RxPONDER Update Explores Benefit of Chemotherapy in Subgroups

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Updated results of the SWOG S1007 RxPONDER trial confirmed the key takeaway from the previous analysis: adjuvant chemotherapy benefits premenopausal women but not postmenopausal women with hormone receptor–positive, HER2-negative disease, one to three positive lymph nodes, and a 21-gene Oncotype DX recurrence score (RS) of 0 to 25.1 The results were presented at the 2021 San Antonio Breast Cancer Symposium (SABCS) by Kevin Kalinsky, MD, MS, Director of the Emory University Winship Cancer Institute’s Glenn Family Breast Center.

Kevin Kalinsky, MD, MS

Kevin Kalinsky, MD, MS

“In our updated analysis with longer follow-up, we report that postmenopausal women with a recurrence score of 0 to 25 continue not to benefit from the addition of chemotherapy to endocrine therapy. But premenopausal women with a recurrence score of 0 to 25 do benefit from adjuvant chemotherapy, which is associated with a 44% to 46% decrease in invasive disease–free survival, distant recurrence–free survival, and disease recurrence–free interval events.”

Initial results from RxPONDER were reported at the 2020 SABCS.2 An update of that analysis, with a median follow-up of 5.3 years, was published in The New England Journal of Medicine.3 In San Antonio, Dr. Kalinsky provided yet another update of this important trial, based on 6.1 months’ median follow-up.

The randomized phase III RxPONDER trial evaluated the benefit of adjuvant chemotherapy in women with hormone receptor–positive, HER2-negative breast cancer and one to three positive lymph nodes. As more analyses are performed on the data, the strategy for this population is becoming increasingly personalized.


The study enrolled 5,000 patients with hormone receptor–positive, HER2-negative breast cancer with one to three positive lymph nodes, no distant metastasis, and an RS ≤ 25. Those with higher scores were treated off study and recommended to receive both endocrine therapy and chemotherapy. Patients with RS ≤ 25 were randomly assigned to receive either chemotherapy followed by endocrine therapy or endocrine therapy alone.

The primary endpoint of the study was invasive disease–free survival, and a secondary endpoint was distant recurrence–free survival. New findings, reported in San Antonio, also evaluated disease recurrence–free interval, which Dr. Kalinsky said is a more informative measure than distant relapse–free survival.

“As opposed to distant relapse–free survival, disease recurrence–free interval excludes death from non–breast cancer or unknown causes and only includes distant recurrence or death from breast cancer,” Dr. Kalinsky explained. “This is a clinically important outcome given its relevance to long-term breast cancer–related survival.”

The updated results were based on 1,654 premenopausal women, 3,329 postmenopausal women, 553 invasive disease–free survival events, and a median of 6.1 years of follow-up. The current analysis found a number of benefits at 5 years for premenopausal patients treated with chemotherapy: an invasive disease–free survival absolute benefit of 4.9% (hazard ratio [HR] = 0.64; P = .004); distant recurrence–free survival absolute benefit of 2.5% (HR = 0.66; P = .033); and disease recurrence–free interval absolute benefit of 2.4% (HR = 0.64; P = .026). By RS strata, the disease recurrence–free interval benefit was 2.3% for RS 0–13 and 2.8% for RS 14–25 (Table 1, see page 28).

Exploratory Analyses

“We then performed exploratory post hoc analyses in premenopausal women, given the number of questions that have arisen since we presented these data,” Dr. Kalinsky said, cautioning that the analyses are based on small subsets. Included were an analysis of outcomes in women with pN1 disease (including pN1 micrometastatic disease),1 a 2-year landmark invasive disease–free survival analysis based on ovarian function suppression or not in the endocrine therapy arm,3 and a 2-year landmark invasive disease–free survival analysis between patients with regular menstrual periods or not in both treatment arms.2 “These data should be interpreted with caution, given that confounding factors can change over time,” he said.

Post hoc analysis in 206 premenopausal women with micrometastases (0.2–2 mm) showed that chemotherapy conveyed a 7.3% absolute benefit in invasive disease–free survival (HR = 0.44; 95% confidence interval [CI] = 0.18–1.08). For the 1,403 patients with pN1 disease (> 2 mm), the absolute benefit was 4.8% (HR = 0.64; 95% CI = 0.46–0.90). Although the data suggest that premenopausal women with micrometastases benefit most from
chemotherapy, Dr. Kalinsky cautioned that the number of events is very small (n = 22), and the confidence interval is wide in that subset.

Interesting observations were also made regarding ovarian function suppression. Though rates of suppression were higher with endocrine therapy, over time (6–60 months), these rates remained low and consistent in both arms. Rates in the endocrine therapy–alone arm were 16% in the first 6 months and 14% at 48 to 60 months; with chemotherapy followed by endocrine therapy, they were 3% and 6%, respectively. The 2-year landmark analysis, adjusting for recurrence score, showed no invasive disease–free survival difference whether women in the endocrine therapy arm underwent ovarian function suppression or not in the first 24 months.

The endocrine therapy arm had double the proportion of women reporting regular menses in the first 6 months (50% vs 25%), but over time, the rate of regular periods decreased in both arms (16% vs 9%). The invasive disease–free survival was numerically improved in patients no longer having regular periods (vs having them) in the first 24 months in both treatment arms, with hazard ratios of 1.48 in the endocrine therapy–alone arm and 1.56 in the chemotherapy arm, though the confidence intervals for these benefits was wide, he noted.

Rates of ovarian function suppression were low in both treatment arms but were higher in the endocrine therapy–alone arm. In brief, the study was not able to establish that the benefit from chemotherapy was related to ovarian function suppression.

“It remains unclear if ovarian function suppression can replace chemotherapy in premenopausal women with hormone receptor–positive, HER2-negative, node-positive breast cancer,” Dr. Kalinsky said. “We conclude that future randomized trials should be considered to address this important clinical question in a genomically defined population.” 

DISCLOSURE Dr. Kalinsky has served as a consultant or advisor to Eli Lilly, Pfizer, Novartis, Eisai, AstraZeneca, Daiichi Sankyo, Puma, 4D Pharma, OncoSec, Immunomedics, Merck, Seattle Genetics, and Cyclacel. His spouse reported relationships with Grail, Array BioPharma, and Pfizer.


1. Kalinsky KM, Barlow WE, Gralow JR, et al: Distant-disease free interval in participants with 1-3 positive lymph nodes, hormone receptor-positive and her2-negative breast cancer with recurrence score < or = 25 randomized to endocrine therapy +/- chemotherapy: SWOG S1007 (RxPONDER). Abstract GS2-07. 2021 SABCS. Presented December 8, 2021.

2. Kalinsky K, Barlow WE, Meric-Bernstam F, et al: First results from a phase III randomized clinical trial of standard adjuvant endocrine therapy +/- chemotherapy in patients with 1-3 positive nodes, hormone receptor-positive and HER2-negative breast cancer with recurrence scores ≤ 25: SWOG S1007 (RxPONDER). 2020 San Antonio Breast Cancer Symposium. Abstract GS3-00. Presented December 10, 2020. 

3. Kalinsky K, Barlow WE, Gralow JR, et al: 21-gene assay to inform chemotherapy benefit in node-positive breast cancer. N Engl J Med. December 1, 2021 (early release online).

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