Significant Interaction Between a Chemotherapy Benefit and Menopausal Status Found in Terms of Invasive Disease–Free Survival

RxPONDER investigators found that postmenopausal women with 1 to 3 positive axillary lymph nodes and a recurrence score of 0 to 25 were able to safely forgo adjuvant chemotherapy for breast cancer without compromising invasive disease–free survival (iDFS) and distant relapse–free survival (DRFS). However, premenopausal women with 1 to 3 positive lymph nodes had a significant benefit from chemotherapy, even with a very low recurrence score. The findings are published by Dr. Kevin Kalinsky of the Winship Cancer Institute at Emory University in Atlanta, GA, US and colleagues on 1 December 2021 in The New England Journal of Medicine.

The authors wrote in the study background that the recurrence score based on the 21-gene breast-cancer assay has been clinically useful in predicting a chemotherapy benefit in hormone receptor–positive, HER2–negative, axillary lymph node–negative breast cancer. However, in women with positive lymph node disease, the role of the recurrence score with respect to predicting a benefit of adjuvant chemotherapy is unclear.

RxPONDER (A Clinical Trial RX for Positive Node, Endocrine Responsive Breast Cancer) randomly assigned participants with hormone receptor–positive, HER2-negative breast cancer, 1 to 3 positive axillary lymph nodes (nodal stage N1), and a recurrence score of 25 or lower to endocrine therapy only or to chemoendocrine therapy. The study tested the hypothesis that in this population the absolute risk of recurrence increases with higher recurrence-score values and the relative benefit of chemotherapy also increases with a higher recurrence score.

The primary objective was to determine the effect of chemotherapy on iDFS and whether the effect was influenced by the recurrence score. Secondary endpoints included DRFS.

A total of 5083 women (33.2% premenopausal and 66.8% postmenopausal) underwent randomisation, and 5018 participated in the study. At the prespecified third interim analysis, the chemotherapy benefit with respect to increasing iDFS 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, iDFS 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, iDFS 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 DRFS (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.

The authors commented that their study did not show a clinically relevant or statistically significant increase in iDFS with the addition of adjuvant chemotherapy to endocrine therapy in the overall population of women who had hormone receptor–positive, HER2-negative breast cancer, 1 to 3 positive axillary lymph nodes, and a recurrence score of 0 to 25. They confirmed the prognostic value of a recurrence score between 0 and 25 in both premenopausal and postmenopausal participants with N1 breast cancer. However, the hypothesis that the relative chemotherapy benefit increases as the recurrence-score value increases was not supported in either population.

The authors concluded that among premenopausal women with 1 to 3 positive lymph nodes and a recurrence score of 25 or lower, those who received chemoendocrine therapy had longer iDFS and DRFS than those who received endocrine only therapy, whereas postmenopausal women with similar characteristics did not benefit from adjuvant chemotherapy.

RxPONDER was sponsored by the US National Cancer Institute (NCI) Cancer Therapy Evaluation Program and coordinated by SWOG, with participation from the UNICANCER Breast Group, the Grupo Español de Investigación en Cáncer de Mama, and other federally funded groups, including the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network Cancer Research Group, the Alliance for Clinical Trials in Oncology, NRG Oncology, and the Canadian Cancer Trials Group. The study was conducted at 632 sites in 9 countries.

The study was funded by grants from the NCI, the Susan G. Komen for the Cure Research Program, the Hope Foundation for Cancer Research, the Breast Cancer Research Foundation, and Genomic Health.


Kalinsky K, Barlow WE, Gralow JR, et al. 21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer. NEJM; Published online 1 December 2021. DOI: 10.1056/NEJMoa2108873