AMH Testing Predicts Chemotherapy Benefit in RxPONDER Breast Cancer

According to results from a secondary analysis of the phase 3 RxPONDER trial (SWOG S1007; NCT01272037), published in Annals of Oncology, premenopausal women with hormone receptor (HR)-positive, HER2-negative, node-positive breast cancer and low baseline anti-Müllerian hormone (AMH) levels did not derive a benefit from adding chemotherapy to endocrine therapy.¹ AMH, a marker of ovarian reserve, was a significantly better predictor of chemotherapy benefit than menopausal status, age, or other reproductive hormones.

The analysis evaluated pretreatment serum estradiol, progesterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), AMH, and inhibin B (INHB) in 1556 patients younger than 55 years from the original RxPONDER trial, which randomly assigned 5083 patients with 1 to 3 positive lymph nodes and a 21-gene recurrence score (RS) of 25 or lower to endocrine therapy (ET) alone or chemotherapy followed by endocrine therapy (CET).^1,2 Using a prespecified cut point of 10 pg/mL, AMH showed a significant interaction with chemotherapy benefit for invasive disease-free survival (IDFS; P_adj =.0034). Among the 998 patients (64%) with AMH of 10 pg/mL or higher, IDFS was superior with CET compared with ET alone (HR, 0.46; 95% CI, 0.33-0.65; P_adj =.0001), an absolute 5-year IDFS benefit of 8.5%. Among the 558 patients (36%) with AMH below 10 pg/mL, CET was not beneficial (HR, 1.27; 95% CI, 0.81-1.99; P_adj =.47). Distant relapse-free survival (DRFS) followed a similar pattern (HR, 0.44; 95% CI, 0.28-0.69; P_adj =.0001 for AMH ≥10 pg/mL vs HR, 1.51; 95% CI, 0.85-2.70; P_adj =.27 for AMH <10 pg/mL; interaction P_adj =.0049).¹

"These results move us closer to precision medicine. Rather than making treatment decisions based solely on age, we may soon be able to use objective biological measurements of menopausal status to identify who truly needs chemotherapy and who does not,” said Kevin Kalinsky, MD, MS, FASCO, professor and division director of medical oncology at Emory University School of Medicine and principal investigator of RxPONDER, said in a news release.³

Study Design

RxPONDER randomly assigned patients with HR-positive, HER2-negative breast cancer, 1 to 3 positive nodes, and RS of 25 or lower to CET or ET.^1,2 For this analysis, hormone levels were assessed in a blinded fashion using magnetic bead-based fluorescent immunoassays for LH, FSH, estradiol, and progesterone, and ultrasensitive colorimetric ELISAs for AMH and INHB, with detection limits of 1.3 pg/mL and 0.77 pg/mL, respectively.¹ Of 2125 eligible patients younger than 55 years, 1556 (73.2%) had baseline serum available; blood was collected only at trial registration and not timed to any phase of the menstrual cycle. Associations with IDFS and DRFS were evaluated by multivariable Cox regression adjusting for continuous RS, with P values adjusted for multiplicity. Median follow-up was 8.0 years, with 232 IDFS and 138 DRFS events.

"For decades we've relied primarily on age and menstrual history to determine menopausal status and in turn chemotherapy recommendations. Our findings suggest that directly measuring ovarian reserve using ultrasensitive assays for AMH and inhibin B provides a much more biologically meaningful assessment,” said Andrew K. Godwin, PhD, deputy director of The University of Kansas Cancer Center and professor of pathology and laboratory medicine and division director of genomic diagnostics at the University of Kansas Medical Center, said in a news release.

Inhibin B and Other Hormone Markers

INHB, another marker of ovarian reserve, was independently predictive of chemotherapy benefit using a prespecified cut point of 12 pg/mL. Among patients with INHB of 12 pg/mL or higher, IDFS was superior with CET (HR, 0.39; 95% CI, 0.26-0.59; P_adj =.0001), whereas patients with INHB below 12 pg/mL derived no benefit (HR, 1.00; 95% CI, 0.70-1.43; P_adj =.997; interaction P_adj =.0036).1 Baseline estradiol, progesterone, and FSH were not predictive of chemotherapy benefit, and LH was only weakly predictive as a dichotomous marker (P_adj =.035). A joint model combining AMH and INHB did not improve overall prediction beyond either marker alone, reflecting high collinearity between the two (r = 0.73).

Among the 1221 patients classified as premenopausal by conventional criteria, AMH remained predictive of chemotherapy benefit (HR, 0.46; 95% CI, 0.33-0.65; P_adj =.0012 for AMH ≥10 pg/mL vs HR, 1.21; 95% CI, 0.60-2.43; P_adj =.73 for AMH <10 pg/mL; interaction P_adj =.035). Low AMH was identified in 9.0% of premenopausal patients younger than 50 years compared with 51.5% of those aged 50 to 54 years.

"Menopausal status is an important decision-making consideration for adjuvant chemotherapy in patients with hormone-positive breast cancer. This analysis shows that, compared with other conventional methods, AMH is a much better measure to indicate which women are truly postmenopausal,” said Priyanka Sharma, MD, professor of medical oncology at the University of Kansas Medical Center and study co-author, in a news release.³

Clinical Context and Limitations

The findings are consistent with the hypothesis that much of the chemotherapy benefit observed in premenopausal women in RxPONDER is mediated by chemotherapy-induced ovarian suppression rather than a direct antitumor effect, particularly given the low rate of ovarian function suppression use in the trial.¹ The authors noted several limitations: serial serum samples were not prospectively collected, precluding longitudinal assessment of ovarian reserve after treatment; gynecologic comorbidities such as polycystic ovary syndrome, which can elevate AMH, were not reliably captured; and the analysis involved multiple comparisons that could lead to overinterpretation of positive results. Prespecified AMH and INHB cut points, set by the assay manufacturer, may not be optimal, and exploratory subgroup analyses by age were underpowered and should be considered hypothesis-generating.

REFERENCES

1. Kalinsky K, Barlow WE, Pathak HB, et al. Ovarian reserve as a measure of adjuvant chemotherapy benefit in hormone receptor positive (HR-positive), HER2-negative, node-positive breast cancer in SWOG S1007 (RxPONDER). Ann Oncol. Published online July 9, 2026. doi:10.1016/j.annonc.2026.05.697

2. Kalinsky K, Barlow WE, Gralow JR, et al. 21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer. N Engl J Med. 2021 Dec 16;385(25):2336-2347. doi: 10.1056/NEJMoa2108873

3. Blood biomarkers identified that may help many women with hormone receptor-positive breast cancer avoid chemotherapy. News release. University of Kansas Cancer Center. August 4, 2026. Accessed August 14, 2026. https://tinyurl.com/5n6sxt3c