NCCN临床实践指南：乳腺癌（2025.V1）

指南肿瘤内科· 乳腺癌 · 2025

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ® ) Breast Cancer

Authors

Keywords

‡ Hematology/Hematology oncology Þ Internal medicine † Medical oncology ≠ Pathology ¥ Patient advocacy § Radiation oncology/ Radiotherapy Ÿ Reconstructive surgery ¶ Surgery/Surgical oncology * Discussion Section Writing Committee 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

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Abstract

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NCCN Guidelines Version 1.2025 Breast Cancer

Version 1.2025, 1/31/25 © 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.

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 kind regarding 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 the express written permission of NCCN. ©2025.

# NCCN Guidelines Index Table of Contents Discussion

Find an NCCN Member Institution: https://www.nccn.org/ home/member-institutions.

NCCN Guidelines Version 1.2025 Ductal Carcinoma In Situ (DCIS)

DCIS-1

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. 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 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). g 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.

DIAGNOSIS

Postsurgical Treatment (DCIS-2)

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). i Principles of Breast Reconstruction Following Surgery (BINV-H). j Invasive disease at total mastectomy or re-excision should be managed as clinical stage l or stage ll 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).

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

DCIS-2

n CYP2D6 genotype testing is not recommended for patients considering tamoxifen. o 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. q 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).

Risk reduction therapy for ipsilateral breast following BCS: • Consider endocrine therapy for 5 years for patients with ERpositive DCIS, if:

Treated with BCS and RT n (category 1) Treated with excision alone o • Endocrine therapy p : 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: 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 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.

NCCN Guidelines Version 1.2025 Invasive Breast Cancer

BINV-2

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

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

BCS i,j ± surgical axillary staging category 1) k,l,m ± oncoplastic reconstruction n pN2-3 r (≥4 positive axillary nodes) pN1a (1-3 positive axillary nodes) pN0 or cN0 o,p,q Whole breast RT ± boost s to tumor bed (category 1) + comprehensive RNI, including any portion of the undissected axilla at risk (category 1)

Whole breast RT with inclusion of any portion of the undissected axilla at risk ± boost s to tumor bed (category 1). Strongly consider comprehensive RNI.

Whole breast RT ± boost s to tumor bed, and consider comprehensive regional 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. t or Consider APBI/PBI in selected patients who are low risk (category 1) s,u or 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) o,t 2) ≥65 y, HR+, HER2-negative, pN0, pT ≤3 cm t m Contraindications 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. o 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 ( q 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. r 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). t For definition of HR-positive, see Principles of Endocrine Therapy (BINV-K). u APBI/PBI may be administered prior to chemotherapy.

Whole breast RT ± boost (use of comprehensive RNI with or without intentional inclusion of axilla at the discretion of the radiation oncologist) (category 1)

Meets ALL of the following criteria:

Strongly consider PMRT s to chest wall + comprehensive RNI (including any portion of the undissected axilla at risk).

Re-excision to negative margins is preferred. If not feasible, then strongly consider PMRT s to chest wall ± comprehensive RNI (including any portion of the undissected axilla at risk).

Consider postmastectomy radiotherapy (PMRT) s to chest wall. For patients with additional high-risk features, y consider addition of comprehensive RNI (including any portion of the undissected axilla at risk).

No RT y

a For 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). r 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).

Negative axillary nodes and pT3 ( > 5 cm)

Consider PMRT s to chest wall ± comprehensive RNI (including any portion of the undissected axilla at risk).

LOCOREGIONAL TREATMENT OF cT1-3, cN0 or cN+, M0 DISEASE a,v : MASTECTOMY ± PMRT v Special Considerations for Breast Cancer in Males (Sex Assigned at Birth) (BINV-J). w Principles of Breast Reconstruction Following Surgery (BINV-H).

x In 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.

BINV-4

z According to WHO, carcinoma of no special type (NST) encompasses multiple patterns including medullary pattern, cancers with neuroendocrine expression, and other rare patterns. 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. -A ). 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). ee Definition of Menopause (BINV-O). Adjuvant chemotherapy a,gg with trastuzumab + pertuzumab ll (category 1, preferred) and endocrine therapy ff,jj,kk or Adjuvant chemotherapy a,gg with trastuzumab (category 1) and endocrine therapy ff,jj,kk 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). 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 decisionmaking. See Principles of Biomarker Testing (BINV-A). ff Adjuvant Endocrine ± CDK/4/6 Inhibitor Therapy and Principles of Adjuvant Endocrine Therapy (BINV-K). gg 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.

HISTOLOGY

Adjuvant chemotherapy a,gg with trastuzumab (category 1) (± pertuzumab for pT2-T3) and endocrine therapy ff,jj

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. jj 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 trastuzumabcontaining 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 adotrastuzumab 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.

BINV-6

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). 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).

SYSTEMIC ADJUVANT TREATMENT: HR-POSITIVE -HER2-NEGATIVE DISEASE d,v,dd POSTMENOPAUSAL ee PATIENTS with pT1-3 AND pN0 or pN+ TUMORS ee Definition of Menopause (BINV-O).

ff Adjuvant Endocrine ± CDK/4/6 Inhibitor Therapy and Principles of Adjuvant Endocrine Therapy (BINV-K). gg Preoperative/Adjuvant Therapy Regimens (BINV-M). jj 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 nodepositive tumors. mm There are few data regarding the role of gene expression assays in those with ≥4 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). oo 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. Adjuvant endocrine therapy (category 1). ff,jj Consider adjuvant abemaciclib or ribociclib for eligible patients. ff See BINV-K 2 of 3 for eligibility criteria.

pT1a ( ≤0.5 cm) and pN0

Adjuvant endocrine therapy. ff,jj Consider adjuvant abemaciclib or ribociclib for eligible patients. ff See BINV-K 2 of 3 for eligibility criteria.

Adjuvant chemotherapy a,gg followed by endocrine therapy ff,jj (category 1). Consider adjuvant abemaciclib or ribociclib for eligible patients. ff See BINV-K 2 of 3 for eligibility criteria.

Adjuvant chemotherapy a,gg followed by endocrine therapy ff,jj (category 1). Select patients may be eligible for treatment with adjuvant abemaciclib ff or ribociclib and/or adjuvant olaparib if germline BRCA1/2 mutation. See BINV-K 2 of 3 and BINV-M for eligibility criteria. Note: All recommendations are category 2A unless otherwise indicated.

BINV-7

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 should be incorporated into decision-making. See Principles of Biomarker Testing (BINV-A). ee Definition of Menopause (BINV-O). NEGATIVE DISEASE d, v ,dd PREMENOPAUSAL ee PATIENTS with pT1-3 AND pN0 TUMORS ff Adjuvant Endocrine ± CDK/4/6 Inhibitor Therapy and Principles of Adjuvant Endocrine Therapy (BINV-K). gg Preoperative/Adjuvant Therapy Regimens (BINV-M). jj 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. 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). oo 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.

SYSTEMIC ADJUVANT TREATMENT: HR-POSITIVE -HER2-

Determine if candidate for chemotherapy pT1b-T3 ( > 0.5 cm) and pN0

Consider adjuvant endocrine therapy (category 2B) Note: All recommendations are category 2A unless otherwise indicated.

BINV-8

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 should be incorporated into decisionmaking. 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). gg Preoperative/Adjuvant Therapy Regimens (BINV-M). NEGATIVE DISEASE d, v ,dd PREMENOPAUSAL ee PATIENTS with pT1-3 AND pN+ TUMORS jj 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 ≥4 ipsilateral axillary lymph nodes. Decisions to administer adjuvant chemotherapy for this group should be based on clinical factors. rr Gene Expression Assays for Consideration of Adjuvant Systemic Therapy (BINV-N).

pN1mi (≤2 mm axillary node metastasis) or pN1 (1-3 positive nodes)

Adjuvant endocrine therapy ± ovarian suppression/ablation. 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).

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

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

z 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. gg Preoperative/Adjuvant Therapy Regimens (BINV-M). jj Consider adjuvant bisphosphonate therapy for risk reduction of distant metastasis for 3-5 years in postmenopausal patients (natural or induced) with high-risk nodenegative 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.

Adjuvant chemotherapy a,gg,jj (category 1) and adjuvant olaparib if germline BRCA1/2 mutation, see BINV-M for eligibility criteria. Olaparib should be given after completion of RT, see BINV-I.

BINV-11

SYSTEMIC ADJUVANT TREATMENT: FAVORABLE HISTOLOGIES v,bb

a For tools to aid optimal assessment and management of older adults, see NCCN Guidelines for Older Adult Oncology. v Special Considerations for Breast Cancer in Males (Sex Assigned at Birth) (BINV-J). 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. 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). gg Preoperative/Adjuvant Therapy Regimens (BINV-M). jj Consider adjuvant bisphosphonate therapy for risk reduction of distant metastasis for 3-5 years in postmenopausal patients (natural or induced) with high-risk nodenegative or node-positive tumors. 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. tt If considering preoperative therapy, consider use of a gene expression assay during workup for postmenopausal patients with cN0, operable ER-positive, HER2negative disease (Iwata H, et uu 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. vv 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. Preoperative systemic therapy based on HR and HER2 status gg (BINV-L 1)

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

BINV-14

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). w Principles 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 preoperatively. 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.

BINV-15

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

w Principles 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 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. ADJUVANT SYSTEMIC THERAPY t,ff,gg,jj RESPONSE/PATHOLOGIC STAGE AFTER PREOPERATIVE THERAPY 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. 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. 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.

LOCOREGIONAL TREATMENT AND ADJUVANT THERAPY

Exam:

• History and physical exam 1-4 times per year as clinically appropriate for 5 years, then annually Genetic screening: Nervous System Cancers. ggg 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 an HR-positive tumor (eg, long disease-free interval, limited sites of recurrence, indolent disease, older age).

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. 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. jjj See 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 ablative metastasis-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.

RECURRENT/STAGE IV (M1

BINV-19

After mastectomy, repeat SLNB may be considered although there are limited data in this setting. In patients who had a prior axillary lymph node dissection (ALND) or mastectomy, repeat SLNB with lymphoscintigraphy may be considered rather than ALND (Poodt IGM, et al. Ann Surg Oncol 2019;26:2417-2427). nnn Repeat BCS ± adjuvant APBI/PBI may be considered in selected patients who decline mastectomy and otherwise meet consensus criteria for radiotherapy omission or APBI/PBI. There are limited data for a repeat BCS in this setting. ooo The decision to use RT to treat locoregional recurrence must factor in any prior radiation to the area and the risk of late normal tissue toxicity from the sum of the prior and planned radiation courses. ppp Consider systemic therapy to best response, then resect if possible. qqq See the Discussion for additional information.

TREATMENT OF LOCAL RECURRENCE: In-breast or

BINV-20

s Principles of Radiation Therapy (BINV-I). jjj See NCCN Guidelines for Palliative Care and NCCN Guidelines for Supportive Care. lll Multidisciplinary approach is especially important in the management of breast cancer recurrence to consider all potential treatment options for optimal outcomes. ooo The decision to use RT to treat locoregional recurrence must factor in any prior radiation to the area and the risk of late normal tissue toxicity from the sum of the prior and planned radiation courses. ppp Consider systemic therapy to best response, then resect if possible. qqq See the Discussion for additional information. 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). 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. rrr 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. ttt 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). ggg 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). vvv 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. ggg 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). vvv 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.

BINV

SYSTEMIC TREATMENT OF RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE: ER-AND

PRINCIPLES OF BIOMARKER TESTING HER2 TESTING a,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.

CONSIDERATIONS FOR SURGICAL AXILLARY STAGING

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. 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 (ie, TUG, VUG, DUG, PAP), or the back (ie, LD, TDAP, LAP). 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.

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

i Consider delaying autologous reconstruction until after RT is completed, as RT to a flap may cause loss of cosmesis and/or fat necrosis. j 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. k Exchange of tissue expander to implant should be timed to avoid any delay in adjuvant RT. 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. o 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. • 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.

PRINCIPLES OF BREAST RECONSTRUCTION AFTER SURGERY

• 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.

Continued

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 site complications 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. 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 se 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, singleagent 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 ystemic 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. Note: All recommendations are category 2A unless otherwise indicated.

BINV-K 2 OF 3 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. g 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 paroxetine 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.

i 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/neoadjuvant 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. j The three selective aromatase inhibitors (ie, anastrozole, letrozole, exemestane) 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).

ADJUVANT ENDOCRINE ± CDK4/6 INHIBITOR THERAPY

Premenopausal at diagnosis a,d,e,f,g Tamoxifen h for 5 y (category 1) ± ovarian suppression or ablation b,f (category 1).

Consider adjuvant abemaciclib in eligible patients i or

Aromatase inhibitor for 5 y j + ovarian suppression or ablation b,f (category 1).

Consider adjuvant abemaciclib or ribociclib in eligible patients i

Postmenopausal a

Premenopausal a,g

Aromatase inhibitor for 5 y j (category 1) or

No further endocrine therapy

Consider aromatase inhibitor for an additional 3-5 y j

Consider tamoxifen h for an additional 5 y to complete 10 y or NCCN Guidelines Version 1.2025 Invasive Breast Cancer

BINV-K 3 OF 3

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. h Some SSRIs like fluoxetine and paroxetine 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.

i 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 high-risk patients who mostly received adjuvant/neoadjuvant 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. j The three selective aromatase inhibitors (ie, anastrozole, letrozole, exemestane) 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. HER2-positive disease and TNBC • Patients in whom definitive surgery may be delayed.

ADJUVANT ENDOCRINE ± CDK4

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 PRINCIPLES OF PREOPERATIVE SYSTEMIC THERAPY

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 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 HER2positive breast cancer • Identifies patients with residual disease at higher risk for relapse to

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 HER2positive 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. • Consider cryotherapy of hands and feet to decrease the risk of peripheral neuropathy when receiving taxane therapies.

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

• 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/m 2 .

• 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. 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.

PREOPERATIVE/ADJUVANT

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. 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/m 2 . 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. Other Recommended Regimens: Preoperative or adjuvant setting: • AC followed by docetaxel c + trastuzumab i (doxorubicin/ cyclophosphamide followed by docetaxel + trastuzumab) • AC followed by docetaxel c + trastuzumab + pertuzumab i (doxorubicin/cyclophosphamide followed by docetaxel + trastuzumab + pertuzumab) • Paclitaxel/carboplatin + trastuzumab + pertuzumab 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/m 2 . 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.

References on BINV

g 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 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. i 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.

HER2-Negative

Preferred Regimens

• Dose-dense AC followed by paclitaxel 2 Doxorubicin 60 mg/m 2 IV day 1 Cyclophosphamide 600 mg/m 2 IV day 1 ◊ Cycled every 14 days for 4 cycles j ◊ Followed by: Paclitaxel 175 mg/m 2 by 3 h IV infusion day 1 ◊ Cycled every 14 days for 4 cycles j

• Dose-dense AC followed by weekly paclitaxel 2 Doxorubicin 60 mg/m 2 IV day 1 Cyclophosphamide 600 mg/m 2 IV day 1 ◊ Cycled every 14 days for 4 cycles j ◊ Followed by: Paclitaxel 80 mg/m 2 by 1 h IV infusion weekly for 12 weeks • Olaparib 6 300 mg PO twice daily Cycled every 28 days for 1 year

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. k Pembrolizumab 400 mg or 4mg/kg every 42 days may be given instead of pembrolizumab 200 mg every 21 days in this regimen.

References on BINV-M 10 of 10

Useful in Certain Circumstances • Capecitabine (maintenance therapy) 19 650 mg/m 2 PO twice daily on days 1-28 Cycled every 28 days for 1 year 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. Note: All recommendations are category 2A unless otherwise indicated.

• Docetaxel + Carboplatin + Pembrolizumab j,k,20 Docetaxel 75 mg/m 2 IV

BINV-M 7 OF 10

DOSING: PREOPERATIVE/ADJUVANT THERAPY REGIMENS

l 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.

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, trastuzumab, and hyaluronidase-zzxf injection for subcutaneous use has different dosing and administration instructions compared to the intravenous products. 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.

HER2-Positive l,m Preferred Regimens

Paclitaxel + trastuzumab 21 Paclitaxel 80 mg/m Note: All recommendations are category 2A unless otherwise indicated.

BINV-M 8 OF 10

j All cycles are with myeloid growth factor support. See NCCN Guidelines for Hematopoietic Growth Factors. l 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.

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, trastuzumab, 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.

HER2-Positive l,m

Useful in Certain Circumstances AC followed by T + trastuzumab 24 Doxorubicin 60 mg/m

Useful in Certain Circumstances

Neratinib 31 120 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 x 1 cycle ◊ Followed by: 240 mg PO daily on days 1-28 ◊ Cycled every 28 days x 12 cycles beginning with cycle 2

Paclitaxel + trastuzumab + pertuzumab 32 Paclitaxel 80 mg/m 2 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 n Ado-trastuzumab emtansine (T-DM1) 33 3.6 mg/kg IV day 1 ◊ Cycled every 21 days for 17 cycles

Other Recommended Regimens AC followed by docetaxel + trastuzumab 21,28 Doxorubicin 60 mg/m 2 IV day 1 Cyclophosphamide 600 mg/m 2 IV day 1 ◊ Cycled every 21 days for 4 cycles ◊ Followed by: Docetaxel 100 mg/m 2 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 AC followed by docetaxel + trastuzumab + pertuzumab 30 Doxorubicin 60 mg/m 2 IV day 1 Cyclophosphamide 600 mg/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/m 2 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 n l 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. 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, trastuzumab, 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.

Paclitaxel/carboplatin + trastuzumab + pertuzumab 29 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. b Special Considerations for Breast Cancer in Males (Sex Assigned at Birth) (BINV-J). c In the overall study population of the RxPONDER trial, 10.3% had high-grade disease and 9.2% had 3 involved nodes.

< 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 RxPONDER study. 2

≥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.

≤15

Premenopausal patients with T1b/c -2, pN0, HR-positive, HER2-negative tumors with RS < 16 derived no benefit from the addition of chemotherapy to endocrine therapy in the prospective TAILORx study. 1

16-25

In premenopausal patients with RS between 16-25, a small benefit from the addition of chemotherapy could not be ruled out, but it is unclear if the benefit was due to the ovarian suppression effect promoted by chemotherapy in premenopausal patients. 1, 2 For this group, consider chemotherapy followed by endocrine therapy or alternatively, ovarian function suppression combined with either tamoxifen or an AI.

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 premenopausal patients with 1-3 positive nodes) c

In premenopausal patients with pT1-3 and pN1 (1-3 positive nodes) tumors and an RS < 26, the addition of chemotherapy to endocrine therapy was associated with a lower rate of distant recurrence compared with endocrine monotherapy 2 but it is unclear if the benefit was due to the ovarian suppression effects promoted by chemotherapy. For this group of patients, consider chemotherapy followed by endocrine therapy or alternatively, ovarian function suppression combined with either tamoxifen or an AI. 2

In premenopausal patients with HR-positive, HER2-negative, pT1-3 and pN1 (1-3 positive nodes) tumors and an RS ≥26, the addition of chemotherapy to endocrine therapy is recommended. 2 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. b Special Considerations for Breast Cancer in Males (Sex Assigned at Birth) (BINV-J). c In the overall study population of the RxPONDER trial, 10.3% had high-grade disease and 9.2% had 3 involved nodes. For patients with T1 and T2 HR-positive, HER2-negative, pN0 tumors, a risk of recurrence score in the low range, regardless of T size, places the tumor into the same prognostic category as T1a-T1b,N0,M0. 4 Node positive: Low (0-40)

References on BINV-N 5 of 5

In patients with HR-positive, HER2-negative, pN+ tumors (1-3 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)

12-gene (EndoPredict) (pN0 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 n 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. 7 High ( > 3.3) 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.

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

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

10] [11] 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. b Special Considerations for Breast Cancer in Males (Sex Assigned at Birth) (BINV-J). e The benefit of testing BCI (H/I) for extended adjuvant endocrine therapy is unknown in patients who had ovarian function suppression, CDK4/6 inhibitors, or olaparib in addition to adjuvant endocrine therapy.

SYSTEMIC THERAPY FOR ER-AND/OR PR-POSITIVE RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE

BINV-P 3 OF 3 SYSTEMIC THERAPY FOR ER-AND/OR PR-POSITIVE RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE a

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. c In phase 3 randomized controlled trials, ribociclib + 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 + ribociclib or abemaciclib has shown OS benefit in the first-line setting f In phase 3 randomized controlled trials, fulvestrant in combination with a CDK4/6 inhibitor (abemaciclib, palbociclib, and ribociclib) has shown OS benefit in the secondline setting. g If there is disease progression while on palbociclib, there are limited phase II data to support the use of ribociclib in the second line setting. h If there is progression while on a PI3K inhibitor, there are limited data to support another line of therapy with a PI3K-pathway inhibitor-containing regimen. i 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 nonsteroidal aromatase inhibitor). k A 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. l Indicated after progression on prior endocrine therapy and prior chemotherapy in the metastatic setting.

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.

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/m 2 . Consider cryotherapy of hands and feet to decrease the risk of peripheral neuropathy. 1, 2 r 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 considered for one line of therapy including both trastuzumab plus pertuzumab in combination with or without cytotoxic therapy (such as vinorelbine or taxane). 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. -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. 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. f Fam-trastuzumab deruxtecan-nxki may be used for HER2 IHC 0+ 1+ or 2+/ISH negative, previously treated with at least one line of endocrine-based therapy in the metastatic setting. 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. g Sacituzumab govitecan-hziy 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. It may be considered for later line if not used as second line therapy. h 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. -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. g PD-L1 expression is assessed using 22C3 antibody. Threshold for positivity combined positive score ≥10. i 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 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 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. n Fam-trastuzumab deruxtecan-nxki 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 deruxtecan-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. o 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. q 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 pertuzumab-based chemotherapy, ado-trastuzumab emtansine, fam-trastuzumab deruxtecan-nxki, or trastuzumab/capecitabine/tucatinib regimens. Thus, the optimal sequence or true benefit of therapy is not known. 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.

SYSTEMIC THERAPY FOR RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE

NCCN Guidelines Index • 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

t 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. v The safety of alpelisib 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 ≥1 prior lines of endocrine therapy, including one line containing a CDK4/6 inhibitor. x Assess for ESR1 mutations at progression following prior lines of endocrine therapy (ctDNA preferred). mutations in homologous recombination-related genes. J Clin Oncol 2020;38:4274-4282. z Larotrectinib and entrectinib are 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. aa Repotrectinib 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. bb 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. cc 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. dd Tissue biopsy is more sensitive than ctDNA (liquid biopsy) at detecting homozygous copy loss of PTEN or TMB-H. ee 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. 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 anticancer agents and the management of associated toxicities in patients with cancer.

TARGETED THERAPIES AND ASSOCIATED BIOMARKER TESTING FOR RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1

BINV-Q 10 OF 15

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 anticancer agents and the management of associated toxicities in patients with cancer.

HER2-Positive Regimens kk,ll :

• Pertuzumab + trastuzumab + docetaxel 35 Pertuzumab 840 mg IV day 1 followed by 420 mg IV Trastuzumab 8 mg/kg IV day 1 followed by • Ado-trastuzumab emtansine (T-DM1) 39 3.6 mg/kg IV day 1 ◊ Cycled every 21 days

• Fam-trastuzumab deruxtecan-nxki 40 5.4 mg/kg IV day 1 ◊ Cycled every 21 days

• Paclitaxel/carboplatin + trastuzumab 41 Carboplatin AUC 6 IV day 1 Paclitaxel 175 mg/m 2 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 days 37

• Weekly paclitaxel/carboplatin + trastuzumab 42 Paclitaxel 80 mg/m

DOSING: SYSTEMIC THERAPY REGIMENS FOR RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE

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, 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.

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 reexcision with risk of recurrence for an individual patient.

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

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.

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 milarly, 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 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 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. 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 sults 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 (AI) (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.

MS-10

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: Imaging 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. [71] [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 o 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 benefit 75 and another without. 76 One systematic review 67 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 east 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 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). 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 HRpositive, 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 netic 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. 4] [85] [86] [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 NCCN Guidelines Version 1.2025 Breast Cancer

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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 cancer [90] [91] [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. 1] [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. 7] [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 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. [111] [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).

4] [115] [116] [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).

9] [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 NCCN Guidelines Version 1.2025 Breast Cancer

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population of young patients with breast cancer, thereby confounding the independent contributions of age and treatment to clinical outcome. 121 3] [124] Some studies have shown improved survival [125] [126] [127] and fewer post-surgical complications 128 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 nalysis 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 hese 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 e 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 r 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

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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 LND 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 9] [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 1.2025 Breast Cancer

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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

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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 Guidelines Version 1.2025 Breast Cancer

kk 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. ll 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, trastuzumab, and hyaluronidase-zzxf injection for subcutaneous use has different dosing and administration instructions compared to the intravenous products. • Trastuzumab + capecitabine 49, 50, 51 Capecitabine 1000-1250 mg/m 2 PO twice daily days 1-14 cycled every 21 days Trastuzumab 4 mg/kg IV day 1 followed by 2 mg/kg IV weekly 43, 50 or Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg IV day 1 every 21 days 35, 37 • Lapatinib + capecitabine 52 Lapatinib 1250 mg PO daily days 1-21 Capecitabine 1000 mg/m 2 PO twice daily days 1-14 ◊ Cycled every 21 days HER2-Positive Regimens (continued) kk :

• Trastuzumab + lapatinib 53 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 days 37

• Margetuximab-cmkb + capecitabine 55 Margetuximab 15 mg/kg IV day 1 Capecitabine 1000 mg/m 2 PO twice daily days 1-14 ◊ Cycled every 21 days

• Margetuximab-cmkb + eribulin 55 Margetuximab 15 mg/kg IV day 1 Eribulin 1.4 mg/m 2 IV days 1 and 8 ◊ Cycled every 21 days

• Margetuximab-cmkb + gemcitabine 55 Margetuximab 15 mg/kg IV day 1 Gemcitabine 1000 mg/m 2 IV days 1 and 8 ◊ Cycled every 21 days

• Margetuximab-cmkb + vinorelbine 55 Margetuximab 15 mg/kg IV day 1 Vinorelbine 25-30 mg/m 2 IV days 1 and 8 ◊ Cycled every 21 days

See dosing for targeted therapies on BINV-Q (14)

References on BINV-Q 12 of 15

BINV-Q 14 OF 15 DOSING: TARGETED THERAPIES AND ASSOCIATED BIOMARKER TESTING FOR RECURRENT UNRESECTABLE (LOCAL OR REGIONAL) OR STAGE IV (M1) DISEASE

• Alpelisib + fulvestrant 1 Alpelisib 300 mg PO daily on days 1-28; fulvestrant 500 mg IM on days 1 and 15 ◊ 28-day cycle for 1 cycle Followed by alpelisib 300 mg PO daily on days 1-28; fulvestrant 500 mg IM on day 1 ◊ Cycled every 28 days until disease progression or unacceptable toxicity

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

See NCCN Guidelines for Noninvasive Breast Cancer for DCIS (DCIS-1) or Invasive Breast Cancer (BINV-1)

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 softtissue sarcoma. f The Panel endorses the College of American Pathologists Protocol for standardized pathology reporting for all phyllodes tumors (https://documents.cap. org/protocols/Breast.Phyllodes_1.1.0.1.REL_CAPCP.pdf).

g Borderline and malignant phyllodes 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). NCCN Guidelines Version 1.2025 Phyllodes Tumor

Benign

PHYLL-2

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 phyllodes tumors from fibroadenomas. In cases with clinical suspicion for phyllodes 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 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.

PHYLLODES TUMOR RECURRENCE

CLINICAL

NCCN Guidelines Index

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.

NCCN Guidelines Version 1.2025 Inflammatory Breast Cancer

IBC-2

i 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. j 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). l 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).

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 2.04 cm is reported as 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. Tumor ≤20 mm in greatest dimension T1mi Tumor ≤1 mm in greatest dimension T1a

Tumor > 1 mm 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.

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.

ST

***N1 includes N1mi. T2, T3, and T4 cancers and N1mi are included for prognostic staging with T2 N1, T3 N1 and T4 N1, respectively.

CAT-1

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.

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.

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-misogynist, 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: 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] [7] [8] [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.

MS-4 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] [18] [19] [20] [21] [22] [23] [24] but not distant metastasis-free survival. 25 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 [CI] ; 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 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 cancers. [30] [31] [32] [33] 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 fo 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 NCCN Guidelines Version 1.2025 Breast Cancer

MS-5

Society for Radiation Oncology [ASTRO]/ASCO definition), the RT boost remained statistically significant for decreasing the rate of local relapse.

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 5year 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.

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.

8] [39] [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 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 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 ≤2.5 cm (n = 561); or 2) high-grade DCIS, tumor size ≤1 cm (n = 104). Protocol specifications included excision of the DCIS tumor with a minimum negative margin width of ≥3 mm. Only 30% of the patients received tamoxifen. Of note, margins were substantially wider than the 3mm protocol requirement in many patients (ie, the low-/intermediate-risk patient group margins were ≥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.

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 lowto 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. reduced by 50% with RT versus without RT (7.1% vs. 15.1%; HR, 0.36; 95% CI, 0.20-0.66). 42 e available evidence from four randomized trials (NSABP B-39/RTOG 0413, 43 OCOG-RAPID, 44 University of Florence, 45 and GEC-ESTRO 46 ) 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 rgin 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 ≥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 > 2 mm to 5 mm or > 5 mm were compared with 2-mm margins. 49 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 cording 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.

2] [53] [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 procedure 55 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.

According to the NCCN Panel, primary treatment options for patients with DCIS along with their respective categories of consensus are: 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).

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.

MS-18

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. 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 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.

NCCN Recommendations for

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

MS-19

breath-hold and prone positioning may be used to try to further reduce dose to adjacent normal tissues, particularly the heart and lung. 164 erification 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 ur randomized clinical trials have investigated hypofractionated WBRT schedules (39-42.9 Gy in single fractions of 2.6-3.3 0] [171] [172] The 10-year follow-up data from the START trials 173 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. 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.

MS-20

8] [179] RT boost treatment in the setting of breast conservation can be delivered using enface electrons, photons, or brachytherapy. 180 CN 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).

MS-21

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 e 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. 7] [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 he 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

MS-22

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 inical 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 I 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).

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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 oncordant 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

9] [200] [201] [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 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

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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). [207] [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 B-51/RTOG 1304 [NCT01872975] and the Alliance A011202/MAC19 trial [NCT01901094]).

Sequencing of RT and Systemic Therapy

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If chemotherapy and radiation are indicated after surgery, adjuvant radiation is typically delivered after the completion of chemotherapy. 209, 210 his 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.

2] [213] [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 capecitabine 215 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.

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. 0] [221] [222] [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. ] [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.

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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.

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 e 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 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 NCCN Guidelines Version 1.2025 Breast Cancer

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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 cancers 276 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 9] [280] [281] [282] [283] [284] [285] [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

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adjuvant endocrine therapy in the majority of patients with HR-positive breast cancer regardless of menopausal status, age, or HER2 status of the tumor.

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,

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results in 5216 postmenopausal patients with HR-positive, early-stage breast cancer enrolled in the ATAC trial demonstrated fewer recurrences (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 G 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 NCCN Guidelines Version 1.2025 Breast Cancer

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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 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 uppression 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 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 NCCN Guidelines Version 1.2025 Breast Cancer

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tamoxifen plus OFS was 85.4% versus 80.2% with tamoxifen alone (HR-0.67; 95% CI, 0.51 to 0.87). 317 e 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 hese data showed a considerable risk of recurrence between years 5 and 20 in these patients treated with initial 5 years of endocrine therapy. 318 ata 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 r 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 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 e 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,

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. 5] [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 NCCN Guidelines Version 1.2025 Breast Cancer

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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 ontraindications 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. ] [244] [245] [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 he 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 vantages 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 mitations 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 NCCN Guidelines Version 1.2025 Breast Cancer

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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.

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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 esults 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. [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 NCCN Guidelines Version 1.2025 Breast Cancer

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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 r 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.

1] [262] [263] [264] [265] [266] [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 cording 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.

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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 CN 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 NCCN Guidelines Version 1.2025 Breast Cancer

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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 th 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 iven 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 he 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. 8] [349] This assay has also been validated to predict the benefit from adding adjuvant chemotherapy to adjuvant endocrine therapy for patients with HR-positive, HER2-negative, node-negative breast cancer. 286, 350, 351 ong 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 owever, 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.

21-gene assay (Oncotype DX) in

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 -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. patients who have a low likelihood of distant recurrence despite high-risk 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.

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 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. 12-gene assay (EndoPredict): 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,

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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.

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).

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Adjuvant therapies are rapidly evolving and CDK 4/6 inhibitors and PARP inhibitors are now indicated in this setting.

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 Guidelines Version 1.2025 Breast Cancer

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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 nosumab: 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 Guidelines Version 1.2025 Breast Cancer

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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 e 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 Guidelines Version 1.2025 Breast Cancer

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chemotherapy and superior to moderate-dose EC in event-free survival and OS.

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 eful 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. Adjuvant 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.)

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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 n-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 Guidelines Version 1.2025 Breast Cancer

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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.

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All of the above adjuvant trials of trastuzumab have demonstrated clinically significant improvements in DFS. Furthermore, the HERA trial 416 and the combined analysis of the NSABP B31 and NCCTG N9831 trials 417 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 e NCCN Panel considers it reasonable to incorporate pertuzumab into the above adjuvant regimens 272, 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 HER2positive 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 e 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 HER2targeted 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 NCCN Guidelines Version 1.2025 Breast Cancer

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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 NCCN Guidelines Version 1.2025 Breast Cancer

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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 e 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. [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. 3] [334] [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 NCCN Guidelines Version 1.2025 Breast Cancer

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citalopram, escitalopram, sertraline, and venlafaxine appear to have no or only minimal effect on tamoxifen metabolism. 330, 338, 339 llow-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 e 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 timal 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 NCCN Guidelines Version 1.2025 Breast Cancer

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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% [448] For management of issues related to survivorship including late/long-term effects of cancer and its treatment, see the NCCN Guidelines for Survivorship. 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. [455] [456] [457] [458] [459] [460] [461] [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.

NCCN Guidelines

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.

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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 cording 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.

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 e 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

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

Bisphosphonates

There are extensive data from randomized trials in support of the use of bisphosphonates for patients with metastatic disease to bone. 2] [483] [484] [485] [486] [487] [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. 0] [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. 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

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 lvestrant + 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

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 e 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 ospective 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.

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

prior endocrine therapy. Pre-or perimenopausal patients also received goserelin. The median PFS was 9.5 months for the combination compared to 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 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.

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 erolimus 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 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 studies 531, 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.

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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.

Regimens Useful in Certain Circumstances for Therapy for HR-Positive, HER2-Negative Breast Cancer

Megestrol acetate, 512,538-540 estradiol 541 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.

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Preferred Regimens for Stage IV/Recurrent HER2-Positive Breast Cancer

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 ompared 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

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 sed 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 chemotherapy 552 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] [553] [554] [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 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. 0] [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 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 cording 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.

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 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 nterstitial 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 ime 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 sults 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

(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.

Adding trastuzumab or lapatinib to an AI has demonstrated a PFS advantage compared with AI alone in postmenopausal patients with stage IV or recurrent HR-positive, HER2-positive tumors.

In the TAnDEM study, postmenopausal patients (n = 207) with metastatic HR-positive and HER2-positive tumors were randomized to receive anastrozole alone or anastrozole plus trastuzumab. 572 Compared with single-agent anastrozole, an improvement in PFS was seen with combination therapy (4.8 vs. 2.4 months; HR, 0.63; 95% CI, 0.47-0.84; P

= .0016). 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 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. . 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 e 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 ( 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 Guidelines Version 1.2025 Breast Cancer

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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. [590] [591] [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 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 termining 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/m 2 ) 595 or every 3 weeks (175 mg/m 2 ). 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 NCCN Guidelines Version 1.2025 Breast Cancer

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administration of paclitaxel resulted in an improvement in OS (HR, 0.78; 95% CI, 0.67-0.89). 597 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] [613] [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 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 or 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 veral 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.

MS-75 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 0] [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 criteria 643 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 NCCN Guidelines Version 1.2025 Breast Cancer

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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 ccording 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. 8] [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 ere 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 2] [653] [654] [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 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 hyllodes 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 ile 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.

MS-80 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 iopsies 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 hen 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 6] [677] Isosulfan blue or methylene blue dye for sentinel node biopsy procedures is discouraged during pregnancy.

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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/m 2 IV days 1 and 4, doxorubicin 50 mg/m 2 by IV infusion over 72 hours, and cyclophosphamide 500 mg/m 2 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.

4] [685] [686] If used, the NCCN Panel recommends weekly administration of paclitaxel after the first trimester if clinically indicated by disease status. 8] [689] [690] [691] [692] [693] [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 docrine 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.

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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. 9] [700] [701] According to the 7 th 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 prognosis [704] [705] [706] and to be younger at the time of disease presentation. 707 e 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. 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 aging 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).

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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 evertheless, 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.

Treatment

The treatment of patients with IBC should involve a combined modality approach 696 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 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 e 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 NCCN Guidelines Version 1.2025 Breast Cancer

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] [721] [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 termination of response to neoadjuvant chemotherapy in IBC should include a combination of physical examination and radiologic assessment.

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 r 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.

|pN2/pN3 (≥4 ipsilateral metastases > 2 mm) qq||

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|Discussion|

|SYSTEMIC ADJUVANT TREATMENT: HR-NEGATIVE -HER2-POSITIVE DISEASE d,v|

|pT1, pT2, or pT3; and pN0 or pN1mi (|

|• Ductal/NST z • Lobular • Mixed • Micropapillary|

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||NCCN Guidelines Index| |---|---|

||Table of Contents|

||Discussion|

|SYSTEMIC ADJUVANT TREATMENT: HR-NEGATIVE -HER2-NEGATIVE DISEASE d,v||

|• Ductal/NST z • Lobular • Mixed • Micropapillary • Metaplastic aa|pT1, pT2, or pT3; and pN0 or pN1mi (≤2 mm axillary node metastasis) pN+ (≥1 ipsilateral metastases > 2 mm)|

||BINV-10|

||||< 1 cm|

|• Adenoid cystic (conventional), secretory carcinoma, and other salivary carcinomas • Rare low-carcinoma aa of metaplastic grade forms • Pure tubular • Pure mucinous • Pure cribriform|ER-positive and/or PR-positive, HER2-negative cc HER2-negative cc PR-negative, and ER-negative|pT1, pT2, or pT3; and pN0 or pN1mi (≤2 mm axillary node metastasis) pN+ (≥1 ipsilateral metastases > 2 mm)|1-2.Adjuvant whole breast RT (BINV-2) or PMRT (BINV-3) as indicated. See BINV-I for sequencing of systemic therapy and RT. and Follow-up (BINV-17)|

|WORKUP PRIOR TO PREOPERATIVE SYSTEMIC THERAPY||

|CLINICAL STAGE|ADDITIONAL WORKUP a|

|see BINV-L 1) systemic therapy criteria, (For preoperative cT1c, cN0 TNBC or disease cT1c, cN0 HER2-positive or c≥T2 tt or cN+ and M0|• Axillary assessment with exam Consider ultrasound Percutaneous biopsy of|

||BINV-12|

|BINV-13|

|RESPONSE ww|| |---|---|

|Preoperative systemic therapy t,gg (BINV-L 1)|Mastectomy and surgical axillary staging k + reconstruction (optional) w or BCS with surgical axillary staging k,aaa ± oncoplastic reconstruction n|

|jj 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.|

|BINV-16|

|ypT1-4,N0 or ypN≥1|eligibility criteria.|-K 2 of 3 for|

|SURVEILLANCE/FOLLOW-UP|

|Recurrent Disease (BINV-18)|

|BINV-17|

|BINV-18|

||) DISEASE| |---|---|

|CLINICAL STAGE|WORKUP a • History and physical exam • Discuss|

|Stage IV (M1) or Recurrent||

||BINV-22|

|Bone disease present|Add denosumab zoledronic acid, or pamidronate sss|

||BINV-26|

|Bone disease not present||

|SYSTEMIC TREATMENT OF|

|BINV-23|

|Consider alternate endocrine therapy, if not endocrine refractory ggg,www ± HER2-targeted therapy vvv|

|Alternate systemic therapy + HER2-targeted therapy vvv|

|BINV-25|

|Progression yyy on first-line endocrine therapy ± HER2-targeted therapy Progression yyy on systemic therapy + HER2-NCCN Guidelines Index No clinical benefit after up to 3 sequential endocrine therapy regimens ± HER2-targeted therapy yyy or Symptomatic visceral disease Table of Contents Discussion| |---|

|BINV-26|

|Systemic therapy + HER2-targeted therapy vvv|Continue therapy until progression yyy or unacceptable toxicity dddd and Survivorship Principles of See BINV-28 for|Alternate systemic therapy + HER2-targeted therapy until progression vvv,yyy,dddd|Consider no further HER2-targeted therapy aaaa and continue supportive care NCCN Guidelines for Palliative Care and NCCN Guidelines for Supportive Care| |---|---|---|---|

|Continue therapy until progression yyy or unacceptable toxicity 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 and benefits of an additional line of systemic therapy, patient performance status, decision-making process. through a shared and patient preferences|Consider no further cytotoxic therapy aaaa and continue supportive care NCCN Guidelines for Palliative Care and NCCN Guidelines for Supportive Care|

|||BINV-27|

|General Principles •|

|BINV-28|

|Nausea/vomiting,| |---|

|making. a||-| |---|---|---|

|HER2 testing by validated|IHC 0,1+ d|HER2 (-)|

|immunohistochemistry (IHC) assay b,c|IHC 2+ IHC 3+|Equivocal result HER2 (+)|

|a NCCN endorses the ASCO/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.|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) 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.|

|0% to < 1% of nuclei stain|0% to < 1% of nuclei stain|ER-negative| |---|---|---|

|1%-100% of nuclei stain|1%-10% of nuclei stain|ER-low-positive (with recommended comment)|

||> 10% of nuclei stain ER-positive||

|Low-grade invasive carcinomas of no ductal carcinoma) special type (also known as invasive|Metaplastic carcinomas of all subtypes| |---|---|

|Lobular carcinomas (classic type)|Adenoid cystic carcinomas and other salivary gland-like carcinomas of the breast|

|Pure tubular, cribriform, or mucinous carcinomas|Secretory carcinoma|

|Encapsulated papillary and solid papillary carcinomas|Carcinomas with apocrine differentiation (apocrine carcinoma)|

|BINV-B|

|FERTILITY, BIRTH|

|BINV-C|

|Sentinel node involvement is defined by multilevel node sectioning with 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.|

|BINV-D|

||SLN negative c||| |---|---|---|---|

|||No|ALND level I/II f|

||||No further axillary surgery i|

||FNA or|||

|US-guided FNA or core biopsy + marker|core biopsy negative d|||

||||SLNB j|

|BINV-E|

|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.|

|1 Moran MS, Schnitt SJ, Giuliano AE, et al. Society of Surgical Oncology-American Society for Radiation Oncology consensus guideline on margins for breast-|

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.

MS-85 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 patients [728] [729] [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 e 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.

MS-86

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.

nt but also to contribute to improving the treatment outcomes.

|||NCCN Guidelines Index| |---|---|---|

|||Table of Contents|

|||Discussion|

|DIAGNOSIS (CLINICAL)|WORKUP a|CLINICAL STAGE|

||• History and physical exam • Imaging: Diagnostic bilateral mammogram Ultrasound as necessary Breast MRI b (optional), with special consideration for mammographically occult tumors • Pathology review c • Estrogen/||

|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.|||

|||BINV-1|

||||See NCCN Guidelines for Occult Primary| |---|---|---|---|

||cT1-T4, ≥cN0,M0|Criteria for preoperative systemic therapy (BINV-L)|Locoregional treatment i • BCS ± surgical axillary staging + whole breast RT (BINV-2) or • Mastectomy + surgical axillary staging ± post-mastectomy RT (PMRT) (BINV-3) (BINV-12) Systemic Therapy Prior to Preoperative Additional Workup|

|Metastatic (M1) invasive breast cancer|Stage IV (M1) or Recurrent disease|||

|cT0,cN+,M0| |---|

|Localized breast cancer: Invasive, non-inflammatory, non-metastatic (M0)|

|pT1b-T3 ( > 0.5 cm) or pN1mi (≤2 mm axillary node metastases) or nodes) positive pN1 (1-3|If candidate for chemotherapy: Strongly consider 21-gene (category 1) nn,oo RT-PCR assay|Not done score < 26 Recurrence Recurrence score ≥26| |---|---|---|

done score < 26 Recurrence Recurrence score ≥26| |---|---|---|

|If candidate for chemotherapy: Strongly consider 21-gene RT-PCR assay (category 1• Ductal/NST z • Lobular • Mixed • Micropapillary| |---|

|Not a candidate for chemotherapy|

|Adjuvant whole breast RT (BINV-2) or PMRT (BINV-3) as indicated. See BINV-I for sequencing of systemic therapy and RT. and Follow-up (BINV-17)|

||Adjuvant whole breast RT (BINV-2) or PMRT (BINV-3)|

|• Ductal/NST z • Lobular • Mixed • Micropapillary|as indicated. See BINV-I for sequencing of systemic therapy and RT. and Follow-up (BINV-17)|

|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 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. 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.|

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

|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.|

|BINV-G|

|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 positive 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). e As 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.|

|a General Principles of Breast Reconstruction (BINV-H 5). b Patient Factors Affecting Choice of Reconstruction (BINV-H 6).| |---|

t Factors Affecting Choice of Reconstruction (BINV-H 6).| |---|

|NCCN Guidelines Index|

|BINV-H 3 OF 7|

|a General Principles of Breast Reconstruction (BINV-H 5). b Patient Factors Affecting Choice of Reconstruction (BINV-H 6). l 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.|

|BINV-H 4 OF 7|

|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|i Consider delaying autologous reconstruction until after RT is completed, as RT to a flap may cause loss of cosmesis and/or fat necrosis. j Consultation with radiation oncologists may be necessary to determine if volume| |---|---|

|failure. h Determined by preoperative size and ptosis, patient desire of postoperative size,|of contralateral tissue expander will affect RT treatment planning. In some cases, contralateral deflation may be required prior to CT simulation. Radiation|

|and assessment intraoperatively of skin and soft-tissue quality and perfusion,|oncology consultation should also be requested in cases of an anticipated|

|with consideration for patient-specific relative contraindications (eg, smoking,|close or positive deep margin, as this may impact the optimal placement of|

|obesity) to single-stage versus two-stage approaches. Healing issues may occur|the expander (pre-vs. subpectoral). Clips to identify the close/positive margins|

|and delay initiation of RT.|should be placed to assist in delineating the tumor bed boost.|

|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.|

|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.|

||• Livi L, Meattini I, Marrazzo 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 I, Marrazzo L, Saieva C, 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.|

|40 Gy/15 fractions|• 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.|

|• 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-breast 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.|

|Cautions • Possible|

|BINV-L 1 OF 2|

|DOSING: PREOPERATIVE/ADJUVANT THERAPY REGIMENS|

|BINV-M 6 OF 10|

|HER2-Negative||| |---|---|---|

|Other Recommended Regimens|||

|• AC followed by docetaxel every 3 weeks 7 Doxorubicin 60 mg/m² IV on day 1 Cyclophosphamide 600 mg/m² IV day 1 ◊ Cycled every 21 days for 4 cycles ◊ Followed by: Docetaxel 100 mg/m² IV on day 1 ◊ Cycled every 21 days for 4 cycles|• EC chemotherapy 8 Epirubicin 100 mg/m² IV day 1 Cyclophosphamide 830 mg/m² IV day 1 ◊ Cycled every 21 days for 8 cycles • TAC chemotherapy 9 ◊ Cycled every 21 days for 6 cycles l Cyclophosphamide 500 mg/m² IV day 1 Doxorubicin 50 mg/m² IV day 1 Docetaxel 75 mg/m² IV day 1|• Paclitaxel + carboplatin Weekly paclitaxel + carboplatin 1,10 (preoperative setting only) ◊ Paclitaxel 80 mg/m 2 days 1, 8, and 15 ◊ Carboplatin AUC 5 or 6 day 1; -Cycled every 21 days x 4 cycles Weekly paclitaxel +|

|||day 1 Carboplatin AUC 7 IV day 1 Pembrolizumab 200 mg IV or 2mg/kg day 1 ◊ Cycled every 21 days x 6 cycles|

|2 IV day 1 Cyclophosphamide 600 mg/m 2 IV day 1 ◊ Cycled every 21 days for 4 cycles. ◊ Followed by: Paclitaxel 80 mg/m 2 by 1 h IV weekly for 12 weeks ◊ With: Trastuzumab 4 mg/kg IV with first dose of paclitaxel|Dose-dense AC followed by paclitaxel + trastuzumab 25 Doxorubicin 60 mg/m 2 IV day 1 Cyclophosphamide 600 mg/m 2 IV day 1 ◊ Cycled every 14 days for 4 cycles ◊ Followed by: Paclitaxel 175 mg/m 2 by 3 h IV infusion day 1 DOSING: PREOPERATIVE/ADJUVANT THERAPY REGIMENS AC or Dose-Dense AC followed by T + trastuzumab + pertuzumab 26 Doxorubicin 60 mg/m 2 IV day 1 Cyclophosphamide 600 mg/m 2 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/m 2 IV days 1, 8, and 15 ◊ Cycled every 21 days for 4 cycles ◊ Followed by: Trastuzumab 6 mg/kg IV day 1 Pertuzumab 420 mg IV day 1 ◊ Cycled every 21 days to complete 1 year of therapy n|Docetaxel/cyclophosphamide + trastuzumab 27 Docetaxel 75 mg/m 2 IV day 1 Cyclophosphamide 600 mg/m 2 IV day 1 ◊ Cycled every 21 days for 4 cycles ◊ With: Trastuzumab 4 mg/kg IV week 1 ◊ Followed by Trastuzumab 2 mg/kg IV weekly for 11 weeks ◊ Followed by Trastuzumab 6 mg/kg IV ◊ Cycled every 21 days to complete 1 year of therapy of trastuzumab therapy n OR Trastuzumab 8 mg/kg IV week 1 ◊ Followed by: Trastuzumab 6 mg/kg IV every 21 days to complete 1 year of Table of Contents Discussion trastuzumab therapy NCCN Guidelines Index| |---|---|---|

|||BINV-M 9 OF 10|

|BINV-M|

|NCCN Guidelines Version 1.2025 Invasive Breast Cancer|NCCN Guidelines Version 1.2025 Invasive Breast Cancer|NCCN Guidelines Version 1.2025 Invasive Breast Cancer|NCCN Guidelines Version 1.2025 Invasive Breast Cancer||NCCN Guidelines Index Table of Contents Discussion| |---|---|---|---|---|---|

|GENE EXPRESSION ASSAYS FOR CONSIDERATION OF ADJUVANT SYSTEMIC THERAPY a,b|GENE EXPRESSION ASSAYS FOR CONSIDERATION OF ADJUVANT SYSTEMIC THERAPY a,b|GENE EXPRESSION ASSAYS FOR CONSIDERATION OF ADJUVANT SYSTEMIC THERAPY a,b|GENE EXPRESSION ASSAYS FOR CONSIDERATION OF ADJUVANT SYSTEMIC THERAPY a,b|GENE EXPRESSION ASSAYS FOR CONSIDERATION OF ADJUVANT SYSTEMIC THERAPY a,b||

|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 Premenopausal: Other|1 2A|BINV-N (2)|

||Predictive|||||

e staged using the N1 category. 4. M0 includes M0(i+). 5. ST-3|

|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|

|NCCN Guidelines Version 1.2025 Breast Cancer NCCN Guidelines Version 1.2025 Breast Cancer|NCCN Guidelines Index Table of Contents Discussion NCCN Guidelines Index Table of Contents Discussion| |---|---|

|Histopathologic Type -WHO Classification 5th Edition (2019)||

|In situ carcinomas|Favorable Histologic Types|

|D uctal carcinoma in situ (DCIS) (low nuclear grade, intermediate nuclear grade, and|Tubular carcinoma|

|high nuclear grade)|Cribriform carcinoma|

|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|Mucinous carcinoma Adenoid cystic Low-grade adenosquamous carcinoma metaplastic carcinoma Low-grade fibromatosis-like metaplastic 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)||

|GX Grade cannot be assessed Sa livary gland-type (acinic cell, adenoid cystic, secretory, mucoepidermoid,||

|G1 Low nuclear grade polymorphous adenocarcinoma)||

|G2 Intermediate nuclear grade Tall cell carcinoma with reversed polarity||

|G3 High nuclear grade||

||Continued|

||ST-4|

|TNM|Grade HER2|ER|PR|Stage|TNM|Grade HER2|ER|PR|Stage|| |---|---|---|---|---|---|---|---|---|---|---|

|T2 N1*** M0 T3 N0 M0|G1|Positive Negative|Positive Negative Positive Negative|Positive Negative Positive Negative IIB IB IIA Positive IIA Negative IIB Positive Negative|T0 N2 M0 T1* N2 M0 T2 N2 M0 T3 N1*** M0 T3 N2 M0|G1|Positive Negative|Positive Negative Positive Negative|Positive Negative Positive Negative Positive Negative Positive Negative IIIB IIA IIIA IIA IIIA||

||G2|Positive Negative|Positive Negative Positive Negative|Positive Negative Positive Negative IIB IB IIA Positive IIA Negative IIB Positive Negative IIIB||G2|Positive Negative|Positive Negative Positive Negative|Positive Negative Positive Negative Positive Negative Positive Negative IIIB IIA IIIA IIA IIIA||

||G3|Positive Negative|Positive Negative Positive Negative|Positive Negative Positive Negative Positive Negative Positive Negative IIIB IB IIB IIIA||G3|Positive Negative|Positive Negative Positive Negative|Positive Negative Positive Negative Positive Negative Positive Negative IIIC IIB IIIA IIIB||

|||||||||||ST-7|

|TNM T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0 Any T Any N M1|Grade HER2 G1 Positive Negative G2 Positive Negative G3 Positive Negative Any Any|ER Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative Any|PR Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative Any|Stage IIIA IIIB IIIC IIIA IIIB IIIC IIIB IIIC IV|Notes: 1. ST-8| |---|---|---|---|---|---|

|TNM|Grade HER2|ER|PR|Stage|TNM|Grade HER2|Grade HER2|ER|PR|Stage|| |---|---|---|---|---|---|---|---|---|---|---|---|

|Tis N0 M0 T1* N0 M0 T0 N1mi M0 T1* N1mi M0|Any G1 G2 G3|Any Positive Negative Positive Negative Positive Negative|Any Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative|Any Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative Negative Positive|0 IA IB IA IB|T0 N1** M0 T1* N1** M0 T2 N0 M0|G1 G2 G3|Positive Negative Positive Negative Positive Negative|Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative|Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative Positive Negative|IA IB IIA IA IB IIA IA IB IIA IA IIA IA IIA IB IIA|

||||||||||||ST-9|

|TNM|Grade HER2|Grade HER2|ER|PR|Stage|TNM|Grade HER2|Grade HER2|ER|PR|Stage| |---|---|---|---|---|---|---|---|---|---|---|---|

||G2|Positive Negative|Positive Negative Positive Negative|Positive Negative Positive Negative Positive Negative Positive Negative|IB IIB IB IIB||G2|Positive Negative|Positive Negative Positive Negative|Positive Negative Positive Negative Positive Negative Positive Negative IIIB IB IIIA IB IIIA||

||G3|Positive Negative|Positive Negative Positive Negative|Positive Negative Positive Negative Positive Negative Positive Negative IIIA IB IIB IIA IIB||G3|Positive Negative|Positive Negative Positive Negative|Positive Negative Positive Negative Positive Negative Positive Negative IIIC IIA IIIA IIB IIIA|||

||||||||||||ST-10|

|TNM T4 N0 M0 T4 N1*** M0 T4 N2 M0 Any T N3 M0|Grade HER2 G1 Positive Negative|ER Positive Negative Positive Negative|PR Positive Negative Positive Negative Positive Negative Negative Positive|Stage IIIA IIIB IIIA IIIB|Notes: 1. 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. 2. For cases where HER2 is determined to be "equivocal" by ISH (FISH or CISH) testing under the 2013 ASCO/CAP HER2 testing guidelines, HER2 "negative" category should be used for staging in the Pathological Prognostic Stage Group. 3. 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).| |---|---|---|---|---|---|

||G2|Positive Negative|Positive Negative Positive Negative|Positive Negative Positive Negative Positive Negative Positive Negative IIIC IIIA IIIB IIIA IIIB||

||G3|Positive Negative|Positive Negative Positive Negative|Positive Negative Positive Negative Positive Negative Positive Negative|IIIB IIIC|

|Any T Any N M1 Any|Any T Any N M1 Any|Any|Any|Any|IV|

|TNM|Grade HER2|ER|PR|Stage|| |---|---|---|---|---|---|

|T1 N0 M0 T2 N0 M0|Any|Negative Positive Any|IA|||

|Notes:||||||

|1. Obtaining genomic profiles is NOT required for assigning Pathological||||||

|Prognostic Stage. However genomic profiles may be performed for use in||||||

|determining appropriate treatment. If the OncotypeDx® test is performed in cases|determining appropriate treatment. If the OncotypeDx® test is performed in cases|determining appropriate treatment. If the OncotypeDx® test is performed in cases|determining appropriate treatment. If the OncotypeDx® test is performed in cases|determining appropriate treatment. If the OncotypeDx® test is performed in cases|determining appropriate treatment. If the OncotypeDx® test is performed in cases|

|with a T1N0M0 or T2N0M0 cancer that is HER2-negative and ER-positive, and|with a T1N0M0 or T2N0M0 cancer that is HER2-negative and ER-positive, and|with a T1N0M0 or T2N0M0 cancer that is HER2-negative and ER-positive, and|with a T1N0M0 or T2N0M0 cancer that is HER2-negative and ER-positive, and|with a T1N0M0 or T2N0M0 cancer that is HER2-negative and ER-positive, and|with a T1N0M0 or T2N0M0 cancer that is HER2-negative and ER-positive, and|

|the recurrence score is less than 11, the case should be assigned Pathological|the recurrence score is less than 11, the case should be assigned Pathological|the recurrence score is less than 11, the case should be assigned Pathological|the recurrence score is less than 11, the case should be assigned Pathological|the recurrence score is less than 11, the case should be assigned Pathological|the recurrence score is less than 11, the case should be assigned Pathological|

|Prognostic Stage Group IA.||||||

|2. If OncotypeDx® is not performed, or if it is performed and the OncotypeDx®|2. If OncotypeDx® is not performed, or if it is performed and the OncotypeDx®|2. If OncotypeDx® is not performed, or if it is performed and the OncotypeDx®|2. If OncotypeDx® is not performed, or if it is performed and the OncotypeDx®|2. If OncotypeDx® is not performed, or if it is performed and the OncotypeDx®|2. If OncotypeDx® is not performed, or if it is performed and the OncotypeDx®|

|score is not available, or is 11 or greater for patients with T1-2 N0 M0 HER2-|score is not available, or is 11 or greater for patients with T1-2 N0 M0 HER2-|score is not available, or is 11 or greater for patients with T1-2 N0 M0 HER2-|score is not available, or is 11 or greater for patients with T1-2 N0 M0 HER2-|score is not available, or is 11 or greater for patients with T1-2 N0 M0 HER2-|score is not available, or is 11 or greater for patients with T1-2 N0 M0 HER2-|

|negative, ER-positive cancer, then the Prognostic Stage Group is assigned based|negative, ER-positive cancer, then the Prognostic Stage Group is assigned based|negative, ER-positive cancer, then the Prognostic Stage Group is assigned based|negative, ER-positive cancer, then the Prognostic Stage Group is assigned based|negative, ER-positive cancer, then the Prognostic Stage Group is assigned based|negative, ER-positive cancer, then the Prognostic Stage Group is assigned based|

|on the anatomic and biomarker categories shown above.||||||

|3. OncotypeDx® is the only multigene panel included to classify Pathologic||||||

|Prognostic Stage because prospective Level I data supports this use for patients|Prognostic Stage because prospective Level I data supports this use for patients|Prognostic Stage because prospective Level I data supports this use for patients|Prognostic Stage because prospective Level I data supports this use for patients|Prognostic Stage because prospective Level I data supports this use for patients|Prognostic Stage because prospective Level I data supports this use for patients|

|with a score less than 11. Future updates to the staging system may include||||||

|results from other multigene panels to assign cohorts of patients to Prognostic|results from other multigene panels to assign cohorts of patients to Prognostic|results from other multigene panels to assign cohorts of patients to Prognostic|results from other multigene panels to assign cohorts of patients to Prognostic|results from other multigene panels to assign cohorts of patients to Prognostic|results from other multigene panels to assign cohorts of patients to Prognostic|

|Stage Groups based on the then available evidence. Inclusion or exclusion in this|Stage Groups based on the then available evidence. Inclusion or exclusion in this|Stage Groups based on the then available evidence. Inclusion or exclusion in this|Stage Groups based on the then available evidence. Inclusion or exclusion in this|Stage Groups based on the then available evidence. Inclusion or exclusion in this|Stage Groups based on the then available evidence. Inclusion or exclusion in this|

|staging table of a genomic profile assay is not an endorsement of any specific|staging table of a genomic profile assay is not an endorsement of any specific|staging table of a genomic profile assay is not an endorsement of any specific|staging table of a genomic profile assay is not an endorsement of any specific|staging table of a genomic profile assay is not an endorsement of any specific|staging table of a genomic profile assay is not an endorsement of any specific|

|assay and should not limit appropriate clinical use of any genomic profile assay|assay and should not limit appropriate clinical use of any genomic profile assay|assay and should not limit appropriate clinical use of any genomic profile assay|assay and should not limit appropriate clinical use of any genomic profile assay|assay and should not limit appropriate clinical use of any genomic profile assay|assay and should not limit appropriate clinical use of any genomic profile assay|

|based on evidence available at the time of treatment.||||||

||||||ST-11|

|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|

|Results 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|

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.

al. Breast Cancer Res Treat 2019;173:123-133; Pease AM, et al. Ann Surg Oncol 2019;26:366-371).

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

Limited data exist for ≥3 positive SLNs. i In the mastectomy setting, in patients who were initially cN0, who have positive nodes on SLNB, and have no axillary dissection, RT to the chest wall should include undissected axilla at risk ± RNI.

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. Version 1.2025, 1/31/25 © 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.

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.SeeBoughey JC, etal. J Clin Oncol 2023;41:3184-3193.

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. Version 1.2025, 1/31/25 © 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.

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.

Methotrexate 40 mg/ m 2 IV day 1 5-fluorouracil 600 mg/m 2 IV day 1 ◊ Cycled every 21 days for 8 cycles

S, Nair NS, Hawaldar RW, et al. Addition of platinum to sequential taxaneanthracycline neoadjuvant chemotherapy in patients with triple-negative breast cancer: A phase III randomized controlled trial. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract GS5-01. Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of intergroup trial C9741/cancer and leukemia group B trial 9741. J Clin Oncol 2003;21:1431-1439. Jones S, Holmes F, O'Shaughnessey J, et al. Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of US Oncology Research trial 9735. J Clin Oncol 2009;27:1177-1183; Nitz U, Gluz O, Clemens M, et al. West German Study PlanB Trial: Adjuvant four cycles of epirubicin and cyclophosphamide plus docetaxel versus six cycles of docetaxel and cyclophosphamide in HER2-negative early breast cancer. J Clin Oncol 2019;37:799-808. Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med, 2020;382:810-821. Masuda N, Lee SJ, Ohtani S, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med 2017;376:2147-2159. Tutt ANJ, Garber JE, Kaufman B, et al. Adjuvant Olaparib for Patients with BRCA1-or BRCA2-Mutated Breast Cancer. N Engl J Med 2021;384:2394-2405. von Minckwitz G1, Raab G, Caputo A, et al. Doxorubicin with cyclophosphamide followed by docetaxel every 21 days compared with doxorubicin and docetaxel every 14 days as preoperative treatment in operable breast cancer: the GEPARDUO study of the German Breast Group. J Clin Oncol 2005;23:2676-2685. Piccart MJ, Di Leo A, Beauduin M, et al. Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. J Clin Oncol 2001;19:3103-3110. Martin, Pienkowski T, Mackey J, et al. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 2005;352:22. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol 2014;15:747-756. 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. Zhang L, Wu ZY, Li J, et al. Neoadjuvant 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. Fisher B, Brown AM, Dimitrov NV, et al. Two months of doxorubicincyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15. Jakesz R, Hausmaninger H, Kubista E, et al. Austrian Breast and Colorectal Cancer Study Group Trial 5. Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and fluorouracil: evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancer--Austrian Breast and Colorectal Cancer Study Group Trial 5. J Clin Oncol 2002;20:4621-4627. 18 Sparano JA, Wang M, Martino S, et al. Weekly paclitaxel in adjuvant treatment of breast cancer. N Engl J Med 2008;258:1663-1671. 19 Wang X, Wang SS, Huang H, et al. Effect of capecitabine maintenance therapy using lower dosage and higher frequency vs observation on disease-free survival among patients with earlystage triple-negative breast cancer who had received standard treatment: The SYSUCC-001 randomized clinical trial. JAMA 2021;325:50-58. 20 Sharma P, Stecklein SR, Yoder R, et al. Clinical and biomarker findings of neoadjuvant pembrolizumab and carboplatin plus docetaxel in triple-negative breast cancer: NeoPACT phase 2 clinical trial. JAMA Oncol 2024;10:227-235.

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

• 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

Abemaciclib in combination with fulvestrant and trastuzumab (category 2B)• Targeted therapy see BINV-Q (7) and emerging biomarker options see BINV-Q(8)

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

At the present time, the data for the emerging biomarkers for the potential targeted agents noted in the table are promising but limited.ggMa CX, Luo J, Freedman RA, et al. The phase II MutHER study of neratinib alone and in combination with fulvestrant in HER2-mutated, non-amplified metastatic breast cancer. Clin Cancer Res 2022;28:1258-1267. hh Jhaveri K, Eli LD, Wildiers H, et al. Neratinib + fulvestrant + 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. ii 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.

Paclitaxel 175mg/m 2 IV day 1 cycled every 21 days 43 or Paclitaxel 80-90 mg/m 2 IV day 1 weekly45Trastuzumab 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

Capivasertib 400 mg PO twice daily on days 1-4, 8-11, 15-18, 22-25 Fulvestrant 500 mg IM day 1 and day 15 ◊ Cycled every 28 days for 1 cycle Followed by Capivasertib 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 Followed by 1000 mg IV on day 1 of cycle 5 ◊ Cycled every 42 days starting with cycle 5 OR Paclitaxel 90 mg/m 2 IV days 1, 8, 15 (given every 28 days)

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 phyllodes 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 phyllodes tumors, wide excision means excision with the intention of obtaining surgical margins ≥1 cm. 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.

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 fluorouracil. 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.

||endocrine therapy|± weekly paclitaxel. Ann Oncol 2017;28:2768-2772. predictive markers for 12 weeks of neoadjuvant dual blockade with trastuzumab and pertuzumab cancer (EBC): final analysis of the WSG-ADAPT HER2+/HR-phase II trial: efficacy, safety, and 32 Nitz UA, Gluz O, Christgen M, et al. De-escalation strategies in HER2-positive early breast placebo-controlled, phase 3 trial. Lancet Oncol 2016;17:367-377. patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, 31 Chan A, Delaloge S, Holmes FA, et al. Neratinib after trastuzumab-based adjuvant therapy in 2012;13:25-32. cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast 30 Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and 2018;19:1630-1640. breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive 29 van Ramshorst MS, van der Voort A, van Werkhoven ED, et al. Neoadjuvant chemotherapy without trastuzumab for breast cancer. N Engl J Med 2006;354:809-820. 28 Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al. Adjuvant docetaxel or vinorelbine with or|± weekly paclitaxel. Ann Oncol 2017;28:2768-2772. predictive markers for 12 weeks of neoadjuvant dual blockade with trastuzumab and pertuzumab cancer (EBC): final analysis of the WSG-ADAPT HER2+/HR-phase II trial: efficacy, safety, and 32 Nitz UA, Gluz O, Christgen M, et al. De-escalation strategies in HER2-positive early breast placebo-controlled, phase 3 trial. Lancet Oncol 2016;17:367-377. patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, 31 Chan A, Delaloge S, Holmes FA, et al. Neratinib after trastuzumab-based adjuvant therapy in 2012;13:25-32. cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast 30 Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and 2018;19:1630-1640. breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive 29 van Ramshorst MS, van der Voort A, van Werkhoven ED, et al. Neoadjuvant chemotherapy without trastuzumab for breast cancer. N Engl J Med 2006;354:809-820. 28 Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al. Adjuvant docetaxel or vinorelbine with or|± weekly paclitaxel. Ann Oncol 2017;28:2768-2772. predictive markers for 12 weeks of neoadjuvant dual blockade with trastuzumab and pertuzumab cancer (EBC): final analysis of the WSG-ADAPT HER2+/HR-phase II trial: efficacy, safety, and 32 Nitz UA, Gluz O, Christgen M, et al. De-escalation strategies in HER2-positive early breast placebo-controlled, phase 3 trial. Lancet Oncol 2016;17:367-377. patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, 31 Chan A, Delaloge S, Holmes FA, et al. Neratinib after trastuzumab-based adjuvant therapy in 2012;13:25-32. cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast 30 Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and 2018;19:1630-1640. breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive 29 van Ramshorst MS, van der Voort A, van Werkhoven ED, et al. Neoadjuvant chemotherapy without trastuzumab for breast cancer. N Engl J Med 2006;354:809-820. 28 Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al. Adjuvant docetaxel or vinorelbine with or||

||||||BINV-N 1 OF 5|

||GENE EXPRESSION ASSAYS FOR CONSIDERATION OF ADJUVANT SYSTEMIC THERAPY a,b||

|Assay|Recurrence Risk|Treatment Implications|

|21-gene (Oncotype Dx) (for postmenopausal patients with pN0 and pN1 [1-3 positive nodes]) c|||

|||BINV-N 2 OF 5|

|70-gene (MammaPrint) (for pN0 and 1-3 positive nodes)|High percentage points [2.1, -4.0 to 4.Low d 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||

|50-gene (Prosigna) nodes) 1-3 positive (for pN0 and|Node negative: Low (0-40), Intermediate (41-60), High (61-100)||

|||BINV-N 3 OF 5|

|NCCN Guidelines Version 1.2025 Invasive Breast Cancer NCCN Guidelines Version 1.2025 Invasive Breast Cancer|NCCN Guidelines Index Table of Contents Discussion NCCN Guidelines Index Table of Contents Discussion|

|DEFINITION OF MENOPAUSE||

||BINV-N 5 OF 5 BINV-O|

|BINV-P 2 OF 3|

|First-Line Therapy|Second-and/or Subsequent-Line Therapy| |---|---|

|Preferred Regimens • Aromatase inhibitor + CDK4/6 inhibitor b Aromatase inhibitor + ribociclib (category 1) c|Preferred Regimens • Fulvestrant + CDK4/6 inhibitor (abemaciclib, palbociclib, or ribociclib) if CKD4/6 inhibitor not previously used (category 1) f,g|

|Aromatase inhibitor + abemaciclib Aromatase inhibitor + palbociclib If disease progression on adjuvant endocrine therapy or relapse within 12|• 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|

|months of adjuvant endocrine therapy completion consider: • Fulvestrant d + CDK4/6 inhibitor b Fulvestrant + abemaciclib (category 1) e Fulvestrant + ribociclib (category 1) e|• Targeted therapy, see BINV-Q (6) and BINV-Q (7), and emerging biomarker options, see BINV-Q (8)|

|Fulvestrant + palbociclib||

|Useful in Certain Circumstances|Useful in Certain Circumstances|

|• For HER2-negative tumors with PIK3CA activating mutations and|• Megestrol acetate|

|disease progression on adjuvant endocrine therapy or relapse within 12 months of adjuvant endocrine therapy completion, see BINV-Q (6)|• Estradiol • Abemaciclib l|

|CDK4/6 inhibitor, see BINV-Q (6) • Fulvestrant) + aromatase inhibitor (anastrozole, letrozole) (category 1) k| |---|

|• Fulvestrant|

|• Anastrozole|

|• Letrozole|

|• Tamoxifen|

|• Exemestane|

|• Aromatase inhibitor ± trastuzumab • Aromatase inhibitor ± lapatinib • Aromatase inhibitor ± lapatinib + trastuzumab • Fulvestrant ± trastuzumab • Tamoxifen ± trastuzumab • NCCN Guidelines Index Table of Contents Discussion| |---|

|BINV-Q 1 OF 15|

||NCCN Guidelines Version 1.2025 Invasive Breast Cancer|NCCN Guidelines Index Table of Contents Discussion|

|SYSTEMIC THERAPY FOR See BINV-Q (1) for Considerations for Systemic Therapy.|SYSTEMIC THERAPY FOR See BINV-Q (1) for Considerations for Systemic Therapy.||

|Setting|Subtype/Biomarker|Subtype/Biomarker|

|First Line|No germline BRCA1/2 mutation b and/or IHC HER2 0+, 1+, or 2+/ISH negative d|No germline BRCA1/2 mutation b and/or IHC HER2 0+, 1+, or 2+/ISH negative d|

||Germline BRCA1/2 mutation b|Germline BRCA1/2 mutation b|

|Second Line HER2 IHC 0+, 1+, or 2+/ISH negative Third Line and Any beyond Biomarker positive (ie, MSI-H, NTRK,|Systemic chemotherapy BINV-Q (5) Targeted agents and emerging biomarker options BINV-Q (6),||

||RET, TMB-H)|RET, TMB-H)|

|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|Other Recommended Regimens Useful in Certain Circumstances|

|• Anthracyclines|• Cyclophosphamide|• AC (doxorubicin/cyclophosphamide)|

|Doxorubicin|• Docetaxel|• EC (epirubicin/cyclophosphamide)|

|Liposomal doxorubicin|• Albumin-bound paclitaxel|• CMF (cyclophosphamide/|

|• Taxanes Paclitaxel • Anti-metabolites Capecitabine Gemcitabine|• Epirubicin • Ixabepilone|methotrexate/fluorouracil) • Docetaxel/capecitabine • GT (gemcitabine/paclitaxel) • Gemcitabine/carboplatin • Carboplatin + paclitaxel or albumin-bound paclitaxel|

|• Microtubule inhibitors|||

|Vinorelbine|||

|Eribulin|||

|||BINV-Q 5 OF 15|

||NCCN Guidelines Version 1.2025 Invasive Breast Cancer|NCCN Guidelines Version 1.2025 Invasive Breast Cancer|NCCN Guidelines Version 1.2025 Invasive Breast Cancer|NCCN Guidelines Version 1.2025 Invasive Breast Cancer|NCCN Guidelines Index Table of Contents Discussion|

||||||Other|

||||||therapy|

|||||Continued|Continued|

|||NCCN Guidelines Version 1.2025 Invasive Breast Cancer NCCN Guidelines Version 1.2025 Invasive Breast Cancer|NCCN Guidelines Version 1.2025 Invasive Breast Cancer NCCN Guidelines Version 1.2025 Invasive Breast Cancer|NCCN Guidelines Version 1.2025 Invasive Breast Cancer NCCN Guidelines Version 1.2025 Invasive Breast Cancer|NCCN Guidelines Version 1.2025 Invasive Breast Cancer NCCN Guidelines Version 1.2025 Invasive Breast Cancer| |---|---|---|---|---|---|

|||EMERGING BIOMARKERS AND NOVEL THERAPIES FOR PATIENTS WITH STAGE IV (M1) DISEASE||||

|Breast Cancer Subtype Breast Cancer Subtype ER+/HER2-|Biomarker Emerging Biomarkers HER2 activating|Detection t Detection t NGS, PCR|FDA-Approved Agents Potential Targeted Therapy ff NCCN Category NCCN Category of Evidence of Evidence NCCN Category of Preference NCCN Category of Preference Neratinib ± fulvestrant gg Category 2B Useful in certain|||

|Any Any Any Any|ER-/HER2-Any Any|Germline BRCA1 or BRCA2 mutation mutations Germline PALB2 NTRK fusion Somatic BRCA1/2 Germline sequencing Germline sequencing FISH, NGS, PCR NGS mutations MSI-H/dMMR IHC, NGS, PCR FGFR1-3 fusion/ NGS mutation|Olaparib Talazoparib Olaparib y Neratinib + trastuzumab/ fulvestrant hh Larotrectinib z Entrectinib z Olaparib ii Repotrectinib aa Erdafitinib jj Pembrolizumab bb Dostarlimab-gxly cc|Category 1 circumstances Preferred • If ER+/HER2-, in Category 2A Other recommended patients who have already received Category 2A CDK4/6 inhibitor regimen therapy. Category 2B Useful in certain Category 2A aa circumstances Useful in certain circumstances Category 2B Useful in certain Category 2A circumstances||

|Any||TMB-H (≥10 mut/Mb) dd|NGS|Pembrolizumab bb|Category 2A|

|Any||RET-fusion|NGS|Selpercatinib ee|Category 2A|

||||||BINV-Q 8 OF 15 BINV-Q 9 OF 15|

|2 IV days 1, 8, and 15| |---|

|Carboplatin AUC 2 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 + paclitaxel 43,44|

|• Trastuzumab + docetaxel 45,46 Docetaxel 80-100 mg/m 2 IV day 1 cycled every 21 days 45|

|Docetaxel 35 mg/m 2 IV days 1, 8, and 15 weekly cycled every 28 days 46|

8 mg/kg IV day 1 followed by 6 mg/kg IV day 1 every 21 days 37|

|BINV-Q 11 OF 15|

|Vinorelbine| |---|

|◊ 25 mg/m 2 IV day 1 weekly; or|

|◊ 20-35 mg/m 2 IV days 1 and 8; cycled every 21|

|days; or|

|◊ 25-30 mg/m 2 IV days 1, 8, and 15; cycled every|

|28 days|

|Trastuzumab 4 mg/kg IV day 1 followed by 2 mg/kg|

|IV weekly|

|BINV-Q|

||NCCN Guidelines Index|

||• Larotrectini 7 100 mg PO twice daily on days 1-28 Cycled every 28 days until disease progression or unacceptable toxicity|

||• Olaparib 8 tablet 300 mg PO twice daily Cycled every 28 days|

|• Capivasertib + fulvestrant 2|• Pembrolizumab 9-12 200 mg IV on day 1, every 21 days until disease progression or unacceptable toxicity, or up to 24 months or 400 mg IV on day 1, every 6 weeks until disease progression or unacceptable toxicity, or up to 24 months|

|• Elacestrant 4 345 mg PO daily on days 1-28 Cycled every 28 days until disease progression or unacceptable toxicity • Entrectinib 5 600 mg PO daily on days 1-28 Cycled every 28 days until disease progression or unacceptable toxicity • Inavolisib + palbociclib + fulvestrant 6 Inavolisib 9 mg PO daily on days 1-28 Palbociclib 125 mg PO daily on days 1-21 Fulvestrant 500 mg IM on days 1 and 15 ◊ 28-day cycle for 1 cycle Followed by Inavolisib 9 mg PO daily on days 1-28 Palbociclib 125 mg PO daily on days 1-21 Fulvestrant 500 mg IM on day 1 ◊ 28-day cycle until disease progression or unacceptable toxicity|OR Pembrolizumab 200 mg IV or 2mg/kg day 1 Gemcitabine 1000 mg/m 2 IV days 1 and 8 Carboplatin AUC 2 IV days 1 and 8 ◊ Given every 21 days • Repotrectinib 14 160 mg PO once daily on days 1-14, then 160 mg twice daily until disease progression or unacceptable toxicity • Selpercatinib 15 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 • Talazoparib 16 tablet 1 mg PO daily Cycled every 28 days|

||References on BINV-Q 14 of 15|

||BINV-Q|

|BINV-R 1 OF 3|

|BINV-R 2 OF 3|

|BINV-R 3 OF 3|

||NCCN Guidelines Version 1.2025 Phyllodes Tumor|NCCN Guidelines Index Table of Contents Discussion||||

|CLINICAL PRESENTATION|WORKUP|CORE BIOPSY RESULTS|TREATMENT|SURVEILLANCE||

|||||Fibroadenoma|Observe|

|||Indeterminate or suspicious for a benign phyllodes b|Excisional biopsy c||Clinical follow-up for 3 y (no RT)|

|Clinical suspicion of phyllodes: • Palpable mass • Rapid growth • Large size ( > 3 cm) • Imaging with ultrasound suggestive of growth and/or history of except for size fibroadenoma|• History and physical exam • Ultrasound • Mammogram for patients ≥30 y|Core needle biopsy a|Wide excision d without axillary staging + consider RT e|Phyllodes, borderline or malignant b,f|Clinical follow-up for 3 y g|

|||Invasive or in situ cancer||||

||||||PHYLL-1|

||NCCN Guidelines V NCCN Guidelines Version 1.2025 ersion 1.2025 Breast Cancer Breast Cancer During Pregnancy|Table of Contents Discussion NCCN Guidelines Index Table of Contents Discussion||

|WORKUP CLINICAL PRESENTATION a If indicated a : • Chest x-ray (with abdominal shielding) • Abdominal assess liver metastases • Consider non-contrast metastases assess for bone if indicated to MRI of spine ultrasound to Clinical pathologic diagnosis of IBC|CLINICAL PRESENTATION If pregnant with confirmed breast cancer; No distant metastases on staging First trimester WORKUP Late third trimester Early third trimester Discuss termination: Non-therapeutic Second trimester/|PRIMARY TREATMENT b Continuing pregnancy Mastectomy e + axillary staging b,c Mastectomy f or BCS e + axillary staging b,c Preoperative chemotherapy, d mastectomy, or BCS e + axillary staging b,c or Mastectomy or BCS e + axillary staging b,c|ADJUVANT TREATMENT d Begin adjuvant chemotherapy in second trimester d ± RT postpartum ± Adjuvant endocrine therapy postpartum therapy postpartum ± Adjuvant endocrine ± RT postpartum Adjuvant chemotherapy d therapy postpartum ± Adjuvant endocrine ± RT postpartum Adjuvant chemotherapy d ± RT postpartum ± Adjuvant endocrine therapy postpartum|

||||PREG-1 IBC-1|

||for T, N, M (continued)|Pathologic (pN)|| |---|---|---|---|

|Regional Lymph Nodes (N) Clinical (cN)|Regional Lymph Nodes (N) Clinical (cN)|pNX|Regional lymph nodes cannot be assessed (e.g., not removed for pathological study or previously removed)|

|cNX* cN0|Regional lymph nodes cannot be assessed (e.g., previously removed) No regional lymph node metastases (by imaging or clinical examination)|pN0 pN0(i+)|No regional lymph node metastasis identified or ITCs only ITCs only (malignant cells clusters no larger than 0.2 mm) in regional lymph node(s)|

|cN1|Metastases to movable ipsilateral level I, II axillary lymph node(s)|pN0(mol+) Positive molecular findings by reverse transcriptase polymerase chain reaction (RT-PCR); no ITCs detected||

|cN1mi** Micrometastases (approximately 200 cells, larger than 0.2 mm, but none larger than 2.0 mm) cN2 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|pN1 pN1mi|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 Micrometastases (approximately 200 cells, larger than 0.2 mm, but none larger than 2.0 mm)||

|cN2a|Metastases in ipsilateral level I, II axillary lymph nodes fixed to one another (matted) or to other structures|pN1a|Metastases in 1-3 axillary lymph nodes, at least one metastasis larger than 2.0 mm|

|cN2b cN3 cN3a cN3b cN3c|Metastases only in ipsilateral internal mammary nodes in the absence of axillary lymph node metastases 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 Metastases in ipsilateral infraclavicular lymph node(s) Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s) Metastases in ipsilateral supraclavicular lymph node(s)|pN1b pN1c pN2 pN2a pN2b|Metastases in ipsilateral internal mammary sentinel nodes, excluding ITCs pN1a and pN1b combined. Metastases in 4-9 axillary lymph nodes; or positive ipsilateral internal mammary lymph nodes by imaging in the absence of axillary lymph node metastases Metastases in 4-9 axillary lymph nodes (at least one tumor deposit larger than 2.0 mm) Metastases in clinically detected internal mammary lymph nodes with or without microscopic confirmation; with pathologically negative axillary nodes|

||||ST-2|

|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; or in ipsilateral supraclavicular lymph nodes|Stage 0 Stage IA Stage IB|Tis T1 T0 N1mi M0 N0 M0 N0 M0 T1 N1mi M0|Stage IIIA|T0 T1 T2 T3|N2 N2 N2 N1|M0 M0 M0 M0||| |---|---|---|---|---|---|---|---|---|---|

|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|Stage IIA|T0 T1 T2|N1 N1 N0|M0 M0 M0|Stage IIIB|T3 T4 T4|N2 N0 N1|M0 M0 M0|

|pN3b|pN1a or pN2a in the presence of cN2b (positive internal mammary nodes by imaging); or pN2a in the presence of pN1b|Stage IIB|T2 T3|N1 N0|M0 M0|Stage IIIC|T4 Any T|N2 N3|M0 M0|

|pN3c Note: (sn) and (f) suffixes should be added to the N category to denote Metastases in ipsilateral supraclavicular lymph nodes|Notes: 1. T1 includes T1mi.|||Stage IV|Any T Any N|M1||||

|confirmation of metastasis by sentinel node biopsy or FNA/core needle|confirmation of metastasis by sentinel node biopsy or FNA/core needle|2. T0 and T1 tumors with nodal micrometastases (N1mi) are staged as Stage IB.||||||||

|biopsy respectively, with NO further resection of nodes Distant Metastasis (M) M0 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|biopsy respectively, with NO further resection of nodes Distant Metastasis (M) M0 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|3. T2, T3, and T4 tumors with nodal micrometastases (N1mi) are staged using the N1 category. 4. M0 includes M0(i+). 5. ST-3|3. T2, T3, and T4 tumors with nodal micrometastases (N1mi) are staged using the N1 category. 4. M0 includes M0(i+). 5. ST-3|3. T2, T3, and T4 tumors with nodal micrometastases (N1mi) are staged using the N1 category. 4. M0 includes M0(i+). 5. ST-3|3. T2, T3, and T4 tumors with nodal micrometastases (N1mi) are staged using the N1 category. 4. M0 includes M0(i+). 5. ST-3|3. T2, T3, and T4 tumors with nodal micrometastases (N1mi) are staged using the N1 category. 4. M0 includes M0(i+). 5. ST-3|3. T2, T3, and T4 tumors with nodal micrometastases (N1mi) are staged using the N1 category. 4. M0 includes M0(i+). 5. ST-3|3. T2, T3, and T4 tumors with nodal micrometastases (N1mi) are staged using the N1 category. 4. M0 includes M0(i+). 5. ST-3|3. T2, T3, and T4 tumors with nodal micrometastases (N1mi) are staged using the N1 category. 4. M0 includes M0(i+). 5. ST-3|

DefinitionsNote: (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.

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. 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.

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.

Clinical Prognostic StageClinical 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 using these tools.

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).

Pathological Prognostic StagePathological 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).

1,2The therapeutic options for patients with noninvasive or invasive breast cancer are complex and varied. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines

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.

59, 397 6Studies of CMF chemotherapy versus no chemotherapy have shown DFS and OS advantages with CMF chemotherapy.59,397

480 cedures 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

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

References

引用 / 出处

NCCN临床实践指南：乳腺癌（2025.V1）. 2025.