Ovarian Reserve as a Measure of Adjuvant ChemotherapyBenefit in Hormone Receptor Positive (HR+), HER2-negative,Node-positive Breast Cancer in SWOG S1007 (RxPONDER)

Abstract
Background: The phase 3 RxPONDER trial compared endocrine therapy (ET) alone or with chemotherapy (CET) in patients with hormone receptor-positive/HER2-negative breast cancer with recurrence score (RS) ≤25. CET benefit for the primary outcome, invasive disease-free survival (IDFS), was limited to premenopausal women who largely did not receive ovarian function suppression. In this study, we assessed hormones associated with ovarian reserve to further refine prediction of CET benefit.
Patients and Methods: Pretreatment serum estradiol, progesterone, follicular stimulating hormone (FSH), luteinizing hormone (LH), anti-Müllerian hormone (AMH), and inhibin B (INHB) were assessed in a blinded fashion from 1,556 participants aged<55. All markers used a predefined cut point. Associations with markers and IDFS and distant relapse-free survival (DRFS) were evaluated for prediction of CET benefit adjusting for RS. Cox regression analyses of assigned treatment and its interaction with potential markers were adjusted for multiplicity.
Results: Baseline estradiol, progesterone, LH, and FSH were not predictive for CET benefit. AMH≥10 pg/mL showed significant interaction with chemotherapy benefit for IDFS (padj=0.0034). In 64% of women with AMH ≥10 pg/mL (cutoff for normal ovarian reserve), iDFS was superior with CET compared to ET alone (HR=0.46; 95% 0.33-0.65; padj=0.00012), whereas CET was not beneficial in the 36% with low ovarian reserve (AMH <10 pg/mL) (HR=1.27; 95% 0.81-1.99; padj=0.47). DRFS showed a similar pattern of results for AMH. Ultrasensitive INHB measured in the pg/mL range was also predictive of CET benefit.
Conclusion: Among premenopausal patients aged<55, participants with baseline AMH <10
pg/mL did not benefit from CET. AMH was a significantly better indicator of CET benefit than
menopause status, age, or other hormones. Measures of ovarian reserve may refine selection of
patients for CET.