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21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer. ​

Literature Information ​

DOI10.1056/NEJMoa2108873
PMID34914339
JournalThe New England journal of medicine
Impact Factor78.5
JCR QuartileQ1
Publication Year2021
Times Cited364
Keywords21-gene assay, chemotherapy benefit, breast cancer, node-positive, endocrine therapy
Literature TypeJournal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
ISSN0028-4793
Pages2336-2347
Issue385(25)
AuthorsKevin Kalinsky, William E Barlow, Julie R Gralow, Funda Meric-Bernstam, Kathy S Albain, Daniel F Hayes, Nancy U Lin, Edith A Perez, Lori J Goldstein, Stephen K L Chia, Sukhbinder Dhesy-Thind, Priya Rastogi, Emilio Alba, Suzette Delaloge, Miguel Martin, Catherine M Kelly, Manuel Ruiz-Borrego, Miguel Gil-Gil, Claudia H Arce-Salinas, Etienne G C Brain, Eun-Sook Lee, Jean-Yves Pierga, Begoña Bermejo, Manuel Ramos-Vazquez, Kyung-Hae Jung, Jean-Marc Ferrero, Anne F Schott, Steven Shak, Priyanka Sharma, Danika L Lew, Jieling Miao, Debasish Tripathy, Lajos Pusztai, Gabriel N Hortobagyi

TL;DR ​

This study investigates the impact of adjuvant chemotherapy on invasive disease-free survival in premenopausal and postmenopausal women with hormone-receptor-positive, HER2-negative breast cancer and one to three positive lymph nodes, finding that premenopausal women benefit from chemoendocrine therapy while postmenopausal women do not show significant advantages. These results highlight the importance of considering menopausal status and recurrence score in treatment decisions for this patient population.

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21-gene assay · chemotherapy benefit · breast cancer · node-positive · endocrine therapy

Abstract ​

BACKGROUND The recurrence score based on the 21-gene breast-cancer assay has been clinically useful in predicting a chemotherapy benefit in hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, axillary lymph-node-negative breast cancer. In women with positive lymph-node disease, the role of the recurrence score with respect to predicting a benefit of adjuvant chemotherapy is unclear.

METHODS In a prospective trial, we randomly assigned women with hormone-receptor-positive, HER2-negative breast cancer, one to three positive axillary lymph nodes, and a recurrence score of 25 or lower (scores range from 0 to 100, with higher scores indicating a worse prognosis) to endocrine therapy only or to chemotherapy plus endocrine (chemoendocrine) therapy. The primary objective was to determine the effect of chemotherapy on invasive disease-free survival and whether the effect was influenced by the recurrence score. Secondary end points included distant relapse-free survival.

RESULTS A total of 5083 women (33.2% premenopausal and 66.8% postmenopausal) underwent randomization, and 5018 participated in the trial. At the prespecified third interim analysis, the chemotherapy benefit with respect to increasing invasive disease-free survival differed according to menopausal status (P = 0.008 for the comparison of chemotherapy benefit in premenopausal and postmenopausal participants), and separate prespecified analyses were conducted. Among postmenopausal women, invasive disease-free survival at 5 years was 91.9% in the endocrine-only group and 91.3% in the chemoendocrine group, with no chemotherapy benefit (hazard ratio for invasive disease recurrence, new primary cancer [breast cancer or another type], or death, 1.02; 95% confidence interval [CI], 0.82 to 1.26; P = 0.89). Among premenopausal women, invasive disease-free survival at 5 years was 89.0% with endocrine-only therapy and 93.9% with chemoendocrine therapy (hazard ratio, 0.60; 95% CI, 0.43 to 0.83; P = 0.002), with a similar increase in distant relapse-free survival (hazard ratio, 0.58; 95% CI, 0.39 to 0.87; P = 0.009). The relative chemotherapy benefit did not increase as the recurrence score increased.

CONCLUSIONS Among premenopausal women with one to three positive lymph nodes and a recurrence score of 25 or lower, those who received chemoendocrine therapy had longer invasive disease-free survival and distant relapse-free survival than those who received endocrine-only therapy, whereas postmenopausal women with similar characteristics did not benefit from adjuvant chemotherapy. (Funded by the National Cancer Institute and others; RxPONDER ClinicalTrials.gov number, NCT01272037.).

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Primary Questions Addressed ​

  1. How does the 21-gene assay specifically differentiate between the chemotherapy benefits in premenopausal versus postmenopausal women?
  2. What are the implications of the recurrence score findings for treatment guidelines in node-positive breast cancer patients?
  3. Can the results of this study influence future research directions regarding adjuvant chemotherapy in breast cancer with positive lymph nodes?
  4. What are the potential biological mechanisms that could explain the lack of chemotherapy benefit in postmenopausal women with node-positive breast cancer?
  5. How might the findings of this trial affect the decision-making process for clinicians treating hormone-receptor-positive, HER2-negative breast cancer patients?

Key Findings ​

Background and Objective ​

The study investigates the role of the 21-gene recurrence score in predicting chemotherapy benefits for women with hormone-receptor-positive, HER2-negative breast cancer, specifically focusing on those with one to three positive axillary lymph nodes and a recurrence score of 25 or lower. The primary aim is to assess the effect of adjuvant chemotherapy on invasive disease-free survival and to evaluate whether this effect is influenced by the recurrence score.

Main Methods/Materials/Experimental Design ​

The research was conducted as a prospective trial with the following design:

  1. Participants: Women diagnosed with hormone-receptor-positive, HER2-negative breast cancer, having one to three positive axillary lymph nodes and a recurrence score of 25 or lower.
  2. Randomization: Participants were randomly assigned to one of two treatment groups:
    • Endocrine therapy only
    • Chemotherapy plus endocrine therapy (chemoendocrine therapy)
  3. Primary Objective: To determine the impact of chemotherapy on invasive disease-free survival.
  4. Secondary Objectives: To evaluate distant relapse-free survival.

The following flowchart outlines the trial design:

Mermaid diagram

Key Results and Findings ​

  • Participants: A total of 5083 women were randomized, with 5018 participating in the trial.
  • Menopausal Status: The chemotherapy benefit varied significantly by menopausal status (P = 0.008).
    • Postmenopausal Women:
      • Invasive disease-free survival at 5 years: 91.9% (endocrine-only) vs. 91.3% (chemoendocrine).
      • No significant benefit from chemotherapy (hazard ratio 1.02; 95% CI, 0.82 to 1.26; P = 0.89).
    • Premenopausal Women:
      • Invasive disease-free survival at 5 years: 89.0% (endocrine-only) vs. 93.9% (chemoendocrine).
      • Significant benefit from chemotherapy (hazard ratio 0.60; 95% CI, 0.43 to 0.83; P = 0.002).
      • Similar findings for distant relapse-free survival (hazard ratio 0.58; 95% CI, 0.39 to 0.87; P = 0.009).
  • Recurrence Score: The relative benefit of chemotherapy did not increase with higher recurrence scores.

Main Conclusions/Significance/Innovation ​

The study concludes that among premenopausal women with one to three positive lymph nodes and a recurrence score of 25 or lower, those receiving chemoendocrine therapy exhibited longer invasive disease-free survival and distant relapse-free survival compared to those receiving endocrine-only therapy. In contrast, postmenopausal women with similar characteristics did not derive any benefit from adjuvant chemotherapy. This finding highlights the importance of considering menopausal status and recurrence scores in treatment decisions for breast cancer.

Limitations and Future Directions ​

  • Limitations:

    • The study primarily focuses on a specific subgroup of breast cancer patients, limiting the generalizability of findings.
    • The impact of other variables (e.g., comorbidities, genetic factors) was not extensively analyzed.

  • Future Directions:

    • Further research is needed to explore the underlying mechanisms of the differential chemotherapy response between premenopausal and postmenopausal women.
    • Investigating the effects of chemotherapy in other subgroups of breast cancer patients with varying recurrence scores and lymph node involvement.
    • Long-term follow-up studies to assess the overall survival benefits and quality of life post-treatment.

References ​

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  2. Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: the STEEP system. - Clifford A Hudis;William E Barlow;Joseph P Costantino;Robert J Gray;Kathleen I Pritchard;Judith-Anne W Chapman;Joseph A Sparano;Sally Hunsberger;Rebecca A Enos;Richard D Gelber;Jo Anne Zujewski - Journal of clinical oncology : official journal of the American Society of Clinical Oncology (2007)
  3. Absolute Improvements in Freedom From Distant Recurrence to Tailor Adjuvant Endocrine Therapies for Premenopausal Women: Results From TEXT and SOFT. - Olivia Pagani;Prudence A Francis;Gini F Fleming;Barbara A Walley;Giuseppe Viale;Marco Colleoni;István Láng;Henry L Gómez;Carlo Tondini;Graziella Pinotti;Angelo Di Leo;Alan S Coates;Aron Goldhirsch;Richard D Gelber;Meredith M Regan; - Journal of clinical oncology : official journal of the American Society of Clinical Oncology (2020)
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  5. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. - Soonmyung Paik;Gong Tang;Steven Shak;Chungyeul Kim;Joffre Baker;Wanseop Kim;Maureen Cronin;Frederick L Baehner;Drew Watson;John Bryant;Joseph P Costantino;Charles E Geyer;D Lawrence Wickerham;Norman Wolmark - Journal of clinical oncology : official journal of the American Society of Clinical Oncology (2006)
  6. 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer. - Fatima Cardoso;Laura J van't Veer;Jan Bogaerts;Leen Slaets;Giuseppe Viale;Suzette Delaloge;Jean-Yves Pierga;Etienne Brain;Sylvain Causeret;Mauro DeLorenzi;Annuska M Glas;Vassilis Golfinopoulos;Theodora Goulioti;Susan Knox;Erika Matos;Bart Meulemans;Peter A Neijenhuis;Ulrike Nitz;Rodolfo Passalacqua;Peter Ravdin;Isabel T Rubio;Mahasti Saghatchian;Tineke J Smilde;Christos Sotiriou;Lisette Stork;Carolyn Straehle;Geraldine Thomas;Alastair M Thompson;Jacobus M van der Hoeven;Peter Vuylsteke;René Bernards;Konstantinos Tryfonidis;Emiel Rutgers;Martine Piccart; - The New England journal of medicine (2016)
  7. Prediction of risk of distant recurrence using the 21-gene recurrence score in node-negative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen: a TransATAC study. - Mitch Dowsett;Jack Cuzick;Christopher Wale;John Forbes;Elizabeth A Mallon;Janine Salter;Emma Quinn;Anita Dunbier;Michael Baum;Aman Buzdar;Anthony Howell;Roberto Bugarini;Frederick L Baehner;Steven Shak - Journal of clinical oncology : official journal of the American Society of Clinical Oncology (2010)
  8. Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer. - Joseph A Sparano;Robert J Gray;Della F Makower;Kathleen I Pritchard;Kathy S Albain;Daniel F Hayes;Charles E Geyer;Elizabeth C Dees;Matthew P Goetz;John A Olson;Tracy Lively;Sunil S Badve;Thomas J Saphner;Lynne I Wagner;Timothy J Whelan;Matthew J Ellis;Soonmyung Paik;William C Wood;Peter M Ravdin;Maccon M Keane;Henry L Gomez Moreno;Pavan S Reddy;Timothy F Goggins;Ingrid A Mayer;Adam M Brufsky;Deborah L Toppmeyer;Virginia G Kaklamani;Jeffrey L Berenberg;Jeffrey Abrams;George W Sledge - The New England journal of medicine (2018)
  9. Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer. - Sandra M Swain;Jong-Hyeon Jeong;Charles E Geyer;Joseph P Costantino;Eduardo R Pajon;Louis Fehrenbacher;James N Atkins;Jonathan Polikoff;Victor G Vogel;John K Erban;Priya Rastogi;Robert B Livingston;Edith A Perez;Eleftherios P Mamounas;Stephanie R Land;Patricia A Ganz;Norman Wolmark - The New England journal of medicine (2010)
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Literatures Citing This Work ​

  1. The incidence of discordant clinical and genomic risk in patients with invasive lobular or ductal carcinoma of the breast: a National Cancer Database Study. - Mary Kathryn Abel;Amy M Shui;Michelle Melisko;A Jo Chien;Emi J Yoshida;Elizabeth M Lancaster;Laura Van 't Veer;Laura J Esserman;Rita A Mukhtar - NPJ breast cancer (2021)
  2. Gene Expression Profiling in Early Breast Cancer-Patient Stratification Based on Molecular and Tumor Microenvironment Features. - Gyöngyi Munkácsy;Libero Santarpia;Balázs Győrffy - Biomedicines (2022)
  3. Therapeutic Targeting of Minimal Residual Disease to Prevent Late Recurrence in Hormone-Receptor Positive Breast Cancer: Challenges and New Approaches. - David W Cescon;Kevin Kalinsky;Heather A Parsons;Karen Lisa Smith;Patricia A Spears;Alexandra Thomas;Fengmin Zhao;Angela DeMichele - Frontiers in oncology (2021)
  4. A Canadian national guideline on the neoadjuvant treatment of invasive breast cancer, including patient assessment, systemic therapy, and local management principles. - Sonal Gandhi;Muriel Brackstone;Nicole J Look Hong;Debjani Grenier;Elysia Donovan;Fang-I Lu;Mia Skarpathiotakis;Justin Lee;Jean-Francois Boileau;Francisco Perera;Christine Simmons;Anil A Joy;William T Tran; - Breast cancer research and treatment (2022)
  5. A prediction model for early systemic recurrence in breast cancer using a molecular diagnostic analysis of sentinel lymph nodes: A large-scale, multicenter cohort study. - Tomo Osako;Masaaki Matsuura;Daisuke Yotsumoto;Shin Takayama;Koji Kaneko;Mina Takahashi;Kenzo Shimazu;Katsuhide Yoshidome;Kazuya Kuraoka;Masayuki Itakura;Mayumi Tani;Takashi Ishikawa;Yasuyo Ohi;Takayuki Kinoshita;Nobuaki Sato;Masahiko Tsujimoto;Seigo Nakamura;Hitoshi Tsuda;Shinzaburo Noguchi;Futoshi Akiyama - Cancer (2022)
  6. Oncotype DX Recurrence Score in premenopausal women. - Shiliang Zhang;Kasey C Fitzsimmons;Sara A Hurvitz - Therapeutic advances in medical oncology (2022)
  7. The Role of the 21-Gene Recurrence Score® Assay in Hormone Receptor-Positive, Node-Positive Breast Cancer: The Canadian Experience. - Mariya Yordanova;Saima Hassan - Current oncology (Toronto, Ont.) (2022)
  8. Feasibility of Adjuvant Treatment with Abemaciclib-Real-World Data from a Large German Breast Center. - Dominik Dannehl;Lea L Volmer;Martin Weiss;Sabine Matovina;Eva-Maria Grischke;Ernst Oberlechner;Anna Seller;Christina B Walter;Markus Hahn;Tobias Engler;Sara Y Brucker;Andreas D Hartkopf - Journal of personalized medicine (2022)
  9. Benefits of Adjuvant Chemotherapy Differ by Menopausal Status in Women with HR+/HER2- Early Breast Cancer, 1-3 Positive Nodes, and a Low Recurrence Score. - Anne Jacobson - The oncologist (2022)
  10. Are we closer to being able to select patients with node-positive hormone receptor-positive breast cancer who can safely omit chemotherapy? - Caitlin Taylor;Jane Meisel;Kevin Kalinsky - Therapeutic advances in medical oncology (2022)

... (354 more literatures)

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