Survival Benefit for Chemotherapy Addition Demonstrated for Premenopausal Patients With HR+/HER2– Breast Cancer

Kevin Kalinsky, MD, MS

Updated results of the SWOG S1007 RxPONDER trial (NCT01272037) showed significant differences in outcomes in premenopausal vs postmenopausal patients with hormone receptor (HR)–positive, HER2-negative breast cancer who had 1 to 3 positive lymph nodes and received adjuvant chemotherapy as well as endocrine therapy, according to an oral presentation by , given at the 2021 San Antonio Breast Cancer Symposium.¹ Results from the study were also published in the New England Journal of Medicine on December 1, 2021.²

The investigators found a statistically significant improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in premenopausal women who received adjuvant chemotherapy, while no improvement was observed in postmenopausal patients. Kalinsky, director of Emory University Winship Cancer Institute’s Glenn Family Breast Center, also reported on post hoc analyses of subgroups among premenopausal patients and observed benefit for chemotherapy in premenopausal patients in terms of disease recurrence-free interval (DRFI), a more informative measure than DRFS.

“As opposed to DFRS, DRFI excludes death from non–breast cancer or unknown cause, and only includes distant recurrence or death from breast cancer,” Kalinsky said in his presentation. “This is a clinically important outcome given its relevance to long-term breast cancer–related survival.”

The randomized phase 3 RxPONDER trial enrolled approximately 5000 patients with HR-positive, HER2-negative breast cancer with 1 to 3 positive lymph nodes, no distant metastasis, and a 21-gene Oncotype DX Recurrence Score (RS) lower than 25. Those with a higher RS were treated off study and recommended to receive both endocrine therapy and chemotherapy, according to Kalinsky. Patients with a score of 25 or below were randomized to receive either chemotherapy followed by endocrine therapy or endocrine therapy alone. Among the 4983 patients evaluated in the updated results were 1654 premenopausal women and 3329 postmenopausal women.1

Patients in the endocrine therapy group received adjuvant endocrine therapy consisting of tamoxifen citrate, 1 of the aromatase inhibitors anastrozole (Arimidex), letrozole (Femara), or exemestane (Aromasin), or both tamoxifen citrate and an aromatase inhibitor. Patients in the chemotherapy group received an endocrine therapy in addition to systemic chemotherapy.

The primary end point of the study was IDFS and a secondary end point was DRFS. The previously reported results showed differences in IDFS and DRFS between premenopausal and postmenopausal patients who received chemotherapy. At a median follow-up of 6.1 years, the updated results contained 553 iDFS events. The results showed that in patients who were premenopausal, there was a 5-year absolute benefit of 4.9% for IDFS with chemotherapy (adjusted HR, 0.64; 95% CI, 0.47-0.87; 2-sided P = .004). There was a 5-year absolute benefit of 2.5% for DRFS with chemotherapy (adjusted HR, 0.66; 95% CI, 0.45-0.97; 2-sided P = .033).1

“In an updated analysis, we report with longer follow-up that postmenopausal women with recurrence scores of 0 to 25 continue to not benefit from adjuvant chemotherapy,” said Kalinsky. In postmenopausal women, the 5-year IDFS rate was 91.2% in those treated with chemotherapy plus endocrine therapy compared with 91.9% in those treated with endocrine therapy alone (adjusted HR, 1.06; 95% CI, 0.87-1.30; 2-sided P = .55). The 5-year DRFS rate was 94.3% with added chemotherapy vs 94.8% without (adjusted HR, 1.12; 95% CI, 0.88-1.44; 2-sided P = .35).

“However, premenopausal women with recurrence scores 0 to 25 do, with a 44% to 46% decrease in IDFS, DRFS, and DRFI events,” Kalinsky added.

For premenopausal patients, those who received chemotherapy demonstrated an improved DRFI of 2.4% (adjusted HR, 0.64; 95% CI, 0.43-0.95; 2-sided P = .026) over those who only received endocrine therapy. For those with an RS of 0 to 13, the DRFI was 2.3%, while it was 2.8% for those with an RS of 14 to 25. However, postmenopausal patients did not show any DRFI benefit from chemotherapy in addition to endocrine therapy (HR, 1.12; 95% CI, 0.82-1.52; 2-sided P = .49).

Post hoc analysis showed that in 206 premenopausal women who had micrometastases of 0.2 to 2 mm in their lymph nodes, a 7.3% absolute benefit in IDFS from chemotherapy was observed with a hazard ratio of 0.44 (95% CI, 0.18-1.08). The absolute benefit in 5-year IDFS for 1403 patients with larger lymph node metastases of over 2 mm was 4.8% (HR, 0.64; 95% CI, 0.46-0.90).

“It does appear that premenopausal women with [only] micrometastases benefit from chemotherapy, though there [was] a limited number of events [n = 22], and there was a wide confidence interval,” Kalinsky noted.

In premenopausal patients who only received endocrine therapy, 50% stopped having periods in the first 6 months, compared with 25% of those who received chemotherapy as well. In the first 24 months, 58.9% of those receiving only endocrine therapy stopped having periods within the first 24 months, while 80.8% of those who also received chemotherapy stopped having periods in the first 24 months. In both arms, patients who stopped having periods also had a higher IDFS rate vs those who continued to have periods, with a hazard ratio of 1.56 (95% CI, 0.85-2.86) in those receiving chemotherapy and endocrine therapy vs a hazard ratio of 1.48 (95% CI, 0.92-2.40) in those receiving only endocrine therapy.

For those only treated with endocrine therapy, a 2-year landmarked analysis of ovarian function suppression (OFS) was meant to determine if it was linked to IDFS. A total 17.2% of premenopausal patients in this group underwent OFS. However, no difference in IDFS was observed based on OFS status (HR, 0.88; 95% CI, 0.47-1.63). The study was not able to establish that the benefit from chemotherapy was related to OFS. OFS rates were low in both treatment arms but were higher in the endocrine therapy–alone arm.

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

_REFERENCES:

_{1. Kalinsky K. Updated results from a phase 3 randomized clinical trial in participants (pts) with 1-3 positive lymph nodes (LN), hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer (BC) with recurrence score (RS) < 25 randomized to endocrine therapy (ET) +/- chemotherapy (CT): SWOG S1007 (RxPONDER). Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS2-07.}

_{2. Kalinsky K, Barlow WE, Gralow JR, et al. 21-gene assay to inform chemotherapy benefit in node-positive breast cancer. Published online December 1, 2021. N Engl J Med. doi:10.1056/NEJMoa2108873}