Winship-led analysis of the landmark RxPONDER trial finds a blood marker may better predict chemotherapy benefit than age or menopausal status in women with breast cancer.
Kevin Kalinsky, MD, MS, FASCO
A blood marker commonly used to measure ovarian reserve may help identify which premenopausal patients with the most common form of breast cancer are most likely to benefit from chemotherapy, according to new research led by Winship Cancer Institute of Emory University.
The findings, published in Annals of Oncology, suggest that anti-Müllerian hormone, or AMH, may provide a more accurate picture of ovarian function, and chemotherapy benefit, than a patient’s age, menstrual history or reported menopausal status in women with estrogen-driven, node-positive breast cancer.
The study was led by first author Kevin Kalinsky, MD, MS, FASCO, Director of the Division of Oncology at Emory University, Co-director of the Glenn Family Breast Center at Winship, and Louisa and Rand Glenn Family Chair in Breast Cancer Research.
“This study suggests that ovarian reserve may be more informative than age or menstrual history when determining which younger patients benefit from chemotherapy,” says Kalinsky. “If validated, an ultrasensitive AMH test could give patients and clinicians another objective piece of information as they weigh the potential benefit of chemotherapy against its short- and long-term effects.”
Building on the landmark RxPONDER trial
The analysis builds on findings from SWOG S1007, also known as RxPONDER, a large, international phase 3 clinical trial led by Kalinsky through the SWOG Cancer Research Network.
RxPONDER enrolled more than 5,000 patients with hormone receptor-positive, HER2-negative breast cancer that had spread to one to three lymph nodes. All randomly assigned participants had a score of 25 or lower on a 21-gene test used to help estimate the likelihood that breast cancer will return and whether chemotherapy may be beneficial.
The original trial found that postmenopausal patients in this group could safely forgo chemotherapy without compromising outcomes. Premenopausal patients, however, experienced better outcomes when chemotherapy was added to endocrine therapy.
Those findings raised an important question: Was chemotherapy benefiting premenopausal patients primarily by attacking cancer cells, by suppressing ovarian function or through a combination of both?
To explore that question, researchers analyzed pretreatment blood samples from 1,556 RxPONDER participants younger than 55. They measured six hormones associated with ovarian function, including AMH and inhibin B, using highly sensitive assays capable of detecting very low hormone levels.
AMH is produced by cells in the ovaries and is widely used as a measure of ovarian reserve—the number of eggs remaining in the ovaries. Unlike several other reproductive hormones, AMH remains relatively stable throughout the menstrual cycle.
Ovarian reserve helps predict chemotherapy benefit
Researchers found that AMH was a better predictor of chemotherapy benefit than age, reported menopausal status or other reproductive hormones, including estrogen, progesterone, follicle-stimulating hormone and luteinizing hormone.
Among participants younger than 55 with AMH levels of at least 10 picograms per milliliter, adding chemotherapy to endocrine therapy was associated with significantly better outcomes than endocrine therapy alone.
At five years, 94.6% of patients in this group who received chemotherapy plus endocrine therapy were alive without an invasive recurrence, a new invasive cancer or death, compared with 86.1% of those who received endocrine therapy alone—an absolute difference of 8.5 percentage points.
In contrast, participants with AMH levels below 10 picograms per milliliter, indicating limited ovarian reserve, experienced no measurable benefit from chemotherapy.
Among the 1,221 participants classified as premenopausal, approximately one in five had AMH levels in this low range.
The researchers observed a similar pattern with inhibin B, another measure of ovarian reserve, although AMH emerged as the strongest individual predictor of chemotherapy benefit.
“RxPONDER helped establish that menopausal status is central to chemotherapy decisions for this group of patients,” says Kalinsky. “These new findings bring us closer to understanding the underlying biology and potentially identifying more precisely who needs chemotherapy and who may be able to avoid it.”
Progress toward more individualized treatment
The study was not designed to determine whether ovarian suppression combined with endocrine therapy can replace chemotherapy. That question is being studied prospectively in clinical trials, including NRG-BR009, also known as OFSET, which is available at Winship. The phase 3 trial is evaluating whether adding chemotherapy to ovarian function suppression and endocrine therapy improves outcomes for certain premenopausal patients with hormone receptor-positive, HER2-negative early breast cancer.
The researchers also caution that the AMH threshold identified in the study requires further validation. Although AMH testing is widely available for fertility assessment, many routine clinical tests are not designed to reliably measure the extremely low concentrations found to be informative in this analysis.
The findings therefore should not be used by patients to make treatment decisions without consulting their oncology team.
“Ultimately, our goal is to give each patient the treatment most likely to benefit them, while avoiding treatment that is unlikely to improve their outcome,” says Kalinsky. “More precise measures of ovarian function could become an important part of that shared decision-making process.”
The hormone testing for the study was conducted by researchers at the University of Kansas Medical Center. Statistical analyses were performed through the SWOG Statistics and Data Management Center. The research involved investigators from cancer centers and research organizations across the world.
The study was supported in part by the Breast Cancer Research Foundation, Cure in Our Lifetime, the National Institutes of Health, including National Institute of General Medical Sciences grant P20GM130423 and National Cancer Institute grants U10CA180888, U10CA180819 and U24CA196175, Exact Sciences Corporation, The Hope Foundation for Cancer Research and participating research institutions.