For many years, if a woman with early breast cancer had a small amount of metastatic cancer detected in axillary lymph nodes, oncologists recommended postoperative chemotherapy. Now, results from the RxPONDER trial suggest some of these patients can forgo chemotherapy – specifically, postmenopausal women with hormone receptor–positive, HER2-negative breast cancer who have one to three involved nodes and a 21-gene recurrence score of 25 or less. Adding chemotherapy to endocrine therapy did not improve invasive disease–free survival (IDFS) or overall survival (OS) for this group of patients. These results were presented at the 2020 San Antonio Breast Cancer Symposium (Abstract GS3-00) by Kevin Kalinsky, MD, of Winship Cancer Institute of Emory University, Atlanta.

Dr. Kevin Kalinsky

Rationale for RxPONDER A retrospective analysis of the SWOG 8814 study suggested that postmenopausal women with endocrine-responsive, HER2-negative breast cancer and positive lymph nodes could avoid receiving adjuvant chemotherapy if the primary tumor had a 21-gene recurrence score of less than 31 (Lancet Oncol. 2010 Jan;11[1]: 55-65). More recently, the prospective MINDACT trial included 1,550 patients who had high clinical risk of distant relapse and low genomic risk with the 70-gene MAMMAPRINT assay (N Engl J Med. 2016;375:717-29). At 5 years, the rate of survival without distant metastasis in this group was 94.7% among those not receiving chemotherapy, which was 1.5% lower than in patients who received chemotherapy. Similar rates of distant metastasis-free survival were observed in patients with node-negative or node-positive disease. Given the importance of the issue, a larger, confirmatory trial was needed.

RxPONDER design The RxPONDER trial randomized 5,083 patients with hormone receptor–positive, HER2-negative early breast cancer, one to three axillary lymph nodes, and a recurrence score of 25 or lower. Patients were randomized to endocrine therapy alone or adjuvant chemotherapy followed by endocrine therapy. Randomization was stratified by recurrence score (0-13 vs. 14-25), menopausal status, and type of axillary surgery. Roughly two-thirds of the patients were postmenopausal and received either tamoxifen or an aromatase inhibitor. The premenopausal patients predominantly received hormonal therapy with tamoxifen alone. Results: IDFS and OS At a median follow-up of 5.1 years, there was no association between chemotherapy benefit and recurrence score values between 0-25 when evaluating the entire study population, but there was a significant association between chemotherapy benefit and menopausal status. For postmenopausal patients, there was no difference in the 5-year IDFS rate between those who received chemotherapy and those who did not. The 5-year IDFS rate was 91.6% with chemotherapy and 91.9% with endocrine therapy alone (hazard ratio, 0.97; P = .82). For premenopausal patients, the 5-year IDFS rate was 94.2% in the chemotherapy arm and 89% in the endocrine therapy arm – a 5.2% absolute difference (HR, 0.54; P = .0004). The IDFS results were similar in premenopausal women with recurrence scores of 0-13 and those with recurrence scores of 14-25. There was a significant benefit in OS for premenopausal patients who received chemotherapy (HR, 0.47; P = .032), but the OS result is considered premature. There was no OS benefit with chemotherapy in postmenopausal patients (HR, 0.96; P = .79). In premenopausal patients, ovarian suppression was performed in 15.9% of those receiving endocrine therapy alone versus 3.7% for patients treated with chemotherapy. Nearly half of patients in the endocrine therapy arm (47.9%) and about a quarter of those in the chemotherapy arm (26.4%) reported menstruation after 6 months of treatment. Top image credit: skynesher/Getty Images Image credit: sturti/Getty Images

Implications and next steps The RxPONDER data definitively establish that postmenopausal women with one to three involved nodes and a 21-gene recurrence score of 25 or less do not benefit from postoperative adjuvant chemotherapy and can be treated with endocrine therapy alone. For physicians who have been giving those patients chemotherapy, these data are immediately practice-changing. In contrast, premenopausal women with one to three involved nodes and a 21-gene recurrence score of 25 or lower should receive adjuvant chemotherapy. There was a meaningful difference in IDFS and an early suggestion that there may be improved OS with chemotherapy among those women. Since most postmenopausal women in this trial had one or two involved nodes, one could legitimately question whether the initial results will apply to women with three involved nodes. Those data will be forthcoming in later analyses. It is possible that the apparent benefit of chemotherapy in premenopausal women is due to drug-induced menopause. To optimize therapy, it is of vital importance that we know with certainty whether this is true. The magnitude of IDFS benefit for adjuvant chemotherapy in RxPONDER was commensurate with what was observed for ovarian function suppression in the SOFT and TEXT trials of ovarian function suppression (N Engl J Med. 2018;379:122-37). The lack of a relationship between continuous plots of recurrence score and chemotherapy benefit is consistent with an ovarian ablative effect. Among young, node-negative women who participated in the TAILORx study, chemotherapy benefit was demonstrated only in those with recurrence scores of 16-25 who were older than 40 years and not already postmenopausal (N Engl J Med. 2019;380:2395-405). The RxPONDER study team plans to determine if there is a difference in outcome for young women who did or did not experience chemotherapy-induced menopause. Since the OS information is immature and more than half of recurrences occur in this type of breast cancer beyond the 5-year mark, follow-up in this trial will extend for 15 years. It is likely that oncologists and their patients will see more practice-modifying information from RxPONDER for years to come. Dr. Kalinsky disclosed relationships with Eli Lilly, Pfizer, Novartis, Eisai, AstraZeneca, Immunomedics, Merck, Seattle Genetics, Cyclocel, Grail, and Array BioPharma.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Dr. Alan P. Lyss