuvant endocrine therapies often requires treatment of hot flashes and the treatment of concurrent depression.

Venlafaxine, a serotonin-norepinephrine reuptake inhibitor (SNRI) has

been studied and is an effective intervention in decreasing hot flashes.332-335 There is evidence suggesting that concomitant use of tamoxifen with

certain SSRIs (eg, paroxetine, fluoxetine) may decrease plasma levels of endoxifen, an active metabolite of tamoxifen.336,337 These SSRIs/SNRIs

may interfere with the enzymatic conversion of tamoxifen to endoxifen by inhibiting a particular isoform of cytochrome P-450 (CYP450) enzyme.

Individuals with wild-type CYP2D6 alleles are classified as extensive

metabolizers of tamoxifen. Those with one or two variant alleles with

either reduced or no activity are designated as intermediate

metabolizers and poor metabolizers, respectively. The mild CYP2D6

inhibitors such as citalopram, escitalopram, sertraline, and venlafaxine

appear to have no or only minimal effect on tamoxifen metabolism.330,338,339

With respect to CYP2D6 mutation status, a large retrospective study of

1325 patients found that time to disease recurrence was significantly

shortened in poor metabolizers of tamoxifen.340 However, the BIG 1-98

trial reported on the outcome based on CYP2D6 genotype in a subset of postmenopausal patients with endocrine-responsive, early invasive breast cancer. The study found no correlation between CYP2D6 allelic status and disease outcome or between CYP2D6 allelic status and tamoxifen-related adverse effects.341 A genetic analysis of the ATAC trial found no

association between CYP2D6 genotype and clinical outcomes.342,343

Given the limited and conflicting evidence at this time,344 the NCCN Breast Cancer Panel does not recommend CYP2D6 testing as a tool to determine the optimal adjuvant endocrine strategy. This recommendation is

consistent with the ASCO Guidelines.345 When prescribing a selective

serotonin reuptake inhibitor (SSRI), it is reasonable to avoid potent and

intermediate CYP2D6 inhibiting agents, particularly paroxetine and

fluoxetine, if an appropriate alternative exists.

For those on tamoxifen, while age-appropriate gynecologic screening is

recommended, the use of routine annual pelvic ultrasound is not

recommended. For those receiving AI or who experience ovarian failure

secondary to treatment should have monitoring of bone health with a bone mineral density determination at baseline and periodically thereafter. .The panel discourages the selective ER modulators to treat osteoporosis or

osteopenia in patients with breast cancer. The use of a bisphosphonate

(oral/IV) or denosumab is recommended to maintain or to improve bone

mineral density and reduce risk of fractures in postmenopausal (natural or induced) patients receiving adjuvant AI therapy. Optimal duration of either therapy has not been established. The optimal duration and benefits

beyond 3 years is not known. Factors to consider for duration of antiosteoporosis therapy include bone mineral density, response to therapy, and risk factors for continued bone loss or fracture. There are case reports of spontaneous fractures after denosumab discontinuation. Patients

treated with bisphosphonates or denosumab should undergo a dental

examination with preventive dentistry prior to the initiation of therapy, and should take supplemental calcium and vitamin D.

The incremental benefit of adding adjuvant chemotherapy to endocrine

therapy in patients with low clinical risk of recurrence such as those with very small, low grade, lymph node-negative tumors is relatively small.346 The decision whether or not to administer adjuvant chemotherapy in

patients with HR-positive, HER2-negative tumors is based on many

factors including lymph node status, size, grade, lymphovascular invasion, age, comorbid conditions and/or the results of a gene expression profile

test using multigene assays.

Several commercially-available gene-based assays are useful in

determining prognosis by predicting distant recurrence, local recurrence, or survival. Of these, only one, the 21-gene assay (Oncotype Dx) has

been clinically validated for predicting the benefit of adding adjuvant

chemotherapy to further reduce the risk of recurrence.

21-gene assay (Oncotype DX) in Node-negative, HR-positive,

HER2-negative disease: The 21-gene recurrence score (RS) is one of the most validated multigene assays. The RS is helpful in determining the

prognosis in patients with HR-positive, HER2-negative tumors treated with

Keywords

286, 350, 351

Among patients with T1b/c and T2, lymph node-negative, HR-positive, HER2-negative tumors with RS between 0-10, the risk of distant recurrence is low and these patients derive no incremental benefit from the addition of adjuvant chemotherapy to endocrine therapy. 286, 352 At the other end of the spectrum, patients with lymph node-negative, HR-positive, HER2-negative cancers with high RS (≥ 31) have a higher risk of distant recurrence and secondary analyses of prospective studies demonstrate a clear benefit from adjuvant chemotherapy. 286, 353 r those with intermediate RS (11-25), the TAILORx trial of postmenopausal patients (n= 6711) with lymph node-negative, HR-positive, HER-2 negative breast cancer, showed similar disease-free survival rates at 9-years in those who received adjuvant chemotherapy followed by endocrine therapy compared with endocrine therapy alone. 353 However, in a subset analysis, patients 50 years of age or younger with RS 16-25 had lower rates of distance recurrence with the addition of adjuvant chemotherapy to endocrine therapy. 353 The cutoff for low, intermediate, and high RS was different in TAILORx versus NSABP B-20. The NSABP-B20 was the first trial to validate the 21-gene assay both as a prognostic as well as a predictive tool and identified RS cut-offs to predict the magnitude of chemotherapy benefit in patients with node-negative, HR-positive breast cancer. 7 21-gene assay (Oncotype DX) in Node-positive, HR-positive, HER2-negative disease: In the West German Plan B study, patients (n = 110) with lymph node-positive, HR-positive, HER2-negative tumors, and a RS of ≤11, were found to have a 5-year disease-free survival of94.4% when treated with endocrine therapy alone. 354 In a secondary analysis of a prospective registry of patients with HR-positive, HER2-negative, lymph node-positive tumors, the 5-year risk of distant recurrence in patients with a RS of < 18, treated with endocrine therapy alone was 2.7%. 355 These results suggest that in patients with limited nodal disease (1-3 positive lymph nodes) and a low RS, the absolute benefit from chemotherapy is likely to be very small. 355, 356 ere is a clear benefit from adjuvant chemotherapy in patients with node positive, HR-positive, HER2-negative tumors, if the RS is high (≥ 31). In a secondary analysis of the SWOG 8814 trial of patients with HR-positive, lymph node-positive tumors, high RS (≥31) was predictive of chemotherapy benefit. This study evaluated breast cancer specimens from node-positive, HR-positive postmenopausal patients (n= 367) randomized to endocrine therapy with tamoxifen alone or chemotherapy with CAF followed by tamoxifen. 350 Compared with tamoxifen alone, treatment with CAF among patients with a high RS (≥31) resulted in improved 10-year DFS (55% vs. 43%; HR 0.59, 95% CI 0.35-1.01) and OS (73% vs. 54%; HR 0.56, 95% CI 0.31-1.02). 350 e Southwest Oncology Group (SWOG) S1007 RxPONDER trial, 357 assigned patients with 1-3 lymph node-positive nodes, HR-positive, HER2-negative breast cancer and a RS ≤ 25 to standard endocrine therapy with or without adjuvant chemotherapy. The results showed that the addition of adjuvant chemotherapy to endocrine therapy improved invasive disease-free survival among premenopausal-but not postmenopausal-women with hormone receptor-positive, HER2negative, node-positive breast cancer and a 21-gene assay recurrence score up to 25.

References

NCCN Guidelines Version 5.2025 Breast Cancer

MS-41

Abstract

clinical features (based on tumor size, grade, nodal status). In this trial, 79% had lymph node-negative disease and 21% had 1-3 positive lymph nodes and all patients underwent risk assessment by clinical criteria (using Adjuvant! Online) and genomic risk assessment by the 70-gene assay.

Abstract

Patients with low-risk disease according to both clinical criteria and genomic assay results did not receive adjuvant chemotherapy, whereas patients categorized as high-risk by both assessments received chemotherapy. Patients with discordant results (i.e., either high clinical risk/low genomic risk or low clinical risk/high genomic risk) were randomized to the chemotherapy group or the no-chemotherapy group on the basis of either the clinical result or the genomic result. The primary outcome of the study was met with the demonstration that among those with high clinical risk/low genomic risk, the 5-year rate of survival without distant metastasis in those did not receive adjuvant chemotherapy was 94.7% (95% CI, 92.5 to 96.2). 359

In the intention-to-treat population, among patients at high clinical risk/low genomic risk by the 70-gene assay, the 5-year rate of survival with no distant metastasis in those who received chemotherapy was 95.9% (95% CI, 94.0 to 97.2) versus 94.4% (95% CI, 92.3 to 95.9) in those who did not receive chemotherapy (adjusted HR for distant metastasis or death with chemotherapy vs.no chemotherapy 0.78; 95% CI, 0.50 to 1.21). 359 Among patients at low clinical risk/ high genomic risk, 5-year survival with no distant metastasis was 95.8% with chemotherapy (95% CI, 92.9 to 97.6), compared with a rate of 95.0% (95% CI, 91.8 to 97.0%) without chemotherapy (adjusted HR for distant metastasis or death with chemotherapy vs. no chemotherapy,1.17; 95% CI, 0.59 to 2.28). These data suggest that the results of the 70-gene signature do not provide evidence for making recommendations regarding chemotherapy for patients at low clinical risk. 359 a subgroup analysis by nodal status, among node-negative patients with high clinical risk/low genomic risk, the 5-year rate of survival with no distant metastasis was 95.7% (95% CI, 93.0 to 97.4) in those who received adjuvant chemotherapy compared with 93.2% (95% CI, 90.1 to 95.4) in those who did not receive chemotherapy. 359 Among patients with 1-3 positive lymph nodes, the rates of survival without distant metastases were 96.3% (95% CI, 93.1 to 98.1) in those who received adjuvant chemotherapy versus 95.6 (95% CI, 92.7 to 97.4) in those who did not receive adjuvant chemotherapy. 359 These data suggest that the additional benefit of adjuvant chemotherapy in patients with high-clinical risk/low genomic risk is likely to be small.

50-gene assay (PAM50):

The 50-gene assay (PAM-50) risk of recurrence (ROR) score stratifies patients with HR-positive disease into high, medium, and low risk groups. 62 In a study from the Danish Breast Cancer Cooperative Group database, patients with lymph node node-negative tumors and low ROR had a distant recurrence risk of 5.0% (95% CI, 2.9% to 8.0%) whereas tumors with high ROR had a distant recurrence risk of 17.8% (95% CI, 14.0% to 22.0%). 361 Based on these analyses, patients with T1 and T2, HR-positive, HER2-negative, lymph node-negative tumors, a ROR score in the low range, regardless of tumor size, places the individual into the same prognostic category as those with T1a-T1b, N0, M0 tumors. 361

In patients with 1-3 lymph-node positive, HR-positive, HER2-negative disease with low-risk of recurrence score, the distant recurrence risk was less than 3.5% at 10 years with endocrine therapy alone. 361 In TransATAC study, no distant recurrence was seen at 10 years in a similar group. 362 NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/10/28,21:39在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。

References

NCCN Guidelines Version 5.2025 Breast Cancer

Abstract

This assay utilizes 12-genes to calculate a prognostic score. This assay appears to be useful in identifying a subgroup of patients with ER-positive, HER2-negative tumors with very low risk of recurrence without adjuvant chemotherapy and helpful in identifying patients at low risk for a late recurrence. 363 Based on results of two Austrian Breast Cancer Study Group trials-ABCSG-6 and ABCSG-8, patients with HR-positive, HER-2 negative, and lymph-node node-negative disease with a low-risk score by the 12-gene assay had risk of distant recurrence of 4% at 10 years. 363 The prognostic value of the risk score from the 12-gene assay was found to be independent of conventional clinicopathological factors. Patients with T1 and T2 HR-positive, HER2-negative, and lymph node-negative tumors, a 12-gene low-risk score, regardless of T size, places the tumor into the same prognostic category as T1a-T1b, N0, M0.

In TransATAC study, patients with 1-3 positive nodes in the low-risk group had a 5.6% risk of distant recurrence at 10 years, 362 suggesting that chemotherapy would be of limited benefit in these patients.

Breast Cancer Index: The Breast Cancer Index (BCI) is a combination of two profiles, the HOXB13-to-IL17BR expression ratio (H:I ratio) and the Molecular Grade Index (MGI). Compared with clinical prognostic factors (eg, age, tumor size, tumor grade, and lymph node status), the H:I ratio has been shown to be prognostic in the setting of adjuvant tamoxifen monotherapy. 362, 364 The addition of MGI to H:I was determined to provide additional prognostic discrimination, leading to the BCI assay. 364 In a secondary analysis of the ATAC trial, BCI was prognostic in node negative breast cancer for both early (years 0-5) and late (years 5-10) distant recurrence. 365 For patients with T1 and T2 HR-positive, HER2-negative, and lymph node-negative tumors, a BCI in the low-risk range, regardless of T size, places the tumor into the same prognostic category as T1a-T1b, N0, M0. 7] [368] Considering the ability of the multigene assays to predict benefit of adjuvant systemic chemotherapy and ability to determine prognosis by predicting risk of distant recurrence, the NCCN Panel has summarized the treatment implications based on risk scores and nodal status.

Multigene Assays for Axillary Lymph Node-Negative HR-Positive, HER2-Negative Tumors

Small tumors (up to 0.5 cm in greatest diameter) that do not involve the lymph nodes have a favorable prognosis so adjuvant chemotherapy is not recommended. According to the NCCN Panel, adjuvant endocrine therapy may be considered in this group of patients to reduce the risk for a second contralateral breast cancer, as well as the small benefit in reducing the risk of local/regional and distant recurrence.(Category 2B).

For patients with invasive ductal or lobular tumors greater than 0.5 cm in diameter and no lymph node involvement (lymph node node-negative), the NCCN panel recommends strongly considering the 21-gene RT-PCR assay to help estimate likelihood of recurrence and benefit from chemotherapy (category 1). The panel has noted that on an exploratory analysis from the TAILORx study, 353 adjuvant chemotherapy may be considered in patients 50 years of age or younger with a 21-gene RS of 16-25. Also, patients with T1b tumors with low grade histology should be considered for endocrine monotherapy, as the TAILORx study 353 did not include patients with such tumors. The panel notes that other prognostic multigene assays may be considered to help estimate risk of recurrence, but these assays have not been validated to predict the benefit of systemic chemotherapy. Also, NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/10/28,21:39在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。

References

NCCN Guidelines Version 5.2025 Breast Cancer

MS-43

Abstract

amongst the other assays, the panel has listed the 70-gene assay as a category 1 option based on the results of the prospective MINDACT 359 trial demonstrating the ability of the 70-gene assay to identify a good genomic risk population despite a high clinical risk, in whom chemotherapy may be omitted without a detrimental effect. High clinical risk in the MINDACT trial was defined for grade 1 tumors as > 3 cm N0 or T2N1, for grade 2 tumors T2N0-1, and for grade 3 tumors T1c-2N0-1.

Abstract

Furthermore, given no difference in outcomes with or without chemotherapy in the discordant low clinical risk/high genomic risk group, the MINDACT study suggests that the 70-gene panel is not useful guiding systemic chemotherapy decisions in this subgroup of patients.

Since results of different assays may not be concordant with each other and these assays have not been compared head-to-head prospectively, clinicians should only order one of the available assays for a specific patient and tumor.

Multigene Assays for Axillary Lymph Node-Positive HR-Positive, HER2-Negative Tumors

For patients with four or more involved nodes the panel recommends systemic adjuvant chemotherapy followed by endocrine therapy (category 1).

Patients with less than four involved nodes or with pN1mi and less than or equal to 2 mm axillary node metastasis, are most often candidates for chemotherapy in addition to endocrine therapy. The panel recommends that clinical decision making for adjuvant chemotherapy be based on elements of clinical risk stratification such as clinical characteristics, tumor stage, pathology and comorbid conditions. If the patient is not a candidate for chemotherapy, the panel recommends adjuvant endocrine therapy alone (category 2A).

For those who are candidates for systemic adjuvant chemotherapy based on clinical characteristics, tumor stage, and pathology, the panel recommends consideration of multigene assays to assess prognosis as a tool to assist with treatment decision making. The panel notes in those with N1mi and N1 tumors, while multigene assays have yet to be proven to be predictive for adjuvant chemotherapy benefit, they are prognostic and can be used to identify low-risk patients who are likely to derive little or no absolute benefit from addition of adjuvant chemotherapy to adjuvant endocrine therapy. A secondary analysis of the prospective SWOG 8814 trial using the 21-gene assay demonstrated no benefit for chemotherapy for patients with 1-3 involved axillary lymph nodes and a low RS, and a significant benefit for the addition of adjuvant chemotherapy in those with high-RS (≥ 31). 350 The phase III RxPONDER trial prospectively demonstrated that for premenopausal patients with hormone receptorpositive, HER2-negative, node-positive breast cancer , a 21-gene assay Recurrence Scores up to 25 had an addition benefit of adjuvant chemotherapy to endocrine therapy for improving invasive disease-free survival . 358 In the MINDACT trial, among patients with 1-3 positive nodes who had a high clinical risk of recurrence but low risk by the 70-gene assay, the rates of survival were similar between those who received adjuvant chemotherapy in addition to adjuvant endocrine therapy versus those received adjuvant endocrine therapy alone, suggesting that chemotherapy could be omitted in this group. 359 Other multigene assays have not proven to be predictive of benefit from chemotherapy.

For those who are candidates for systemic adjuvant chemotherapy based on clinical characteristics, tumor stage, and pathology, if multigene assay is not available, the panel recommends systemic adjuvant chemotherapy followed by endocrine therapy (category 1).

References

Adjuvant CDK 4/6 inhibitors: In the MonarchE study, the addition of 2 years of abemaciclib to endocrine therapy reduced the absolute risk of recurrence at 4 years by 6.4% (HR 0.664, 95% CI 0.578-0.762, P < .0001) in patients with HR-positive/HER2-negative, high-risk breast cancer, defined as 4 or more pathologically involved lymph nodes confirmed preoperatively and/or at surgery, or 1-3 pathologically involved lymph nodes with additional high risk features (grade 3 or size ≥5 cm based on pre-operative imaging and/or pathologically at surgery). 369 o trials of palbociclib as adjuvant therapy in HR-positive, HER2negative early breast cancer did not show benefit of adding palbociclib to adjuvant endocrine therapy in terms of invasive disease-free survival. 370, 371 e results from the NATALEE trial reported after a median follow-up of 34 months, showed a statistically significant improvement (3.3%) in invasive disease-free survival with the addition of ribociclib to adjuvant endocrine therapy (HR-0.75, 95% CI 0.62-0.91, P = .003).) for stage II and stage III HR-positive, HER2-negative breast cancer. 372 Additional follow-up is needed to characterize the long-term efficacy of ribociclib in this setting.

According to the current guidelines, 2 years of adjuvant CDK 4/6 therapy with abemaciclib should be considered in combination with endocrine therapy in patients with HR-positive/HER2-negative, high-risk breast cancer (as detailed above). This is a category 1, preferred option for this setting.

Adjuvant Olaparib: In patients with germline BRCA 1/2 mutations and high-risk HER2-negative tumors, the results of the OlympiA trial showed that the 4-year OS in the group that received 1 year of adjuvant olaparib was 89.8% and 86.4% in the placebo group (95% CI -0.1% -6.8%). The 4-year invasive DFS for the olaparib group versus placebo group was 82.7% versus 75.4% (95% CI 3.0% -11.5%) and 4-year distant DFS was 86.5% versus 79.1% (95% CI 3.6% -11.3%). 373 cording to the NCCN panel, addition of adjuvant olaparib for 1 year may be considered for those with germline BRCA 1/2 mutations in patients with HR-positive, HER2-negative tumors with ≥4 positive lymph nodes after adjuvant chemotherapy or residual disease after preoperative therapy and a clinical stage, pathologic stage, ER status, and tumor grade (CPS+EG) score ≥3 (category 2A).

Adjuvant olaparib may be used concurrently with endocrine therapy. In patients eligible for both adjuvant olaparib and abemaciclib, the optimal sequencing is not known. (For sequencing of olaparib and/or abemaciclib with RT, see BINV-I on nccn.org)

Adjuvant bisphosphonate therapy

Antiresorptive agents (bisphosphonates and denosumab) have an established role as preventative and therapeutic agents for the management of osteoporosis, hypercalcemia of malignancy, and bone metastases.

Bisphosphonates: In the Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) trial, for patients over 40 years, zoledronic acid significantly reduced the risk of recurrence by 34% (HR, 0.66; P=.014) and the risk of death by 49% (HR, 0.51; P=.020). However, no improvement was seen in either DFS or OS in this post hoc analysis among patients under 40 years. 374 In a planned subgroup analysis of the AZURE trial, zoledronic acid improved DFS in patients who were more than 5 years since menopause at trial entry. 375 A meta-analysis of data from seven adjuvant bisphosphonate trials (AZURE, ABCSG-12, ZO-FAST, Z-FAST, EZO-FAST, NSABP-B34, GAIN), including only those known to be over 50 years, postmenopausal, or with ovarian suppression, showed a significant NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/10/28,21:39在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。

References

NCCN Guidelines Version 5.2025 Breast Cancer

MS-45

Abstract

benefit for the use of adjuvant bisphosphonates in patients with a low-estrogen state and early-stage breast cancer. 376 More recently, the Early Breast Cancer Trialists' Collaborative Group (EBTCG) conducted a meta-analysis of all randomized adjuvant bisphosphonate studies (26 studies) and reported convincing evidence that adjuvant bisphosphonates provide benefits to postmenopausal (natural or induced) patients with breast cancer. 377 With bisphosphonate therapy, the greatest improvement was seen in bone recurrence (RR=0.83, P = .004) and bone fractures (RR=0.85, P = .02). No effect was seen on distant recurrence outside bone (RR =0.98, P =0.69). 377 In premenopausal patients, bisphosphonate therapy did not seem to have a significant effect on bone recurrence. However, in postmenopausal patients, zoledronic acid significantly reduced bone recurrence (3.4% vs. 4.5%, RR=0.73, 99% CI 0.53 to 1.00); the difference in breast cancer mortality was not statistically significant (7.1% vs. 7.9%, RR=0.88, 99% CI 0.69 to 1.11). 377

Denosumab: In the adjuvant setting, the ABCSG-18 trial studied the effect of denosumab in postmenopausal patients treated with adjuvant AIs and showed a reduction in clinical fractures (HR 0.5, P < .0001), which was the primary endpoint of this study. 378 The final analysis after a median followup of 8 years continued to show a benefit with denosumab. Adjuvant denosumab improved bone metastasis-free survival (88.9 vs. 86.4%; HR, 0.81; 95% CI, 0.65 to 1.00) and OS (90.9 vs. 89.9%; HR, 0.80; 95% CI, 0.64 to 1.01). 379 In contrast, results of the phase III trial (D-Care) trial failed to demonstrate a difference in bone metastasis-free survival in those receiving denosumab versus placebo. 380 e to these conflicting results from phase III trials, denosumab is currently not recommended in the adjuvant setting. 379 The panel recommends considering adjuvant bisphosphonate therapy for risk reduction of distant metastasis for 3-5 years in patients with high-risk node negative or node-positive tumors.

Adjuvant Therapy for HER2-negative tumors

Several combination chemotherapy regimens are appropriate to consider for HR-positive or negative and HER2-negative tumors. All adjuvant chemotherapy regimens listed in the NCCN Guidelines have been evaluated in phase III clinical trials and are category 1 unless otherwise noted.

Preferred Regimens

Regimens listed as preferred include dose-dense doxorubicin and cyclophosphamide (AC) followed or preceded by paclitaxel either weekly or biweekly; docetaxel plus cyclophosphamide (TC); olaparib for germline BRCA 1/2 mutations; pembrolizumab for high-risk ER-disease; and capecitabine for residual ER-disease after preoperative chemotherapy.

Meta-analysis from Early Breast Cancer Trialists' Collaborative Group (EBCTCG) has shown that anthracycline and taxane-based combination chemotherapy reduces the risk of breast cancer mortality compared with no chemotherapy. The use of dose-dense schedules has shown to further reduce the risk of breast cancer recurrence or death without increasing mortality. 381 e results of two randomized trials comparing AC chemotherapy with or without sequential paclitaxel chemotherapy in patients with axillary node-positive breast cancer suggest improved disease-free rates and results from one of the trials showed an improvement in OS, with the addition of paclitaxel. 382, 383 On retrospective analysis, the apparent advantage of the paclitaxel-containing regimen appears greater in patients with ER-negative breast cancers.

A randomized trial evaluated the use of concurrent versus sequential chemotherapy (doxorubicin followed by paclitaxel followed by cyclophosphamide vs. doxorubicin plus cyclophosphamide followed by NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/10/28,21:39在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。

References

NCCN Guidelines Version 5.2025 Breast Cancer

MS-46

Abstract

paclitaxel) given either every 2 weeks with filgrastim support or every 3 weeks. The results show no significant difference between the two chemotherapy regimens but demonstrate a 26% reduction in hazard of recurrence (P = .01) and a 31% reduction in the hazard of death (P = .013) for the dose-dense regimens. 384

The ECOG E1199 study was a four-arm trial that randomized 4950 patients to receive AC chemotherapy followed by either paclitaxel or docetaxel given by either an every-3-week schedule or a weekly schedule. 385 In a secondary series of comparisons, weekly paclitaxel was superior to every-3-week paclitaxel in DFS (HR, 1.27; 95% CI, 1.03-1.57; P = .006) and OS (HR, 1.32; 95% CI, 1.02-1.72; P = .01), and every-3-week docetaxel was superior to every-3-week paclitaxel in DFS (HR, 1.23; 95% CI, 1.00-1.52; P = .02) but not in OS. 385 Based on these results, as well as the findings from the CALGB trial 9741 that showed dose-dense AC followed by paclitaxel every 2 weeks to have a survival benefit when compared with the regimen of AC followed by every-3-week paclitaxel, 384 the every-3-week paclitaxel regimen has been removed from the guidelines.

Combination TC was compared with AC chemotherapy in a trial that randomized 1016 patients with stage I to III breast cancer. 386 At a median follow-up of 7 years, overall DFS (81% vs. 75%; HR, 0.74; 95% CI, 0.56-0.98; P = .033) and OS (87% vs. 82%; HR, 0.69; 95% CI, 0.50-0.97; P = .032) were significantly improved with TC compared with AC. Nonanthracycline, taxane-based regimen, such as TC may be preferred options in patients for whom anthracyclines are contraindicated.

Residual disease after preoperative systemic therapy indicates higher risk (20% to 30%) of disease relapse. 256,387 CREATE-X, a multicenter, openlabel, randomized, phase 3 trial evaluated the efficacy and safety of adjuvant capecitabine in patients with HER2-negative primary breast cancer who had residual invasive disease after standard (anthracycline and/or taxane-based) preoperative chemotherapy. The results showed improved DFS (HR 0.70, 95% CI 0.53-0.92, P = .01) and OS (HR for death 0.59, 95% CI 0.39-0.90, P = .01) with adjuvant capecitabine. The OS was higher in those with TNBC (HR for death, 0.52). Results of two other similar trials with adjuvant capecitabine have showed a similar impact with adjuvant capecitabine in patients with TNBC with no significant impact in those with HR-positive disease. 388, 389 Based on the above trial results, the NCCN panel has included adjuvant capecitabine an adjuvant therapy option for those with TNBC and residual disease after preoperative therapy. For those with germline BRCA 1/2 mutations and TNBC, according to the NCCN panel, based on the results of OlympiA trial (discussed in section adjuvant therapy for HR-positive, HER2-negative disease) adjuvant olaparib for 1 y may be considered if tumors ≥ pT2 or ≥ pN1 disease after adjuvant chemotherapy or in those with residual disease after preoperative chemotherapy (catgeory1). Patients in the OlympiA trial did not receive capecitabine; thus, there are no data on sequencing or to guide selection of one agent over the other. (For sequencing of capecitabine or Olaparib with RT, see BINV-I on nccn.org)

If pembrolizumab was given in combination with chemotherapy in the preoperative setting, based on the KEYNOTE-522 trial data, the panel recommends adjuvant pembrolizumab. 274

Other Recommended Regimens

Other recommended regimens included in the guidelines include: AC; epirubicin and cyclophosphamide (EC); docetaxel, doxorubicin, and cyclophosphamide (TAC); paclitaxel + carboplatin (various schedules); and docetaxel + carboplatin.

A trial compared 2 dose levels of EC chemotherapy with CMF chemotherapy in patients with node-positive breast cancer. 390 This study showed that higher-dose EC chemotherapy was equivalent to CMF NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/10/28,21:39在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。

References

Final results from a randomized trial of TAC versus FAC chemotherapy in node-positive breast cancer demonstrated that TAC is superior to FAC. 391 Estimated 5-year DFS was 75% with TAC and 68% with FAC (HR, 0.72; 95% CI, 0.59-0.88; P =.001); survival was 87% with TAC and 81% with FAC (HR, 0.70; 95% CI, 0.53-0.91; P = .008). DFS favored TAC in both ER-positive and ER-negative tumors. At a median follow-up of 73 months, results from the 3-arm randomized NSABP B-30 trial comparing TAC versus AT versus AC followed by docetaxel (AC followed by T) demonstrated that AC followed by T had a significant advantage in DFS (HR, 0.83; P = .006) but not in OS (HR, 0.86; P = .086) when compared with TAC. In addition, both DFS (HR, 0.080; P = .001) and OS (HR, 0.83; P = .034) were significantly increased when AC followed by T was compared with AT, with AT demonstrating non-inferiority compared with TAC. 392

Useful in Certain Circumstances:

Regimens included in this category include dose dense AC; AC every 3 weeks (Category 2B); CMF; AC followed by weekly paclitaxel; and capecitabine as maintenance therapy for TNBC after adjuvant chemotherapy.

The phase III E1199 trial compared patients with node-positive or high-risk node-negative breast cancer who received 4 cycles of AC every 3 weeks, followed by either paclitaxel or docetaxel, either weekly or every 3 weeks. The 10-year updated results of this trial showed that incorporation of weekly paclitaxel and docetaxel every 3 weeks was associated with significant improvements in DFS, and marginal improvements in OS, compared with paclitaxel given every 3 weeks. Among patients with triple-negative disease, the10-year DFS rate with weekly paclitaxel was 69% and the 10-year OS rate was 75%. 393 e AC regimen for four cycles has been studied in randomized trials, resulting in relapse-free survival and OS equivalent to CMF chemotherapy. 394, 395 No benefit from dose escalation of either doxorubicin or cyclophosphamide was shown. 382, 396 Studies of CMF chemotherapy versus no chemotherapy have shown DFS and OS advantages with CMF chemotherapy. 59, 397 sults of a randomized trial in patients with TNBC (n=434) who received standard adjuvant chemotherapy demonstrated that maintenance therapy with low-dose capecitabine (dose of 650 mg/m 2 twice a day by mouth for 1 year) improved 5-year DFS and OS. The invasive DFS in those who receive adjuvant low-dose capecitabine was 85.8% compared with 75.8% in those who did not (HR for risk of distant metastasis or death, 0.60 [95% CI, 0.38-0.92]; P = .02), the estimated 5-year OS with maintenance capecitabine was 85.5% versus 81.3% (HR for risk of death, 0.75 [95% CI, 0.47-1.19]; P = .22). 398 juvant Therapy for HER2-positive tumors Trastuzumab containing chemotherapy regimens followed by one year of HER2-targeted therapy are a backbone of adjuvant therapy patients with HER2-positive disease.

The panel recommends HER2-targeted therapy in patients with HER2-positive tumors (see Principles of HER2 Testing in the NCCN Guidelines for Breast Cancer). Pre-operative systemic therapy incorporating HER-2 targeted agent(s) should be considered for HER-2 positive patients presenting with clinical node-positive tumors or those measuring > 2 cm (cT2) at presentation.)

References

The NCCN Panel suggests trastuzumab and chemotherapy be used for patients with HER2-positive, node-negative tumors measuring 0.6 to 1.0 cm (T1b) and for smaller tumors that have less than or equal to 2 mm axillary node metastases (pN1mi). Some support for this recommendation comes from studies showing a higher risk of recurrence for patients with HER2-positive, node-negative tumors less than or equal to 1 cm compared to those with HER2-negative tumors of the same size. 399

Ten-year breast cancer-specific survival and 10-year recurrence-free survival were 85% and 75%, respectively, in patients with tumors characterized as HER2-positive, ER-positive tumors, and 70% and 61%, respectively, in patients with HER2-positive, ER-negative tumors. Two additional retrospective series report recurrence-free survival in this subpopulation of HER-2 positive, node-negative tumors measuring 0.6 to 1.0 cm (T1b) and/or pN1mi. all treated without trastuzumab. In the first study, 5-year recurrence-free survival rates of 77.1% and 93.7% (P < .001) were observed for patients with HER2-positive and HER2-negative T1a-bN0M0 breast tumors, respectively, with no recurrence-free survival differences seen in the HER2-positive group when hormonal receptor status was considered. 400 In the other retrospective study of patients with small HER2-positive tumors, the risk of recurrence at 5 years was low (99% [95% CI; 96%-100%] for HER2-negative disease and 92% [95% CI; 86%-99%] for HER2-positive disease). 401 Subgroup analyses from several of the randomized trials have shown consistent benefit of trastuzumab irrespective of tumor size or nodal status. 402, 403 eferred Regimens:

The NCCN Panel has included paclitaxel and trastuzumab as an option for patients with low-risk, HER2-positive, stage 1 tumors, based on a trial of 406 patients with small, node-negative, HER2-positive tumors treated with this combination. The 3-year rate of DFS was 98.7% (95% CI, 97.6-99.8) and the risk of serious toxic effects with this regimen was low (incidence of heart failure reported was 0.5%). 404 The long-term follow-up data reported 10-year invasive DFS of 91.3%, breast cancer-specific survival of 98.8% and OS rates of 94.3%. 405 Accordingly, NCCN panel has listed paclitaxel and trastuzumab as a less intensive therapeutic option, preferred for patients with low-risk T1,N0,M0, HER2-positive disease, particularly those not eligible for other standard adjuvant regimens due to comorbidities. 405 e BCIRG 006 study randomized 3222 patients with HER2-positive, node-positive, or high-risk node-negative breast cancer to AC followed by docetaxel; AC followed by docetaxel plus trastuzumab for one year; or carboplatin, docetaxel, and trastuzumab for one year. 403 At 65-month follow-up, patients receiving AC followed by docetaxel with trastuzumab (AC-TH) had an HR for DFS of 0.64 (P < .001) when compared with the group of patients in the control arm receiving the same chemotherapy regimen without trastuzumab (AC-T). The HR for DFS was 0.75 (P = .04) when patients in the carboplatin/docetaxel/ trastuzumab (TCH)-containing arm were compared to patients in the control arm. No statistically significant difference in the HR for DFS was observed between the two trastuzumab-containing arms. An OS advantage was reported for patients in both trastuzumab-containing arms relative to the control arm (HR for AC-TH vs. AC-T = 0.63; P = .001; HR for TCH vs. AC-T = 0.77; P = .04). Cardiac toxicity was significantly lower in the TCH arm (9.4% patients with > 10% relative decline in left ventricular ejection fraction) compared with the AC-TH arm (18.6%; P < .0001). CHF was also more frequent with AC-TH than TCH (2% vs. 0.4%; P < .001). Analysis of this trial by critical clinical event revealed more distant breast cancer recurrences with TCH (144 vs. 124) but fewer cardiac events with TCH compared with AC-TH (4 vs. 21). 403 In the FinHer trial, 1010 patients were randomized to 9 weeks of vinorelbine followed by 3 cycles of FEC chemotherapy versus docetaxel for 3 cycles followed by 3 cycles of FEC chemotherapy. 406 Patients (n = 232) with HER2-positive cancers that were either node-positive or node-negative and greater than or equal to 2 cm and PR-negative were NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/10/28,21:39在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。

References

Abstract

further randomized to receive or not receive trastuzumab for 9 weeks during the vinorelbine or docetaxel portions of the chemotherapy only. With a median follow-up of 3 years, the addition of trastuzumab was associated with a reduction in risk of recurrence (HR, 0.42; 95% CI, 0.21-0.83; P = .01). No statistically significant differences in OS (HR, 0.41; 95% CI, 0.16-1.08; P = .07) or cardiac toxicity were observed with the addition of trastuzumab. 406 At 5-year follow-up, a comparison of the two arms (ie, chemotherapy with and without trastuzumab) demonstrated that the HRs for distant DFS (HR, 0.65; 95% CI, 0.38-1.12; P = .12) and OS (HR, 0.55; 95% CI, 0.27-1.11; P = .094) were higher relative to those reported at 3 years. 407 The TCH regimen is a preferred regimen, especially for those with risk factors for cardiac toxicity, based on the results of the BCIRG 006 study.

The APHINITY trial compared adjuvant trastuzumab plus pertuzumab with trastuzumab-placebo, both in combination with standard adjuvant chemotherapy in patients with node-positive or high-risk node-negative HER2-positive, operable tumors. The study demonstrated that trastuzumab plus pertuzumab significantly improved 3-year iDFS (HR 0.81, 95% CI 0.66-1.00, P =.045). 408 With long-term (8-year) follow-up, the node positive subgroup maintained a clear invasive DFS benefit favoring the dual HER-2 agent arm demonstrating 8-year invasive DFS of 86% versus 81% (HR; 0.72, 95% CI 0.60-0.87) with no OS difference; no benefit was seen in the node-negative subgroup. 409 These updated results from the adjuvant APHINITY trial confirm the long-term benefit of adding pertuzumab to trastuzumab plus chemotherapy for node positive disease. The panel has designated use of trastuzumab with chemotherapy as a category 1 recommendation for all HER2-positive tumors > 1 cm, and based on the data above, chemotherapy plus trastuzumab and pertuzumab as a category 1, preferred regimen for all HER-2 positive, node-positive disease.

The data from the phase III KATHERINE trial reported improved outcomes in patients who had residual invasive cancer and received adjuvant trastuzumab emtansine (T-DM1). Invasive DFS at 3 years was 88.3% with T-DM1 versus 77.0% with trastuzumab. 410 T-DM1 significantly decreased the invasive breast cancer recurrence risk or death (HR 0.50, 95% CI 0.39-0.64, P < .001). 410 e ATEMPT trial was designed to determine whether T-DM1 was more toxic than paclitaxel/Trastuzumab. The long-term followup data of patients who received 1 year of adjuvant T-DM1 (n = 383) or trastuzumab/paclitaxel (n = 114) reported the 5-year invasive disease free survival rate with T-DM1 of 97.0% (95% CI, 95.2%-98.7%), the 5-year recurrence-free interval of 98.3% (95% CI, 96.3%-99.0%), and the 5-year OS rate of 97.8% (95% CI, 96.3%-99.3%). 411 The study was not powered to evaluate the efficacy of paclitaxel/trastuzumab, among those who received it, the reported 5-year invasive disease-free survival with this combination was 91.3% (95% CI: 86.0-96.9%), 5-year recurrence free interval was 93.3% (95% CI: 88.6-98.2%) and 5-year OS was 97.9% (95% CI: 95.2-100%). 411 Based on these data, T-DM1 may be considered an alternative for these patients ineligible for paclitaxel/Trastuzumab. Other recommended regimens: Anthracycline followed by taxane-containing chemotherapy regimens were used in the NSABP trial B-31, 412 NCCTG trial, 413 and BCIRG 006 trial. 403 the NOAH trial, patients were given concurrent taxane and anthracycline, then taxane alone followed by cyclophosphamidemethotrexate-fluorouracil. 414 In the FinHER patients were randomized to docetaxel or vinorelbine before anthracyclines, 406 and PACS 04 randomized patients to fluorouracil/epirubicin/cyclophosphamide or to epirubicin plus docetaxel. 415 The HERA trial did not mandate the choice of chemotherapy, 94% receiving anthracyclines and 26% receiving a taxane in addition to an anthracycline.

References

All of the above adjuvant trials of trastuzumab have demonstrated

clinically significant improvements in DFS. Furthermore, the HERA trial416 and the combined analysis of the NSABP B31 and NCCTG N9831 trials417 showed significant improvement in OS with the use of trastuzumab. A

more recent meta-analysis of all the above (excluding the BCIRG 006

Trial) showed that addition of trastuzumab resulted in an average absolute reduction in 10-year risk of recurrence of 9.0% (95% CI 7.4 to 10.7; P < . 0001), a reduction in 10-year breast cancer mortality by 6.4% (4.9 to 7.8; P < .0001), and a reduction in mortality (all causes) by 6.5% (5.0 to 8.0; P <.0001).418 The benefits of trastuzumab are independent of ER

status.412,419

The NCCN Panel considers it reasonable to incorporate pertuzumab into the above adjuvant regimens272,420,421

The results of theTRAIN-2 trial showed high pCR rates after treatment

regimen with anthracycline plus trastuzumab and pertuzumab (67%) and also without anthracycline plus trastuzumab and pertuzumab (68%).420

Patients who received anthracycline-containing regimen experienced more febrile neutropenia, hypokalemia, and left ventricular ejection fraction

(LVEF) decline to grade 2 or worse (≥10% or to <50%).420

A follow-up analysis of the TRAIN-2 study showed similar 3-year EFS and OS with or without anthracyclines in patients with stage II and III HER2-

positive breast cancer. Based on these results, considering the added

toxicity of anthracycline containing regimens the panel has added nonanthracycline containing regimens with trastuzumab and pertuzumab as

treatment options.422

The NCCN panel has included the following regimen as other

recommended regimens for HER2-positive disease:

doxorubicin/cyclophosphamide (AC) followed by docetaxel + trastuzumab (followed by docetaxel + trastuzumab); AC followed by docetaxel +

trastuzumab + pertuzumab and paclitaxel/carboplatin + trastuzumab +

pertuzumab.

Regimens Useful in Certain Circumstances:

One year of extended therapy with neratinib after completion of 1 year of adjuvant trastuzumab without pertuzumab was evaluated in the phase III ExteNET trial. Neratinib improved invasive DFS (HR 0.73, 95% CI 0.57-

0.92, P = .0083) primarily in the subgroup of HR-positive tumors (HR 0.60, 95% CI 0.43-0.83, P = .063). Neratinib is associated with moderate to

severe diarrhea.

Based on the trials listed in the section for “other recommended regimen and the above data from ExteNET, the NCCN panel has included following regimens have been included as useful in certain circumstances:

Docetaxel + cyclophosphamide + trastuzumab; AC followed by paclitaxel

+ trastuzumab followed by paclitaxel plus trastuzumab, various

schedules); AC followed by paclitaxel + trastuzumab + pertuzumab,

various schedules); Paclitaxel + trastuzumab + pertuzumab; adjuvant

neratinib and adjuvant T-DM1.

Therapeutic duration and Other Considerations in those receiving HER2-

targeted therapy

The length of trastuzumab administration in the adjuvant setting trials

listed above is 12 months. The HERA trial demonstrated no additional

benefit extending trastuzumab to 2 years compared with 1 year.

With respect to a duration less than 12 months, the results of the

PERSEPHONE trial showed non-inferiority for 6 months versus 12 months of trastuzumab treatment,423 However, the PHARE study observed more events in the 6 month cohort compared to the 12 month cohort, and noninferiority was not established.424 Furthermore, adverse events over time

remained similar in both arms, and comparable to data reported in other

trials.

Considering the conflicting results between PERSEPHONE and PHARE, in addition to the protocol design of the majority of the randomized trials

establishing the benefits of trastuzumab which utilized 12 months of

therapy, the NCCN panel recommends up to one year of HER2-targeted therapy with trastuzumab. Based on the updated APHINITY trial data, the addition of pertuzumab may be considered with trastuzumab in those with node-positive disease.

Increased cardiac toxicity has been observed in patients treated with

trastuzumab.412,425,426 In addition, anthracycline and taxane-based

regimens in combination with HER2-targeted agents are associated with further increased risk of cardiac toxicity.427 The panel recommends

evaluation of left ventricular ejection fraction (LVEF) prior to and during

treatment. The optimal frequency of LVEF assessment during adjuvant

trastuzumab therapy is not known. The FDA label recommends LVEF

measurements prior to initiation of trastuzumab and every 3 months during therapy.

According to the panel, use of a FDA-approved biosimilar is an

appropriate substitute for trastuzumab. Trastuzumab and hyaluronidaseoysk injection approved for subcutaneous use may be substituted for

intravenous trastuzumab. It is important to note that it has a different

dosage and administration compared to intravenous trastuzumab.

Adjuvant Therapy for Tumors of Favorable Histologies

The guidelines provide systemic treatment recommendations for the

favorable histology of invasive breast cancers (including pure tubular and pure mucinous cancers, pure cribriform, adenoid cystic secretory

carcinoma and other salivary carcinoma, rare low-grade forms of

metaplastic carcinoma) based on ER/PR status, tumor size and ALN

status. If used, the treatment options for endocrine therapy,

chemotherapy, and sequencing of treatment with other modalities are

similar to those of the usual histology of breast cancers. There are rare

subtypes of metaplastic carcinoma (eg, low-grade adenosquamous and

low-grade fibromatosis-like carcinoma) that have a favorable prognosis

even without administration of adjuvant systemic therapies.

The vast majority of pure tubular, pure mucinous, and pure cribriform

breast cancers are both ER-positive and HER2-negative. To be

associated with favorable prognosis, the favorable histologic type should not be high grade, should be pure (>90% as classified on the surgical

excision, not core biopsy alone), and should be HER-2 negative. If atypical pathologic or clinical features are present, consider treating as ductal/NST.

The pathology evaluation and accuracy of the ER and/or HER2

determination should be reviewed if these are ER-negative and/or

HER2-positive, or if a tumor with an ER- and PR-negative status is grade

1.276 Should a breast cancer be histologically identified as a pure tubular or mucinous breast cancer and be confirmed as ER-negative, then the tumor should be treated according to the guideline for the usual histology,

ER-negative breast cancers. The panel acknowledges that prospective

data regarding systemic adjuvant therapy of pure tubular and mucinous

histologies are lack

Post-Therapy Surveillance and Follow-up for T0–3, N1, M0 and T1–3, N0–1, M0 Tumors

Post-therapy follow-up is optimally performed by members of the

treatment team and includes the performance of regular history/physical

examinations every 4 to 6 months for the first 5 years after primary therapy and annually thereafter. Mammography should be performed annually.

Regarding frequency of mammograms after BCS followed by radiation, the NCCN Panel agrees with ASTRO’s “Choosing Wisely” list of

recommendations released in 2014.428 The recommendations state that

“annual mammograms are the appropriate frequency for surveillance of

breast cancer patients who have had BCS and RT with no clear

advantage to shorter interval imaging. Patients should wait 6 to 12 months after the completion of RT to begin their annual mammogram surveillance. Suspicious findings on physical examination or surveillance imaging might warrant a shorter interval between mammograms.”

The NCCN Panel notes that any imaging of reconstructed breast is not

indicated.

According to the NCCN Panel, in the absence of clinical signs and

symptoms suggestive of recurrent disease, laboratory or imaging studies to screen for metastasis are not necessary. The routine performance of

alkaline phosphatase tests and LFTs are not included in the guidelines.429-431 In addition, the Panel notes no evidence to support the use of “tumor

markers” for breast cancer, and routine bone scans, CT scans, MRI scans, PET scans, or ultrasound examinations in the asymptomatic patient

provide no advantage in survival or ability to palliate recurrent disease and are, therefore, not recommended.110,432

The use of breast MRI in follow-up of patients with prior breast cancer is

undefined. It may be considered as an option in patients with high lifetime risk (>20% based on models largely dependent on family history) of

developing a second primary breast cancer. Rates of contralateral breast cancer after either breast-conserving therapy or mastectomy have been

reported to be increased in patients with BRCA1/2 mutations when

compared with patients with sporadic breast cancer.433-435

The Panel recommends that patients with intact uteri who are taking

adjuvant tamoxifen should have yearly gynecologic assessments and

rapid evaluation of any vaginal spotting that might occur because of the

risk of tamoxifen-associated endometrial carcinoma in postmenopausal

patients.436 The performance of routine endometrial biopsy or

ultrasonography in the asymptomatic woman is not recommended. Neither test has demonstrated utility as a screening test in any population of

patients. The vast majority of patients with tamoxifen-associated uterine

carcinoma have early vaginal spotting.

If an adjuvant AI is considered in patients with amenorrhea following

treatment, baseline levels of estradiol and gonadotropin followed by serial monitoring of these hormones should be performed if endocrine therapy

with an AI is initiated.330 Bilateral oophorectomy assures postmenopausal status in young patients with therapy-induced amenorrhea and may be

considered prior to initiating therapy with an AI in a young woman.

Symptom management for patients on adjuvant endocrine therapies often requires treatment of hot flashes and the treatment of concurrent

depression. Venlafaxine, a serotonin-norepinephrine reuptake inhibitor

(SNRI), has been studied and is an effective intervention in decreasing hot flashes.332-335 There is evidence suggesting that concomitant use of

tamoxifen with certain selective serotonin reuptake inhibitors (SSRIs) (eg, paroxetine, fluoxetine) may decrease plasma levels of endoxifen, an active metabolite of tamoxifen.336,337 These SSRIs/SNRIs may interfere with the enzymatic conversion of tamoxifen to endoxifen by inhibiting a particular

isoform of CYP2D6. However, the mild CYP2D6 inhibitors such as

citalopram, escitalopram, sertraline, and venlafaxine appear to have no or only minimal effect on tamoxifen metabolism.330,338,339

Follow-up also includes assessment of patient adherence to ongoing

medication regimens such as endocrine therapies. Predictors of poor

adherence to medication include the presence of side effects associated with the medication, and incomplete understanding by the patient of the

benefits associated with regular administration of the medication.437 The

Panel recommends the implementation of simple strategies to enhance

patient adherence to endocrine therapy, such as direct questioning of the patient during office visits, as well as brief, clear explanations on the value of taking the medication regularly and the therapeutic importance of longer durations of endocrine therapy.

Lymphedema is a common complication after treatment for breast

cancer. Factors associated with increased risk of lymphedema include

extent of axillary surgery, axillary radiation, infection, and patient

obesity.438,439 The Panel recommends educating the patients on

lymphedema, monitoring for lymphedema, and referring for lymphedema management as needed.

Many young patients treated for breast cancer maintain or regain

premenopausal status following treatment for breast cancer. For these

patients, the NCCN Panel discourages the use of hormonal birth control

methods, regardless of the HR status of the tumor.440 Alternative birth

control methods are recommended, including intrauterine devices, barrier methods, and, for those with no intent of future pregnancy, tubal ligation or vasectomy. Breastfeeding during endocrine or chemotherapy treatment is not recommended by the NCCN Panel because of risks to the infant.

Breastfeeding after breast-conserving treatment for breast cancer is not

contraindicated. However, lactation from an irradiated breast may not be possible, or may occur only with a diminished capacity.440,441

The Panel recommends that patients on an adjuvant AI or who experience ovarian failure secondary to treatment should have monitoring of bone

health with a bone mineral density determination at baseline and

periodically thereafter. The use of estrogen, progesterone, or selective ER modulators to treat osteoporosis or osteopenia in patients with breast

cancer is discouraged. The use of a bisphosphonate is generally the

preferred intervention to improve bone mineral density. A single phase 3 study, ABCSG12, demonstrated improved outcomes with the addition of zoledronic acid in premenopausal patients receiving endocrine therapy

with ovarian suppression.442 Use of bisphosphonates in such patients and in other subgroups remains controversial. Denosumab has shown to

significantly reduce fractures in postmenopausal patients receiving

adjuvant therapy AIs, and improves bone mineral density.378

Optimal duration of bisphosphonate therapy has not been established.

Factors to consider for duration of anti-osteoporosis therapy include bone mineral density, response to therapy, and risk factors for continued bone loss or fracture. Patients treated with a bisphosphonate should undergo a dental examination with preventive dentistry prior to the initiation of

therapy, and should take supplemental calcium and vitamin D.

Evidence suggests that a healthy lifestyle may lead to better breast cancer outcomes. A nested case control study of 369 patients with ER-positive

tumors who developed a second primary breast cancer compared with

734 matched control patients who did not develop a second primary tumor showed an association between obesity (body mass index [BMI] ≥30),

smoking, and alcohol consumption and contralateral breast cancer.443 A

prospective study of 1490 patients diagnosed with stage I–III breast

cancer showed an association between high fruit and vegetable

consumption, physical activity, and improved survivorship, regardless of

obesity.444 There is emerging evidence that obesity is associated with

poorer outcomes for certain subtypes of breast cancers. The study by the

Women’s Intervention Nutrition group randomized patients with

early-stage breast cancer to an intervention group and a control group.

The intervention consisted of eight one-on-one visits with a registered

dietitian who had been trained on a low-fat eating plan. OS analysis

showed no significant difference between the two study arms (17% for the intervention vs. 13.6% without); however, subgroup analysis showed that those with ER- and PR-negative disease who were part of the intervention group saw a 54% improvement in OS.445

The NCCN Panel recommends an active lifestyle and ideal body weight

(BMI 20–25) for optimal overall health and breast cancer outcomes as

there are reports of proven benefits of exercise and active lifestyle during and after treatment.446-448

For management of issues related to survivorship including late/long-term effects of cancer and its treatment, see the NCCN Guidelines for

Survivorship.

Recurrent/Stage IV Breast Cancer

Staging and Workup for Recurrent and Stage IV Breast Cancer

The staging evaluation of patients who present with recurrent or stage IV breast cancer includes: history and physical examination; the performance of a CBC, LFTs, chest diagnostic CT, bone scan, and radiographs of any long or weight-bearing bones that are painful or appear abnormal on bone scan; diagnostic CT of the abdomen (with or without diagnostic CT of the pelvis) or MRI scan of the abdomen; and biopsy documentation of first

recurrence if possible. The NCCN Panel generally discourages the use of sodium fluoride PET or PET/CT scans for the evaluation of patients with

recurrent disease. There is limited evidence (mostly from retrospective

studies) to support the use of PET/CT scanning to guide treatment

planning through determination of the extent of disease in select patients with recurrent or metastatic disease.110,111,449,450 In general, the

non-diagnostic CT scans used for PET under-evaluate the lungs and the

liver compared with contrast-enhanced diagnostic CT scans. The Panel

considers biopsy of equivocal or suspicious sites to be more likely than

PET/CT scanning to provide accurate staging information in this patient

population.

The consensus of the NCCN Panel is that FDG-PET/CT is optional and

most helpful in situations where standard imaging results are equivocal or suspicious. The NCCN Panel recommends bone scan or sodium fluoride

PET/CT (category 2B) to detect bone metastases. However, if the FDGPET results clearly indicate bone metastases, these scans can be omitted.

The NCCN Panel recommends that metastatic disease at presentation or first recurrence of disease should be biopsied as a part of the workup for

patients with recurrent or stage IV disease. This ensures accurate

determination of metastatic/recurrent disease and tumor histology, and

allows for biomarker determination and selection of appropriate treatment. Soft tissue tumor biopsy is preferred over bone sites unless a portion of

the biopsy can be protected from harsh decalcification solution to preserve more accurate biomarker assessment.

Determination of HR status (ER and PR) and HER2 status should be

repeated in all cases when diagnostic tissue is obtained. ER and PR

assays may be falsely negative or falsely positive, and there may be

discordance between the primary and metastatic tumors.451,452 The

reasons for the discordance may relate to change in biology of disease,

differential effect of prior treatment on clonal subsets, tumor heterogeneity, or imperfect accuracy and reproducibility of assays.452 Discordance

between the receptor status of primary and recurrent disease has been

reported in a number of studies. The discordance rates are in the range of

3.4% to 60% for ER-negative to ER-positive; 7.2% to 31% for ER-positive to ER-negative; and 0.7% to 11% for HER2.453-462

The NCCN Panel recommends that re-testing the receptor status of

recurrent disease be performed, especially in cases when it was

previously unknown, originally negative, or not overexpressed. For

patients with clinical courses consistent with HR–positive breast cancer, or with prior positive HR results, the Panel has noted that a course of

endocrine therapy is reasonable, regardless of whether the receptor assay is repeated or the result of the most recent HR assay.

Genetic counseling is recommended if the patient is considered to be at

high risk for hereditary breast cancer, as defined by the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and

Pancreatic.

Genetic testing: In the metastatic setting, results from genetic testing may have therapeutic implications. Germline mutations in BRCA1/2 have

proven clinical utility and therapeutic impact. Therefore, germline BRCA1/2 mutations should be assessed in all patients with recurrent or metastatic

breast cancer to identify candidates for PARP inhibitor therapy.

Management of Locally Recurrent Disease

Patients with local recurrence only are divided into three groups: 1) those who had been treated initially by mastectomy alone; 2) those who had

been treated initially by mastectomy plus RT; and 3) those who had

received breast-conserving therapy plus RT.

In one retrospective study of local recurrence patterns in patients with

breast cancer who had undergone mastectomy and adjuvant

chemotherapy without RT, the most common sites of local recurrence

were at the chest wall and the supraclavicular lymph nodes.463 The

recommendations for treatment of the population of patients experiencing a local recurrence only are supported by analyses of a combined database of patients from the EORTC 10801 and Danish Breast Cancer

Cooperative Group 82TM trials. The analyses compared

breast-conserving therapy with mastectomy in patients with stage I and

stage II disease. The 133 (approximately 8%) patients experiencing a local recurrence as an initial event were approximately equally divided between those who had undergone mastectomy and those who had received

breast-conserving therapy as initial treatment for breast cancer. Of those in the former group, 51 (76%) were able to undergo RT with or without

surgery as treatment for local disease recurrence. No difference in survival emerged between patients receiving treatment after initial treatment with mastectomy or breast-conserving therapy; approximately 50% of both

groups were alive at 10-year follow-up.464

According to the NCCN Panel, mastectomy-treated patients should

undergo surgical resection of the local recurrence (if it can be

accomplished with limited morbidity) and involved-field RT to the chest

wall and supraclavicular area (if the chest wall was not previously treated or if additional RT may be safely administered). The use of surgical

resection in this setting implies the use of limited excision of disease with the goal of obtaining clear margins of resection. Unresectable chest wall

recurrent disease should be treated with RT if no prior radiation has been given.

In patients with a local breast recurrence after BCS and RT who had a

prior sentinel lymph node (SLN) biopsy, a repeat SLNB may be

considered although the accuracy of repeat SLNB is unproven, and the

prognostic significance of repeat SLNB after mastectomy is unknown and its use is discouraged.465,466 On the other hand, the prognostic significance of repeat SLNB after mastectomy is unknown and its use is discouraged.

The consensus recommendation of the Panel for most patients with a local recurrence following breast-conserving therapy and SLNB is mastectomy and a level I/II axillary dissection.

The results of the CALOR trial found that after complete resection in

patients with isolated locoregional recurrence, adjuvant chemotherapy

improves both DFS and OS.467 After a median follow-up of 4.9 years, the

overall DFS was 69% in the chemotherapy group versus 57% in the group that did not receive chemotherapy (HR, 0.59; P = .046).467 Five-year OS in all patients in the study was also significantly improved with chemotherapy (88% vs. 76%, P = .024).467 The benefit of adjuvant chemotherapy was

mostly seen in patients with ER-negative disease. Among patients with

ER-negative disease, 5-year DFS was 67% versus 35% (HR, 0.32; 95%

CI, 0.14–0.73) and in those ER-positive disease, the 5-year DFS was 70% versus 69% (HR, 0.94; 95% CI, 0.47–1.89).467 However these patients

received endocrine therapy.

According to the NCCN Panel, after local treatment, patients with local

recurrences only should be considered for limited duration systemic

chemotherapy or endocrine therapy similar to that outlined in the adjuvant chemotherapy section. The Panel emphasized the importance of

individualizing treatment strategies in patients with a recurrence of disease limited to a local site.

From the time of diagnosis of recurrent/stage IV metastatic disease, patients should be offered appropriate supportive care and symptom-related interventions as a routine part of their care. NCCN recognizes the importance of clinical trials and encourages participation when applicable and available.

Surgery for Recurrent or Stage IV Disease

The primary treatment approach recommended by the NCCN Panel for patients with metastatic breast cancer and an intact primary tumor is systemic therapy, with consideration of surgery after initial systemic treatment for those requiring palliation of symptoms or with impending complications, such as skin ulceration, bleeding, fungation, and pain. 468 enerally such surgery should be undertaken only if complete local clearance of tumor may be obtained and if other sites of disease are not immediately life-threatening. Alternatively, RT may be considered instead of surgery. Often such surgery requires collaboration between the breast surgeon and the reconstructive surgeon to provide optimal cancer control and wound closure.

0] [471] [472] Substantial selection biases exist in all of these studies and are likely to confound the study results. 473, 474 o prospective, randomized studies assessed whether or not surgery on the primary tumor in the breast is necessary for patients who are diagnosed with metastatic/stage IV breast cancer. 475, 476 In the first prospective trial, patients (n = 350) with de novo metastatic breast cancer who achieved a partial or complete response to anthracycline-based chemotherapy were randomly assigned to either surgery of the primary tumor plus adjuvant radiation or no locoregional treatment. 475 There was no difference in the OS between the group that received surgery and the group that did not (19.2 vs. 20.5 months; HR, 1.04; 95% CI, 0.81-1.34). 475 n a separate multicenter prospective registry study patients whose disease responded to first-line systemic therapy were randomized to management of the primary tumor by surgery or not. 477 Preliminary data showed no difference in OS between the two groups 477 However, in another trial by the Turkish Federation (MF07-01), patients (n = 274) with de novo metastatic breast cancer who were randomized to local management (mastectomy, or BCS with radiation) followed by systemic therapy versus systemic therapy only observed a benefit with surgery. 478 While no difference in survival was seen at 36 months, at 40 months, patients treated with local management showed an improvement in survival with locoregional treatment (46.4% vs. 26.4%; HR, 0.66; 95% CI, 0.49-0.88). 478 The design of this trial is different from the other, the first difference being the inclusion of two prospective studies described above in which patients were included only if they had experienced a response to systemic therapy. Second, randomization in the Turkish trial was not balanced. Patients who received surgery had lower rates of triple-negative disease (7% vs. 17%), visceral metastases (29% vs. 45%), and many had solitary bone metastases only (33% vs. 20%). 478 In an unplanned subgroup analysis, patients who appeared to derive the greatest OS benefit from local management included those with HR-positive disease (HR, 0.63; 95% CI, 0.44-0.89; P = .008); those with HER2-negative disease (HR, 0.64; 95% CI, 0.45-0.91; P = .01); those < 55 years (HR, 0.57; 95% CI, 0.38-0.86; P = .007); and those with solitary bone metastases (HR, 0.47; 95% CI, 0.23-0.98; P = .04). 478

The Panel recognizes the need for more data from randomized clinical trials that will address the risks and benefits of local therapy for patients with stage IV disease while eliminating selection biases. Though the available data do not support broadly considering local therapy with NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/10/28,21:39在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。

References

surgery and/or RT, this may be reasonable in select patients with disease responding to initial systemic therapy. In such clinical scenarios, patient engagement in the decision is encouraged.

Guideline Stratification for Systemic Therapy for Stage IV/Recurrent Disease

The systemic treatment of breast cancer recurrence or stage IV disease prolongs survival and enhances QOL but is not curative. Therefore,

treatments associated with minimal toxicity are preferred. Thus, the use of the minimally toxic endocrine therapies is preferred to the use of cytotoxic therapy whenever reasonable.479 Guidance for treatment of patients with breast cancer and brain metastases is included the NCCN Guidelines for Central Nervous System Cancers.

Patients with recurrent or stage IV breast cancer at diagnosis are initially stratified according to whether bone metastases are present. These two patient subsets (those with and without bony metastases) are then further stratified by tumor HR and HER2 status.

Therapy for Bone Metastases

Complications from bone metastases include pain, decreased

performance status, and decreased QOL, as well as skeletal-related

events (SREs), which are defined as the need for radiation or surgery to

bone, pathologic fractures, spinal cord compression, and hypercalcemia of malignancy.

The NCCN Panel recommends treatment with a bone-modifying agent

such as zoledronic acid, pamidronate, or denosumab (category 1) in

addition to chemotherapy or endocrine therapy if bone metastasis is

present; expected survival is ≥3 months. Patients should undergo a dental examination with preventive dentistry prior to initiation of this therapy. The bisphosphonates and denosumab are associated with a risk of

development of osteonecrosis of the jaw (ONJ). Poor baseline dental

health or dental procedures during treatment are known risk factors for

ONJ. Thus, a dental examination with preventive dentistry intervention is recommended prior to treatment with intravenous bisphosphonate or

denosumab, and dental procedures invasive of gum or bone during

treatment should be avoided if at all possible. Additional risk factors for the development of ONJ include administration of chemotherapy or

corticosteroids and poor oral hygiene with periodontal disease and dental abscess.480

Bisphosphonates

There are extensive data from randomized trials in support of the use of

bisphosphonates for patients with metastatic disease to bone. The

randomized clinical trial data include the use of zoledronic acid and

pamidronate in the United States and ibandronate and clodronate in

European countries.481-488 In metastatic bone disease, bisphosphonate

treatment is associated with fewer SREs, fewer pathologic fractures, and less need for RT and surgery to treat bone pain.

The use of bisphosphonates in metastatic disease is a palliative care

measure. No impact on OS has been observed in patients treated with

bisphosphonates.

The data indicate that zoledronic acid and pamidronate may be given on a 3- to 4-week schedule in conjunction with antineoplastic therapy (ie,

endocrine therapy, chemotherapy, biologic therapy) or every 12 weeks. Three randomized trials have compared zoledronic acid dosed every 4

weeks versus every 12 weeks.489-491 Data from these trials show that

among patients with breast cancer and bone metastases zoledronic acid administered once every 12 weeks versus once every 4 weeks does not compromise efficacy and has similar rates of SREs.489,490,492 In the ZOOM trial,489 the rate of skeletal morbidities was 0.22 (95% CI, 0.14–0.29) in

those receiving zoledronic acid every 4 weeks versus 0.26 (95% CI, 0.15–

0.37) in those receiving zoledronic acid every 12 weeks. In the CALGB

70604 trial,490 the rate of SREs in the 4-week arm was 29.5% versus

28.6% in the 12-week arm. In OPTIMIZE-2 trial,491 the rate of SREs was 22% in the 4-week arm and 23.2% in the 12-week arm.491 The NCCN

Panel recommends an optimal dosing of every 12 weeks.

The use of bisphosphonates should be accompanied by calcium and

vitamin D supplementation with daily doses of calcium of 1200 to 1500 mg and vitamin D3 of 400 to 800 IU. Recommended agents for use in the

United States are pamidronate 90 mg intravenously over 2 hours or

zoledronic acid 4 mg intravenously over 15 minutes. The original studies continued treatment for up to 24 months; however, there are limited

long-term safety data indicating treatment can continue beyond that

time.484,486,493 The risk of renal toxicity necessitates monitoring of serum

creatinine prior to administration of each dose and dose reduction or

discontinuation if renal function is reduced. Current clinical trial results

support the use of bisphosphonates for up to 2 years. Longer durations of bisphosphonate therapy may provide additional benefit, but this has not

yet been tested in clinical trials.

Denosumab

Patients with metastatic breast cancer to bone who are candidates for

bisphosphonate therapy may also be considered for treatment with

denosumab. This recommendation is based on the results of a single

randomized trial comparing denosumab to zoledronic acid.494 All trial

patients were recommended to supplement with vitamin D and calcium.

Patients on the experimental arm were given 120 mg of denosumab

injected subcutaneously every 4 weeks plus intravenous placebo versus the control arm where patients were given an intravenous infusion of 4 mg of zoledronic acid every 4 weeks, and a subcutaneous placebo. In this trial with non-inferiority as the primary endpoint, denosumab was shown to

significantly delay time to first SRE by 18% as compared with zoledronic acid (HR, 0.82; 95% CI, 0.71–0.95; P < .001 for non-inferiority; P = .01 for

superiority) and time to first and subsequent SREs (rate ratio, 0.77; 95% CI, 0.66–0.89; P = .001). No difference in time to progression or OS was observed.494 Dosing of denosumab outside of every 3 to 6 weeks has not been studied.

Systemic Therapy for Stage IV or Recurrent Metastatic HR-Positive, HER2-Negative Breast Cancer

Patients with stage IV or recurrent disease characterized by HR-positive, HER2-negative tumors with no visceral crisis are treated with endocrine therapy alone or endocrine therapy in combination with targeted agents. Patients whose disease progresses after a year from the end of adjuvant endocrine-based therapy and those who present with de novo stage

IV/metastatic breast cancer are eligible for first-line endocrine therapies.

Many premenopausal and postmenopausal patients with HR-positive

breast cancer benefit from sequential use of endocrine therapies at

disease progression. Therefore, patients with breast cancers whose

disease responds to an endocrine-based therapy with either shrinkage of the tumor or long-term disease stabilization (clinical benefit) should

receive additional endocrine therapy at disease progression. For disease progression on or within 12 months of completing adjuvant endocrine

therapy or for disease progression on first-line endocrine therapy for

metastatic disease, patients are eligible for second-line endocrine therapy either as monotherapy or in combination with a targeted agent. The

optimal sequence for endocrine therapy is not well defined. The choice

would depend on previous tolerance of treatment and patient preference.

Many trials in HR-positive patients have not included premenopausal

patients. The NCCN Panel recommends that patients with HR-positive

disease should have adequate ovarian suppression/ablation and then be treated in the same way as postmenopausal patients. The NCCN Panel has outlined endocrine-based therapies that would be used in the first-line versus second- and subsequent-line settings.

NCCN Guidelines Version 5.2025 Breast Cancer

Abstract

In postmenopausal patients or premenopausal patients receiving ovarian ablation or ovarian function suppression with a luteinizing hormone-releasing hormone (LHRH) agonist, combinations of AIs with CDK 4/6 inhibitors (palbociclib, ribociclib, or abemaciclib) have demonstrated improved progression-free survival (PFS) relative to an AI alone.

Palbociclib in combination with letrozole was studied in a phase III study that included postmenopausal patients (n = 666) with metastatic, HR-positive, HER2-negative breast cancer who had not received prior treatment for advanced disease. 495 An improvement in PFS (24.8 vs. 14.5 months; HR, 0.58; 95% CI, 0.46-0.72) and objective response rate (ORR; 42% vs. 35%) was seen with the combination of palbociclib and letrozole compared with letrozole alone. 495 Grade 3 and 4 adverse effects seen with the combination of palbociclib and letrozole included neutropenia (66.5% vs. 1.4%), leukopenia (24.8% vs. 0%), anemia (5.4% vs. 1.8%) and fatigue (1.8% vs. 0.5%). 495 bociclib in combination with letrozole was also studied as first-line therapy in a phase III study of postmenopausal patients (n = 668) with HR-positive, HER2-negative recurrent/stage IV breast cancer. At a median follow-up of 26.4 months, an improvement in PFS (25.3 vs. 16.0 months; HR for progression or death was 0.56; 95% CI, 0.45-0.70) and improved ORR of 43% vs. 29% was seen with ribociclib plus letrozole compared with letrozole alone. 496 Grade 3 or 4 adverse events were more common with the combination and included neutropenia (62% vs. 1.2%), leukopenia (21.3% vs. 0.9%), and abnormal LFTs (10.2% vs. 2.4%). 496 e phase III MONARCH trial studied the combination of abemaciclib with either an AI (letrozole or anastrozole) or AI monotherapy as first-line treatment of patients with advanced HR-positive, HER2-negative breast cancer. The combination of abemaciclib with the AI improved PFS, compared with the AI alone (median not reached vs. 14.7 months, respectively; HR, 0.54; 95% CI, 0.41-0.72). 497 The ORR was higher with the combination compared with AI monotherapy (59% vs. 44 %). 497 The most frequent grade 3 or higher adverse events for abemaciclib versus placebo included diarrhea (9.5% vs.1.2%), neutropenia (21.1% vs. 1.2%), leukopenia (8% vs. 0.6%), and fatigue (2% vs. 0%). 497 st trials studying CDK 4/6 inhibitor with an AI have mainly included postmenopausal patients and only a small subset of premenopausal patients on ovarian suppression. However, in the phase III MONALEESA-7 trial, 672 pre-or perimenopausal patients with HR-positive, HER2-negative advanced breast cancer were randomly assigned to first-line treatment with ribociclib or placebo with goserelin plus either a nonsteroidal AI or tamoxifen. 498 An improvement in PFS was seen with the addition of ribociclib (median PFS, 24 vs. 13 months; HR, 0.55; 95% CI, 0.4-0.69). 498 3.5 years, an improvement in OS was reported with ribociclib (70% vs. 46%; HR, 0.71; 95% CI, 0.54-0.95). 499 Grade 3 and 4 adverse events reported in > 10% of patients in either group included neutropenia (61% vs. 4%) and leukopenia (14% vs. 1%). 498 sed on the above data, the NCCN Panel has included AI in combination with CDK 4/6 inhibitors as a category 1 first-line option for postmenopausal patients and premenopausal patients with ovarian ablation/suppression with HR-positive, HER2-negative recurrent/stage IV breast cancer.

Single-Agent Fulvestrant: Fulvestrant is an ER antagonist and was originally approved as a monthly intramuscular injection (250 mg per month); higher dose has been proven to be more effective in subsequent randomized trials. In the first-line setting, fulvestrant was found to be as NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/10/28,21:39在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。

References

MS-61

effective as anastrozole in terms of ORR (36.0% vs. 35.5%; OR, 1.02; 95% CI, 0.56-1.87). 500 An improved time to progression was seen with fulvestrant compared to anastrozole (median time to progression was 23.4 months for fulvestrant vs. 13.1 months for anastrozole; HR, 0.63; 95% CI, 0.39-1.00; P = .0496). 501 This study also used a higher loading dose of 500 mg every 2 weeks for 3 doses and then maintenance dose of 500 mg monthly. 500 The median OS was observed to be longer in the fulvestrant group than in the anastrozole group (54.1 months vs. 48.4 months; HR, 0.70; P = .041). 502 separate phase III randomized study in postmenopausal patients with metastatic HR-positive breast cancer compared fulvestrant 500 mg every 2 weeks for 3 doses followed by 500 mg monthly versus fulvestrant 250 mg monthly. The PFS was superior with the fulvestrant 500 mg regimen (HR, 0.80; 95% CI, 0.68-0.94; P = .006), 503 indicating an increased duration of response with the higher dose of fulvestrant. The final analyses demonstrated an increase in median OS (4.1 months) and reduced risk of death (19%) with a dose of 500 mg compared with 250 mg. Median OS was 26.4 versus 22.3 months (HR, 0.81; 95% CI, 0.69-0.96; P = .02). 504 sults from another phase III trial (FALCON) of first-line treatment with fulvestrant compared with anastrozole in endocrine therapy-naïve patients with metastatic ER-positive breast cancer, demonstrated improved PFS with fulvestrant (at the higher dose, 500 mg) over anastrozole at a median follow-up of 25.0 months (16.6 vs. 13.8 months; HR for progression or death, 0.797; 95% CI, 0.637-0.999). 505 The QOL outcomes were similar between the two groups, with the most common adverse effects being arthralgia (17% vs. 10%) and hot flashes (11% vs. 10%) for fulvestrant and anastrozole, respectively. 505 Fulvestrant + CDK 4/6 Inhibitor: In the phase III trial, MONALEESA-3, in patients (n = 726) with advanced HR-positive breast cancer who had no prior endocrine therapy or had disease progression on prior therapy, the combination of ribociclib with fulvestrant showed improved PFS versus fulvestrant alone (21 vs. 13 months; HR, 0.59; 95% CI, 0.48-0.73). 506 The PFS benefits were consistent across patients with and without prior endocrine treatment. In a subsequent analysis, a significant improvement in OS was observed. 507 At 42 months the estimated OS was 57.8% (95% CI, 52.0-63.2) in the ribociclib group and 45.9% (95% CI, 36.9-54.5) in the placebo group. 507 mparison across multiple trials, including those in the second-line settings studying combination of fulvestrant with palbociclib or abemaciclib have shown statistically significant improvement in PFS. Based on the results of the MONALEESA-3 trial and extrapolation results from the second-line setting, the NCCN Panel has included fulvestrant in combination with CDK 4/6 inhibitors as a category 1 first-line option for postmenopausal patients and premenopausal patients with ovarian ablation/suppression with HR-positive, HER2-negative recurrent/stage IV breast cancer.

Fulvestrant + Nonsteroidal AI: The combination of two endocrine agents as first-line treatment in postmenopausal patients with HR-positive, metastatic breast cancer has been reported from studies comparing single-agent anastrozole versus anastrozole plus fulvestrant.

In one study (FACT), combination of fulvestrant with anastrozole was not superior to single-agent anastrozole (time to progression HR, 0.99; 95% CI, 0.81-1.20; P = .91). 508 In a second phase III trial (SoFEA), the effect of fulvestrant alone or in combination with anastrozole or exemestane was studied in patients with advanced breast cancer with acquired resistance to a nonsteroidal AI. 509 An AI had been given as adjuvant treatment to 18% of patients for a median of 27.9 months, and to 82% of patients for locally advanced/metastatic disease for a median of 19.3 months. Median PFS was 4.8 months, 4.4 months, and 3.4 months for patients treated with fulvestrant alone, anastrozole plus fulvestrant, and fulvestrant plus NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/10/28,21:39在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。

References

exemestane, respectively. No differences were observed for ORR, clinical benefit rate, and OS.

In the trial by the Southwest Oncology Group (SWOG), S0226, PFS (HR,

0.80; 95% CI, 0.68–0.94; stratified log-rank P = .007) and OS (HR, 0.81; 95% CI, 0.65–1.00; stratified P = .049) were superior with combination

anastrozole plus fulvestrant.510 A subgroup analysis in this trial suggested that patients without prior adjuvant tamoxifen experienced the greatest OS benefit with combination therapy compared with monotherapy (median,

52.2 months vs. 40.3 months, respectively; HR, 0.73; 95% CI, 0.58–

0.92).511

The reasons for the divergent outcomes in the above trials is not very

clear. The three trials discussed above had slightly different patient

populations—there were more cases of patients with no prior endocrine

exposure (with de novo stage IV metastatic disease) in the SWOG S0226 trial compared with the FACT trial. The FACT trial included a more

heterogeneous population of both premenopausal and postmenopausal

patients with locally advanced and metastatic disease. The SoFEA trial

only enrolled patients with acquired endocrine resistance (who had

disease progression while they were receiving an AI). Further studies are needed to confirm the results of the SWOG S0226 trial.

The NCCN Panel has included an AI and fulvestrant as first-line therapy (category 1) for postmenopausal patients based on the above data.

Monotherapy with Endocrine Agents: In postmenopausal patients there is evidence supporting the use of an AI as first-line therapy for their recurrent disease.512,513

Prospective randomized trials comparing the AI head-to-head have

demonstrated that all AIs are the same.514 Tamoxifen is the commonly

used selective estrogen receptor modulator (SERM) for premenopausal

patients.515 In postmenopausal patients, AI monotherapy has been shown to have superior outcome compared with tamoxifen, although the

differences are modest.516-520 A randomized phase III trial comparing

tamoxifen with exemestane as first-line endocrine therapy for

postmenopausal patients with metastatic breast cancer showed no

significant differences in PFS or OS between the two arms.518

NCCN recommendations for first-line therapy: For postmenopausal

patients with HR-positive, HER2-negative recurrent/stage IV breast

cancer, NCCN category 1, preferred regimens include a cyclin-dependent kinase CDK 4/6 inhibitor with an AI; fulvestrant with or without a CDK 4/6 inhibitor; and fulvestrant with a nonsteroidal AI. The NCCN category 2A, preferred regimen includes nonsteroidal AI (ie, anastrozole, letrozole);

steroidal AI (exemestane), and selective ER modulator (tamoxifen or

toremifene). For premenopausal patients, first-line endocrine treatment

includes ovarian suppression/ablation and endocrine therapy listed above for postmenopausal patients or alternately with a SERM alone.

Preferred Regimens for Second and Subsequent Lines of Therapy for HR-Positive, HER2-Negative Breast Cancer

Fulvestrant-Containing Regimens

Fulvestrant + CDK 4/6 Inhibitors: Fulvestrant in combination with a CDK 4/6 inhibitor may be offered to patients who experienced disease

progression during prior treatment with AIs with or without one line of prior chemotherapy (category 1), because PFS was improved compared with fulvestrant alone in a phase III trial (PALOMA-3).521 The NCCN Panel

notes that treatment should be limited to those without prior exposure to CDK 4/6 inhibitors.

The PALOMA-3 compared the combination of palbociclib and fulvestrant to fulvestrant in pre- or postmenopausal patients with HR-positive,

HER2-negative advanced breast cancer, whose disease progressed on

MS-63

prior endocrine therapy. Pre-or perimenopausal patients also received goserelin. The median PFS was 9.5 months for the combination compared 4.6 months for fulvestrant (HR, 0.46; P < .000001) 522 Grade 3/4 adverse events of palbociclib and fulvestrant were mainly confined to neutropenia (in 65% of patients).

In the MONARCH 2 phase III trial, patients who had disease progression while receiving endocrine therapy were randomly assigned to fulvestrant with or without abemaciclib. 523 Those receiving combination therapy experienced an improved PFS relative to those receiving fulvestrant alone (16.4 vs. 9.3 months; HR, 0.55; 95% CI, 0.45-0.68). The ORR was higher in those receiving abemaciclib and fulvestrant (48% vs. 21%). 523 In addition, an improvement was seen in OS with abemaciclib plus fulvestrant compared with fulvestrant alone (46.7 vs. 37.3 months; HR, 0.757; 95% CI, 0.606-0.945). 524 sed on the above data that shows addition of a CDK 4/6 inhibitor to fulvestrant in patients previously exposed to prior endocrine therapy provides a significant improvement in median PFS, the NCCN Panel has included fulvestrant in combination with a CDK 4/6 inhibitor as a category 1 option for postmenopausal patients and premenopausal patients with ovarian ablation/suppression with HR-positive, HER2-negative, recurrent/stage IV breast cancer. The Panel notes that if there is disease progression while on CDK 4/6 inhibitor therapy, there are limited data to support an additional line of therapy with another CDK 4/6 inhibitor-containing regimen.

Fulvestrant Monotherapy: Fulvestrant monotherapy appears to be at least as effective as anastrozole in patients whose disease progressed on previous tamoxifen. 525, 526 A randomized phase II study compared anastrozole versus fulvestrant in over 200 patients with advanced breast cancer. 500, 501 In the initial analysis, fulvestrant was as effective as anastrozole in terms of ORR (36.0% vs. 35.5%; OR, 1.02; 95% CI, 0.56-1.87; P = .947) in evaluable patients (n = 89 for fulvestrant and n = 93 for anastrozole). 500 An improved time to progression was seen with fulvestrant compared to anastrozole (median time to progression was 23.4 months for fulvestrant vs. 13.1 months for anastrozole; HR, 0.63; 95% CI, 0.39-1.00; P = .0496). 501 This study used a higher 500 mg loading dose every 2 weeks for 3 doses and then 500 mg monthly. 500 The median OS was observed to be longer in the fulvestrant group than in the anastrozole group (54.1 months vs. 48.4 months; HR, 0.70; P = .041). 502

A phase II study of fulvestrant in postmenopausal patients with advanced breast cancer and disease progression following AI therapy documented a partial response rate of 14.3% with an additional 20.8% of patients achieving stable disease for at least 6 months. 527 The clinical benefit rates of exemestane versus fulvestrant observed in a phase III trial of postmenopausal patients with HR-positive advanced breast cancer who experienced disease progression on prior nonsteroidal AI therapy were comparable (32.2% vs. 31.5%; P = .853). 528 In that study, fulvestrant was administered as a 500 mg loading dose followed by doses of 250 mg on day 14, day 28, and then monthly. 528 lvestrant Plus Alpelisib: In a randomized phase III trial, patients (n = 572) with advanced HR-positive breast cancer and confirmed PIK3CA status had received a prior AI either for local or advanced disease. Patients were enrolled into either the PIK3CA mutant (n = 341) cohort or the PIK3CA non-mutant cohort and each cohort was randomized to receive fulvestrant plus the phosphoinositide 3-kinase (PI3K) inhibitor, alpelisib versus fulvestrant plus placebo. Patients with a PIK3CA mutation receiving alpelisib showed improved PFS compared to fulvestrant alone. At a median follow-up of 20 months PFS was 11.0 months (95% CI, 7.5-14.5) in the alpelisib group compared with 5.7 months (95% CI, 3.7-7.4) in the group that received fulvestrant alone (HR for progression or death, 0.65; 95% CI, 0.50-0.85; P < .001); in the cohort without PIK3CA-mutated NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/10/28,21:39在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。

References

tumors, the HR was 0.85 (95% CI, 0.58–1.25). In the overall population,

the most frequently reported grade 3 or 4 adverse events seen with

alpelisib and fulvestrant versus fulvestrant alone were hyperglycemia

(36.6% vs. 0.7%), rash (9.9% vs. 0.3%), and diarrhea (6.7% vs. 0.3%)

(grade 3); no diarrhea or rash of grade 4 were reported.529

Everolimus Plus Endocrine Therapy: Resistance to endocrine therapy in patients with HR-positive disease is frequent. One mechanism of

resistance to endocrine therapy is activation of the mammalian target of

rapamycin (mTOR) signal transduction pathway.

A randomized phase II study estimated the efficacy of tamoxifen alone

versus tamoxifen combined with everolimus, an oral inhibitor of mTOR, in patients with HR-positive, HER2-negative metastatic breast cancer

previously treated with an AI.530 After a median follow-up of 13 months, an intent-to-treat analysis showed that the clinical benefit was 42.1% (95%

CI, 29.1–55.9) with tamoxifen alone and 61.1% (95% CI, 46.9–74.1) with tamoxifen plus everolimus. An improvement in median time to progression was seen when everolimus was combined with tamoxifen compared with tamoxifen alone. Median time to progression was 4.5 months (95% CI,

3.7–8.7) with tamoxifen alone versus 8.5 months (95% CI, 6.01–13.9) with everolimus and tamoxifen.530

In a phase III trial in postmenopausal patients with advanced, HR-positive breast cancer with no prior endocrine therapy for advanced disease,

randomized subjects to letrozole with or without the mTOR inhibitor

temsirolimus,531 PFS was not different between the treatment arms (HR,

0.89; 95% CI, 0.75–1.05; log-rank P = .18).

The results of this trial differ from that of the BOLERO-2 trial (described

below). The reasons for the differences in the outcomes of these two

randomized phase III studies531,532 is uncertain, but may be related to the issues of patient selection and extent of prior endocrine therapy.

A phase III study (BOLERO-2) randomized postmenopausal patients with HR-positive advanced breast cancer that had disease progression or

recurrence during treatment with a nonsteroidal AI to exemestane with or without the mTOR inhibitor everolimus.533 Final results reported after

median 18-month follow-up show that median PFS (by central review)

remained significantly longer with everolimus plus exemestane versus

placebo plus exemestane at 11.0 versus 4.1 months, respectively (HR,

0.38; 95% CI, 0.31–0.48; P < .0001).532 The adverse events (all grades)

that occurred more frequently in those receiving everolimus included

stomatitis, infections, rash, pneumonitis, and hyperglycemia.532,533 Analysis of safety and efficacy in the older patients enrolled in this trial showed that older patients treated with an everolimus-containing regimen had similar

incidences of these adverse events, but the younger patients had more

on-treatment deaths.534 Based on the evidence from the BOLERO-2 trial, the NCCN Panel has included everolimus plus exemestane as an option for patients who fulfill the entry criteria for BOLERO-2. Tamoxifen or

fulvestrant in combination with everolimus have also been included as

options. The NCCN Panel also notes that if there is disease progression

while on an everolimus-containing regimen, there are no data to support

an additional line of therapy with another everolimus regimen.

Aromatase Inhibitors: AIs as monotherapy are options as subsequent-line therapy. The three AIs (anastrozole, letrozole, and exemestane) have

shown similar efficacy in the second-line setting.514,535,536 AI monotherapy maybe be useful in patients desiring single-agent treatment, if they have

not received an AI as first-line treatment or if they may not be suitable for combination therapy. Patients who have received a prior nonsteroidal AI

may benefit from a steroidal AI as a subsequent line of therapy or vice

versa.

Selective ER Modulator: An analysis of two randomized studies of first-line treatment with anastrozole followed by second-line tamoxifen and vice

versa showed that tamoxifen is effective as a second-line option.537

NCCN Recommendations for Second-line Therapy: For postmenopausal patients with HR-positive, HER2-negative recurrent/stage IV breast

cancer, the preferred options available include fulvestrant with a CDK 4/6 inhibitor (ie, palbociclib, ribociclib, abemaciclib) (category 1), or for those with tumor PIK3CA mutations, fulvestrant with alpelisib; everolimus with

either an AI, tamoxifen, or fulvestrant; monotherapy with fulvestrant;

nonsteroidal or steroidal AI; or SERM. Estrogen receptor 1 (ESR1)

activating mutations are frequently detected in patients with prior exposure to AIs. Tumors with these mutations are generally resistant to both AIs and tamoxifen. Certain tumors with these mutations retain sensitivity to

fulvestrant. All may benefit by adding one of the following to fulvestrant: a CDK 4/6-inhibitor, or an mTOR-inhibitor, or alpelisib, if the tumor has

PIK3CA mutation.

Regimens Useful in Certain Circumstances for Therapy for HR-Positive, HER2-Negative Breast Cancer

Megestrol acetate,512,538-540 estradiol541 androgens such as

fluoxymesterone, and single-agent abemaciclib have been listed as

options useful in certain circumstances.

The phase II MONARCH 1 trial evaluated the activity of abemaciclib as a single agent in patients (n = 132) with refractory HR-positive,

HER2-negative metastatic breast cancer who had disease progression

while on endocrine therapy and already received multiple systemic

therapies (average of three prior systemic regimens).542 Ninety percent of patients had visceral disease and 50.8% had more than three sites of

metastases.542 Single-agent abemaciclib induced a partial response in 26 patients (19.7%) and demonstrated an ORR of 19.7% (95% CI, 13.3–

27.5).542 Median PFS was 6 months (95% CI, 4.2–7.5). At the final

analysis, at 18 months, median OS was 22.3 months (95% CI, 17.7–not reached).542 Diarrhea was the most frequent adverse event reported in

90.2% of patients. Other common adverse events were fatigue (65.2%), nausea (64.4%), and decreased appetite (45.5%). Grade 3 and 4

neutropenia occurred in 26.9% of patients.542 The NCCN Panel has

included single-agent abemaciclib as an option for those with disease progression on prior endocrine therapy and prior chemotherapy in the metastatic setting.

Systemic Therapy for Stage IV or Recurrent HR-Negative, HER2-Positive Breast Cancer

For patients with HER2-positive, HR-negative recurrent/stage IV breast

cancer, the treatment approach is HER2-targeted therapy in combination with systemic chemotherapy. The NCCN Panel notes that an

FDA-approved biosimilar is an appropriate substitute for trastuzumab.

Also, trastuzumab and hyaluronidase-oysk injection for subcutaneous use may be substituted for trastuzumab. This subcutaneous option has

different dosage and administration instructions compared to intravenous trastuzumab. Doses and schedules of representative regimens for use in HER2-positive metastatic breast cancer are also included in NCCN

Guidelines.

Patients with disease progression while being treated with HER2-targeted therapy should be offered an additional line of treatment with a

HER2-targeted therapy since it is beneficial to continue suppression of the HER2 pathway. The choice of the HER2-targeted therapy will depend on previously administered therapy, relapse-free interval, and patients’

preference and access.

The optimal sequence of available HER2-targeted therapies and the

optimal duration of HER2-targeted therapy for recurrent/stage IV breast

cancer is currently unknown. The NCCN Panel recommends continuing

HER2-targted therapy until progression/unacceptable toxicity.

Preferred Regimens for Stage IV/Recurrent HER2-Positive Breast Cancer

Abstract

A randomized, double-blind, phase III study (CLEOPATRA) compared the efficacy and safety of pertuzumab in combination with trastuzumab and docetaxel versus trastuzumab and docetaxel as first-line treatment for 808 patients (n = 808) with HER2-positive metastatic breast cancer. 543 This trial included patients (about 10%) who had previously received trastuzumab in the adjuvant or neoadjuvant setting. At a median follow-up of 19 months, the addition of pertuzumab to docetaxel plus trastuzumab resulted in improvement in PFS compared with placebo (median, 18.5 vs. 12.4 months; HR, 0.62; 95% CI, 0.51-0.75; P < .001). 543 At a median follow-up of 30 months the results showed a statistically significant improvement in OS in favor of the pertuzumab-containing regimen, with a 34% reduction in the risk of death (HR, 0.66; 95% CI, 0.52-0.84; P = .0008). 544 The most common adverse reactions reported in the pertuzumab group compared to the control group were diarrhea (67% vs. 46%), rash (34% vs. 24%), mucosal inflammation (27% vs. 20%), febrile neutropenia (14% vs. 8%), and dry skin (10% vs. 4%). Peripheral edema and constipation were greater in the control group. 543 Cardiac adverse events or left ventricular systolic dysfunction were reported slightly more frequently in the control group. 545 HRQOL was not different in the two treatment groups. 546 In the PERUSE study, patients (n = 1436) with advanced HER2-positive breast cancer and no prior systemic therapy (except endocrine therapy) received docetaxel, paclitaxel, or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The preliminary results after 52 months of median follow-up show that median PFS was comparable between docetaxel, paclitaxel, and nab-paclitaxel (median PFS reported was 19.6, 23.0, and 18.1 months with docetaxel, paclitaxel, and nab-paclitaxel, respectively). 547 Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (31% vs. 16%), but less febrile neutropenia (1% vs. 11%) and mucositis (14% vs. 25%).

Phase II trials have also found activity and tolerability for pertuzumab, pertuzumab with trastuzumab, and for other regimens combining pertuzumab and trastuzumab together with other active cytotoxic agents (ie, paclitaxel, vinorelbine). 548, 549, 550 Phase III trials of pertuzumab plus chemotherapy without trastuzumab have not been reported.

The NCCN Panel recommends pertuzumab plus trastuzumab in combination with a taxane as a preferred option for first-line treatment of patients with HER2-positive metastatic breast cancer. Pertuzumab plus trastuzumab in combination with docetaxel is an NCCN category 1 and in combination with paclitaxel is an NCCN category 2A recommendation.

Other Regimens for Stage IV/Recurrent HER2-Positive Breast Cancer

Ado-trastuzumab emtansine (T-DM1):

T-DM1 is an antibody-drug conjugate that stably links the HER2-targeting property of trastuzumab to the cytotoxic activity of the microtubule-inhibitory agent DM1 (derivative of maytansine).

In a phase III trial (MARIANNE), 1095 patients with locally advanced or metastatic breast cancer were randomized to first-line treatment with T-DM1 with or without pertuzumab or trastuzumab plus a taxane. The primary endpoints were safety and PFS assessed by independent review. The PFS for T-DM1 with pertuzumab was found to be non-inferior to trastuzumab and a taxane (15.2 and 13.7 months, respectively; HR, 0.87; 97.5% CI, 0.69-1.08; P = .14). 551 The PFS for T-DM1 alone was non-inferior to trastuzumab plus a taxane (14.1 and 13.7, respectively; HR, 0.91; 97.5% CI, 0.73-1.13; P = .31). 551 The incidence of grade 3-5 adverse events was 54.1%, 45.4%, and 46.2% in the trastuzumab plus a taxane arm, T-DM1 arm, and T-DM1 plus pertuzumab arm, respectively. HRQOL was maintained for a longer duration with a median of 7.7 months for T-DM1 (HR, 0.70; 95% CI, 0.57-0.86) and a median of 9 months for NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/10/28,21:39在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。

References

T-DM1 plus pertuzumab (HR, 0.68; 95% CI, 0.55–0.84) compared with a

median of 3.9 months for trastuzumab and a taxane.551

Based on the MARIANNE trial data demonstrating T-DM1 and T-DM1 with pertuzumab being non-inferior, with better QOL compared with

trastuzumab plus a taxane and possibly better tolerated for some patients, 551 the NCCN Panel included T-DM1 as an option for treatment of patients with HER2-positive metastatic breast cancer. Pertuzumab, trastuzumab,

and a taxane, however, remains the preferred first-line regimen for

HER2-positive metastatic disease based on data demonstrating improved OS compared to trastuzumab and a taxane. TDM-1 as first-line therapy

should be considered only in those not suitable for the preferred treatment.

First-line trastuzumab in combination with selected chemotherapy552 are

additional options for patients with HER2-positive metastatic breast

cancer. Randomized trials demonstrate benefit from adding trastuzumab to other agents including paclitaxel with or without carboplatin,552-555

docetaxel,553 and vinorelbine,553 for patients with HER2-positive metastatic disease. In addition, the combination of trastuzumab and capecitabine has also shown efficacy as a first-line trastuzumab-containing regimen in this setting.556,557 The NCCN Panel believes the 27% frequency of significant cardiac dysfunction in patients treated with the combination of

trastuzumab and doxorubicin/cyclophosphamide chemotherapy in the

metastatic setting is too high for use of this combination outside the

confines of a prospective clinical trial.552,557,558

In those with disease progression on first-line trastuzumab-containing

regimens, the NCCN Panel recommends continuation of HER2 blockade. This recommendation also applies to patients who are diagnosed with

HER2-positive metastatic disease after prior exposure to trastuzumab in

the adjuvant setting. Several trials have demonstrated benefit of

continuation of trastuzumab therapy following disease progression on a

trastuzumab-containing regimen.559-561 However, the optimal duration of

trastuzumab in patients with long-term control of disease is unknown.

Pertuzumab is active in patients beyond the first-line setting. The results of a multicenter, open-label, single-arm, phase II study (n = 66) show that the combination of pertuzumab and trastuzumab is active and well tolerated in patients with HER2-positive metastatic breast cancer that has progressed on prior trastuzumab therapy.562 The trial reported an ORR of 24.2% (16 patients out of 66). The median PFS time observed with pertuzumab and trastuzumab combination was 15.5 months (range, 0.9–17.0 months; 80% CI, 18–31 months).562 The reported median duration of response with the combination was 5.8 months (range, 2.9–15.3 months).562

To determine whether the clinical benefit seen in the study was from

pertuzumab alone or was a result of the combined effect of pertuzumab

and trastuzumab, a cohort of patients (n = 29) whose disease progressed during prior trastuzumab-based therapy received pertuzumab

monotherapy until progressive disease or unacceptable toxicity. Of these, patients with disease progression (n = 17) continued to receive

pertuzumab with the addition of trastuzumab. In the 29 patients who

received pertuzumab monotherapy, the ORR and clinical benefit rate

reported were 3.4% and 10.3%, respectively, whereas in the patients who received dual blockade after disease progression while on pertuzumab,

the ORR and clinical benefit rate were 17.6% and 41.2%, respectively.563

According to the NCCN Panel, for patients with disease progression after treatment with trastuzumab-based therapy without pertuzumab, a line of

therapy containing both trastuzumab plus pertuzumab with or without a

cytotoxic agent (such as vinorelbine or taxane) may be

considered. Further research is needed to determine the ideal sequencing strategy for HER2-targeted therapy.

Abstract

T-DM1 also has also shown activity in the second-line setting. A randomized, international, multicenter, open-label, phase III study (EMILIA) evaluated the safety and efficacy of T-DM1 compared with lapatinib plus capecitabine for HER2-positive patients with locally advanced breast cancer or metastatic breast cancer previously treated with trastuzumab and a taxane. 564 The primary endpoints of this study were PFS, OS, and safety. T-DM1 demonstrated a statistically significant improvement in both primary endpoints of PFS and OS. PFS (assessed by independent review) was significantly improved with T-DM1 with median PFS of 9.6 months vs. 6.4 months with lapatinib plus capecitabine; HR for progression or death from any cause was 0.65 (95% CI, 0.55-0.77; P < .001). At the first interim analysis, T-DM1 also demonstrated significant improvement in OS. The stratified HR for death from any cause with T-DM1 versus lapatinib plus capecitabine was 0.62 (95% CI, 0.48-0.81; P = .0005). 564 Rates of grade 3 or 4 adverse events were higher with lapatinib plus capecitabine than with T-DM1 (57% vs. 41%). The incidences of thrombocytopenia and increased serum aminotransferase levels were higher with T-DM1 (frequency > 25%), whereas the incidences of diarrhea, nausea, vomiting, and palmar-plantar erythrodysesthesia were higher with lapatinib plus capecitabine. 564

A phase II single-arm study evaluated fam-trastuzumab deruxtecan-nxki, a HER2 antibody conjugated with a topoisomerase I inhibitor, in adults (n = 184) with pathologically documented HER2-positive metastatic breast cancer who had received multiple previous treatments including treatment with T-DM1. 565 After a median duration of follow-up of 11.1 months (range 0.7-19.9), the median response duration with fam-trastuzumab deruxtecan-nxki was 14.8 months (95% CI, 13.8-16.9), and the median PFS was 16.4 months (95% CI, 12.7-not reached). 565 Most commonly reported adverse events (grade 3 or higher) were a decreased neutrophil count (20.7%), anemia (8.7%), nausea (7.6%), and fatigue (6%). 565 Interstitial lung disease (ILD) was reported in 13.6% of the patients (grade 1 or 2, 10.9%; grade 3 or 4, 0.5%; and grade 5, 2.2%). Based on this study and the approval from the FDA, the NCCN Panel has included this as an option for HER2-positive metastatic disease noting that it is indicated in patients after two or more lines of prior HER2-targeted therapy in the metastatic setting and contraindicated for those with a history of or active ILD.

Lapatinib in combination with capecitabine or trastuzumab are options for patients with HER2-positive disease following disease progression on a trastuzumab-containing regimen.

A phase III study compared lapatinib plus capecitabine with capecitabine alone in patients with advanced or metastatic breast cancer refractory to trastuzumab in the metastatic setting and with prior treatment with an anthracycline and a taxane in either the metastatic or adjuvant setting. 566 Time to progression was increased in the group receiving combination therapy when compared with the group receiving capecitabine monotherapy (8.4 months vs. 4.4 months; HR, 0.49; 95% CI, 0.34-0.71; P < .001). The patients who had disease progression on monotherapy were allowed to cross over to the combination arm. This resulted in insufficient power to detect significant differences in OS; an exploratory analysis demonstrated a trend toward a survival advantage with lapatinib plus capecitabine. 567 The analysis reported a median OS of 75.0 weeks for the combination arm and 64.7 weeks for the monotherapy arm (HR, 0.87; 95% CI, 0.71-1.08; P = .210). 567

Results from a phase III trial in which patients with heavily pretreated metastatic breast cancer and disease progression on trastuzumab therapy randomly assigned to trastuzumab plus lapatinib or lapatinib monotherapy showed that PFS was increased from 8.1 weeks to 12 weeks (P = .008) with the combination. 568 The OS analysis data showed that lapatinib plus trastuzumab improved median survival by 4.5 months, with median OS of 14 months for the combination therapy and 9.5 months for lapatinib alone NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/10/28,21:39在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。

References

MS-69

(HR, 0.74; 95% CI, 0.57-0.97; P = .026). 569 This improvement in OS analysis included patients who were initially assigned to monotherapy and crossed over to receive combination therapy at the time of progression. 569 ased on the absence of data, the Panel does not recommend the addition of chemotherapy to the trastuzumab and lapatinib combination.

In a phase II trial of patients (n = 49) with progressive, HER2-positive disease and brain metastases (92% received CNS surgery and/or radiotherapy), 570 patients were treated with capecitabine plus neratinib, a second-generation (irreversible) pan-HER tyrosine kinase inhibitor (TKI) of the tyrosine kinase domains of EGFR, HER2, and HER4. The patients were separated based on prior lapatinib treatment. The combination therapy resulted in a CNS ORR of 49% (95% CI, 32%-66%), among lapatinib-naïve patients, and 33% (95% CI, 10%-65%) among those with prior lapatinib treatment. 570 Median PFS and OS among lapatinib-naïve patients was 5.5 and 13.3 months, and 3.1 and 15.1 months among those with prior lapatinib treatment. Grade 3 diarrhea occurred in 29% of patients. 570 prospective randomized phase III trial (NALA) randomized patients (n = 621) with HER2-positive breast cancer to neratinib in combination with capecitabine or lapatinib plus capecitabine until disease progression. 571 All enrolled patients received a least two lines of prior HER2-targeted treatment in the metastatic setting. Approximately 30% had received ≥3 prior treatment lines. About a third of all patients had received prior treatment with trastuzumab, pertuzumab, and T-DM1.

The ORR (32.8% vs. 26.7%; P = .1201), clinical benefit rate (44.5% vs. 35.6%; P = .0328), and median duration of response (8.5 vs. 5.6 months) all favored the neratinib arm. Fewer patients required intervention for CNS metastases with neratinib. The risk of progression was reduced by 24% in the neratinib group (HR, 0.76; 95% CI, 0.63-0.93; P = .0059). There was a non-significant trend towards improved survival. The OS rates at 6 and 12 months were 90.2% versus 87.5% with neratinib + capecitabine compared with 72.5% versus 66.7% for lapatinib in combination with capecitabine (HR, 0.88; 95% CI, 0.72-1.07; P = .2086). Diarrhea was the most frequently reported side effect in the NALA trial in both arms, but a higher rate was observed in patients in the neratinib group (any grade diarrhea, 83% vs. 66%; grade 3/4 diarrhea, 24% vs. 13%).

Based on the results of the NALA trial and the recent FDA approval, NCCN has included neratinib plus capecitabine as a category 2A option in this setting.

Systemic Therapy for Recurrent or Stage IV HR-Positive, HER2-Positive Breast Cancer

Patients with stage IV or recurrent disease characterized by tumors that are HR-positive, HER2-positive tumors have the option of receiving HER2-directed therapy as a component of their treatment plan. Options include treatment with a HER2-targeted therapy plus chemotherapy or endocrine therapy alone or in combination with HER2-targeted therapy. Endocrine therapy alone or in combination with HER2-targeted therapy is a less toxic approach compared with HER2-targeted therapy combined with chemotherapy. Premenopausal patients treated with HER2-targeted therapy and endocrine therapy should receive ovarian suppression or ablation.

References

Abstract

The combination was associated with a higher incidence of toxicities (all grades), fatigue (21% vs. 9%), diarrhea (20% vs. 8%), vomiting (21% vs. 4%), and pyrexia (18% vs. 7%); serious (grade 3/4) toxicities were rare in both treatment arms.

The phase III eLEcTRA trial studied the efficacy and safety of trastuzumab plus letrozole in patients (n = 93) with HER2-positive and HR-positive metastatic breast cancer. Median time to progression was 3.3 months with letrozole and 14.1 months with trastuzumab plus letrozole. The results are consistent with the TAnDEM trial; however, due to smaller numbers of patients enrolled in this trial, this was not statistically significant (HR, 0.67; 95% CI, 0.35-1.29; P = .23). 573 a phase III study of postmenopausal patients (n = 219) with HER2positive and HR-positive disease, first-line treatment with lapatinib plus letrozole reduced the risk of disease progression compared to treatment with letrozole alone (median PFS, 8.2 months vs. 3.0 months; HR, 0.71; 95% CI, 0.53-0.96; P = .019). 574 The combination of letrozole plus trastuzumab was associated with a higher rate of grade 3 or grade 4 toxicities, including diarrhea (10% vs. 1%) and rash (1% vs. 0%). 574

In the randomized phase II study (PERTAIN), postmenopausal patients (n = 258) were randomly assigned to either first-line pertuzumab plus trastuzumab and an AI (anastrozole or letrozole) or trastuzumab plus an AI. There was an improvement in PFS with the three-drug combination (18.9 vs. 15.8 months; HR, 0.65; 95% CI, 0.48-0.89). 575 Grade 3 or higher adverse events observed were higher trastuzumab and pertuzumab versus pertuzumab alone (50% vs. 39%). Of note, about half of patients received induction therapy with a taxane for 18 to 24 weeks prior to the initiation of endocrine therapy. Based on the results of the PERTAIN trial, 575 the NCCN Panel notes that if treatment was initiated with chemotherapy and trastuzumab plus pertuzumab, and the chemotherapy was stopped, endocrine therapy may be added to the trastuzumab plus pertuzumab.

In the ALTERNATIVE trial, postmenopausal patients (n = 355) with HER2-positive, HR-positive metastatic breast cancer were randomized to receive lapatinib plus trastuzumab plus an AI, lapatinib plus an AI, or trastuzumab plus an AI without chemotherapy. 576 All patients in the trial received prior trastuzumab and prior endocrine therapy, either in the adjuvant or metastatic disease setting. An AI in combination with lapatinib plus trastuzumab demonstrated a significant increase in PFS compared with trastuzumab without lapatinib (11 vs. 5.7 months; HR, 0.62; 95% CI, 0.45-0.88, P = .0064). 576 The most common adverse events with the combination compared with trastuzumab or lapatinib monotherapy were diarrhea (69%, 9%, 51%), rash (36%, 2%, 28%), nausea (22%, 9%, 22%), and paronychia (30%, 0%, 15%).

The NCCN Panel has also included other combinations of available endocrine therapies such as fulvestrant or tamoxifen with trastuzumab as options for HR-positive and HER2-positive metastatic disease. These options would be mostly considered after completion of chemotherapy plus HER2-therapy or in a few patients with indolent or asymptomatic disease based on the need for continuing HER2-targeted therapy for disease control. The selection of appropriate endocrine therapy would depend on agents the patient has already received.

Systemic Therapy for Recurrent or Stage IV Disease with Germline BRCA1/2 Mutations

About 5% of all patients with breast cancer carry the germline breast cancer susceptibility gene (BRCA) mutations, and rates of these mutations are higher among those with HER2-negative disease.

References

NCCN Guidelines Version 5.2025 Breast Cancer

MS-71

Abstract

mutations to the PARP inhibitor, olaparib (n = 205) or physician's choice (n = 97) of non-platinum chemotherapy (capecitabine, eribulin, or vinorelbine). 579 An improvement in PFS was seen in those receiving olaparib relative to those receiving chemotherapy [7.0 vs. 4.2 months; HR, 0.58; 95% CI, 0.43-0.80; P < .001]. 579 The study, included all subtypesthose with HR-positive, HER2-negative and -positive, and triple-negative disease. The PFS improvements noted with olaparib were noted in all subtypes and were greatest in the triple-negative population. Subsequent follow-up did not show a statistically significant difference in OS between treatment arms and the study was also not powered to evaluate OS. The median OS with olaparib compared with treatment of physician's choice was 19.3 months versus 17.1 months, respectively (HR, 0.90; 95% CI, 0.66-1.23; P = .513). 580 The QOL was significantly better in the olaparib arm. It is interesting to note that patients who had not received prior chemotherapy in the metastatic setting achieved a 7.9-month longer median OS with olaparib compared with treatment of physician's choice. 580

The phase III EMBRACA trial of patients with advanced breast cancer harboring the germline BRCA mutations and no prior exposure to a PARP inhibitor, were randomized to talazoparib (n = 287) or to physician's choice of single-agent chemotherapy (n = 144). 581 The median PFS among patients in the talazoparib group was longer than in the control group (8.6 months [95% CI, 7.2-9.3] vs. 5.6 months [95% CI, 4.2-6.7]; HR for disease progression or death, 0.54; 95% CI, 0.41-0.71; P < .001). 581

Based on the results of the above phase III trials, the two FDA-approved PARP inhibitors, olaparib and talazoparib, are included as category 1, preferred options for those with germline BRCA1/2 mutations. The NCCN Panel recommends assessing germline BRCA1/2 mutations in all patients with recurrent or metastatic breast cancer to identify candidates for PARP inhibitor therapy. While olaparib and talazoparib are FDA-indicated in HER2-negative disease, the NCCN Panel supports use in any breast cancer subtype associated with germline BRCA1/2 mutations.

Platinums: The phase III TNT trial compared docetaxel with carboplatin in the first-line setting in patients (n = 376) with triple-negative breast cancer.

In the unselected population, carboplatin was not more active than docetaxel (ORR, 31.4% vs. 34.0%; P = .66). 582 Patients with a germline BRCA1/2 mutation had a significantly better response to carboplatin than docetaxel (ORR, 68.0% vs. 33.3%, absolute difference, 34.7%; P = .03). 582 PFS was also improved with carboplatin treatment in patients with a germline BRCA1/2 mutation (median PFS, 6.8 months vs. 4.4 months); no difference was found in OS. However, patients with somatic BRCA1/2 mutation in the tumor DNA did not appear to have the same advantage.

For those with triple-negative recurrent/stage IV breast cancer and germline BRCA1/2 mutations, the NCCN Panel has included platinum agents (cisplatin and carboplatin) as preferred treatment options. It is unknown how PARP inhibitors compare with platinums in this setting.

Systemic Chemotherapy for Recurrent or Stage IV Disease

Patients with HR-negative tumors not localized to the bone or soft tissue only, or that are associated with symptomatic visceral metastasis irrespective of HR-or HER-status, or that have HR-positive tumors that are refractory to endocrine therapy should receive systemic chemotherapy.

A variety of chemotherapy regimens are felt to be appropriate, as outlined in the treatment algorithm. Combination chemotherapy generally provides higher rates of objective response and longer time to progression, in comparison to single-agent chemotherapy. 4] [585] [586] [587] Furthermore, administering single agents sequentially decreases the likelihood that dose reductions will be needed. Thus, the NCCN 授权医脉通提供NCCN指南全文下载。wmlsyy于2025/10/28,21:39在医脉通平台下载，仅供个人使用，严禁分发。2025 美国国家综合癌症网络版权所有。

References

NCCN Panel finds no compelling evidence that combination

chemotherapy is superior to sequential single agents. Therefore,

sequential monotherapy is preferred and combination therapy is useful in patients with rapid clinical progression or need for rapid symptom and/or disease control.

Usually the first-line regimens are given until progression or unacceptable toxicity. Considering what is unacceptable toxicity and considering no

further cytotoxic therapy should be decided together with the patient.

Adverse effects may require dose reduction and cessation of

chemotherapy prior to disease progression.

The NCCN Panel recommends considering scalp cooling to reduce

incidence of chemotherapy-induced alopecia for patients receiving

chemotherapy. The data on efficacy of scalp cooling is mainly from the

adjuvant setting and also show that results may be less effective with

anthracycline-containing regimens.588-592

A meta-analysis showed favorable impact on OS by prolonging treatment until disease progression.593 In this analysis, data from four studies

involving 666 patients indicated that median OS was increased by 23%

(95% CI, 9–38%; P = .01) in patients receiving longer durations of

chemotherapy versus a limited number of cycles.593 In a systematic

review, longer durations of chemotherapy demonstrated a marginal

increase in OS (HR, 0.91; 95% CI, 0.84–0.99) and a significant

improvement in PFS (HR, 0.66; 95% CI, 0.6–0.72), compared with shorter durations.587

A more recent study of patients (n = 420) with HER2-negative, advanced breast cancer showed that intermittent first-line treatment with paclitaxel plus bevacizumab was not inferior to continuous treatment. The median overall PFS for intermittent versus continuous treatment was 7.4 months and 9.7 months, respectively (HR, 1.17; 95% CI, 0.88–1.57). Median OS

was 17.5 months versus 20.9 months for intermittent versus continuous treatment (HR, 1.38; 95% CI, 1.00–1.91).594

Determining the duration of chemotherapy in an individual patient typically depends on the efficacy and tolerability and shared decision-making

between the treating physician and patient.

Most patients will be candidates for multiple lines of systemic therapy for palliation. At each reassessment clinicians should assess the value of

ongoing treatment, the risks and benefits of an additional line of systemic therapy, patient performance status, and patient preferences through a

shared decision-making process.

Preferred Chemotherapy Regimens for Stage IV or Recurrent Metastatic Disease

The NCCN Panel has classified the chemotherapy agents into three

categories: preferred, other recommended, and useful in certain

circumstances. The treatment decision should be individualized and

consider previous therapies, pre-existing comorbidities, nature of the

disease, toxicity profiles, patient preferences, and in some cases access to agents.

Among preferred single agents, the NCCN Panel has included taxanes (paclitaxel), anthracyclines (doxorubicin and liposomal doxorubicin),

antimetabolites (capecitabine and gemcitabine), microtubule inhibitors

(eribulin and vinorelbine), and platinum agents for patients with triplenegative tumors and germline BRCA1/2 mutations.

Paclitaxel can be administered weekly (80 mg/m2)595 or every 3 weeks

(175 mg/m2).596 A meta-analysis of randomized controlled trials that

compared weekly and every-3-week taxane regimens in advanced breast cancer showed that compared with every-3-week treatment, weekly

9] [600] [601] Liposomal doxorubicin (50 mg/m 2 every 4 weeks) has been shown to have efficacy similar to doxorubicin (60 mg/m 2 every 3 weeks). 602 It has also been shown to have efficacy in the second-line setting for patients with metastatic breast cancer. 602 Compared with doxorubicin, liposomal doxorubicin has a less frequent dosing schedule, decreased risk of cardiotoxicity (7% vs. 26%; HR, 3.16; 95% CI, 1.58-6.31), decreased rate of nausea (37% vs. 53%) and vomiting (19% vs. 31%), lower rates of alopecia (20% vs. 66%), and lower rates of neutropenia (4% vs. 10%). 602 However, compared with doxorubicin it was associated with a higher rate of palmar-plantar erythrodysesthesia (48% vs. 2%), stomatitis (22% vs. 15%), and mucositis (23% vs. 13%). 602 e benefit of capecitabine as a treatment option for patients with metastatic breast cancer has been demonstrated in multiple phase II trials. Results of one study of patients (n = 126) treated with capecitabine showed an ORR of 28%, median time to progression of 4.9 months, and median OS of 15.2 months (95% CI, 13.5-19.6 months). 603 In another study, patients (n = 95) were randomized to receive capecitabine or cyclophosphamide, methotrexate, and fluorouracil (CMF). 604 Treatment with single-agent capecitabine resulted in a higher ORR compared with CMF (30% vs. 16%). The median time to progression and OS were similar in both groups. 604 ibulin is a non-taxane microtubule inhibitor used for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting. In a phase III trial, patients (n = 762) with metastatic breast cancer were randomized 2:1 to eribulin or treatment of physician's choice. OS was improved in patients assigned to eribulin (median 13.1 months; 95% CI, 11.8-14.3) compared with those receiving other treatments (10.6 months, 9.3-12.5), a 19% statistically significant risk reduction (HR, 0.81; 95% CI, 0.66-0.99; P = .041). 605 phase III trial compared eribulin with capecitabine in patients with metastatic breast cancer and showed that both treatments were similar with respect to OS and PFS. 606 The median PFS times for eribulin and capecitabine were 4.1 and 4.2 months, respectively (HR, 1.08; 95% CI, 0.93-1.25; P = .30), and the OS with eribulin versus capecitabine was 15.9 months versus 14.5 months (HR, 0.88; 95% CI, 0.77-1.00). 606

[610] Among other recommended single agents, the NCCN Panel has included taxanes (docetaxel, 611 albumin-bound paclitaxel 612-614 ), anthracyclines (epirubicin 615 ), and ixabepilone [616] [617] [618] as other recommended regimens.

Ixabepilone as monotherapy has been evaluated in several phase II trials of patients with metastatic breast cancer: in a first-line setting in patients previously treated with anthracycline chemotherapy 616 ; in patients with taxane-resistant metastatic breast cancer 617 ; and in patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. 618 In the phase II trials, ORR, median duration of response, and median OS duration were 41.5% (95% CI, 29.4%-54.4%), 8.2 months (95% CI, 5.7-10.2 months), and 22.0 months (95% CI, 15.6-27.0 months) in the first-line setting; 616 12% (95% CI, 4.7%-26.5%), 10.4 months, and 7.9 months for the taxane-resistant patients; 617 and 11.5% (95% CI, 6.3%-18.9%), 5.7 months, and 8.6 months for the patients previously treated with an anthracycline, a taxane, and capecitabine. 618 In the study by Perez

References

NCCN Guidelines Version 5.2025 Breast Cancer

MS-74

Abstract

et al, 618 grade 3/4 treatment-related toxicities included peripheral sensory neuropathy (14%) and neutropenia (54%).

The NCCN Panel has included combination chemotherapy regimens as useful in certain circumstances. The combination regimen options include doxorubicin/cyclophosphamide (AC) 619, 620 ; epirubicin/cyclophosphamide (EC) 621 ; docetaxel/capecitabine 585 ; gemcitabine/paclitaxel (GT) 622 ; cyclophosphamide/methotrexate/fluorouracil (CMF) 623 ; gemcitabine/ carboplatin [624] [625] [626] ; carboplatin with paclitaxel or albumin-bound paclitaxel 627- 629 ; and paclitaxel/bevacizumab. [630] [631] [632] For the doublet regimens that are included, randomized phase III trials have shown that the ORR with first-line AC treatment ranges from 47% to 54% and OS is around 20 months. 619, 620 For first-line EC, a phase III trial reported the ORR of 55%, PFS of 7.1 months, and OS of 14 months. 621 For first-line capecitabine/docetaxel, a phase III trial reported an ORR of 53% and time to progression of 11 months. 633 In the second-line setting, another phase III trial compared the efficacy and tolerability of capecitabine/docetaxel therapy in anthracycline-pretreated patients and showed significantly superior efficacy in time to disease progression (HR, 0.652; 95% CI, 0.545-0.780; P = .0001; median, 6.1 vs. 4.2 months), OS (HR, 0.775; 95% CI, 0.634-0.947; P = .0126; median, 14.5 vs. 11.5 months), and ORR (42% vs. 30%, P = .006) compared with single-agent docetaxel. 585 mbination chemotherapy regimens containing a platinum agent or a taxane have been shown to be efficacious in patients with metastatic triple-negative breast cancer. A randomized phase II study compared the addition of iniparib to gemcitabine/carboplatin versus gemcitabine/carboplatin in patients with triple-negative breast cancer who had received no more than two prior chemotherapies. ORR was similar in both groups, 30.2% (95% CI, 24.6-35.8) with gemcitabine/carboplatin, 624 and the median OS was 11.1 months with gemcitabine/carboplatin (HR, 0.88; 95% CI, 0.69-1.12). 624

Several phase II studies have evaluated the efficacy of paclitaxel/carboplatin as first-line treatment for patients with metastatic breast cancer and found the combination to be an effective therapeutic option in this setting. 628, 629 The randomized trial, tnAcity, evaluated the efficacy and safety of first-line albumin-bound paclitaxel plus carboplatin, albumin-bound paclitaxel plus gemcitabine, and gemcitabine plus carboplatin in patients with metastatic triple-negative breast cancer. 627 he results of this trial reported that median PFS was significantly longer with albumin-bound paclitaxel plus carboplatin versus albumin-bound paclitaxel/gemcitabine (8.3 vs. 5.5 months; HR, 0.59; 95% CI, 0.38-0.92; P = .02) or gemcitabine/carboplatin (8.3 vs. 6.0 months; HR, 0.58; 95% CI, 0.37-0.90; P = .02). The median OS was also longer with albumin-bound paclitaxel plus carboplatin versus albumin-bound paclitaxel/gemcitabine (16.8 vs. 12.1 months; HR, 0.73; 95% CI, 0.47-1.13; P = .16) or gemcitabine/carboplatin (16.8 vs. 12.6 months; HR, 0.80; 95% CI, 0.52-1.22; P = .29). The ORR was 73%, 39%, and 44%, respectively. 627 e NCCN Panel notes that albumin-bound paclitaxel may be substituted for paclitaxel or docetaxel due to medical necessity (ie, hypersensitivity reaction). If substituted for weekly paclitaxel or docetaxel, then the weekly dose of nab-paclitaxel should not exceed 125 mg/m 2 .

The only triplet regimen listed as an option in the metastatic setting is CMF. This regimen was compared in the first-line setting with capecitabine monotherapy, and results show similar ORR and PFS. 623 However, CMF resulted in a shorter OS (median, 22 vs. 18 months; HR, 0.72; 95% CI, 0.55-0.94) compared to capecitabine.

References

Additional Targeted Therapies for Stage IV Disease Useful in Certain Circumstances

NTRK gene fusions are seen in a few rare types of cancer, such as

secretory carcinoma of the breast or salivary gland and infantile

fibrosarcoma and also infrequently in some common cancers, such as

melanoma, glioma, and carcinomas of the thyroid, lung, and

colon.634 NTRK fusions are identified by fluorescence in situ hybridization (FISH), next-generation sequencing (NGS), or polymerase chain reaction (PCR). Larotrectinib635-637 and entrectinib637,638 are two NTRK inhibitors

that are FDA-approved for the treatment of solid tumors that have an

NTRK gene fusion without a known acquired resistance mutation and

have no satisfactory alternative treatments or that have progressed

following treatment. If a patient with recurrent/stage IV breast cancer

presents with a tumor with an NTRK fusion, treatment with an NTRK

inhibitor is an option if no satisfactory alternative treatments exist or for

disease progression following treatment.

Pembrolizumab is FDA-approved for the treatment of patients with

unresectable or metastatic, microsatellite instability-high (MSI-H) or

mismatch repair deficient (dMMR) solid tumors that have progressed

following prior treatment and who have no satisfactory alternative

treatment options.639-641 Pembrolizumab has demonstrated anti-tumor

activity in heavily pretreated patients with metastatic breast cancer and

high tumor mutational burden (≥9 mutations/megabase) determined by

commercially available tests.642 If a patient with recurrent/stage IV breast cancer presents with a tumor with MSI-H/mismatch repair (MMR)

mutation, whose disease has progressed following prior treatments and no satisfactory alternative treatment options, treatment pembrolizumab is an option.

Monitoring Metastatic Disease

Monitoring the treatment of metastatic breast cancer involves a wide array of assessments and the need for the clinician to integrate several different forms of information to decide on the effectiveness of treatment and the

acceptability of toxicity. The information includes those from direct

observations of the patient, including patient-reported symptoms,

performance status, change in weight, and physical examination;

laboratory tests such as alkaline phosphatase, liver function, blood counts, and calcium; radiographic imaging; functional imaging; and, where

appropriate, tumor biomarkers. The results of these evaluations generally are classified as response, continued response to treatment, stable

disease, uncertainty regarding disease status, or progression of disease. The clinician typically must assess and balance multiple different forms of information to decide, along with the patient, whether disease is being

controlled and the toxicity of treatment is acceptable. Sometimes individual pieces of information can be conflicting with regard to disease response, and clinical judgment along with patient input is critical.

The NCCN Panel recommends using widely accepted criteria for reporting response, stability, and progression of disease such as the RECIST

criteria643 and the WHO criteria.644 The Panel also recommends using the same method of response assessment over time. For example, an

abnormality initially found on diagnostic CT scan of the chest should be

monitored with repeat diagnostic CT scans of the chest.

The optimal frequency of testing is uncertain and primarily based on the

monitoring strategies utilized in breast cancer clinical trials. The page titled Principles of Monitoring Metastatic Disease in the algorithm provides a

table outlining general recommendations for the frequency and type of

monitoring as a baseline before initiation of a new therapy, for monitoring the effectiveness of cytotoxic chemotherapy and endocrine therapy, and

as an assessment when there is evidence of disease progression. The

Panel has indicated in a footnote that the frequency of monitoring can be reduced in patients who have long-term stable disease. These are

guidelines and should be modified for the individual patient using clinical

judgment, especially for those with stable or responding disease for long periods of time.

The clinical use of circulating tumor cells (CTC) or circulating tumor DNA (ctDNA) in metastatic breast cancer is not yet included in the NCCN

Guidelines for Breast Cancer for disease assessment and monitoring.

Patients with persistently increased CTC after 3 weeks of first-line

chemotherapy have a poor PFS and OS.645 In spite of its prognostic ability, CTC count has failed to show a predictive value. A prospective,

randomized, phase 3 trial (SWOG S0500) evaluated the clinical utility of

serial enumeration of CTC in patients with metastatic breast cancer. 645

According to the study results, switching to an alternative cytotoxic therapy after 3 weeks of first-line chemotherapy in patients with persistently

increased CTC did not affect either PFS or OS.645

Special Situations

Paget Disease

Paget disease of the breast is a rare manifestation of breast cancer

characterized by neoplastic cells in the epidermis of the NAC.646 It most

commonly presents with eczema of the areola, bleeding, ulceration, and itching of the nipple. The diagnosis is often delayed because of the rare

nature of the condition and confusion with other dermatologic conditions. There is an associated cancer elsewhere in the breast in up to about 80% to 90% of cases.647-649 The associated cancers are not necessarily located adjacent to the NAC and may be either DCIS or invasive cancer.

Patients with clinical signs that raise suspicion for Paget disease require a complete history and physical examination and diagnostic breast imaging. Any breast lesion identified by imaging or examination should be

evaluated according to the NCCN Guidelines for Breast Cancer Screening and Diagnosis. The skin of the NAC should undergo surgical biopsy,

including the full thickness of the epidermis including at least a portion of any clinically involved NAC. When biopsy of the NAC is positive for Paget disease, breast MRI is recommended to define the extent of disease and identify additional disease.649,650

There are no category 1 data that specifically address local management of Paget disease. Systemic therapy is based on the stage and biological characteristics of any underlying cancer, and is supported by the evidence cited in the relevant stage-specific breast cancer treatment guidelines.

Management of Paget disease has traditionally been total mastectomy

with axillary dissection. Total mastectomy remains a reasonable option for patients regardless of the absence or presence of an associated breast

cancer.648 Data demonstrate that satisfactory local control may be

achieved with BCS including the excision with negative margins of any

underlying breast cancer along with resection of the NAC followed by

WBRT.651-655 The risk of ipsilateral breast recurrence after

breast-conserving NAC resection and RT with or without an associated

cancer is similar to that with BCS and RT with the typical invasive or in situ cancer.

For Paget disease without an associated cancer (ie, no palpable mass or imaging abnormality), it is recommended that BCS consist of removal of

the entire NAC with a negative margin of underlying breast tissue. In

cases with an associated cancer elsewhere in the breast, the surgery

includes removal of the NAC with a negative margin and removal of the

peripheral cancer using standard breast-conserving technique to achieve a negative margin. It is not necessary to remove the NAC and the

peripheral cancer in continuity in a single surgical specimen or through a single incision. Mastectomy also remains an appropriate treatment option.

ALN staging is not necessary when breast-conserving therapy is used to treat Paget disease with underlying DCIS without evidence of invasive

cancer following clinical examination, imaging evaluation, and

full-thickness skin biopsy of the involved NAC. In the presence of an

underlying invasive breast cancer treated with BCS, axillary surgery

should be performed according to the Considerations for Surgical Axillary Staging outlined in the NCCN Guidelines algorithm. In cases treated by

total mastectomy, axillary staging is recommended for patients with

invasive disease and should also be considered for patients with

underlying DCIS without evidence of invasive disease. This is because the final pathology may reveal an invasive cancer in the mastectomy

specimen and the mastectomy precludes subsequent sentinel node

biopsy. Two retrospective studies have provided evidence for a high

degree of accuracy in the identification of the sentinel node(s) in patients with Paget disease.656,657 Patients treated with breast conservation should receive whole breast radiation. Extended-field radiation to regional lymph nodes should be used in cases of an associated invasive breast cancer

with involved lymph nodes as for any breast cancer as described in the

initial sections of the NCCN Guidelines. A radiation boost should be

considered for the site of the resected NAC and any associated resected cancer site, if applicable.

Patients with an associated invasive cancer have substantial risk of

developing metastases. Adjuvant systemic therapy should be

administered according to the stage of the cancer. Patients with Paget

disease treated with breast conservation and without an associated cancer or those with associated ER-positive DCIS should consider tamoxifen for risk reduction. Those with an associated invasive cancer should receive

adjuvant systemic therapy based on the stage and HR status.

Phyllodes Tumors of the Breast

(also known as phyllodes tumors, cystosarcoma phyllodes)

Phyllodes tumors of the breast are rare tumors comprised of both stromal and epithelial elements.658 Phyllodes tumors exist in benign, borderline,

and malignant subtypes, although there is not uniform agreement on the criteria for assigning subtype or for predicting biological behavior.659 The

subtype of phyllodes tumor appears less important for risk of recurrence

than does the margin of tumor-free resection achieved by surgical

treatment. Diagnosis of phyllodes tumors prior to excisional

biopsy/lumpectomy is uncommon. Phyllodes tumors occur in an older age distribution than fibroadenoma, a younger age distribution than the

invasive ductal and lobular cancers, and with a mean age of 40 years.660 Phyllodes tumors often enlarge rapidly and are usually painless. Phyllodes tumors often appear on ultrasound and mammography as fibroadenomas, and FNA cytology and even core needle biopsy are inadequate to reliably distinguish phyllodes tumors from fibroadenomas.660 Thus, in the setting of a large or rapidly enlarging clinical fibroadenoma, excisional biopsy should be considered to pathologically exclude a phyllodes tumor. Patients with

Li-Fraumeni syndrome (germline TP53 mutation, see NCCN Guidelines for Genetic/Familial High Risk Assessment: Breast, Ovarian, and Pancreatic) have an increased risk for phyllodes tumors.661 Local recurrences of

phyllodes tumors are the most common site of recurrence. Most distant

recurrences occur in the lung, and may be solid nodules or thin-walled

cavities.

Treatment of phyllodes tumors (which includes benign, borderline, and

malignant subtypes) is with local surgical excision with tumor-free margins of ≥1 cm. Lumpectomy or partial mastectomy is the preferred surgical

therapy. Total mastectomy is necessary only if negative margins cannot

be obtained by lumpectomy or partial mastectomy.662 Since phyllodes

tumors rarely metastasize to the ALNs, surgical axillary staging or ALND is not necessary unless the lymph nodes are pathologic on clinical

examination.663 In those patients who experience a local recurrence,

resection of the recurrence with wide, tumor-free surgical margins should be performed. Some Panel members recommend local RT of the

remaining breast or chest wall following resection of a local recurrence,

but this recommendation is controversial (category 2B).664

While the epithelial component of most phyllodes tumors contains ER

(58%) and/or PR (75%),665 endocrine therapy has no proven role in the

treatment of phyllodes tumors. Similarly, there is no evidence that adjuvant cytotoxic chemotherapy provides benefit in reduction of recurrences or

death. In the rare patient who experiences a systemic recurrence (usually in the lung), treatment should be as recommended in the NCCN

Guidelines for Soft Tissue Sarcoma.

Breast Cancer During Pregnancy

Breast cancer occurring concurrently with pregnancy is an infrequent

clinical event. In a California registry study, there were 1.3 breast cancers diagnosed per 10,000 live births.666 Unfortunately, breast cancer during

pregnancy is most often ALN-positive and with larger primary tumor size. Histologically the tumors are poorly differentiated, are more frequently

ER/PR-negative, and approximately 30% are HER2-positive.667,668 The

diagnosis is often delayed because neither the patient nor the physician

suspects malignancy.

Evaluation of the pregnant patient with suspected breast cancer should

include a physical examination with particular attention to the breast and regional lymph nodes. Mammogram of the breast with shielding can be

done safely and the accuracy is reported to be >80%.669 Ultrasound of the breast and regional lymph nodes can be used to assess the extent of

disease and also to guide biopsy. Ultrasound has been reported to be

abnormal in up to 100% of breast cancers occurring during pregnancy.669 Biopsies for cytologic evaluation of a suspicious breast mass may be done with FNA of the breast and suspicious lymph nodes. However, the

preferred technique is core needle biopsy. This provides tissue for

histologic confirmation of invasive disease as well as adequate tissue for HR and HER2 analyses.

Staging assessment of the pregnant patient with breast cancer may be

guided by clinical disease stage. The staging studies should be tailored to minimize fetal exposure to radiation. For clinically node-negative T1–T2

tumors, a chest x-ray (with shielding), liver function and renal function

assessment, and a CBC with differential are appropriate. In patients who have clinically node-positive or T3 breast lesions, in addition to the

aforementioned tests an ultrasound of the liver and consideration of a

screening MRI of the thoracic and lumbar spine without contrast may be employed. The documentation of the presence of metastases may alter

the treatment plan and influence the patient’s decision regarding

maintenance of the pregnancy. Assessment of the pregnancy should

include a maternal fetal medicine consultation and review of antecedent

maternal risks such as hypertension, diabetes, and complications with

prior pregnancies. Documentation of fetal growth and development and

fetal age by means of ultrasonographic assessment is appropriate.

Estimation of the date of the delivery will help with systemic chemotherapy planning. In addition, maternal fetal medicine consultation should include counseling regarding maintaining or terminating pregnancy. Counseling of the pregnant patient with breast cancer should include a review of the

treatment options, which include mastectomy or BCS as well as the use of systemic therapy. The most common surgical procedure has been

modified radical mastectomy. However, BCS is possible if RT can be

delayed to the postpartum period,670 and breast-conserving therapy during pregnancy does not appear to have a negative impact on survival.670,671

When surgery is performed at 25 weeks of gestation or later, obstetrical

and prenatal specialists must be onsite and immediately available in the

event of precipitous delivery of a viable fetus.

Although there are a limited number of isolated case reports and small

retrospective studies evaluating use of SLNB in pregnant patients,672,673

the sensitivity and specificity of the procedure have not been established in this setting. Thus, there are insufficient data on which to base

recommendations for its use in pregnant patients. Decisions related to use of SLNB in pregnancy should be individualized. A review of the relative

and absolute contraindications to sentinel node biopsy concluded that

sentinel node biopsy should not be offered to pregnant patients <30 weeks gestation.674 There are limited data with only case reports and estimations of fetal radiation dose regarding use of radioactive tracer (eg, technetium 99m sulfur colloid).675-677 Isosulfan blue or methylene blue dye for sentinel node biopsy procedures is discouraged during pregnancy.

The indications for systemic chemotherapy are the same in the pregnant patient as in the non-pregnant patient with breast cancer, although

chemotherapy should not be administered at any point during the first

trimester of pregnancy. The largest experience in pregnancy has been

with anthracycline and alkylating agent chemotherapy.678,679 Collected data of chemotherapy exposure in utero indicate that the first trimester has the greatest risk of fetal malformation.680,681 Fetal malformation risks in the

second and third trimester are approximately 1.3%, not different than that of fetuses not exposed to chemotherapy during pregnancy. If systemic

therapy is initiated, fetal monitoring prior to each chemotherapy cycle is

appropriate. Chemotherapy during pregnancy should not be given after

week 35 of pregnancy or within 3 weeks of planned delivery in order to

avoid the potential for hematologic complications during delivery. Data

from a single-institution prospective study indicate that FAC chemotherapy (5-fluorouraci 500 mg/m2 IV days 1 and 4, doxorubicin 50 mg/m2 by IV

infusion over 72 hours, and cyclophosphamide 500 mg/m2 IV day 1) may be given with relative safety during the second and third trimesters of

pregnancy.679 As reported by Gwyn et al, the median gestational age at

delivery was 38 weeks, more than 50% of the patients had a vaginal

delivery, and there were no fetal deaths.667 An update of this experience

reported on 57 patients treated with FAC in the adjuvant or neoadjuvant

setting. There were 57 live births. A survey of parents/guardians reported on the health of 40 children. There was one child with Down syndrome

and two with congenital abnormalities (club foot, congenital bilateral

ureteral reflux). The children are reported to be healthy and progressing

well in school.679,682 Ondansetron, lorazepam, and dexamethasone can be used as part of the pre-chemotherapy antiemetic regimen.

There are limited data on the use of taxanes during pregnancy.683-686 If

used, the NCCN Panel recommends weekly administration of paclitaxel

after the first trimester if clinically indicated by disease status. There are

only case reports of trastuzumab use during pregnancy.687-694 The majority

of these case reports indicated oligohydramnios or anhydramnios with

administration of trastuzumab; fetal renal failure occurred in one case. If trastuzumab is otherwise indicated, it should be administered in the

postpartum period; the Panel recommends against its use during

pregnancy.

A single case report of first-trimester exposure to lapatinib during

treatment for breast cancer reported an uncomplicated delivery of a

healthy female neonate.695

Endocrine therapy and RT are contraindicated during pregnancy.

Endocrine therapy and RT, if indicated, should thus not be initiated until the postpartum period.

Communication between the oncologist and maternal fetal medicine

specialist is essential at every visit and for every treatment decision point for the patient.

Inflammatory Breast Cancer

IBC is a rare, aggressive form of breast cancer estimated to account for

1% to 6% of breast cancer cases in the United States.696,697 IBC is a

clinical diagnosis that requires erythema and dermal edema (peau

d’orange) of a third or more of the skin of the breast.

IBC is usually HR-negative and is more frequently HER2-positive than the usual ductal breast cancers. Studies on gene expression profiling of IBC have demonstrated that all the subtypes of IBC exist, but basal and HER2 overexpressed are more frequent.698-701 According to the 7th edition of the AJCC Cancer Staging Manual, IBC is classified as stage IIIB, stage IIIC, or stage IV breast cancer, depending on the degree of nodal involvement and whether distant metastases are present. The primary tumor of IBC is classified as T4d by definition, even when no mass is specifically apparent in the breast. On radiographic imaging, findings of skin thickening and, in some cases, an underlying mass are observed. Despite use of the term

“inflammatory,” the characteristic clinical features of IBC are due to

blockage of dermal lymphatics by tumor emboli. Although a biopsy is

required to evaluate for the presence of cancer in breast tissue and the

dermal lymphatics, a diagnosis of IBC is based on clinical findings, and

dermal lymphatic involvement is neither required, nor sufficient by itself, to assign a diagnosis of IBC.702,703 The differential diagnosis includes cellulitis of the breast and mastitis.

In the past, IBC has often been placed under the general heading of

locally advanced breast cancer. There is a growing body of evidence that patients with IBC, when compared with patients with noninflammatory

forms of locally advanced breast cancer, are more likely to have a less

favorable prognosis704-706 and to be younger at the time of disease

presentation.707

The NCCN Panel acknowledges that studies focusing on genetic

characterization of IBC are needed to more clearly define IBC as a

disease entity and to optimize treatment.708,709 Nevertheless, current

evidence provides justification for a separate guideline for the workup and treatment of patients diagnosed with IBC.

StageT4d, N0–N3, M0 Workup

Patients with a clinical/pathologic diagnosis of IBC without distant

metastasis (stage T4d, N0–N3, M0) should undergo a thorough staging

evaluation by a multidisciplinary team.

Recommendations for workup include a complete history and physical

examination involving a CBC and platelet count.

A pathology review and pre-chemotherapy determinations of tumor

HR- and HER2- status should be performed. HER2 has a predictive role in determining which patients with IBC will benefit from HER2-targeted

therapy. The NCCN Panel endorses the CAP protocol for pathology

reporting (www.cap.org) and endorses the ASCO CAP recommendations for quality control performance of HER2 testing and interpretation of IHC and ISH results.710

Imaging studies help facilitate image-guided biopsy, delineate locoregional disease, and identify distant metastases. Evaluation of all patients

suspected with IBC must include diagnostic bilateral mammogram, with

the addition of ultrasound as necessary. A breast MRI scan is optional.

Evaluations for the presence of distant metastasis in the asymptomatic

patient include LFTs, bone scan or sodium fluoride PET/CT (category 2B), and diagnostic CT imaging of the chest, abdomen, and pelvis (category

2B; category 2A for diagnostic CT imaging of the chest when pulmonary

symptoms are present).

FDG-PET/CT may be most helpful in situations where standard imaging

results are equivocal or suspicious. However, there is limited evidence

suggesting that PET/CT may be a useful adjunct to standard imaging of

IBC due to the increased risk of regional lymph node involvement and

distant spread of disease in this group of patients.110,111,711,712

Nevertheless, equivocal or suspicious sites identified by FDG-PET/CT

scanning or other imaging methods should be biopsied for confirmation of stage IV disease whenever possible. FDG-PET/CT is a category 2B

recommendation. The consensus of the Panel is that FDG-PET/CT can be performed at the same time as diagnostic CT. If FDG-PET and diagnostic CT are performed and both clearly indicate bone metastases, bone scan or sodium fluoride PET/CT may not be needed.

Genetic counseling is recommended if the patient is considered to be at

high risk for hereditary breast cancer as defined by the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian and

Pancreatic.

Treatment

The treatment of patients with IBC should involve a combined modality

approach696 comprising preoperative systemic therapy followed by surgery (mastectomy)

and

radiotherapy.

Preoperative Chemotherapy

There are no large randomized trials evaluating the optimal systemic

treatment of IBC, since it is a rare disease. The systemic therapy

recommendations are based on data from retrospective analyses, small

prospective studies, and data from non-IBC, locally advanced breast

cancer.

The benefit of preoperative systemic therapy followed by mastectomy over preoperative systemic therapy alone in patients with IBC was shown in a retrospective analysis in which lower local recurrence rates and longer

disease-specific survival were reported for the combined modality

approach.713 Results from a large retrospective study of patients with IBC performed over a 20-year period at The University of Texas MD Anderson Cancer Center demonstrated that initial treatment with doxorubicin-based chemotherapy followed by local therapy (ie, RT or mastectomy, or both)

and additional postoperative chemotherapy resulted in a 15-year DFS rate of 28%.714

A retrospective study demonstrated that the addition of a taxane to an

anthracycline-based regimen improved PFS and OS in patients with

ER-negative IBC.715 A systematic review found evidence for an

association between the intensity of preoperative therapy and the

likelihood of a pCR.716 A study of IBC patients, with cytologically confirmed ALN metastases, treated with anthracycline-based chemotherapy with or without a taxane indicated that more patients receiving the

anthracycline-taxane combination achieved a pCR compared with those who received only anthracycline-based therapy. In addition, patients who had a pCR in the ALNs had superior OS and DFS compared with those

with residual axillary disease.717

The NCCN Panel recommends preoperative systemic therapy with an

anthracycline-based regimen with or without taxanes for the initial

treatment of patients with IBC. The Panel also recommends completing

the planned chemotherapy prior to mastectomy. If the chemotherapy was not completed preoperatively, it should be completed postoperatively.

Targeted Therapy

All patients with HR-positive IBC are recommended to receive endocrine therapy sequentially after completing the planned preoperative systemic therapy.

HER2-positive IBC is associated with a poor prognosis.700,718 For patients with HER2-positive disease, the addition of trastuzumab to primary

systemic chemotherapy is associated with better response rates.414,719-722 A prospective study that randomized patients with locally advanced breast cancers, including those with IBC, to neoadjuvant anthracycline-based

chemotherapy with or without trastuzumab for 1 year demonstrated that

the addition of trastuzumab significantly improved the response rate and event-free survival.414 The NCCN Panel recommends inclusion of

trastuzumab in the chemotherapy regimen and is recommended for

patients with HER2-positive disease

There are no available data to

indicate the optimal duration of trastuzumab, specifically among patients with IBC. However, based on the available data,414 the Panel recommends continuing trastuzumab therapy for up to 1 year.

Results of small phase II trials indicate that other HER2-targeting agents such as lapatinib and pertuzumab have a clinical benefit in IBC.723,724 The results of the NEOSPHERE trial that included patients with IBC showed

increased pCR with the pertuzumab-containing regimens. Therefore, the NCCN Panel has included in a footnote that a pertuzumab-containing

regimen may be administered preoperatively in patients with

HER2-positive IBC.724

Determination of response to neoadjuvant chemotherapy in IBC should

include a combination of physical examination and radiologic assessment.

Surgery

Patients with a clinical/pathologic diagnosis of IBC should always be

treated with chemotherapy before surgery. It has been known for many

years that surgical treatment as primary treatment of patients with IBC is associated with poor outcomes.725 SLN dissection is not a reliable method of assessing ALNs among patients with IBC.726 Use of BCS in patients

with IBC has been associated with poor cosmesis, and limited data

suggest that rates of local recurrence may be higher when compared with mastectomy. Breast-conserving therapy is not recommended for patients with IBC.

Mastectomy with level I/II ALND is the recommended surgical procedure recommended by the NCCN Panel for patients whose tumor responds to neoadjuvant chemotherapy. The NCCN Panel has listed delayed breast reconstruction as an option that can be recommended to patients with

IBC who have undergone a modified radical mastectomy. Reconstruction of the breasts soon after mastectomy may compromise the

post-mastectomy RT outcomes.727

For patients with IBC who do not respond to preoperative systemic

therapy, mastectomy is not generally recommended. Additional systemic chemotherapy and/or preoperative radiation should be considered for

these patients. Patients with tumors responding to this secondary

therapy should undergo mastectomy and subsequent treatment as

described above.

Radiation

After mastectomy, RT is recommended after the completion of the

planned chemotherapy.

The probability of locoregional lymph node involvement is high for

patients with IBC. To reduce the risk of local recurrence, the Panel

recommends RT to the chest wall and the supraclavicular region. If the internal mammary lymph node(s) is clinically or pathologically involved, RT should include the internal mammary nodes. If the internal mammary nodes are not clinically or pathologically involved, then including the

internal mammary nodes in the RT field is at the discretion of the treating radiation oncologist (category 3). For HER2-positive disease,

trastuzumab may be administered concomitantly with RT.

Stage IV or Recurrent IBC

Patients with stage IV or recurrent IBC should be treated according to the guidelines for recurrence/stage IV breast cancer.

Axillary Breast Cancer

Occult breast cancer presenting with axillary metastases is an unusual presentation that can be a diagnostic and therapeutic challenge.

Evidence to support recommendations for patients presenting with

axillary breast cancer comes from a limited number of retrospective

studies involving small numbers of patients728-730 (see also references therein). Although treatment of patients with axillary metastases from an unknown primary tumor has typically involved mastectomy and axillary nodal dissection, some of these patients have also been successfully

treated with axillary nodal dissection followed by RT.729,730

Patients with a suspected occult primary breast cancer will typically

present to the oncologist after undergoing an initial biopsy: core needle biopsy (preferred), and/or FNA. Accurate pathologic assessment of the biopsied material is most important. Therefore, the pathologist must be consulted to determine whether the available biopsy material is

adequate, or if additional biopsy material is necessary (eg, core needle, incisional, or excisional biopsy) to provide an accurate and complete

diagnosis.

Workup for Possible Primary Breast Cancer

MRI of the breast can facilitate the identification of occult breast cancer, and can help select those patients most likely to benefit from

mastectomy.731 For example, in a study of 40 patients with biopsy-proven breast cancer in the axilla, and a negative or indeterminate

mammogram, MRI identified the primary breast lesion in 70% of the

patients.729 In addition, of the 7 patients with a negative MRI who

subsequently underwent ALND and RT to the whole breast, no evidence of local recurrence was evident at a median follow-up of 19 months.

The NCCN Guidelines for Occult Primary provide guidance on the

diagnosis and initial workup of patients with a suspicious axillary mass

without any signs of a primary tumor. A small subset of these patients

may have a primary cancer in the axillary tail of the breast.

Adenocarcinoma with positive axillary nodes and mediastinal nodes is

highly suggestive of a breast primary. Adenocarcinoma in the

supraclavicular nodes, chest, peritoneum, retroperitoneum, liver, bone, or brain could also indicate primary breast cancer in patients. The

guidelines suggest the use of a mammogram and breast ultrasound for such patients.

Testing for immunohistochemical markers including ER/PR and HER2 is recommended. Elevated ER/PR levels provide strong evidence for a

breast cancer diagnosis.732 MRI of the breast should be considered for a patient with histopathologic evidence of breast cancer when

mammography and ultrasound are not adequate to assess the extent of the disease. MRI may be especially helpful in patients with dense breast tissue, positive axillary nodes, and suspected occult primary breast

tumor or to evaluate the chest wall.733 Breast MRI has been shown to be useful in identifying the primary site in patients with occult primary breast cancer and may also facilitate breast conservation in selected patients by allowing for lumpectomy instead of mastectomy.729,734 In one report, the primary site was identified using MRI in about half of the patients

presenting with axillary metastases, irrespective of the breast density.735

The NCCN Guidelines for Occult Primary also provide recommendations for additional workup, including chest and abdominal CT to evaluate for evidence of distant metastases for patients diagnosed with

adenocarcinoma (or carcinoma not otherwise specified) of the axillary

nodes without evidence of a primary breast lesion. In particular, breast

MRI and ultrasound are recommended. Axillary ultrasound should also

be performed.

Treatment for Possible Primary Breast Cancer

Patients with MRI-positive breast disease should undergo evaluation with ultrasound or MRI-guided biopsy and receive treatment according to the clinical stage of the breast cancer. Treatment recommendations for those with MRI-negative disease are based on nodal status. For patients with T0, N1, M0 disease, options include mastectomy plus axillary nodal

dissection or axillary nodal dissection plus whole breast irradiation with

or without nodal irradiation. Systemic chemotherapy, endocrine therapy, or trastuzumab is given according to the recommendations for stage II or III disease. Neoadjuvant chemotherapy, trastuzumab, and endocrine

therapy should be considered for patients with T0, N2–N3, M0 disease

followed by axillary nodal dissection and mastectomy as for patients with locally advanced disease.

Summary

The therapeutic options for patients with noninvasive or invasive breast cancer are complex and varied. In many situations, the patient and

physician have the responsibility to jointly explore and select the most

appropriate option from among the available alternatives. With few

exceptions, the evaluation, treatment, and follow-up recommendations in these guidelines are based on the results of past and present clinical

trials. However, there is not a single clinical situation in which the

treatment of breast cancer has been optimized with respect to either

maximizing cure or minimizing toxicity and disfigurement. Therefore,

patient/physician participation in prospective clinical trials allows patients to not only receive state-of-the-art cancer treatment but also to contribute to improving the treatment outcomes.

References

Abstract

NCCN Guidelines Version 5.2025 Breast Cancer MS-92 74. Turnbull LW, Brown SR, Olivier C, et al. Multicentre randomised controlled trial examining the cost-effectiveness of contrast-enhanced high field magnetic resonance imaging in women with primary breast cancer scheduled for wide local excision (COMICE). Health Technol Assess 2010;14:1-182.

References

Abstract

Identification and resection of clipped node decreases the false-negative rate of sentinel lymph node surgery in patients presenting with node-positive breast bancer (T0-T4, N1-N2) who receive neoadjuvant chemotherapy: results from ACOSOG Z1071 (Alliance).

References

Abstract

LBA9500. 493. Rosen LS, Gordon D, Kaminski M, et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter,

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Global phase III study of gemcitabine plus paclitaxel (GT) vs. paclitaxel (T) as frontline therapy for metastatic breast cancer (MBC): First report of overall survival [abstract].

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Clin Oncol 2014;32:3840-3847. Available at:

http://www.ncbi.nlm.nih.gov/pubmed/25349301.

625. Yardley DA, Brufsky A, Coleman RE, et al. Phase II/III weekly nabpaclitaxel plus gemcitabine or carboplatin versus gemcitabine/carboplatin as first-line treatment of patients with metastatic triple-negative breast

cancer (the tnAcity study): study protocol for a randomized controlled

trial. Trials 2015;16:575. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/26673577.

626. Nelli F, Moscetti L, Natoli G, et al. Gemcitabine and carboplatin for pretreated metastatic breast cancer: the predictive value of

immunohistochemically defined subtypes. Int J Clin Oncol 2013;18:343-349. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22350024.

627. Yardley DA, Coleman R, Conte P, et al. nab-Paclitaxel plus

carboplatin or gemcitabine versus gemcitabine plus carboplatin as firstline treatment of patients with triple-negative metastatic breast cancer:

results from the tnAcity trial. Ann Oncol 2018;29:1763-1770. Available at:https://www.ncbi.nlm.nih.gov/pubmed/29878040.

628. Perez EA, Hillman DW, Stella PJ, et al. A phase II study of

paclitaxel plus carboplatin as first-line chemotherapy for women with

metastatic breast carcinoma. Cancer 2000;88:124-131. Available at:

https://www.ncbi.nlm.nih.gov/pubmed/10618614.

629. Fountzilas G, Kalofonos HP, Dafni U, et al. Paclitaxel and epirubicin versus paclitaxel and carboplatin as first-line chemotherapy in patients

with advanced breast cancer: a phase III study conducted by the Hellenic Cooperative Oncology Group. Ann Oncol 2004;15:1517-1526. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15367413.

630. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab

versus paclitaxel alone for metastatic breast cancer. N Engl J Med

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http://www.ncbi.nlm.nih.gov/pubmed/18160686.

631. Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: Randomized,

double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab (B) for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer (MBC) [abstract]. J Clin Oncol

2009;27(Suppl):Abstract 1005. Available at:

http://meeting.ascopubs.org/cgi/content/abstract/27/15S/1005.

632. Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: randomized,

double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer.

J Clin Oncol 2011;29:1252-1260. Available at:

http://www.ncbi.nlm.nih.gov/pubmed/21383283.

633. Mavroudis D, Papakotoulas P, Ardavanis A, et al. Randomized

phase III trial comparing docetaxel plus epirubicin versus docetaxel plus capecitabine as first-line treatment in women with advanced breast

cancer. Ann Oncol 2010;21:48-54. Available at:

http://www.ncbi.nlm.nih.gov/pubmed/19906761.

634. Stransky N, Cerami E, Schalm S, et al. The landscape of kinase

fusions in cancer. Nat Commun 2014;5:4846. Available at:

635. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med

2018;378:731-739. Available at:

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636. Meric-Bernstam F, Shukla N, Peled N, et al. Abstract P6-20-02:

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receptor kinase, in TRK fusion breast cancers. Cancer Research

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entrectinib in patients with NTRK fusion-positive tumours: Pooled

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734. Stomper PC, Waddell BE, Edge SB, Klippenstein DL. Breast MRI in the evaluation of patients with occult primary breast carcinoma. Breast J 1999;5:230-234. Available at:

http://www.ncbi.nlm.nih.gov/pubmed/11348292.

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Surg Oncol 2005;12:1045-1053. Available at:

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表 1
ypT0N0 or pCR→	For high risk: Adjuvant pembrolizumab(if pembrolizumab-containing regimen was given preoperatively), see BINV-M 3 of 10.
HR-negative/ HER2-negative	Adjuvant pembrolizumab(if pembrolizumab-containing regimen was given preoperatively) cccc and/or Adjuvant capecitabine(6-8 cycles)bbb,ccc and/or Adjuvant olapib for 1 year if germline BRCA1/2 mutationCCC(category 1)

表 2
Results (following ER testing by validated IHC assay)	Interpretation/ Report As:
0% to <1% of nuclei stain	ER-negative
1%-100% of nuclei stain	ER-negative
1%-100% of nuclei stain	ER-low-positive (with recommended comment)
>10% of nuclei stain	ER-positive

表 3
Highly Unusual ER-Negative Results	Highly Unusual ER-Positive Results
Low-grade carcinomas of no special type (also known as invasive ductal carcinoma)	Metaplastic carcinomas of all subtypes
Lobular carcinomas (classic type)	Adenoid cystic carcinomas and other salivary gland-like carcinomas of the breast
Pure tubular,cribiform, or mucinous carcinomas	Secretory carcinoma
Encapsulated papillary and solid papillary carcinomas	Carcinomas with apocrine differentiation (apocrine carcinoma)

表 4
	No ink on tumor	2-mm margin	No margin necessary
Invasive breast cancer	X	X
Invasive breast cancer + DCIS	X	X
Invasive breast cancer + extensive DCIS	X	X
Invasive breast cancer (treated with neoadjuvant chemotherapy followed by breast-conservation therapy),4,5	X
Pure DCIS		X
DCIS with microinvasion		X
Classic LCIS* at surgical margin		X	X
Atypia at surgical margin			X

表 5
Dose	Regimen
EBRT APBI	EBRT APBI
30 Gy/5 fractions QOD (preferred); IMRT/VMAT protocol mandated	-Livi L,Meattini,Imrazzo L,et al.Accelerated partial breast irradiation using intensity-modulated radiotherapy versus whole breast irradiation: 5-year survival analysis of a phase 3 randomised controlled trial. Eur J Cancer 2015;51:451-463. ● Meattini,Imrazzo L,Saieve Ca,et al.Accelerated partial-breast irradiation compared with whole-breast irradiation for early breast cancer: Long-term results of the randomized phase III APBI-IMRT-Florence Trial. J Clin Oncol 2020;38:4175-4183. ● Franceschini D, Loi M, Chiola I, et al. Preliminary results of a randomized study on postmenopausal women with early stage breast cancer: Adjuvant hypofractionated whole breast irradiation versus accelerated partial breast irradiation (HYPAB Trial). Clin Breast Cancer 2021;21:231-238. ● Lo Faro L, Fogliata A, Franceschini D, et al. Adjuvant hypofractionated whole breast irradiation (WBI) vs. accelerated partial breast irradiation (APBI) in postmenopausal women with early stage breast cancer: 5 years update of the HYPAB trial. Clin Breast Cancer 2024;24:253-260. ● Coles CE,Griffin CL, Kirby AM, et al. Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomised, controlled, phase 3, non-inferiority trial. Lancet 2017;390:1048-1060. ●Brachytherapy APBI (including balloon/interstitial) ● Vicini FA, Cecchini RS, White JR, et al. Long-term primary results of accelerated partial breast irradiation after breast-conserving surgery for early-stage breast cancer: a randomised, phase 3, equivalence trial. Lancet 2019;394:2155-2164. ●Strnad V, Ott OJ, Hildebrandt G, et al. 5-year results of accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy versus whole- breast irradiation with boost after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: a randomised, phase 3, non-inferiority trial. Lancet 2016;387:229-238. ●Polgár C, Ott OJ, Hildebrandt G, et al. Late side-effects and cosmetic results of accelerated partial breast irradiation with interstitial brachytherapy versus whole-reliobreast irradiation after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: 5-year results of a randomised, controlled, phase 3 trial. Lancet Oncol 2017;18:259-268.

表 6
HR-positive or negative and HER2-Positive
Patients with HR-positive disease are recommended to receive adjuvant endocrine therapy ± CDK4/6 inhibitor therapy(see BINV-K).
Preferred Regimens: Preoperative or adjuvant setting:
●Paclitaxel+trastuzumabf ●TCHD(docetaxel/carboplatin/trastuzumab) ●TCHP(docetaxel/carboplatin/trastuzumab/pertuzumab) Adjuvant setting only:
●If no residual disease after preoperative therapy or no preoperative therapy: Complete up to 1 year of HER2-targeted therapy with trastuzumabh,(category 1)±pertuzumab.If node positive at initial staging,trastuzumab(category 1)^9 ●If residual disease after preoperative therapy: Ado-trastuzumab emansine(category 1) alone. If ado-trastuzumab emansine discontinued for toxicity, then trastuzumab(category 1)±pertuzumab to complete 1 year of therapy.n If node positive at initial staging,trastuzumab+ pertuzumab(category 1)^9
Useful in Certain Circumstances: Preoperative or adjuvant setting:	Other Recommendeded Regimens: Preoperative or adjuvant setting:
●AC followed by Tc+ trastuzumab,h (doxorubicin/cyclophosphamide followed by paclitaxel plus trastuzumab, various schedules)	●AC followed by docetaxelc+ trastuzumab,i (doxorubicin/cyclophosphamide followed by docetaxel+ trastuzumab)
●AC followed by Tc+ trastuzumab+pertozubam[h (doxorubicin/cyclophosphamide followed by paclitaxel plus trastuzumab plus pertuzumab, various schedules)	●AC followed by docetaxelc+ trastuzumab+pertuzumab+(doxorubicin/cyclophosphamide followed by docetaxel+ trastuzumab+pertuzumab)
●Paclitaxel+ trastuzumab+ pertuzumab pHertuzumab, various schedules)	●Paclitaxel/cyclophosphamide followed by docetaxel+ pertuzumab
●Paclitaxel+trastuzumab pertuzumab
●Adu-trastuzumab emansine(TDM-1)

表 7
HER2-Negative	• Preoperative pembrolizumab + chemotherapy followed by adjuvant pembrolizumab4,j,k
Doxorubicin 60 mg/m2 IV day 1	Pemrolizumab 200 mg IV or 2mg/kg day 1
Cyclophosphamide 600 mg/m2 IV day 1	Pooperative:
$\bigcirc$ Cycled every 14 days for 4 cycles	Pemblizumab 200 mg IV or 2mg/kg day 1
$\bigcirc$ Followed by:	$\bigcirc$ Paclitaxel 80 mg/m2 IV days 1,8,15
Paclitaxel 175 mg/m2 by 3 h IV infusion day 1	$\bigcirc$ Carboplatin AUC 5 IV day 1
$\bigcirc$ Cycled every 14 days for 4 cycles	Or
Dose-dense AC followed by weekly paclitaxel2	$\bigcirc$ Carboplatin AUC 1.5 IV days 1,8,15
Doxorubicin 60 mg/m2 IV day 1	- Cycled every 21 days x 4 cycles (cycles 1-4)
Cyclophosphamide 600 mg/m2 IV day 1	Followed by:
$\bigcirc$ Cycled every 14 days for 4 cycles	Pemblizumab 200 mg IV or 2mg/kg day 1
$\bigcirc$ Followed by:	Doxorubicin 60 mg/m2 IV day 1 or Epirubicin 90 mg/m2 IV day 1
Paclitaxel 80 mg/m2 by 1 h IV infusion weekly for 12 weeks	$\bigcirc$ Cycledphosphamide 600 mg/m2 IV day 1
$\cdot$ TC3	- Cycled every 21 days x 4 cycles (cycles 5-8)
Docetaxel 75 mg/m2 IV day 1	Followed by:
Cyclophosphamide 600 mg/m2 IV day 1	Adjuvant pembrolizumab 200 mg IV or 2mg/kg day 1
$\bigcirc$ Cycled every 21 days for 4 -6 cycles	$\bigcirc$ Cycled every 21 days x 9 cycles
$\bullet$ Riboclicun (in combination with an aromatase inhibitor)	$\bullet$ Capecitabine 5
400 mg PO once daily	1000-1250 mg/m2 PO twice daily on days 1-14
21 days on/7 days off for 3 years	$\bigcirc$ Cycled every 21 days for 6-8 cycles
	$\bullet$ Olaparib6
	300 mg PO twice daily
	Cycled every 28 days for 1 year

表 8
HER2-Positive${}^{1,m}$
TCH+pertuzumab23	TCH+pertuzumab23	TCH+pertuzumab23	TCH+pertuzumab23
Paclitaxel+trastuzumab21	TCH22	TCH+pertuzumab23	TDM-1
Paclitaxel 80 mg/m2 IV weekly for 12 weeks	Docetaxel 75 mg/m2 IV day 1	Docetaxel 75 mg/m2 IV day 1	3.6 mg/kg day 1
With:	Carboplatin AUC 6 IV day 1	Carboplatin AUC 6 IV day 1	$\diamond$ Cycled every 21 days for 6 cycles
Trastuzumab 4 mg/kg IV with first dose of paclitaxel	O Cycled every 21 days for 6 cycles	$\diamond$ Cycled every 21 days for 6 cycles	14 cycles
Followed by:	Followed by:	With:
Trastuzumab 2 mg/kg IV weekly to complete 1 year of treatment. As an	Trastuzumab 2 mg/kg IV for 17 weeks	Trastuzumab 8 mg/kg IV for 17 weeks
alternative, trastuzumab 6 mg/kg IV every 21 days may be used following	Followed by:	Trastuzumab 6 mg/kg IV on day 1	▶ Followed by:
every 21 days may be used following the completion of paclitaxel,	Cycled every 21 days to complete	Pertuzumab 420 mg IV day 1
and given to complete 1 year of	OR	$\diamond$ Cycled every 21 days to complete	1 year of therapyn
trastuzumab treatment.	Followed by:	of therapyn
	Trastuzumab 8 mg/kg IV week 1
	Followed by:
	Trastuzumab 6 mg/kg IV
	1 year of therapyn

表 9
Assay	Predictive	Prognostic	NCCN Category of Preference	NCCN Category of Evidence and Consensus	Recurrence Risk and Treatment Implications
21-gene (Oncotype Dx) (for pN0)	Yes	Yes	Preferred	1	BINV-N (2)
21-gene (Oncotype Dx) for pN1 (1-3 positive nodes)c	Yes	Yes	Postmenopausal: Preferred	1	BINV-N (2)
21-gene (Oncotype Dx) for pN1 (1-3 positive nodes)c	Yes	Yes	Premenopausal: Other	2A	BINV-N (2)
70-gene (MammaPrint) for pN0 and pN1 (1-3 positive nodes)	Not determined	Yes	Other	1	BINV-N (3)
50-gene (Prosigna) for pN0 and pN1 (1-3 positive nodes)	Not determined	Yes	Other	2A	BINV-N (3)
12-gene (EndoPredict) for pN0 and pN1 (1-3 positive nodes)	Not determined	Yes	Other	2A	BINV-N (3)
Breast Cancer Index (BCI)	Predictive of benefit of extended adjuvant endocrine therapy	Yes	Other	2A	BINV-N (4)

表 10
Assay	Recurrence Risk	Treatment Implications
21-gene (Oncotype Dx) (for postmenopausal patients with pN0 and pN1 [1-3 positive nodes])^c	<26	Patients with T1b/c-2, pN0, HR-positive, HER2-negative tumors, with recurrence scores (RS) between 0-10 have a risk of distant recurrence of <4% and those with RS 11-25 derived no benefit from the addition of chemotherapy to endocrine therapy in the prospective TAILORx study.1 Postmenopausal patients with pT1-3, pN1, HR-positive, HER2-negative, with RS <26 derived no benefit from the addition of chemotherapy to endocrine therapy in the prospective RxONDER study.2
21-gene (Oncotype Dx) (for postmenopausal patients with pN0 and pN1 [1-3 positive nodes])^c	≥26	In postmenopausal patients with pT1-3, HR-positive, HER2-negative, and pN0 and pN1 (1-3 positive nodes) tumors and an RS ≥ 26, the addition of chemotherapy to endocrine therapy is recommended.1,2
21-gene (Oncotype Dx) (for premenopausalpatients):pN0)	≤15	Premenopausal patients with T1b/c -2, pN0, HR-positive, HER2-negative, HER2-negative tumors with RS <16 derived no benefit from the addition of chemotherapy to endocrine therapy in the prospective TAILORx study.1
21-gene (Oncotype Dx) (for premenopausalpatients):pN0)	16-25	In premenopausal patients with RS between 16-25, a small benefit from the addition of chemotherapy to endocrine therapy in the prospective TAILORx study.1
21-gene (Oncotype Dx) (for premenopausalpatients):pN0)	≥26	In premenopausal patients with HR-positive, HER2-negative, and pN0 tumors and an RS ≥ 26, the addition of chemotherapy to endocrine therapy is recommended.1
21-gene (Oncotype Dx) (for premenopausalpatients with 1-3 positive nodes)c	<26	In premenopausal patients with pT1-3 and pN1 (1-3 positive nodes) tumors and an RS ≥ 26, the addition of chemotherapy to endocrine therapy in the prospective RxONDER study.2
21-gene (Oncotype Dx) (for premenopausalpatients with 1-3 positive nodes)c	≥26	In premenopausal patients with HR-positive, HER2-negative, and pN0 and pN1 (1-3 positive nodes) tumors and an RS ≥ 26, the addition of chemotherapy to endocrine therapy is recommended.
70-gene (MammaPrint) (for pNO and 1-3 positive nodes)	High	Patients with high clinical risk and low genomic risk were randomly assigned to receive chemotherapy (n=749) or not (n=748); this was the intention-to-treat population. The 8-year estimates for distant metastasis-free survival in the intention-to-treat population were 92.0% (95% CI, 89.6-93.8) for chemotherapy versus 89.4% (86.8-91.5) for no chemotherapy (HR, 0.66; 95% CI, 0.48-0.92). An exploratory analysis confined to the subset of patients with HR-positive, HER2-negative disease (1358 [90.7%] of 1497 randomly assigned patients, of whom 676 received chemotherapy and 682 did not) shows different effects of chemotherapy administration on 8-year distant metastasis-free survival according to age:93.6% (95% CI, 89.3-96.3) with chemotherapy versus 88.6% (83.5-92.3) without chemotherapy in 464 patients aged ≤50 years (absolute difference 5.0 percentage points [SE, 2.8; 95% CI ,-0.5 to 10.4]) and 90.2% (86.8-92.7) versus 90.0% (86.6-92.6) in 894 females >50 years (absolute difference 0.2 percentage points [2.1,-4.0 to 4.4]). The 8-year distant metastasis-free survival in the exploratory analysis by nodal status in these patients was 91.7% (95% CI, 88.1-94.3) with chemotherapy and 89.2% (85.2-92.2) without chemotherapy in 699 patients who are node-negative (absolute difference 2.5 percentage points [SE, 2.3; 95% CI, -2.1 to 7.2]) and 91.2% (87.2-94.0) versus 89.9% (85.8-92.8) for 658 patients with 1-3 positive nodes (absolute difference 1.3 percentage points [2.4,-3.5 to 6.1]). ${}^{3}$
70-gene (MammaPrint) (for pNO and 1-3 positive nodes)	50-gene (Prosigna) (for pNO and 1-3 positive nodes)	Patients with high clinical risk and low genomic risk were randomly assigned to receive chemotherapy (n=749) or not (n=748); this was the intention-to-treat population. The 8-year estimates for distant metastasis-free survival in the intention-to-treat population were 92.0% (95% CI, 89.6-93.8) for chemotherapy versus 89.4% (86.8-91.5) for no chemotherapy (HR, 0.66; 95% CI, 0.48-0.92). An exploratory analysis confined to the subset of patients with HR-positive, HER2-negative disease (1358 [90.7%] of 1497 randomly assigned patients, of whom 676 received chemotherapy and 682 did not) shows different effects of chemotherapy administration on 8-year distant metastasis-free survival according to age:93.6% (95% CI, 89.3-96.3) with chemotherapy versus 88.6% (83.5-92.3) without chemotherapy in 464 patients aged ≤50 years (absolute difference 5.0 percentage points [SE, 2.8; 95% CI ,-0.5 to 10.4]) and 90.2% (86.8-92.7) versus 90.0% (86.6-92.6) in 894 females >50 years (absolute difference 0.2 percentage points [2.1,-4.0 to 4.4]). The 8-year distant metastasis-free survival in the exploratory analysis by nodal status in these patients was 91.7% (95% CI, 88.1-94.3) with chemotherapy and 89.2% (85.2-92.2) without chemotherapy in 699 patients who are node-negative (absolute difference 2.5 percentage points [SE, 2.3; 95% CI, -2.1 to 7.2]) and 91.2% (87.2-94.0) versus 89.9% (85.8-92.8) for 658 patients with 1-3 positive nodes (absolute difference 1.3 percentage points [2.4,-3.5 to 6.1]). ${}^{3}$
Node positive: Low (0-40)	50-gene (Prosigna) (for pNO and 1-3 positive nodes)	In patients with HR-positive, HER2-negative, pN+ tumors (3-1 positive lymph nodes) with low risk of recurrence score, treated with endocrine therapy alone, the distant recurrence risk was less than 3.5% at 10 years and no distant recurrence was seen at 10 years in the TransATAC study in a similar group. ${}^{5}$
Node positive: High (41-100)		In patients with HR-positive, HER2-negative, pN+ tumors (3-1 positive lymph nodes) with low risk of recurrence score, treated with endocrine therapy alone, the distant recurrence risk was less than 3.5% at 10 years and no distant recurrence was seen at 10 years in the TransATAC study in a similar group. ${}^{5}$
12-gene (EndoPredict) (pNO and 1-3 positive nodes)	Low (≤3.3)	For patients with T1 and T2 HR-positive, HER2-negative, and pN0 tumors, a 12-gene low-risk score, regardless of T size, places the tumor into the same prognostic category as T1a-T1b,N0,M0.6 In ABCSG 6/8, patients in the low-risk group had risk of distant recurrence of 4% at 10 years and in the TransATAC study, patients with 1-3 positive nodes in the low-risk group had a 5.6% risk of distant recurrence at 10 years. ${}^{6,7}$ The assay is prognostic in patients treated with endocrine and chemo-endocrine.
12-gene (EndoPredict) (pNO and 1-3 positive nodes)	High (>3.3)	For patients with T1 and T2 HR-positive, HER2-negative, and pN0 tumors, a 12-gene low-risk score, regardless of T size, places the tumor into the same prognostic category as T1a-T1b,N0,M0.6 In ABCSG 6/8, patients in the low-risk group had risk of distant recurrence of 4% at 10 years and in the TransATAC study, patients with 1-3 positive nodes in the low-risk group had a 5.6% risk of distant recurrence at 10 years. ${}^{6,7}$ The assay is prognostic in patients treated with endocrine and chemo-endocrine.

表 12
Assay	Recurrence Risk/ Predictive Result	Treatment Implications
Breast Cancer Index (BCI)e	BCI (H/I) Low	●For patients with T1 and T2 HR-positive,HER2-negative, and pN0 tumors, a BCI (H/I) in the low-risk range (0-5),regardless of T size, places the tumor into the same prognostic category as T1a-T1b, N0, M0. ●Patients with BCI (H/I) low demonstrated a lower risk of distant recurrence (compared to BCI [H/I] high) and no significant improvement in disease-free survival (DFS) or OS compared to the control arm in terms of extending endocrine therapy duration.8
Breast Cancer Index (BCI)e	BCI (H/I) High	●For patients with T1 HR-positive,HER2-negative, and pN0 tumors, a BCI (H/I) high (5.1-10) demonstrated significant rates of late distant recurrence. ●In secondary analyses of the MA.17, Trans-aTTom, and IDEAL trials, patients with HR-positive, T1-T3, pN0 or pN+ who had a BCI (H/I) high demonstrated significant improvements in DFS when adjuvant endocrine therapy was extended, compared to the control arm.8-11

表 13
HER2-Positive and Postmenopausal or Premenopausal Receiving Ovarian Ablation or Suppression
See BINV-Q (1) for Considerations for Systemic Therapy.
If treatment was initiated with chemotherapy and trastuzumab+ pertuzumab, and the chemotherapy was stopped, endocrine therapy may be added to trastuzumab+ pertuzumab.
● Aromatase inhibitor ± trastuzumab
● Aromatase inhibitor ± lapatinib
● Fulvestant ± trastuzumab
● Fulvestant ± trastuzumab
● Tamoxifen ± trastuzumab
● Abemaciblin in combination with fulvestant and trastuzumab(category 2B)
● Targeted therapy see BINV-Q (7) and emerging biomarker options see BINV-Q (8)

表 14
HR-Positive and HER2-Negative with Visceral Crisis ${}^{+}$ or Endocrine Refractory
See BINV-Q(1) for Considerations for Systemic Therapy.
Setting	Subtype/Biomarker	Regimen
First Line	No germline BRCA1/2 mutationb and/or HER2 IHC 0+, 1+, or 2+/ISH negative	Systemic chemotherapy (category 1, preferred) BINV-Q(5), or fam-trastuzumab deruxtecan-nxki${}^{f}$ (other recommended regimen)
First Line	Germline BRCA1/2 mutationb	PARPi (olaparib, talazoparib) ${}^{c}$ (category 1, preferred)
Second Line	HER2 IHC 1+ or 2+/ISH negative	Fam-trastuzumab deruxtecan-nxki${}^{f}$ (category 1, preferred)
Second Line	HER2 IHC 0+d	Fam-trastuzumab deruxtecan-nxki${}^{f}$ (other recommended regimen)
Second Line	Not a candidate for fam-trastuzumab deruxtecan-nxki	Sacituzumab govitecan9(category 1, preferred)
Second Line	Not a candidate for fam-trastuzumab deruxtecan-nxki	Systemic chemotherapy BINV-Q (5)
Targeted therapy BINV-Q (6) and BINV-Q(7)	Not a candidate for fam-trastuzumab deruxtecan-nxki
For HER2 IHC 0, 1+, or 2+/ISH negative:d Datopotamab deruxtecan-dlnk${}^{h}$ (other recommended regimen)
Third Line and beyond	Any	Systemic chemotherapy BINV-Q(5)
Third Line and beyond	Biomarker positive(ie,MSI-H,NTRK,RET, TMB-H)	Targeted agents and emerging biomarker options BINV-Q(6). BINV-Q(7), and BINV-Q(8)

表 15
HR-Negative and HER2-Negative (Triple-Negative Breast Cancer; TNBC)
See BINV-Q(1) for Considerations for systemic therapy.
Setting	Subtype/Biomarker	Regimen
First Line	PD-L1 CPS ≥109 regardless of germline BRCA mutation statusb	Pembrolizumab + chemotherapy (albumin-bound paclitaxel, paclitaxel, or gemcitabine and carboplatin)（category 1, preferred）
First Line	PD-L1 CPS <109 and no germline BRCA1/2 mutationb	Systemic chemotherapy BINV-Q (5)
First Line	PD-L1 CPS <109 and germline BRCA1/2 mutationb	● PARPi (olaparib, talazoparib) (category 1, preferred) ● Platinum (cisplatin or carboplatin)（category 1, preferred）
Second Line	Germline BRCA1/2 mutationb	PARPi (olaparib, talazoparib) (category 1, preferred)
Second Line	Any	Sacituzumab govitecanj (category 1,preferred)
Second Line	No germline BRCA1/2 mutationb and HER2 IHC 1+ or 2+/ISH negatively	Fam-trastuzumab deruxecan-nxkik (other recommended regimen)
Third Line and beyond	Biomarker positive (ie, MSI-H, NTRK, RET, TMB-H)	Targeted agents and emerging biomarker options BINV-Q(7) and BINV-Q(8)
Third Line and beyond	Any	Systemic chemotherapy BINV-Q (5)

表 16
HR-Positive or -Negative and HER2-Positive
See BINV-Q(1) for Considerations for systemic HER2-targeted therapy.
Setting	Regimen
First Line	Pertuzumab+ trastuzumab+ docetaxel(category 1, preferred)
First Line	Pertuzumab+ trastuzumab+ paclitaxel(preferred)
Second Line°	Fam-trastuzumab deruxtecan-nxki^n(category 1, preferred)
Third Line	Tucatinib+ trastuzumab+ capecitabine (category 1, preferred)
Third Line	Ado-trastuzumab emtansine(T-DM1)p
Fourth Line and Beyond (optimal sequence is not known)q	Trastuzumab+ docetaxel or vinorelbine
Fourth Line and Beyond (optimal sequence is not known)q	Trastuzumab+ paclitaxel± carboplatin
Fourth Line and Beyond (optimal sequence is not known)q	Capecitabine+ trastuzumab or lapatinib
Fourth Line and Beyond (optimal sequence is not known)q	Trastuzumab+ lapatinib(without cytotoxic therapy)
Fourth Line and Beyond (optimal sequence is not known)q	Trastuzumab+ other chemotherapy agents$r,s
Fourth Line and Beyond (optimal sequence is not known)q	Neratinib+ capecitabine
Fourth Line and Beyond (optimal sequence is not known)q	Margetuximab-cmkb + chemotherapy
Abemaciblin in combination with fulvestant and trastuzumab (for HR+ only)(category 2B)
Targeted Therapy and emerging biomarker Options BINV-Q(7) and BINV-Q(8)

表 17
Biomarkers Associated with FDA-Approved Therapies
Breast Cancer Subtype	Biomarker	Detectiont	FDA-Approved Agents	NCCN Category of Evidence	NCCN Category of Preference
HR-positive, HER2-negative	PIK3CA activating mutation	NGS,PCR	Inavolisib + palbociclib + fulvestant	Category 1	Useful in certain circumstances first-line therapy
HR-positive/ HER2-negative	PIK3CA activating mutation	NGS,PCR	Alpelisib + fulvestant	Category 1	Preferred second- or subsequent-line therapy
HR-positive/ HER2-negative	PIK3CA or AKT1 activating mutations or PTEN alterations	NGS,PCR	Capivasertib + fulvestantW	Category 1	Preferred second- or subsequent-line therapy in select patientsW
HR-positive/ HER2-negativex	ESR1 mutationX	NGS,PCR	Elacestranty	Category 2A	Other recommended regimen first-line or subsequent-line therapy
HR-positive/ HER2-negativex	ESR1 mutationX	NGS,PCR	Imlunestrantz,aa	Category 2A	Other recommended regimen first-line or subsequent-line therapy

表 18
Biomarkers Associated with FDA-Approved Therapies
Breast Cancer Subtype	Biomarker	Detectiont	FDA-Approved Agents	NCCN Category of Evidence	NCCN Category of Preference
Any	Germline BRCA1 or BRCA2 mutation	Germline sequencing	Olaparib Talazoparib	Category 1	Preferred
Any	Germline PALB2	Germline sequencing	Olaparibbb	Category 2A	Other recommended regimen
Any	NTRK fusion	FISH,NGS,PCR	Larrotectinibcc Entrectinibcc Repotrectinibdd	Category 2Add	Useful in certain circumstances
Any	MSI-H/dMMR	IHC,NGS,PCR	Pembrolizumabe	Category 2A	Useful in certain circumstances
Any	TMB-H (≥10 mut/Mb)99	NGS	Pembrolizumabe	Category 2A	Useful in certain circumstances
Any	RET-fusion	NGS	Selpercatinibhh	Category 2A	Useful in certain circumstances

表 19
Breast Cancer Subtype	Emerging Biomarkers	Detectiont	Potential Targeted Therapy''	NCCN Category of Evidence	NCCN Category of Preference
ER+/HER2-ER-/HER2-	HER2 activating mutations	NGS,PCR	Neratinib $\pm$ fulvestant	Category 2B	Useful in certain circumstances ● If ER+/HER2-, in patients who have already received CDK4/6 inhibitor therapy.
ER+/HER2-ER-/HER2-	HER2 activating mutations	NGS,PCR	Neratinib $\pm$ fulvestumab/ fulvestan ${}^{kk}$	Category 2A	Useful in certain circumstances ● If ER+/HER2-, in patients who have already received CDK4/6 inhibitor therapy.
Any	Somatic BRCA1/2 mutations	NGS	Olaparib ${}^{ll}$	Category 2B	Useful in certain circumstances
Any	FGFR1-3 fusion/ mutation	NGS	Erdafitinib ${}^{ll}$ mm	Category 2B	Useful in certain circumstances

表 20
	Baseline Prior to New Therapy	Chemotherapy or Targeted Therapy	Endocrine Therapy Alone or Combination with CDK 4/6 Inhibitor or Other Targeted Therapy	Restaging if Concern for Progression of Disease
Symptom Assessment	Yes	Prior to each cycle	Every 1-3 months	Yes
Physical Examination	Yes	Prior to each cycle	Every 1-3 months	Yes
Performance Status	Yes	Prior to each cycle	Every 1-3 months	Yes
Weight	Yes	Prior to each cycle	Every 1-3 months	Yes
LFTs,CBC	Yes	Prior to each cycle, as indicated	Every 1-3 months	Yes
CT Chest/Abdomen/ Pelvis with Contrast	Yes	Every 2-4 cycles	Every 2-6 months	Yes
Bone Scan	Yes	Every 4-6 cycles	Every 2-6 months	Yes
PET/CT	As clinically indicated	As clinically indicated	As clinically indicated	As clinically indicated
Tumor Markers	As clinically indicated	As clinically indicated	As clinically indicated	As clinically indicated
Brain MRI with contrast	As clinically indicated	As clinically indicated	As clinically indicated	As clinically indicated

表 21
Stage 0	Tis	NO	M0	Stage IIIA	T0	N2	M0
Stage IA	T1	NO	M0		T1	N2	M0
Stage IB	T0	N1mi	M0		T2	N2	M0
Stage IIA	T1	N1mi	M0		T3	N1	M0
Stage IIA	T1	N1mi	M0		T3	N2	M0
Stage IIA	T0	N1	M0		T3	N2	M0
Stage IIA	T1	N1	M0	Stage IIIB	T4	N0	M0
Stage IIB	T2	N1	M0		T4	N1	M0
Stage IIB	T2	N1	M0		T4	N2	M0
Stage IIB	T3	N0	M0	Stage IIIC	Any T	N3	M0
Stage IIB	Stage IV Any T Any N M1

表 22
TNM	Grade	HER2	ER	PR	Stage
Tis N0 M0	Any	Any	Any	Any	0
T1* N0 M0 T0 N1mi M0 T1* N1mi M0	G1	Positive	Positive	Positive	IA
T1* N0 M0 T0 N1mi M0 T1* N1mi M0	G1	Positive	Positive	Negative	IA
T1* N0 M0 T0 N1mi M0 T1* N1mi M0	G1	Positive	Negative	Positive	IA
T1* N0 M0 T0 N1mi M0 T1* N1mi M0	G1	Positive	Negative	Positive	IA
T1* N0 M0 T0 N1mi M0 T1* N1mi M0	G1	Negative	Negative	Positive	IA
T1* N0 M0 T0 N1mi M0 T1* N1mi M0	G1	Negative	Negative	Positive	IA
T1* N0 M0 T0 N1mi M0 T1* N1mi M0	G1	Negative	Negative	Positive	IA
T1* N0 M0 T0 N1mi M0 T1* N1mi M0	G1	Negative	Negative	Positive	IA
T1* N0 M0 T0 N1mi M0 T1* N1mi M0	G1	G2	Positive	Positive	IA
T1* N0 M0 T0 N1mi M0 T1* N1mi M0	G1	G2	Positive	Positive	IA
T1* N0 M0 T0 N1mi M0 T1* N1mi M0	G1	G2	Positive	Negative	IA
T1* N0 M0 T0 N1mi M0 T1* N1mi M0	G1	G2	Positive	Negative	IA
Negative	Positive	G2	Positive	Positive
Negative	Positive	G2	Negative	Positive
Negative	Negative	G2	IB
T0$N1*$M0 T1$N1**$M0 T2$N0$M0	G1	Positive	Positive	Positive	IB
T0$N1*$M0 T1$N1**$M0 T2$N0$M0	G1	Positive	Positive	Negative	IIA
T0$N1*$M0 T1$N1**$M0 T2$N0$M0	G1	Positive	Positive	Negative	IIA
T0$N1*$M0 T1$N1**$M0 T2$N0$M0	G1	Positive	Positive	Negative	Negative
T0$N1*$M0 T1$N1**$M0 T2$N0$M0	G1	Negative	Positive	Positive	IB
T0$N1*$M0 T1$N1**$M0 T2$N0$M0	G1	Negative	Positive	Negative	IIA
T0$N1*$M0 T1$N1**$M0 T2$N0$M0	G1	Negative	Positive	Negative	Negative
T0$N1*$M0 T1$N1**$M0 T2$N0$M0	G1	Negative	Positive	Negative	Positive
T0$N1*$M0 T1$N1**$M0 T2$N0$M0	G1	Negative	Negative	Negative	Positive
T0$N1*$M0 T1$N1**$M0 T2$N0$M0	G1	Negative	IIA	Negative
T0$N1*$M0 T1$N1**$M0 T2$N0$M0	G1	G2	Positive	Negative	Positive
T0$N1*$M0 T1$N1**$M0 T2$N0$M0	G1	G2	Positive	Negative	Positive
T0$N1*$M0 T1$N1**$M0 T2$N0$M0	G1	G2	Positive	Negative	Positive
T0$N1*$M0 T1$N1**$M0 T2$N0$M0	G1	G2	Positive	Negative	Negative
T0$N1*$M0 T1$N1**$M0 T2$N0$M0	G1	G2	Positive	Negative	Negative
Negative	Positive	Positive	Positive	IB
Negative	Positive	Positive	Negative	Negative
Negative	Positive	Negative	Negative	IIA
Negative	Positive	Negative	Negative	Negative	IIB
Negative	Positive	Negative	Positive	Positive	Positive
Negative	Negative	Negative	Positive	Positive
Negative	Negative	Negative	Positive	IIB
Negative	Negative	Negative	Positive	Negative	IIB
Negative	Positive	Negative	Positive	Positive	Positive
Negative	Positive	Negative	Negative	Positive
Negative	Positive	Negative	Negative	Negative
Negative	Positive	Negative	IB	IIB
T2 N1*** M0 T3 N0 M0	G1	Positive	Positive	Positive	IB
T2 N1*** M0 T3 N0 M0	G1	Positive	Positive	Negative	IAI
T2 N1*** M0 T3 N0 M0	G1	Positive	Negative	Negative	IAI
T2 N1*** M0 T3 N0 M0	G1	Positive	Negative	Positive	Positive
T2 N1*** M0 T3 N0 M0	G1	Negative	Negative	Positive	IA
T2 N1*** M0 T3 N0 M0	G1	Negative	Negative	Negative	Positive
T2 N1*** M0 T3 N0 M0	G1	Negative	Negative	Negative	Negative
T2 N1*** M0 T3 N0 M0	G1	G2	Positive	Positive	Positive
T2 N1*** M0 T3 N0 M0	G1	G2	Positive	Positive	Negative
T2 N1*** M0 T3 N0 M0	G1	G2	Positive	Negative	Negative
T2 N1*** M0 T3 N0 M0	G1	G2	Positive	Negative	Positive
T2 N1*** M0 T3 N0 M0	G1	Negative	IB	Negative	Positive
Negative	Negative	IB		Negative
Negative	Positive	Positive	IB	Negative
Negative	Positive	Negative	Negative
Negative	Negative	IB
Negative	G3	Positive	Positive	Positive	Positive
Negative	G3	Positive	Positive	Negative	IIIB
Negative	G3	Positive	Positive	Positive	IB
Negative	G3	Positive	Positive	Negative	Negative
Negative	Negative	IIIB
Negative	Negative	Positive		Positive	Positive
Negative	Negative	Positive	Negative	Negative
Negative	Negative	Positive	Positive	Positive	IIIB
Negative	Negative	Positive	Negative	IIIB	Negative
T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $	G1	Positive	Positive	Positive	IIA
T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $	G1	Positive	Positive	Negative	Positive
T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $	G1	Positive	Negative	Positive
T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $	G1	Positive	Negative	Negative	IIA
T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $	G1	Positive	G2	Positive	Positive
T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $	G1	Negative	G2	Positive	Positive
T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $	G1	Negative	G2	Positive	Positive
T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $	G1	Negative	G2	Positive	Negative
T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $	G1	G2	G2	Positive	Positive
T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $	G1	G2	Negative	IIIA	Positive
T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $	G1	G2	Negative	Negative	Positive
T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $	G1	G2	Negative	Negative	Positive
T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $	G1	G2	G3	Positive	Positive
T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $	G1	Negative	G3	Positive	Negative
T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $	G1	Negative	G3	Positive	Negative
Negative	Negative	IIIB	G3	Positive
Negative	G3	Positive	G3	Positive	Positive
Negative	G3	Positive	Negative	Negative
Negative	G3	Positive	Negative	Negative
Negative	G3	Positive	Negative	IIIB
Negative	G3	Positive	Negative	Negative	IIIC
T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0	G1	Positive	Positive	Positive	IIIA
T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0	G1	Positive	Positive	Negative	Positive
T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0	G1	Positive	Negative	Negative
T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0	G1	Positive	Negative	Positive	Positive
T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0	G1	Negative	Negative	Positive	IIIC
T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0	G1	G2	Negative	Positive	Positive
T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0	G1	G2	Negative	Positive	Positive
T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0	G1	G2	Negative	Positive	Positive
T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0	G1	G2	Negative	Positive	Positive
T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0	G1	Negative	Negative	IIIC	Positive
T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0	G1	G3	Negative	Positive	Positive
T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0	G1	G3	Negative	Positive	Negative
T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0	G1	G3	Negative	Positive	Positive
T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0	G1	G3	Negative	Positive	Positive
T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0	G1	Any TAny N M1	Negative	Any	Any
Tis N $\text{O}$ M0	Any	Any	Any	Any	0
T1* N $\text{O}$ M $\text{O}$ T1* N1mi M0 T1* N1mi M0	G1	Positive	Positive	Positive	IA
T1* N $\text{O}$ M $\text{O}$ T1* N1mi M0 T1* N1mi M0	G1	Positive	Positive	Negative	IA
T1* N $\text{O}$ M $\text{O}$ T1* N1mi M0 T1* N1mi M0	G1	Negative	Positive	Negative	IA
T1* N $\text{O}$ M $\text{O}$ T1* N1mi M0 T1* N1mi M0	G1	Negative	Negative	IIA	IA
T1* N $\text{O}$ M $\text{O}$ T1* N1mi M0 T1* N1mi M0	G1	Negative	Positive	IIA	IA
T1* N $\text{O}$ M $\text{O}$ T1* N1mi M0 T1* N1mi M0	G1	Negative	Positive	Negative	IA
T1* N $\text{O}$ M $\text{O}$ T1* N1mi M0 T1* N1mi M0	G1	Negative	G2	Positive	IA
T1* N $\text{O}$ M $\text{O}$ T1* N1mi M0 T1* N1mi M0	G1	Negative	G2	Positive	IA
T1* N $\text{O}$ M $\text{O}$ T1* N1mi M0 T1* N1mi M0	G1	Negative	G2	Positive	IA
T1* N $\text{O}$ M $\text{O}$ T1* N1mi M0 T1* N1mi M0	G1	Negative	G2	Positive	IA
T1* N $\text{O}$ M $\text{O}$ T1* N1mi M0 T1* N1mi M0	G1	Negative	G3	Positive	IA
T1* N $\text{O}$ M $\text{O}$ T1* N1mi M0 T1* N1mi M0	G1	Negative	G3	Positive	IA
Negative	Positive	Positive	G3	IA
Negative	Positive	Negative	G3	IA
Negative	Negative	Positive	Positive	IA
Negative	Negative	Negative	Positive	IA
Negative	Negative	Positive	Positive	IIA
Negative	Negative	Positive	Negative	IIA
Negative	Negative	Positive	Positive	IIA	Positive
Negative	Negative	Positive	Negative	IIA	Positive
Negative	Negative	Positive	Positive
Negative	Negative	Negative	IB
T0$N1*$M0$ T$1$N1$M0$ T$2$ N$O$ M0	G1	Positive	Positive	Positive	IA
T0$N1*$M0$ T$1$N1$M0$ T$2$ N$O$ M0	G1	Positive	Positive	Negative	IB
T0$N1*$M0$ T$1$N1$M0$ T$2$ N$O$ M0	G1	Positive	Negative	Positive
T0$N1*$M0$ T$1$N1$M0$ T$2$ N$O$ M0	G1	Positive	Negative	IA
T0$N1*$M0$ T$1$N1$M0$ T$2$ N$O$ M0	G1	Positive	Negative	Positive	Positive
T0$N1*$M0$ T$1$N1$M0$ T$2$ N$O$ M0	G1	Negative	Negative	Positive	IB
T0$N1*$M0$ T$1$N1$M0$ T$2$ N$O$ M0	G1	Negative	Negative	Positive	Positive
T0$N1*$M0$ T$1$N1$M0$ T$2$ N$O$ M0	G1	Negative	Negative	Positive	IA
T0$N1*$M0$ T$1$N1$M0$ T$2$ N$O$ M0	G1	Negative	Negative	IA
T0$N1*$M0$ T$1$N1$M0$ T$2$ N$O$ M0	G1	Negative	Positive	Positive	Positive
T0$N1*$M0$ T$1$N1$M0$ T$2$ N$O$ M0	G1	Negative	Positive	Positive	Negative
T0$N1*$M0$ T$1$N1$M0$ T$2$ N$O$ M0	G1	Negative	Positive	Negative	Negative
T0$N1*$M0$ T$1$N1$M0$ T$2$ N$O$ M0	G1	Negative	Positive	Negative	Positive
T0$N1*$M0$ T$1$N1$M0$ T$2$ N$O$ M0	G1	Negative	Positive	Negative	Negative
T0$N1*$M0$ T$1$N1$M0$ T$2$ N$O$ M0	G1	Negative	Positive	Positive	IA
Negative	Negative	Negative	Positive	IA
Negative	Negative	Positive	Positive	IA	IIA
Negative	Negative	Positive	Negative	Negative	IIA
Negative	Negative	Positive	Negative	Negative	IIA
Negative	Negative	Positive	Negative	Positive	IIA
Negative	Negative		Negative	Positive
Negative	Negative	Negative	Negative	Positive
T2 N1*** M0 T3 N0 M0	G1	Positive	Positive	Positive	IA
T2 N1*** M0 T3 N0 M0	G1	Positive	Positive	Negative	IIB
T2 N1*** M0 T3 N0 M0	G1	Positive	Negative		IIB
T2 N1*** M0 T3 N0 M0	G1	Positive	Negative	Positive	Positive
T2 N1*** M0 T3 N0 M0	G1	Negative	Negative	Positive	I B
T2 N1*** M0 T3 N0 M0	G1	Negative	Negative	Negative	I B
T2 N1*** M0 T3 N0 M0	G1	Negative	Negative	Negative	I B
T2 N1*** M0 T3 N0 M0	G1	G2	Positive	Positive	I B
T2 N1*** M0 T3 N0 M0	G1	G2	Positive	Positive	Negative
T2 N1*** M0 T3 N0 M0	G1	G2	Positive	Negative	Negative
T2 N1*** M0 T3 N0 M0	G1	G2	Positive	Negative	Positive
T2 N1*** M0 T3 N0 M0	G1	Negative	Negative	Negative	Positive
Negative	IB		Negative	Negative
G3	Positive	Positive	Positive	Negative	IB
G3	Positive	Negative	Negative	Positive
G3	Positive	Negative	Positive	Positive	Positive
G3	Positive	Negative	Positive	Negative	Negative
Negative	Positive	Negative	Positive	Positive
Negative	Positive	Negative	Negative	Negative
Negative	Negative	Positive	Positive	Positive
Negative	Negative	Positive	Negative	Negative
Negative	Negative	Positive	II A
Negative	Negative	Positive	Positive	Positive	II B
Negative	Negative	Negative	Positive
Negative	Negative	Positive	Positive	Positive
Negative	Negative	Positive	Negative	Negative
Negative	Negative	Positive	IIIA
T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $	G1	Positive	Positive	Positive	IB
T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $	G1	Positive	Positive	Negative	Positive
T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $	G1	Positive	Negative	Positive
T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $	G1	Positive	Negative	Positive	Negative
T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $	G1	Positive	G2	Positive	Positive
T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $	G1	Negative	G2	Positive	Positive
T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $	G1	Negative	G2	Positive	Negative
T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $	G1	Negative	G2	Positive	Negative
T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $	G1	Negative	G2	Positive	Negative
T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $	G1	G3	Positive	Positive	Positive
T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $	G1	G3	Positive	Positive	Negative
T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $	G1	G3	Positive	Negative	Negative
T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $	G1	G3	Positive	Negative	Negative
T0$N2$M0 $T2$ N2$M0 $T3$ N1$^{***}$ $M0 $T3$ N2$M0 $ $	G1	G3	Positive
T4 N0 M0 T4 N1*** M O T4 N2 M0 Any T N3 M0	G1	Positive	Positive	Positive	IIIA
T4 N0 M0 T4 N1*** M O T4 N2 M0 Any T N3 M0	G1	Positive	Positive	Negative	IIIB
T4 N0 M0 T4 N1*** M O T4 N2 M0 Any T N3 M0	G1	Positive	Positive	Negative	IIIA
T4 N0 M0 T4 N1*** M O T4 N2 M0 Any T N3 M0	G1	Negative	Positive	IIIA
T4 N0 M0 T4 N1*** M O T4 N2 M0 Any T N3 M0	G1	Negative	Negative	IIIB
T4 N0 M0 T4 N1*** M O T4 N2 M0 Any T N3 M0	G1	Negative	Negative	Positive	IIIA
T4 N0 M0 T4 N1*** M O T4 N2 M0 Any T N3 M0	G1	Negative	Negative	IIIB
T4 N0 M0 T4 N1*** M O T4 N2 M0 Any T N3 M0	G1	Negative	Negative	Positive	IIIB
T4 N0 M0 T4 N1*** M O T4 N2 M0 Any T N3 M0	G1	Negative	Negative	IIIC
T4 N0 M0 T4 N1*** M O T4 N2 M0 Any T N3 M0	G1	Negative	G2	Positive	Positive
T4 N0 M0 T4 N1*** M O T4 N2 M0 Any T N3 M0	G1	Negative	G2	Positive	Positive
T4 N0 M0 T4 N1*** M O T4 N2 M0 Any T N3 M0	G1	Negative	G2	Positive	Positive
T4 N0 M0 T4 N1*** M O T4 N2 M0 Any T N3 M0	G1	Negative	G2	Positive	Negative
T4 N0 M0 T4 N1*** M O T4 N2 M0 Any T N3 M0	G1	Negative	G3	Positive	Positive
T4 N0 M0 T4 N1*** M O T4 N2 M0 Any T N3 M0	G1	Negative	G3	Positive	IIIB
Negative	Positive	IIIC	G3	Positive
Negative	Negative	IIIB	G3	Positive
Negative	Negative	Positive	G3	IIIC
Negative	Negative	IIIB	G3
Negative	Negative	Positive	G3	IIIB
Negative	Negative	IIIC

表 32
3D-CRT	three dimensional radiation therapy	DMMR
AI	aromatase inhibitor	DVH
APBI	accelerated partial breast irradiation	EIC
ALND	axillary lymph node dissection	EPC
ALT	alanine aminotransferase	FDG
AST	aspartate aminotransferase	FSH
AST	aspartate aminotransferase	FNA
AUC	area under the curve	GnRH
BCs	breast cancers	H&E
BCI	breast cancer index	IBC
BCS	breast-conserving surgery	IBTR
BCT	breast-conservation therapy	IGRT
BIA-	breast implant-associated	IHC
ALCL	apanlastic large cell	ILD
lymphoma
BIA-	breast implant-associated	IMRT
SCC	squamous cell	ISH
carcinoma
BMI	body mass index	LH
CBC	complete blood count	LVEF
CEA	carcinoebryonic antigen	LVI
CPS	combined positive score	MSI-H
CRF	cancer-related fatigue	NAC
ctDNA	circulating tumor deoxyribonucleic acid	NGS
DCIS	ductal carcinoma in situ	NST
DCIS-M	DCIS with microinvasion	OS
DFS	disease-free survival	PBI
DIBH	deep-inspiratory breath hold	pCR

表 33
dMMR	mismatch repair deficient
DVH	dose-volume histogram
EBRT	external beam radiation therapy
EIC	extensive inductal component
EPC	encapsulated papillary carcinoma
FDG	fluorodeoxyglucose
FSH	follicle-stimulating hormone
FNA	fine-needle aspiration
GnRH	gonadotropin-releasing hormone
H&E	hematoxylin and eosin
IBC	inflammatory breast cancer
BCS	IBTR
BCT	breast-conservation therapy
BIA-	breast implant-associated
ALCL	anaplastic large cell
lymphoma
BIA-	breast implant-associated
SCC	IMRT
SCC	ISH
carcinoma	LFTs
BMI	body mass index
CBC	complete blood count
CEA	carcinoebryonic antigen
CPS	combined positive score
CRF	cancer-related fatigue
ctDNA	circulating tumor deoxyribonucleic acid
DCIS	ductal carcinoma in situ
DCIS-M	DCIS with microinvasion
DCIS	dcis-free survival
DIBH	deep-inspiratory breath hold

表 34
PCP	primary care physician
PD-1	programmed cell death protein 1
PD-L1	programmed death ligand 1
PFS	progression-free survival
PMRT	postmastectomy radiotherapy
PTSD	post-traumatic stress disorder
PTV	planning target volume
RCB	residual cancer burden
RECIST	response evaluation criteria in solid tumors
RNI	regional nodal irradiation
RS	recurrence score
RT-PCR	reverse transcriptase polymerase chain reaction
SBRT	stereotactic body radiation therapy
SE	standard error
SLN	sentinel lymph node
SLN	sentinel lymph node biopsy
SPC	solid papillary carcinoma
SNRI	serotonin and norepinephrine
reuptake inhibitors
SSRI	selective serotonin reuptake inhibitors
TF	tumor fraction
TIPN	taxane-induced peripheral
neuropathy	neuropathy
TMB-H	tumor mutational burden-high
TNBC	triple-negative breast cancer
VMAT	volumetric modulated arc therapy

表 35
	NCCN Categories of Evidence and Consensus
Category 1	Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus(≥85% support of the Panel) that the intervention is appropriate.
Category 2A	Based upon lower-level evidence, there is uniform NCCN consensus(≥85% support of the Panel) that the intervention is appropriate.
Category 2B	Based upon lower-level evidence, there is NCCN consensus(≥50%, but <85% support of the Panel) that the intervention is appropriate.
Category 3	Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

表 36
NCCN Categories of Preference
Preferred intervention	Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.
Other recommended intervention	Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.
Useful in certain circumstances	Other interventions that may be used for selected patient populations (defined with recommendation).

图示：Continue

图示：DIAGNOSIS WORKUP PRIMARY TREATMENT Whole breast RT(category 1) with or without boost to tumor bedj,k,l,m or accelerated partial breast irradiation/partial breast radiation(APBI/PBI)j,k,l or No RTj,k,m(category 2B) DCIS Tis,N0,M0, Encapsulated or solid papillary carcinoma (SPC)a ● Diagnostic bilateral mammogram ● Pathology reviewb ● Determination of tumor estrogen receptor (ER) status ● Determination of tumor estrogen receptor (ER) status ● Genetic counseling for patients at riskc of hereditary breast cancer ● Breast MRId,e as indicated Total mastectomy with sentinel lymph node biopsy Spectralal treatment(DCIS-2) or irradiation/partial breast radiation(APBI/PBI)j,k,l or No RTj,k,m(category 2B) Postsurgical treatment(DCIS-2) Treatment(DCIS)2)

图示：DIAGNOSIS (CLINICAL) WORKUPa CLINICAL STAGE ● History and physical exam ● Diagnostic bilateral mammogram Ultrasound as necessary Breast MRlb (optional), with special consideration for mammographically occult tumors ● Estrogen/progesterone receptor (ER/PR) status and HER2 status dTM) ● Genetic counseling and testing if patient is at riské for hereditary breast cancer, has triple-negative breast cancer (TNBC) (at any age), or is a candidate for adjuvant olaparib ● Address fertility and sexual health concerns as appropriate! ● Pregnancy test in all patients of childbearing potential (lf pregnant), see PREG-1) ● Assess for distress9 ● Consider additional imaging studies only in the presence of signs and symptoms of metastatic disease and for patients who are clinically high risk (BINV-18) h ● Consider baseline lymphedema screening, as per NCCN Guidelines for Survivorship INflammatory breast cancer (IBC) ● Estrogen/progesterone receptor (ER/PR) status and HER2 status dTM) ● Genetic counseling and testing if patient is at riské for hereditary breast cancer, has triple-negative breast cancer (TNBC) (at any age), or is a candidate for adjuvant olaparib ● Address fertility and sexual health concerns as appropriate! ● Pregnancy test in all patients of childbearing potential (lf pregnant), see PREG-1) ● Assess for distress9 ● Consider additional imaging studies only in the presence of signs and symptoms of metastatic disease and for patients who are clinically high risk (BINV-18) h ● Consider baseline lymphedema screening, as per NCCN Guidelines for Survivorship INflammatory breast cancer (IBC) ● Estrogen/progesterone receptor (ER/PR) status and HER2 status dTM) ● Genetic counseling and testing if patient is at riské for hereditary breast cancer, has triple- and/or internal mammary nodal disease. See Principles of Dedicated Breast MRI Testing (BINV-B) and NCCN. # Guidelines for Breast Cancer Screening and Diagnosis. # The panel endorses the College of American Pathologists The panel endorses the College of American Pathologists for pathology reporting for all invasive and noninvasive carcinomas of the breast. http://www.cap.org. # Principles of Biomarker Testing (BINV-A). # The panel endoers the College of American Pathologists for disease and disease is suspected, see Workup on BINV-18. # Principles of Biomarker Testing (BINV-A). # The panel endoers the College of American Pathologists for disease and disease is suspected, see Workup on BINV-18.

图示：SURGERY ADJUVANT SYSTEMIC THERAPY NODAL STATUS RT nodal irradiation(RNI) in patients with central/medial tumors, pT3 tumors, or pT2 tumors and one of the following high-risk features: grade 3, extensive lymphovascular invasion (LVI), or hormone-receptor (HR)-negative.1 or Consider APBI/PBI in selected patients who are low risk (category 1)s,u Consider omitting breast irradiation if adjuvant endocrine therapy is planned and following criteria are met (category 1):1)≥70 y, HR+, HER2-negative, cN0, pT1 (≤2cm)0,t ASCTAN 2)≥65 y, HR+, HER2-negative, pN0, pT≤3 cm BCSi,j±surgical systemic RT is typically given after systemic therapy. See BINV-I for sequencing of systemic and systemic therapy and RT. See BINV-4 to determine whether adjuvant systemic study. 2)≥65 y, HR+, HER2-negative, cN0, PNT1 (≤2cm)0,t ASCTAN 3)≥1.4°.4°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.6°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5°.5

图示：SURGERY ADJUVANT SYSTEMIC THERAPY PATHOLOGIC NODAL STATUS RT 0 Negative axillary nodes and pSt2 (≤5 cm) and margins≥1 mm Negative axillary nodes and sT2 (≤5 cm) and negative margins but <1 mm Nipple.sparing, try the asymptotic therapy is indicated. RT RT RT is given after systemic therapy. See BINV-I for sequencing therapy and RT. Negative axillary nodes and sT2 (≤5 cm and negative margins but <1 mm Negative axillary nodes and pSt3 (≤5 cm) and negative margins but <1 mm Nipple.sparing, try the asymptottic activity for other systemic study. See BINV-I for sequencing therapy and RT. Negative axillary nodes Right DODAR Negative axillary nodes Nipple.sparing, try the asymptottic and reconstruction 1-3 positive axillary nodes Strongly consider PMRT$ to chest wall + comprehensive RNI(including any portion of the undissected axilla at risk). Margins Re-excision to negative margins is preferred. If not feasible, then strongly consider PMRT$ to chest wall ± comprehensive RNI(including any portion of the undissected axilla at risk).

图示：HISTOLOGY HR STATUS HR STATUS HER2 STATUS BINV-5 ER2-positivecc dd and/or PR-positivecc,dd HER2-negativecc INV-5 Postmenopausalee PIT1-3 AND pN0 or pN+ BINV-6 Prenmenopausalee PPT1-3 AND pN0 BINV-7 P1-3 AND pN0 PT1-3 AND pN+ BINV-8 PINV-8 ER-negative and PR-negativecc,dd ER2-negativecc INV-10 Favorable histologic typebb: Pure tubular ●Pure mucinous IP, pure cribiformr ● Adenoid cystic ● Conventional),secretory ● Resilaryive ● Adilary carcinoma ● Ares low-grade forms of salivary carcinomas ● Other rare forms CC ER -rate of dly ● Adil. For the same time and time of the group of health is considered in the context of human cancer,discretation of theoretical results. BINV-8 PIT1-3 AND pN0 Prenmenopausalee PPT1-3 AND pN0 BINV-8 PER-negative dek INV-9 HER2-positivecc BINV-9 HER2-negativecc BIN-10 Favorable histologic typebb: Pure tubular ● Pure mucinous ER-positivedd and/or PR-positivedd or ER-negative and PR-negative Favorable Histologies (BINV-11) ER-positive and PR-negative OR PIT1-3 AND pN0 BINV-7 PPT1-3 AND pN+ BINV-8 SERovicand HER2-negative BINV-8 CA Correlation of histology, HR, and HER2 status should always be done with awareness of unusual/discordant or borderline results. See Principles of Biomarker Testing (BINV-A).

图示：DisERASE c pN0 r n pT1a(≤0.5cm) pN1mi pN1i i pN2-0 pT2-0 n pT3-0 n pT1b(0.6-1.0 cm) i pN1mi i pT1c(pT3(>1 cm) O pN0 r n pN+ (≥1 ipsilateral metastases >2 mm) pN+（≥1 ipsilateral metastases n pN+（≥1 ipsilateral metastases n pN+（≥1 200000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000

图示：Ductal/NST$^{2}$ ·Mixed pT1a(≤0.5 cm) |Dual ·Mixed ·Micropapillary pN0 pT1-3 t(>0.5 cm) or pN1 mi(≤2 mm axillary node metastases) pN1(1-3 positive nodes) pT1b-T3 (>0.5 cm) or pN1 mi(≤2 mm axillary node metastases) Determine if candidate for chemotherapy Not a candidate for chemotherapy Not done |Adjuvant endocrine therapy.f,jj Consider adjuvant abemaciclib or riboclicib for eligible patients. See BINV-K 2 of 3 for eligibility criteria Adjuvant whole chemotherapy Not done Adjuvant endocrine therapy.f,gg followed by endocrine therapy.f,category 1). Consider adjuvant abemaciclib or riboclicib for eligible patients. Recurrence 1).Consider adjuvant endroduct therapy.f,ij Score 26 Asult. In the following case Adjuvant chemotherapy.f,99 BINV-K 2 of 3 for EMBIV-N. Adjuvant endocrine therapy,f,ij 1).Consider adjuvant abemaciclib or riboclicib for eligible patients. Adjuvant whole therapy.f,ij 1).Consider adjuvant exedocrine therapy. Respeciclet See BINV-K 2 of 3 for EMBIV-N Adjuvant whole therapy.f,ii 1.1 Aschiciblic for eligible patients. Recurrence 1).Consider adjuvant abemaciclib or riboclicib for eligible patients. See BINV-K 2 of 3 for eligibility criteria Adjuvant echoine therapy.f,ij Adjuvant whole chemotherapy.f,as ·V8n1-2 Adjuvant endroduct Oncology. PPr準policif Adjuvant endocrine

图示：pT1a (≤0.5 cm) and pN0 Ductal/NSTZ ·Ductal/NSTZ ·Mided ·Micropapillary Determine if candidate for chemotherapy ·Ductal/NSTZ ·Mixed ·Micropapillary Determine if candidate for chemotherapy ·Determine if candidate for chemotherapy ·Mancend for chemotherapy ·Not a candidate for chemotherapy ·Ductal/NSTZ ·Mancend for chemotherapy ·Mancend ·Mancend ·Mancend ·Mancend ·Mancend ·Mancend ·Mancend ·Mancend ·Mancend ·Mancend ·Mancend ·Mancend ·Mancend ·Mancend ·Mancend ·Mancend

图示：Determine if candidate for chemotherapy P1N1 mi (≤2 mm axillary node metastasis) or pN1 (1-3 positive nodes) Not a candidate for chemotherapy |lib|ly by end of chemotherapy |fl consider adjuvant abemacic lib or adjuvant abemacic liboriblic for eligible patients. See BINV-K 2 of 3 for eligibility criteria. Adjuvant endocrine therapy | 2 Adjuvant adjuvant ademacic liboriblic adjuvant abemacic liborib by endocrine therapy | 2 Adjuvant endocrine therapy Adjuvant chemotherapy | Adjuvant endocrine therapy | Adjuvant adjuvant ademic lorty by endocrine therapy | 2 Adjuvant adjuvant echoprial by endocrine therapy:emother gene expression | 2 Adjuvant endocrine therapy | 2 Adjuvant adjuvant ademic lorty by 2 Adjuvant adjuvant echoprial by 2 Adjuvant adjuvant ech by end erner and end erner's Adjuvant end erner3 Adjuvant end erner3 Adjuvant end erner3 Adjuvant end erner3 Adjuvant end erner3 Adjuvant end erner3 Adjuvant end erner3 Adjuvant end erner3 Adjuvant end erner3 Adjuvant end erner3 Adjuvant end erner3 Adjuvant end erner3 Adjuvant end erner3 Adjuvant end erner3 Adjuvant end erner3 Adjuvant end erner3 Adjuvant end erner3 Adjuvant end erner3 Adjuvant end erner3 Adjuvant end erner3 Adjuvant end erner3 Adjuvant end erner3 Adjuvant end erner3 Adjuvant end erner3 Adjuvant end erner3 Adjuvant end erner3 Adjuvant end erner3 Adjuvant end

图示：pT1, pT2, or pT3; and pN0 or pN1mi(≤2 mm axillary node metastasis) pT1b(0.6-1.0 cm) Olaparib should be given after completion Ductal/NSTZ Lobular Mixed o(Mixedapillary Metaplastica Metaplastica pN+(21 ipsilateral metastases>2 mm) pN+（≥1 ipsilateral metastases） Adjuvant chemotherapy Pn1ci Oaparib Adjuvant chemotherapy ya,gg.jj 1) and adjuvant olaparib if germline BRCA1/2 mutation, see BINV-M for eligibility by different completion pN1mi Adjuvant chemotherapy ya,gg.ij Adujuant chemotherapya,gg.gg 2) and adjuvant olaparib if germline BRCA1/2 mutation, see BINV-M for eligibility by different completion PnM1ni Oaparib should be given after completion Adjuvant chemotherapy ya,gg.ij Adujant chemotherapy ya,gg.ij (category 1) and adjuvant olaparib if germline BRCA1/2 mutation, see BINV-M for eligibility by different completion Adjuvant chemotherapy ya,gg.ij Oaparib or DINV-I.} Adjuvant chemotherapy ya,gg.ij D2) and adjuvant odaroparib if germline BRCA1/2 mutation, see BINV-M for different completion PnN+(21 ipsilateral metastases>2 mm) Adjuvant chemotherapy ya,gg.ij A2) and adjuvant chemotherapy ya,gg.ij PnN+(21 ipsilateral metal metastases>2 mm) Adjuvant chemotherapy ya,gg.ij D2) and adjuvant odaroparib if germline BRCA1/2 mutation, see BINV-M Alduovant PnN+(21 1ipsilateral metal metalstase Genv1-1 emphas

图示：1cm Consider adjuvant endocrine therapy of nP1 mi 1-2.9 cm 3 Consider adjuvant endocrine therapy of f )and node metastasis) 32 mm axillary therapyff 1-2.9 cm 3 Consider aduvent syndrome therapy ●Pure tubular / .Pure mucinous . ● Pure mucinous .$$ ER-positive and/or PR-positive,HER2-negative cc pN+(21 ipsilateral metastases>2 mm) 1-2.9 cm 32 cm 44.4 Adjuvant endocrine therapy of jjj ADjuvant endocrine therapy of ggg 23 cm 1-2.9 cm 32 cm Adjuvant endocrine therapy of jjj ADjuvant end giving 2mm Adjuvant endocrine therapy agg 32 cm 1-2.9 cm 32 cm 52cm 44.4 Adjuvant end giving 2mm Adjuvant end giving 2mm Adjuvant end giving 2mm Adjuvant end giving 2mm Adjuvant end giving 2mm Adjuvant end giving 2mm Adjuvant end giving 2mm end Adjuvant end giving 2mm end Adjuvant end giving 2mm end Adjuvant end giving 2mm end Adjuvant end giving 2mm end Adjuvant end giving 2mm end Adjuvant end giving 2mm end Adjuvant end giving 2mm end Adjuvant end giving 2mm end Adjuvant end giving 2mm end Adjuvant end giving 2mm end Adjuvant end giving 2mm end Adjuvant end giving 2mm end Adjuvant end giving 2mm end Adjuvant end giving 2mm end Adjuvant end获得 agg, R.21103745953-233-361149-255-36161526-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-266-

图示：● Adenoid cystic (conventional),secretory carcinoma, and other salivary carcinoma, and and PR-negative,HER2-negativecc Limited available data support local therapy only with consideration for systemic/targeted therapies only in pN+ disease ● Rare low-grade forms of metaplastic carcinomaaa

图示：c≥T2tt or cN+ and M0 or Ct71c, cN0 HER2-positive or cT1c, cN0 HER2-positive and NCG O percutaneous biopsy of suspicious nodesuu O complete blood count (CBC) O Comprehensive metabolic panel, including liver function tests and alkaline phosphatase Additional tests to consider as clinically indicated Ct71c, cN0 TNBC (For preoperative systemic therapy criteria, see BINV-L 1) ● FDG-PET/CTV ● Breast MRIb (optional), with special consideration for mammographically occult tumors, if not previously done For inoperable Braest cancer: see Preoperative Systemic Therapy (BINV-15) ● FDG-PET/CTV ● Cancer's: see Breast and Axillary Evaluation Prior To Preoperative Systemic Therapy (BINV-13) ● 03.333.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.33.3

图示：BCS possible BCS possible BCS not possible Mastectomy and surgical aaxillary staging (BIN-V-1 axillary axillary staging (BINV-D) $\bullet$ BCS with surgical staging (BINV-D) $\bullet$ BCS with aaxillary staging (BINV-D) $\bullet$ OK n+2, Induysant ventioarial ventical ventical $\bullet$ axillary staging (BINV-D) $\bullet$ BCS not possible $\rightarrow$ 0.25 NCCN Guidelines $\bullet$ AC n+2, Induysant ventioarial ventical ventical ventical $\bullet$ AC n+2, Induysant ventioarial ventical ventical $\bullet$ AC n+2, Induysant ventioarial ventical ventical $\bullet$ AC n+2, Induysant ventioarial ventical ventical $\bullet$ AC n+2, Induysant ventioarial ventical ventical $\bullet$ AC n+2, Induysant ventioarial ventical ventical $\bullet$ AC n+2, Induysant ventioarial ventical ventical $\bullet$ AC n+2, Induysant ventioarial ventical ventical $\bullet$ AC n+2, Induysant ventioarial ventical ventical $\bullet$ AC n+2, Induysant ventioarial ventical ventical $\bullet$ AC n+2, Induysustnance $\bullet$ BCS possible BCS possible Mastectomy and surgical aaxillary staging (BIN-V-1 axillary staging (BINV-D) $\bullet$ BC S not possible $\pm$ reconstruction $\pm$ reconstruction $\bullet$ AC n+2, Induysant vorgic 92.6 NCCN Mastectomy and surgical aaxillary staging (BINV-V-1 axillary axillary axillary axillary stectioarial ventical ventical $\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk. $\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk. $\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk. $\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk. $\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk. $\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk. $\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk. $\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk. $\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk. $\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk. $\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk. AC NCCN 11.22 NCCN 12.33 NCCN 13.33 NCCN Mastectomy and surgical aaxillary staging (BINV-V-1 axillary axillary axectia or early passage $\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk. $\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk. AC NCCN 12.33 NCCN 13.33 NCCN $\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk. AC NCCN 13.33 NCCN 13.33 NCCN $\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk. AC NCCN 13.33 NCCN 13.33 NCCN $\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk. AC NCCN 13.33 NCCN 13.33 NCCN $\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk. AC NCCN 13.33 NCCN 13.33 NCCN $\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk. AC NCCN 13.33 NCCN 13.33 NCCN $\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk. AC NCCN 13.33 NCCN 13.33 NCCN 13.33 NCCN 13.33 NCCN $\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk. AC NCCN 13.33 NCCN 13.33 NCCN 13.33 NCCN 13.33 NCCN $\bullet$ AC n+2, Induysustnance and image of any portion of the undissected axilla at risk. AC NCCN 13.33 NCCN 13.33 NCCN 13.33 NCCN 13.33 NCCN 13.33 NCCN 13.33 NCCN 13.33 NCCN 13.33 NCCN 13.33 NCCN 13.33 NCCN 13.33 NCCN 13.33 NCCN 13.33 NCCN 13.33 NCCN 13.33 NCCN 13.33 NCCN 13.33 NCCN 13.33 NCCN 13.33 NCCN 13.33 NCCN 13.33 NCCN 13.33 NCCN 13.33 NCCN 13.33 NCCN

图示：RESPONSEww ADJUVANT TREATMENT AND ADJUVANT THERAPY Response to preoperative and tumor is operable Response to other systemic therapy and tumor is operable Mastectomy and surgical axillary staging^{k}^{x} 40 and reconstruction (optional)^{w} ADJUVN 16) ADJUVANT STREATNESS ADjuvant systemic therapy^{xx}^{(BINV-16)} and ADjuvant RTS^{s}$ ADjuvant RTS to the whole breast or chest wall and comprehensive RNI with inclusion of any portion of the undissected axilla at risk. Response to preoperative therapy^{\text{WW-1}} ADJUVW and/or preoperative remains inoperable Consider additional systemic therapy and/or preoperative therapy/and/or tumor radiations No response to preoperative systemic therapy and/or preoperative remains inoperable No response to preoperative systemic therapy w and tumor is inoperable

图示：BCS No Yes No Bostum Yes Bustc No Surgical resection if feasiblePPP+consider surgical axillary stagingmm+PMRT$ (BINV-28 axillary stagingmm+repeat RT,if feasible and indicated 5,000 Mastectomy No Yes Surgical resection if feasiblePPP+consider surgical axillary stagingmm+PARTMS(BINV-3) \Consider appropriate systemic therapyqqq Binv-K, BINV-M, BINV-K, BINV-M, and see Principles of Survivorship BINV-28 Survivorship BINV-28

图示：Axillary ALND SOLNB only Surgical resection if feasiblePPP with ALND(for axillary recurrence) + RT if feasibles,000 No prior RT ALND RTP<\text{comprehensive on localized} Surgical resection of gross diseasePPP ALND(for axillary recurrence) if feasible+RT if feasibles,000 Supra/infra-clavicular, Internal mammary No prior RT RRT(comprehensive or localized) Prior RT Repeat RT, if feasibles,000

图示：ER- and/or PR-positive; HER2-negative^{dd,dd,ttt} BINV-22 ER- and/or PR-positive; HER2-positive; HERV-24 BINV-24 Recurrent unresectable (local or regional) or stage IV (M1) Disease kkk,rrr Bone disease present Add denosumab zoonedronic acid, or pamidronatesss ER- and/or PR-positive; HER2-positive; HER2-positive d,dd,ttt BINV-24 ER- and/or/or PR-positive; HER2-positive; HER2-positive d,dd,ttt BINV-24 ER- and PR-negative; HER2-positive; HER2-positive d,dd,ttt BINV-24 ER- and PR-negative; HER2-negative d,dd,ttt

图示：Visceral crisisuu$\longrightarrow$Consider initial systemic therapyvvv No visceral crisis and Prior endocrine therapy within 1 y$\_$ $\_$ and therapy within 1 y$\_$ $\_$ Postmenopausalee$\longrightarrow$Systemic therapywww or Continue systemic therapy until progression\→ Notain ocrystalline - $\_$ and \(\operatorname{Glyv} \longrightarrow \operatorname{Glyv} \longrightarrow \operatorname{Glyv} \longrightarrow \operatorname{Glyv} \longrightarrow \operatorname{Glyv} \longrightarrow\longrightarrow$ Postmenopausalee$\longrightarrow$Systemic therapywww or Isentic therapy therapy\longdots Non visceral crisis and cancer to cancel or selective ER modulators//www long 2025\longdots therapy therapy\longdots\ No visceral crisis and Therapy within 1 y Postmenopausalee$\longrightarrow$Systemic therapywww or Continue systemic therapy during progression until progression\→ Notantic therapy or Discrular therapy Progression and gly for Principles or/Sivorship No visceral crisis and endocrine therapy within 1 y$\_$ $\_$ $\longrightarrow$

图示：Progressionyy y or unacceptable toxicity on first-line endocrine therapy for other endocrine therapy (see second-line therapy options on BINV-P) Noncali ngedinoE 9000-0596-0696-04880 Alternative endocrine therapy ,Myte oscine therapy (see second-line therapy options on BINV-P) No clinical benefit after up to 3 sequential endocrine therapy may be needed for these 2000 systemic therapy (vvv,Yyyu or Systemic therapy) Systemic therapy Most patients will be candidates for multiple lines of systemic therapy to palliate advanced breast cancer. At each reassessment clinicians should and ensure that of ongoing treatment, the risks and benefits of an additional line of systemic therapy, patient performance status, and patient preferences through a shared decision-making process .- Systemic therapy vvv,yyy For those with visceral crisis:Progressionyy or unacceptable therapy vvv,yyy incersal therapy 0000-06800 Alternate systemic, and patient performance status, and patient preferences through a shared decision-making process .- Systemic therapy vvv,Yyyu or Sonic and NCCN Guidelines for Palliative Care and NCCN Guidelines for Supportive Care)

图示：Systemic therapy + HER2-targeted therapy\v,www end or endocrine therapy + HERb$\pm$ HER2-targeted therapy if premenopausal,ee consider ovarian ablation or suppression)ww,ccccc Continue therapy until progressiony OK Progression and See BINV-28 for Principles of Survivorship

图示：Progressionyyy Consider alternate endocrine therapy, $ endocrine therapy of not endocrine refractory 100,28,21:39在中医脉通平台下载，仅供个人使用，严禁分发。2025美国国家综合癌症网络版权所有。 Progressionyyy on first-line endocrine $\rightarrow$ $\leftarrow$ for other RER2-targeted therapy of ER2-targeted therapy ± 更换成RER2-targeted therapy of ER2-targeted therapy to 3 sequential endocrine therapy endocrine therapy $\rightarrow$ $\pm$ HER2-targeted therapy until progression vv,yyy,dddd and higher assessment of the systemic therapy. $ Most patients will be considered in the 29th 20th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30th 30t

图示：Progressionyy y on systemic time HER2-targeted therapy HER2-targeted + HER2-targeted therapy vvv HER2-targeted 999-False-negative ER and/or PR determinations occur, and there may be discordance between the ER and/or PR determination between the primary and metastatic tumor(s). Therefore, endocrine therapy with its low attendant toxicity may be considered in patients with non-visceral or asymptomatic visceral tumors, especially in patients with clinical characteristics predicting for a HR-positive tumor(eg), long disease-free interval, limited sites of recurrence, indolent disease, older age). YR2-Plincples of Monitoring Metastatic Disease(BINV-R). aaaa The potential side effects of additional lines of therapy may outweigh any clinical benefit in a patient who has a compromised performance status. Patient preference must be taken into account.

图示：Continue therapy until progressiony or unacceptable or unacceptable toxicity dddd and See BINV-28 for Principles of Survivorship Most patients will be candidates for multiple lines of systemic therapy to palliate advanced breast cancer. At each reassessment clinicians should assess value of ongoing treatment, the risks targeted therapy until and some other patients as the future of the future of the research > 2 NCCN Her2-rotated to toxicity dddd ngressionxy therapy + HER2-targeted therapy until progressionv v, yyy,dddd Mainpleative systemic therapy and service g pregression vv, v, y,y,dddd NCCN Guidelines for Palliative Care and nCCN Supportive Care 2 3 NCCN Guidelines for NCCN Guidelines for Supportive Care

图示：Continue therapy until progressionary or unacceptable to toxicity and See BINV-28 for Survivorship Most patients will be candidates for multiple lines of systemic therapy to palliate advanced breast cancer. At each reassessment clinicians should assess value of ongoing treatment, the risks and benefits of an additional line of systemic therapy, patient performance status, and patient preferences through a shared decision-making process.

图示：HER2 testing by validated immunohistochemistry (IHC) assayb,c IHC 0,1+d IHC 2+ IHC 3+ IHC 3+ IHER 2(+) U HER2(-) Must reflex test with ISH (if same specimen), I OFivocal result/or order new test with IHC or dual probe ISH (if new specimen available). HER2(+) IHC 3+ IHER 2(+)

图示：HER2-Negative:●(Group 5) HER2/CEP17 ratio <2.0 AND average HER2 copy number <4.0 signals/cell HER2-Negative(fetermined by concurrent IHC and ISH results): HER2-Negative(Determined by concurrent IHC and ISH results): ●(Group 2) HER2/CEP17 ratio ≥ 2.0 AND average HER2 copy number ≥ 6.0 signals/cell and concurrent IHC 0-1+ or 2+●(Group 4) HER2/CEP17 ratio \ge 2.0 AND average HER2 copy number ≥ 6.0 signals/cell and concurrent IHC 0-1+ or 2+●(Group 3) HER2/CEP17 ratio \ge 2.0 AND average HER2 copy number \ge 6.0 signals/cell and concurrent IHC 3+●(Group 4) HER2/CEP17 ratio \ge 2.0 AND average HER2 copy number ≥ 6.0 signals/cell and concurrent IHC 3+●(Group 4) HER2/CEP17 ratio \ge 2.0 AND average HER2 copy number ≥ 4.0 and <6.0 signals/cell and concurrent IHC 3+●(Group 1) HER2/CEP17 ratio ≥2.0 AND average HER2 copy number ≥ 4.0 signals/cell and concurrent IHC 3+●(Group 2) HER2/CEP17 ratio \ge 2.0 AND average HER2 copy number ≥ 6.0 signals/cell and concurrent IHC 3+●(Group 4) HER2/CEP17 ratio \ge 2.0 AND average HER2 copy number ≥ 4.0 signals/cell and concurrent IHC 3+●(Group 1) HER2/CEP17 ratio ≥2.0 AND average HER2 copy number ≥ 4.0 signals/cell and concurrent IHC

图示：No palpable lymph node at diagnosis or limited axillary lymph node involvement involving needle biopsy and marker placement a in the most suspicious or imaging of manipulation of blood and suspicious solutions as imaging of blood and suspicious solutions as imaging of blood and suspicious solutions as imaging of blood on imaging confirmed by needle biopsy and marker needle biopsy and marker (palpable) lymph nodes or limited axillary lymph node involvement in the most suspicious node in the ollm lymph nodes at diagnosis on exam or imaging of blood or imaging of blood as important information. In 2023-2024-2025-2026. In the following criteria9: Meets ALL of the following criteria9: cT1-T2, T3° cN0 or pN1mic No| 2-2 positive SLNs" 1-2 positive SLNs" 1-3. No preoperative chemotherapy No further end to all any 2-3. No preoperative The most suspicious cancer and risk and suspicious on exam or imaging of blood as suspicious node in the ollm lymph nodes at diagnosis on exam or imaging of blood as suspicious node in the ollm lymph nodes at diagnosis on exam or imaging of blood as suspicious node in the ollm lymph nodes at disease burden on imaging of blood on marker nucleation. In addition, this message and risk and suspicious on exam or imaging of blood as suspicious node in the ollm lymph nodes at diagnosis on exam or imaging of blood as suspicious node in the ollm lymph node in the ollm lymph nodes at diagnosis on exam or imaging of blood as suspicious node in the ollm lymph node in the ollm lymph node at diagnosis on exam or imaging of blood as suspicious node in the ollm lymph nodes at diagnosis on exam or imaging of blood as suspicious node in the ollm lymph node. In the ollm lymph node at the time of surgery. Only the most suspicious node should be marked and retrieved on the post-19:79-GS4-01-GS04-01-SENOMAC: de Boniface J,et al.N Engl J Med 2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SINODAR-2024:390:1163-1175. OTOASAR: Savolt A,et al.Ann Oncol 2017:28:v49.SIN

图示：BCSC (mark cavity with clips for subsequent RT planning, particularly in cases of oncoplastic tissue rearrangement/ reduction)d Carcinoma in situa,b or Invasive bepaned BCSC (mark block with clips for subsequent RT planning, particularly in cases of oncoplastic tissue rearrangement/ reduction)d No reconstruction required if ratio of tumor to breast volume is small and minimal cosmetic deformity will result or Consider oncoplastic reduction or mastopexy and simultaneous or delayed contralateral matching procedure or Consider bilateral breast reduction if symptoms warrant breast reduction or Local tissue rearrangement, regional flap (LD, partial LD, TDAP) RT red ondo F 4 No history of RT no adjuvant RT needed Delayed flap for correction of contour defects performed≥6 months after RT for symmetry Carcinoma in situa,b or Invasive carcinoma</n Mastectomy IBC No history of RT no adjuvant RT needed Reconstruction Based on Planning Adjuvant RT (BINV-H 2) $No history of RT/no adjuvant RT needed Implant, autologous, or combination reconstruction Unknown RT history or need for RT Reconstruction Based on Unknown History of RT or Unknown Need for Postmastectomy (BINV-H 7)

图示：Intersspace expansion followed by exchange to implant prior to the initiation of RT$^{k,k}_{1}$ implant- implant (prepectoral, partial submuscular, or total submuscular tissue expander) 2 stage: tissue expander followed by permanent implant (prepectoral, partial submuscular, or total submuscular tissue expander) Implant-based reconstruction plannedef 1 stage: direct to implant${}^{h}$ 26 months after completion of RT$^{h}$ I g Immediate autologous reconstruction ${}^{1}$ Delayed reconstruction ${}^{2}$ 6 months after the completion of RT Place tissue expander at the time of surgery, followed by expansion, RT, and delayed autologous reconstruction ${}^{1}$ 26 months after completion of RT$^{6}$

图示：Recurrent carcinoma after breast conservation including RT Assess soft tissue preoperatively and intraoperatively! Inadequate Adequatem 2 stage: tissue expander followed by implant Inadequate 00 2 stage: tissue expander followed by implant 0

图示：Delayed reconstruction after mastectomy and RT Assess soft tissue preoperatively and intraoperatively Adequate 2 stage: tissue expander followed by implant or autologous tissue Inadequate Inadequateem 8 Autologous(preferred) or combination,no

图示：No RT planned :Convert to autologous tissue reconstruction Adjuvant chemotherapy planned Tissue expansion during chemotherapy RT planned Prior to initiation of RT, if no delay to initiation of RT or6 months after RT) Immediate placement of tissue expander at the time of mastectomy (prepectoral, partial submuscular, total submuscular tissue expander placement)^{f} No adjuvant chemotherapy planning RT planned R RT planned 1 stage:direct to implant ${^{\varepsilon}}$ or the ipsalateral or contralateral breast after RT if needed ed autologous tissue reconstruction 8 Conversion to autologous tissue reconstruction 6 months after RT RT planned Tissue expansion followed by exchange to permanent implant or autologous tissue reconstruction 1 stage:direct to implant ${^{\varepsilon}}$ or immediate autologous tissue ${\varepsilon}$ and delay initiation of RT Consider revisional surgeries to the ipsilateral or contralateral breast after RT if needed deformation or mastectomy Layed reconstruction RT not required Reconstruction with implant, autologous tissue, or a combination Delayed reconstruction R RT required Reconstruction Based on History of RT (BINV-H 3)

图示：1 stage: direct to implant or Consider reversal surgeries or leptital or contralateral reconstruction or latissimus dorsi with implant at time of mastectomy i or RT not required→Reconstruction with implant, autologous tissue, or a combination

图示：Tissue expansion followed by RT; conversion to permanent implant or autologous tissue≥6 months after completion of RT (category 2B)j or Tissue expansion followed by exchange to permanent implant before RT (if no delay to initiation of RT)

图示：Delayed reconstruction RT not required→Reconstruction with implant, autologous tissue, or a combination Redelayed reconstruction RT required→Reconstruction Based on History of RT(BINV-H 3)

图示：Aromatase inhibitor for 5 y (category 1) Postmenopausala or Consider tamoxifen h for a additional 5 y to complete 10 y asymptosis, and, e,f,g or eligible or Aromatase inhibitor for 5 y or Consider tamoxifen h for a additional 5 y to complete 10 y asymptosis, and, e,f,g or Aromatase inhibitor for 5 y or ablationb,f (category 1). Consider adjuvant abemaciclib or ribociblc in eligible patientsi or Aromatase inhibitor for 5 y or ablationb,f (category 1). Consider adjuvant abemaciclib or ribociblc in eligible patientsi

图示：Aromatase inhibitor for 5 y (category 1). Consider arombe inhibitor for an additional 3-5 yj in eligible patientsi Aromatase inhibitork for 2-3 y (category 1). Tamoxifen\ to complete 5 y of endocrine therapy (category 1) Postmenopausalat diagnosis a,d,e,k at diagnosis Tamoxifen\ to for 4.5-6 y Patients with a contraindication to aromatase inhibitors, or inhibitors, who decline aromatase inhibitors, or who are intolerant to aromatase inhibitors Toamixenfh Aromatase inhibitor to complete 5 yj of endocrine therapy in eligible patients Aromatase inhibitor to complete 5 yj of endocrine therapy in or Thamoxifen Aromatase inhibitor to complete 5 yj of endocrine therapy in or Thamoxifen Aromatase inhibitor for yj of endino echnology therapy (category 1) Up to 5 y of an aromatase inhibitor (category 2B) Aromatase inhibitor for 5 yj (category 1) Stemaseartol.considerabaseartchol.24 Anatomase inhibitors in an eneckal therapy can Aromatase inhibitor for 5 yj (category 1) Atomoxifen hj calacturak.25 Bimberseartol.26 Aromataseolin.26 Aromatase inhibitor for aromatase inhibitors Aromatase inhibitor for 5 yj (category 1) Stemaseartol.26 Aromatase inhibitor for 6 yj (category 2B) Atomaseartol.26 Aromataseolin hchentabach.3 Aromatasebiol.26 Aromatasebiol chchentabach.4 Aromatasebiol chchentabach.5 Aromatasebiol chchentabach.6 Anatomaseartol.26 Aromatasebiol chchentabach.5 Aromatasebiol chchentabach.5 Aromatasebiol chchentabach.6 Anatomaseartol.26 Aromatasebiol chchentabach.5 Aromatasebiol chchentabach.5 Aromatasebiol chchentabach.5 Aromatasebiol chchentabach.5 Aromatasebiol chchentabach.5 Aromatasebiol chchentabach.5 Aromatasebiol chchentabach.5 Aromatasebiol chchentabach.5 Aromatasebiol chchentabach.5 Aromatasebiol chchentabach.5 Aromatasebiol chchentabach.5 Aromatasebiol chchentabach.5 Aromatasebiol chchentabach.5 Aromatasebiol chchentabach.5 Aromatasebiol chchentabach.5 Aromatasebiol chchentabach.5 Aromatasebiol chchentabach.

图示：NCCN National Comprehensive Cancer Cancer Network®

图示：CLINICAL PRESENTATION WORKUP CORE BIPSY TREATMENT RESULTS Fibroadenoma Observe Fibroadenoma Observe Indeterminate Benign phyllodesb,f Follow-follow-up for for a benign phylodesb Infinite phonetsb Disyncional Phyllodesb Fibrousologis born a biopsc or suspicious biopsc Benign phylodesb,f Phyllodesb Follow-up for phylodesb Follow Clinical suspicion of phylodesb Phyllodesb Suspicious for malignant Phyllodesb in situ cancer Invasive or in situ cancer See NCCN Guidelines for Noninvasive Breast Cancer for DCIS (DCIS-1) or Invasive Breast Cancer (BINV-1)

图示：Locally recurrent breast of phylodes tumor of phylodes tumor in disease No metastatic disease Re-excision with wide margins without axillary Consider post-operative radiation (category 2B)${}^{e}$(category 2B)${}^{e}$(Section NCCN Guidelines for Soft Tissue Sarcoma)

图示：Clinical suspicion of Paget disease · Clinical breast exam · Diagnostic bilateral mammogram,ultrasound as necessary Examination and imaging negative for breast lesion

图示：WORKUP CLINICAL PRESENTATION FRARYARY TREATMENT\b Discussion primalary TREATMENT\b Beginjuvant chemotherapy in second trimester tingerd prepanng Continuing Mastectomy eaxary stagingb,c ADJUVANT TREATMENTd Beginjuatmentov mperregnative chemotherapye+adjuvant endocrine ±± Adjuvant endocrine therapy postpartum Adjuvant chemotherapyd 4 ± Adjuvant endocrine and infection 3 2 1 2 1 0 1 2 1 0 1 2 1 2 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1

图示：Responsei→ Total mastectomy + level l/ll axillary dissection+ RT to chest wall and comprehensive RNI with inclusion of any portion of the undissected axilla at risk±delayed breast reconstruction Responsei→ Total mastectomy + level l/ll axillary dissection+ RT to chest wall and comprehensive RNI with inclusion of any portion of the undissected axilla at risk±delayed breast reconstruction No response→ Total mastectomy + RT to chest wall and comprehensive RNI with inclusion of any portion of the undissected axilla at risk±delayed breast reconstruction This may be candidates for multiple lines of systemic therapy to palliate advanced breast cancer. At each reassessment and clinicians should assess value of ongoing treatment, the risks and benefits of an additional line of systemic therapy, patient performance status, and patient preferences through a shared decision-making process.

图示：No response Consider additional systemic therapy and chemotherapy or preoperative radiation. Patients may be candidates for multiple lines of systemic therapy to palliate advanced breast cancer. At each reassessment at each reassessment at the risks and benefits of an additional line of systemic therapy, patient performance status, and patient preferences through a shared decision-making process. No response ${}^{i}$ No response ${}^{i}$ Individualized treatment 'principles of Radiation Therapy(BINV-K) Systemic Therapy Regimens for Recurrent Unresectable (Local or Regional) or Stage IV (M1) Disease (BINV-Q) Response ${}^{i}$ See above pathway Principles of Radiation Therapy(BINV-I) No response ${}^{i}$ Individualized treatment

引用 / 出处

（2025.V5）NCCN临床实践指南：乳腺癌. 2025.