NCCN Guidelines® Insights: Breast Cancer, Version 4.2021

Featured Updates to the NCCN Guidelines

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  • 1 Robert H. Lurie Comprehensive Cancer Center of Northwestern University;
  • | 2 Yale Cancer Center/Smilow Cancer Hospital;
  • | 3 Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute;
  • | 4 Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine;
  • | 5 The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute;
  • | 6 Stanford Cancer Institute;
  • | 7 UC San Diego Moores Cancer Center;
  • | 8 Dana-Farber/Brigham and Women’s Cancer Center;
  • | 9 Memorial Sloan Kettering Cancer Center;
  • | 10 University of Colorado Cancer Center;
  • | 11 The University of Texas MD Anderson Cancer Center;
  • | 12 Mayo Clinic Cancer Center;
  • | 13 Fox Chase Cancer Center;
  • | 14 UCLA Jonsson Comprehensive Cancer Center;
  • | 15 Massachusetts General Hospital Cancer Center;
  • | 16 Abramson Cancer Center at the University of Pennsylvania;
  • | 17 Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance;
  • | 18 Fred & Pamela Buffet Cancer Center;
  • | 19 UT Southwestern Simmons Comprehensive Cancer Center;
  • | 20 Vanderbilt-Ingram Cancer Center;
  • | 21 City of Hope National Medical Center;
  • | 22 University of Wisconsin Carbone Cancer Center;
  • | 23 University of Michigan Rogel Cancer Center;
  • | 24 UCSF Helen Diller Family Comprehensive Cancer Center;
  • | 25 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins;
  • | 26 Research Advocacy Network;
  • | 27 Moffitt Cancer Center;
  • | 28 O'Neal Comprehensive Cancer Center at UAB;
  • | 29 Huntsman Cancer Institute at the University of Utah;
  • | 30 Roswell Park Comprehensive Cancer Center; and
  • | 31 National Comprehensive Cancer Network.

The NCCN Guidelines for Breast Cancer include up-to-date guidelines for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, male breast cancer, and breast cancer during pregnancy. These guidelines are developed by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer–focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy. These NCCN Guidelines Insights focus on the most recent updates to recommendations for adjuvant systemic therapy in patients with nonmetastatic, early-stage, hormone receptor–positive, HER2-negative breast cancer.

NCCN: Continuing Education

Target Audience: This activity is designed to meet the educational needs of oncologists, nurses, pharmacists, and other healthcare professionals who manage patients with cancer.

Accreditation Statements

In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

Medicine (ACCME): NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nursing (ANCC): NCCN designates this educational activity for a maximum of 1.0 contact hour.

Pharmacy (ACPE): NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-21-008-H01-P All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: (1) review the educational content; (2) take the posttest with a 66% minimum passing score and complete the evaluation at https://education.nccn.org/node/89715; and (3) view/print certificate.

Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please e-mail education@nccn.org.

Release date: May 10, 2021; Expiration date: May 10, 2022

Learning Objectives:

Upon completion of this activity, participants will be able to:

  • Integrate into professional practice the updates to the NCCN Guidelines for Breast Cancer

  • Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Breast Cancer

Disclosure of Relevant Financial Relationships

The NCCN staff listed below discloses no relevant financial relationships:

Kerrin M. Rosenthal, MA; Kimberly Callan, MS; Genevieve Emberger Hartzman, MA; Erin Hesler; Kristina M. Gregory, RN, MSN, OCN; Rashmi Kumar, PhD; Karen Kanefield; and Kathy Smith.

Individuals Who Provided Content Development and/or Authorship Assistance:

William J. Gradishar, MD, Panel Chair, has disclosed serving as a scientific advisor for AstraZeneca Pharmaceuticals LP, MacroGenics, Inc., Roche Laboratories, Inc./Genentech, Inc., Pfizer Inc., and Seattle Genetics, Inc.

Jame Abraham, MD, Panel Member, has disclosed no relevant financial relationships.

Kimberly H. Allison, MD, Panel Member, has disclosed serving as a scientific advisor for Mammotome.

Chau Dang, MD, Panel Member, has disclosed receiving grant/research support from PUMA and Roche/Genentech.

Anthony D. Elias, MD, Panel Member, has disclosed serving as a scientific advisor for Seiyax.

Sharon H. Giordano, MD, MPH, Panel Member, has disclosed no relevant financial relationships.

Matthew P. Goetz, MD, Panel Member, has disclosed serving as a scientific advisor for Biotheranostics, Novartis Pharmaceuticals Corporation, Context Therapeutics, Eagle Pharmaceuticals, Sermonix, and Pfizer Inc.; and receiving grant/research support from Eli Lilly and Company, Sermonix, and Pfizer Inc.

Sara A. Hurvitz, MD Panel Member, has disclosed receiving grant/research support from Ambrx, Amgen, AstraZeneca, Arvinas, Bayer, Daiichi-Sankyo, Genentech/Roche, Gilead, GlaxoSmithKline, Immunomedics, Lilly, Macrogenics, Novartis Pharmaceuticals Corporation, Pfizer, OBI Pharma, Pieris, PUMA, Radius, Sanofi, Seattle Genetics, Dignitana, Zymeworks, and Phoenix Molecular Designs, Ltd.; having stock in NK Max; receiving consulting fees from Eli Lilly and Company; and spouse having stock in ROMTech and Ideal Implant.

Ingrid A. Mayer, MD, Panel Member, has disclosed receiving consulting fees from AbbVie, Inc., AstraZeneca Pharmaceuticals LP, Genentech, Inc., GlaxoSmithKline, Immunomedics, Inc., Novartis Pharmaceuticals Corporation, Eli Lilly and Company, MacroGenics, Inc., Puma Biotechnology, and Seattle Genetics, Inc.; honoraria from AstraZeneca Pharmaceuticals LP, Genentech, Inc., and Novartis Pharmaceuticals Corporation; and grant/research support from Genentech, Inc., Novartis Pharmaceuticals Corporation, and Pfizer Inc.

Karen Lisa Smith, MD, MPH, Panel Member, has disclosed receiving equity interest/stock options in Abbott Laboratories and AbbVie, Inc.; and grant/research support from Pfizer Inc.

Hatem Soliman, MD, Panel Member, has disclosed receiving consulting fees from Immunomedics, Eisai, Novartis Pharmaceuticals Corporation, AstraZeneca, and Seattle Genetics.

John H. Ward, MD, Panel Member, has disclosed no relevant financial relationships.

Kari B. Wisinski, MD, Panel Member, has disclosed receiving grant/research support from Pfizer, AstraZeneca, Novartis Pharmaceuticals Corporation, Context, Genentech, and Sanofi; and serving as a scientific advisor for Pfizer, AstraZeneca, and Eisai.

Jennifer L. Burns, Manager, Guidelines Support, NCCN, has disclosed no relevant financial relationships.

To view all of the conflicts of interest for the NCCN Guidelines panel, go to NCCN.org/disclosures/guidelinepanellisting.aspx

This activity is supported by educational grants from Agios Pharmaceuticals; AstraZeneca; Clovis Oncology, Inc.; Daiichi Sankyo; Eisai; Epizyme Inc.; Novartis; and Pharmacyclics LLC, an AbbVie Company and Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC. This activity is supported by an independent medical education grant from Bristol-Myers Squibb, and Regeneron Pharmaceuticals, Inc. and Sanofi Genzyme. This activity is supported by an independent medical educational grant from Mylan Inc. This activity is supported by a medical education grant from Karyopharm Therapeutics. This activity is supported by an independent educational grant from AbbVie.

Overview

Breast cancer is the most commonly diagnosed cancer globally and continues to be second only to lung cancer as a cause of cancer death.1 The American Cancer Society estimates that 284, 200 Americans will be diagnosed with breast cancer and 44, 130 will die of the disease in the United States in 2021.2 The therapeutic options for patients with noninvasive or invasive breast cancer are complex and varied. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer include up-to-date guidelines for the clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, male breast cancer, and breast cancer during pregnancy. These guidelines are developed by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer–focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy.

In the 2021 version of the NCCN Guidelines for Breast Cancer, the panel included updated recommendations for axillary staging; adjuvant radiation therapy; adjuvant systemic therapy for patients with hormone receptor–positive (HR+) and HER2-negative (HER2−) breast cancer; and systemic therapy for metastatic disease. This report summarizes the rationale behind the recommendations specific to adjuvant systemic therapy for patients with nonmetastatic early-stage HR+/HER2− breast cancer.

Adjuvant Systemic Therapy

In patients with early-stage breast cancer, systemic adjuvant therapy is administered to reduce risk of breast cancer recurrence. The decision is often based on individual risk of relapse and predicted sensitivity to treatment (eg, estrogen and progesterone receptors and HER2 status). The decision to use systemic adjuvant therapy requires consideration and balancing of 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 healthcare team and the patient.

Pathologic T1–3 HR+/HER2− Tumors

Patients with HR+/HER2− tumors receive adjuvant endocrine therapy to reduce the risk of recurrence. Those deemed at high risk for distant recurrence despite adjuvant endocrine therapy may also receive adjuvant chemotherapy. The decision whether to administer adjuvant chemotherapy in patients with HR+/HER2− tumors is based on many factors, including lymph node (LN) status, tumor size, patient age, comorbid conditions, and risk assessment based on results of a validated gene expression assay.

Among patients with pathologic T1–3 (pT1–3) HR+/HER2− tumors, on one end of the spectrum are those with small (pT1mi and T1a) and node-negative (pN0) tumors. These patients with small tumors up to 0.5 cm in greatest diameter that do not involve the LNs have low clinical risk of recurrence and a favorable prognosis. The incremental benefit of adding adjuvant chemotherapy to endocrine therapy in patients with such tumors is minimal.3 On the other end of the spectrum are patients with high-risk features, such as ≥4 positive LNs. In this group, the addition of systemic chemotherapy to adjuvant endocrine therapy may play a role in reducing recurrence risk.

For patients in whom the decision whether to use chemotherapy is unclear, gene expression assays may be used to assess recurrence risk. The primary role of the gene expression assays is to determine clinical situations that warrant addition of chemotherapy to endocrine therapy to further reduce recurrence risk.

The 21-gene assay (Oncotype Dx), which determines recurrence risk using a recurrence score (RS), is one of the most validated multigene assays. The RS is helpful in determining the prognosis in patients with HR+/HER2− tumors treated with endocrine therapy alone by predicting locoregional and distant recurrence.46 This assay has also been validated to predict the benefit from adding adjuvant chemotherapy to adjuvant endocrine therapy for patients with HR+/HER2− breast cancer.710

The TAILORx study evaluated outcomes in patients (n=9,719) with HR+/HER2− axillary LN-negative breast cancer.10 At 9 years, among patients (n=1,619) with low RS (≤10), all of whom received endocrine therapy alone without chemotherapy, the rate of freedom from recurrence of breast cancer at local/regional or distant site was 96.8% and the rate of invasive disease-free survival (DFS) was 84%. Among patients (n=1,389) with a high RS (≥26), all of whom received chemotherapy, the rate of freedom from recurrence of breast cancer at local/regional or distant site was 84.8% and of invasive DFS was 75.7%.10 The overall results from TAILORx are similar to those from the West German Study Group Plan B trial11 and NSABP B-20 trial8 for patients with low RS and high RS. The NSABP B-20 was the first trial to validate the 21-gene assay as both a prognostic and a predictive tool and identified RS cutoffs to predict the magnitude of chemotherapy benefit in patients with node-negative, HR+ breast cancer.8 It is important to remember that the cutoff for low, intermediate, and high RS was different in TAILORx versus NSABP B-20.

Among patients (n=6,711) with intermediate RS (11–25) in the TAILORx trial, outcomes were similar between the group that received adjuvant chemotherapy followed by endocrine therapy versus endocrine therapy alone. At 9 years, the rate of freedom from recurrence of breast cancer at distant site was 95% for those who received adjuvant chemotherapy followed by endocrine therapy versus 94.5% for those who received endocrine therapy alone; invasive DFS rates were 83.3% versus 84.3, and overall survival (OS) rates were 93.8% versus 93.9%.10 In an exploratory subset analysis of the TAILORx trial, among patients aged ≤50 years, with an RS of 0 to 15, and receiving endocrine therapy alone, the rate of distant recurrence was 3% at 9 years. However, those with an RS of 16 to 25 had significantly lower rates of distance recurrence with the addition of adjuvant chemotherapy to endocrine therapy.10 At 9 years, among patients with an RS of 16 to 20, the absolute difference was 3.4% lower rates of local and distant recurrences, 9% reduction in invasive DFS, and 1.6% reduction in distant recurrence in those receiving chemotherapy plus endocrine therapy. In the group with an RS of 21 to 25, the absolute difference was 8.7% lower rates of local and distant recurrence and 6.6% reduction in distant recurrence in those receiving chemotherapy in addition to endocrine therapy.10 No benefit of chemotherapy was observed among patients aged >50 years or in the overall population. The TAILORx study did not collect data on chemotherapy-induced menopause and only 12.5% of the premenopausal patients enrolled in the trial underwent ovarian suppression.10 A much discussed hypothesis is that chemotherapy effect may have been the result of ovarian suppression.

Results of the TAILORx trial in patients with low-risk, node-negative disease were similar to those of the MINDACT trial.12 In the MINDACT trial, patients were stratified into clinical high- or low-risk categories using the Adjuvant! Online criteria and genomic high- or low-risk categories by 70-gene assay (MammaPrint). Clinical low-risk was defined as low histologic grade and tumor size ≤3 cm, intermediate histologic grade and tumor size ≤2 cm, or high histologic grade and tumor size ≤1 cm, and clinical high-risk was defined as all other cases with known values for grade and tumor size. Patients with clinical-high/genomic-low risk were randomized to receive chemotherapy in addition to endocrine therapy or to endocrine therapy alone. At 8 years, the distant metastasis–free survival rates were 92.0% (95% CI, 89.6–93.8) versus 89.4% (95% CI, 86.8–91.5), respectively.12 The OS at 8 years was 95.7% (95% CI, 93.9–97.0) for those receiving chemotherapy plus endocrine therapy versus 94.3% (95% CI, 92.2–95.8) for those receiving endocrine therapy alone.12 In a subset analyses, the benefit of chemotherapy was mostly seen in patients aged <50 years. The absolute difference in distant metastasis–free survival at 8 years in those receiving chemotherapy was 5.4% ± 2.8% for patients aged ≤50 years versus 0.2% ± 2.3% for those aged >50 years.13 It is not known whether the benefit of chemotherapy observed in premenopausal patients, in both the TAILORx and MINDACT trials, is related to chemotherapy-induced ovarian function suppression.

The RxPONDER study randomized patients (n=5,083) with HR+, pN1 (1–3 positive LNs) disease and RS ≤25 to receive adjuvant chemotherapy plus endocrine therapy or endocrine therapy alone.14 In the overall study population, 66.8% of patients were postmenopausal and 33.2% premenopausal; 10.3% had high-grade disease; 9.2% had 3 involved nodes; and 62.6% received complete axillary node dissection and 37.4% received sentinel LN dissection. Chemotherapy and RS were both independently prognostic for invasive DFS. There was no interaction seen between RS and chemotherapy. The benefit for chemotherapy in the overall randomized cohort was 1.4% at 5 years.14

In a planned secondary analysis, a correlation was seen between chemotherapy benefit and menopausal status. In postmenopausal patients with RS ≤25 and pN1 (1–3 positive LNs) disease, the 5-year invasive DFS rate was 91.6% with adjuvant chemotherapy in addition to adjuvant endocrine therapy versus 91.9% with endocrine therapy alone (hazard ratio [HR], 0.97; 95% CI, 0.78–1.22), indicating no benefit from chemotherapy.14 In the premenopausal patients with RS ≤25, the addition of adjuvant systemic chemotherapy improved outcomes. There was a 5.2% increase in invasive DFS with the addition of chemotherapy to endocrine therapy (HR, 0.45; 95% CI, 0.38–0.76),14 and an absolute decrease in distant recurrence by 2.9% with chemotherapy. The 5-year OS was 1.3% better in chemotherapy-treated premenopausal patients (97.3 vs 98.6%; 95% CI, 0.24–0.94).14 When further analyzed according to RS, the premenopausal patients with an RS of 0 to 13 received less absolute benefit from chemotherapy (3.9% reduction in invasive DFS) compared with those with an RS of 14 to 25 (6.2% reduction in invasive DFS). Approximately 16% of patients receiving endocrine therapy alone received ovarian suppression, compared with 4% in the chemotherapy/endocrine therapy arm.14 However, it is also important to note that it is not clear whether the benefit seen in premenopausal patients is related to chemotherapy-induced ovarian function suppression.

Gene Expression Assays

In addition to the 21-gene assay and the 70-gene assay (MammaPrint), other gene expression assays can also provide prognostic information on outcomes with endocrine treatment, such as the 50-gene assay (Prosigna), 12-gene assay (EndoPredict), and Breast Cancer Index (BCI; HOXB13/IL17BR ratio [H/I]). None of these assays have been compared head-to-head in randomized trials and, except for the 21-gene assay, no others have been validated to predict the benefit from adding adjuvant chemotherapy to adjuvant endocrine therapy in patients with early-stage HR+/HER2− disease.

Use of gene expression assays in early-stage breast cancer continues to evolve. The clinical utility of the BCI assay was studied in the prospective phase III IDEAL trial, which randomized postmenopausal patients (n=1,824) with early-stage HR+ breast cancer to receive either 2.5 or 5 years of letrozole after completing 5 years of adjuvant endocrine therapy.15 Patients with BCI (H/I) low demonstrated a lower risk of distant recurrence (compared with BCI [H/I] high) and no significant improvement in DFS or OS compared with the control arm with extended endocrine therapy duration.16 Patients with T1, HR+/HER2−, pN0 tumors with BCI (H/I) high (5.1–10) demonstrated significant rates of late distant recurrence. In contrast, patients with BCI (H/I) low derived no benefit from extended adjuvant therapy.16 These data are similar to those seen in secondary analyses of the MA.17 and Trans-aTTom studies, in which patients with HR+, T1–3, pN0 or pN+ tumors with BCI (H/I) high demonstrated significant improvements in DFS when adjuvant endocrine therapy was extended, compared with the control arm.17,18

NCCN Recommendations: pT1–3 HR+/ HER2− Tumors

Patients With Tumors ≤0.5 cm and LN-Negative

The panel does not recommend adjuvant systemic chemotherapy in premenopausal or postmenopausal patients with tumors ≤0.5 cm and pN0. Adjuvant endocrine therapy alone is an option to reduce the recurrence risk. Because the benefit of adjuvant endocrine therapy in reducing the recurrence risk, particularly distant metastatic disease, is very small in this group of patients, this is a category 2B recommendation (see BINV-6 and BINV-7, pages 486 and 487).

Patients With ≥4 Positive LNs

Considering the high risk of recurrence in patients with pN2/pN3 tumors, regardless of menopausal status, the panel recommends addition of systemic adjuvant chemotherapy followed by endocrine therapy (category 1) (see BINV-6 and BINV-8, pages 486 and 488).

Patients With Tumors >0.5 cm or pN1mi or pN1 (1–3 Positive LNs)

For HR+/HER2− tumors that fall between the 2 previous extremes (>0.5 cm or either pN1mi or pN1 with 1–3 positive LNs), the panel has additionally stratified the recommendations based on menopausal status and risk assessment based on gene expression assay results. Of note, patients with pNmi disease were not studied in either the TAILORx or the RxPONDER trials.

Results from TAILORx and RxPONDER show that the 21-gene assay RS is helpful in identifying patients who can be spared adjuvant chemotherapy, especially those who are postmenopausal (or with stage pN0 and age >50 years) and have an RS ≤25, as well as patients aged ≤50 years with an RS ≤15. If a patient is a candidate for chemotherapy based on clinical characteristics, tumor stage, and pathology with a tumor >0.5 cm or with 1 to 3 involved LNs, and a multigene assay is not available or not performed to assess recurrence risk, the panel recommends systemic adjuvant chemotherapy followed by endocrine therapy (category 1). Patients who are not candidates for chemotherapy, including those with contraindications to chemotherapy or who do not wish to undergo chemotherapy treatment, gene expression assay results would not alter management, and therefore such patients may be treated with endocrine therapy alone with the consideration of ovarian ablation/suppression, if premenopausal.

For postmenopausal patients with tumors >0.5 cm or 1 to 3 positive LNs, the panel strongly recommends considering the 21-gene RT-PCR assay to help estimate likelihood of recurrence and benefit from chemotherapy (category 1) (see BINV-6, page 486). The panel notes that although several other prognostic assays are available to estimate recurrence risk, only the 21-gene assay RS has been validated for predicting the benefit of adding adjuvant chemotherapy to further reduce the recurrence risk. Results of the RxPONDER trial show that postmenopausal patients with 1 to 3 positive LNs might not have a risk as high as previously assumed. Therefore, taking together the results of the RxPONDER and TAILORx trials, endocrine therapy alone is recommended for those with RS <26,14,19 and based on the results of the TAILORx study, addition of adjuvant chemotherapy to adjuvant endocrine therapy is recommended for those with RS ≥26.7,8

For premenopausal patients, the recommendations are further stratified based on nodal status. The TAILORx analyses were performed by age and demonstrated that patients with RS ≥16 and aged ≤50 years with node-negative disease derived benefit from chemotherapy (reduction in distant recurrence) at 9 years.19 Based on this, the NCCN panel strongly recommends considering the 21-gene RT-PCR assay to help estimate likelihood of recurrence and benefit from chemotherapy (category 1) (see BINV-7, page 487). In those with RS ≤15, the NCCN panel recommends considering endocrine therapy alone.19 Also, patients with T1b tumors with low-grade histology should be considered for endocrine monotherapy, given that the TAILORx19 did not include patients with such tumors.

Based on the exploratory analysis from the TAILORx study, which showed benefit of adjuvant chemotherapy in patients aged ≤50 years with an RS of 16 to 25, the panel recommends the addition of chemotherapy to adjuvant endocrine therapy or adjuvant endocrine therapy alone with or without consideration of ovarian ablation/suppression.19 Because the TAILORx study did not collect data on chemotherapy-induced menopause and only a small portion (12.5%) of the patients on the trial underwent ovarian suppression, it remains unclear whether similar benefits could be achieved with ovarian suppression plus endocrine therapy instead of chemotherapy20 (see BINV-7, page 487).

No randomized trial has addressed the benefit of chemotherapy for those with high RS (26–100) among premenopausal patients with early stage, node-positive disease. Because the benefit of adjuvant chemotherapy for those with RS ≤25 is significant in the RxPONDER trial, it can be inferred that the benefit for those with RS ≥26 would be substantial.14

The RxPONDER results demonstrated premenopausal patients with early-stage pN1 disease and an RS of 0 to 25 derived benefit from chemotherapy14 For patients with pN1mi (≤2 mm axillary node metastases) or pN1 (1–3 positive LNs) disease, the panel recommends assessing whether the patient is a candidate for chemotherapy based on patient factors and tumor characteristics before mandating adjuvant chemotherapy in all patients with 1 to 3 positive nodes. The decision regarding the addition of chemotherapy versus ovarian function suppression to adjuvant endocrine therapy must be individualized, and can be aided by results of gene expression assays. At this time, it is unclear whether ovarian suppression plus endocrine therapy alone will provide the same benefits as addition of chemotherapy. According to the panel, either addition of adjuvant chemotherapy to adjuvant endocrine therapy based on the RxPONDER results14 or adjuvant endocrine therapy with ovarian ablation/suppression20 are options for this group.

The panel has provided a list of available assays along with their treatment implications in a table on BINV-N (page 489-493). The table was revised to include updated references for the 21-gene and BCI assays.

T1
T2
T3
T4

Summary

The updated recommendations in the NCCN Guidelines for Breast Cancer provide guidance on tailoring chemotherapy recommendations for patients with HR+/HER2− early-stage breast cancer based on clinicopathologic characteristics, menopausal status, LN status, and results of gene expression assays. Use of gene expression assays in early-stage breast cancer continues to evolve. Risk assessment using the BCI gene expression assay has also shown potential to spare certain patients from prolonged endocrine therapy.

References

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    Francis PA, Pagani O, Fleming GF, et al. Tailoring adjuvant endocrine therapy for premenopausal breast cancer. N Engl J Med 2018;379:122137.

NCCN CATEGORIES OF EVIDENCE AND CONSENSUS

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based uponlower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus 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 noted.

Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

PLEASE NOTE

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. The NCCN Guidelines Insights highlight important changes in the NCCN Guidelines recommendations from previous versions. Colored markings in the algorithm show changes and the discussion aims to further the understanding of these changes by summarizing salient portions of the panel’s discussion, including the literature reviewed.

The NCCN Guidelines Insights do not represent the full NCCN Guidelines; further, the National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application of the NCCN Guidelines and NCCN Guidelines Insights and disclaims any responsibility for their application or use in any way.

The complete and most recent version of these NCCN Guidelines is available free of charge at NCCN.org.

© National Comprehensive Cancer Network, Inc. 2021.

All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.

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