The risk of death does not appear to increase with the use of menopausal hormone therapy in women with early-onset, BRCA-mutated breast cancer who began hormone supplementation after diagnosis, based on preliminary data presented during the 2025 ASCO Annual Meeting.¹ “Management of early surgical menopause continues to be a clinical challenge for clinicians and the women they see, and we are working toward a more evidence-based and personalized approach for this population,” said lead study author Joanne Kotsopoulos, PhD, of Women’s College Hospital, Toronto. “Hopefully, this may also include the safe use of menopausal hormone therapy.”

Joanne Kotsopoulos, PhD

“Menopausal hormone therapy currently is, for the most part, contraindicated following a diagnosis of breast cancer,” Dr. Kotsopoulos explained. “This is based on data from very few studies showing an increased risk of local recurrence and/or contralateral breast cancer in women…who had initiated hormone replacement therapy after their diagnosis.” Prior to the present analysis, the impact of exogenous hormone use on survival among high-risk women had yet to be evaluated.

“[We] need to mitigate the adverse impacts of early-onset menopause in young breast cancer survivors…,” Dr. Kotsopoulos remarked. Given all the previously mentioned considerations, she and her colleagues proposed the following research question: Does menopausal hormone therapy after a diagnosis of BRCA-mutated breast cancer increase the risk of death?

Study Details and Key Results

To address their question, the investigators leveraged their international longitudinal study of BRCA carriers, whom they had been following since 1995. The present matched prospective analysis (target trial) focused on those who were diagnosed with breast cancer prior to age 50, had no history of another cancer or menopausal hormonal therapy, and provided at least one follow-up questionnaire.

Women who did and did not initiate menopausal hormone therapy after their diagnosis were matched based on several demographic and clinical characteristics, resulting in 183 pairs. The investigators followed each from the date of first hormone supplementation.

A total of 9 (4.9%) and 22 (12.0%) deaths were reported in the groups of menopausal hormone therapy users and nonusers, respectively, after 6.0 years of follow-up (P = .01). Among those who died, breast cancer was the most common cause. “This is the take-home message of the study,” Dr. Kotsopoulos remarked. She furthermore described significant differences in the 10-year survival curves between the groups. The rate was 93% in patients who used menopausal hormone therapy and 80% in those who did not.

“Even though we had matched on most of the important factors, there were some differences by [BRCA] gene mutation and country of residence,” she commented. After the investigators adjusted for these factors, the multivariate hazard ratio for death with vs without menopausal hormone therapy was 0.30 for all subjects (P = .003), 0.25 for invasive disease (P = .002), and 0.54 for ductal carcinoma in situ (P = .54).

Study Limitations and Next Steps

“There are several limitations to this preliminary analysis,” acknowledged Dr. Kotsopoulos, including a small sample size and short duration of follow-up. Additionally, the analysis did not account for distant recurrence or tumor characteristics; however, “we are trying to…do a more robust medical record review to get information on stage, nodes, and hormone receptor status,” she noted.

“These preliminary findings suggest no increase in the risk of dying with menopausal hormone therapy in BRCA carriers who are diagnosed with breast cancer under the age of 50,” concluded Dr. Kotsopoulos. “[It is] prudent to replicate these findings in a larger study population and with contemporary hormone formulations. Our next step is to try to capitalize on a large study of treatment for BRCA1-mutated breast cancer, led by my colleague Dr. Steven Narod, where we are collecting detailed information on epidemiologic factors and pathology records from over 3,000 women.”

DISCLOSURE: Dr. Kotsopoulos reported no conflicts of interest. For full disclosures of the other study authors, visit coi.asco.org.

REFERENCE

1. Kotsopoulos J, et al: 2025 ASCO Annual Meeting. Abstract 10506.

EXPERT POINT OF VIEW

In his presentation, invited discussant Neil M. Iyengar, MD, Co-Director, Breast Oncology, and Director, Cancer Survivorship, Winship Cancer Institute, Emory University, Atlanta, contextualized the findings of Kotsopoulos et al within the broader framework of how they may inform pharmacologic approaches for targeting modifiable risks.

Neil M. Iyengar, MD

“Menopausal hormone therapy has certainly had a controversial history,” Dr. Iyengar remarked. The Women’s Health Initiative study led to a “dramatic” decrease in its use because of its reported association with cardiovascular risk. However, upon reviewing longer-term follow-up data and an age-stratified analysis, Dr. Iyengar shared these comments: “The risks and benefits of menopausal hormone therapy depend on age, time since menopause, and the presence of other comorbidities. The effects…vary by hormone formulation, dose, and administration….”

Kotsopoulos et al provided new data in a high-risk population, according to Dr. Iyengar, with an observational approach he described as “rigorous.” He went on to highlight key considerations for interpreting the data showing improvements in 10-year breast cancer–specific and overall survival with menopausal hormone therapy: the median age at diagnosis was 38 years; approximately 75% of patients had germline BRCA1 mutations; approximately 90% underwent oophorectomy; more than 90% had remaining breast tissue; and 76% received tamoxifen.

“In the setting of long-term follow-up and stratified secondary analyses of completed randomized and observational data sets, we now know that a personalized approach to hormone therapy counseling is needed…,” Dr. Iyengar remarked. He furthermore concluded that, also now, we have evidence supporting the consideration of supplementation—specifically, with estrogen-only formulations—for certain populations of women, particularly those who are younger and within 10 years of menopause.

DISCLOSURE: Dr. Iyengar has served as a consultant or advisor to AstraZeneca, BD Biosciences, Daiichi Sankyo/Lilly, Genentech/Roche, Gilead Sciences, Novartis, Pfizer, Seagen, SynDevRx, and TerSera; and has received research funding from the American Cancer Society, Breast Cancer Research Foundation, Conquer Cancer Foundation, National Cancer Institute, Novartis, and SynDevRx.