HRT Does Not Adversely Affect Breast Cancer Risk in BRCA Variant Population

"To summarize, I think the overall conclusion is that we saw no adverse effect of [HRT] on BRCA breast cancer risk," according to study investigator Joanne Kotsopoulos, PhD.

The use of hormone replacement therapy (HRT) did not confer an adverse effect on breast cancer risk among individuals at a high risk of developing breast or ovarian cancer with the BRCA1/2 variants, according to findings from an ongoing study presented at the 2025 San Antonio Breast Cancer Symposium (SABCS).1

Data were presented by Joanne Kotsopoulos, PhD, scientist at the Women’s College Hospital, professor at the University of Toronto, and Canada Research Chair in Hereditary Breast and Ovarian Cancer Prevention.

“We’re not really in a position to conduct a clinical trial of HRT, so instead we thought we’d take a more matched approach where we’d match women who did and did not initiate HRT after surgery,” said Kotsopoulos.

The cumulative incidence (CI) of breast cancer among BRCA carriers by an any HRT use was significantly lower in patients who did use HRT compared to patients who did not (24.5% vs 42.9%).

“Use of any type of [HRT] was inversely associated with risk,” explained Kotsopoulos. “Then when we stratified by estrogen alone, which is used in women who don’t have uteruses, and then in the estrogen and progestin combination, used in women who do have a uterus, we see that the inverse association was limited to women who used [estrogen] alone. The patterns were similar whether we looked at BRCA1 or BRCA2.”

A total of 676 matched pairs were included in the analysis. The number of patients exposed to any HRT use with either BRCA variant was 87, and the number of unexposed patients was n 128 (HR, 0.48; 95% CI, 0.36–0.63, P <.0001).

In patients with an estrogen-alone formulation, there was statistically significant association with reduced mortality (HR, 0.37; 95% CI, 0.24–0.57, P <.0001). In patients with an estrogen plus progestin formulation, a statistically significant risk reduction was not observed (HR, 0.94; 95% CI, 0.54–1.63, P =.82).

Kotsopoulos noted that the number of patients with BRCA2 were too few to deliver robust results.

Study Rationale

The research addresses a critical clinical challenge for women with a pathogenic variant in the BRCA1 or BRCA2 genes who have a history of breast cancer.

The standard medical guidance contraindicates the use of menopausal HRT for any woman with a personal history of breast cancer.

This issue is particularly important for BRCA carriers due to 2 key factors: a tendency to develop breast cancer at an early age, and the common recommendation to undergo risk-reducing oophorectomy prior to natural menopause, which induces menopausal symptoms.

The study aimed to prospectively analyze the association between menopausal HRT use after a breast cancer diagnosis in BRCA carriers and the subsequent risk of death.

Research Methodology

The study was a prospective analysis conducted using data from a longitudinal study cohort.

The analysis included BRCA carriers with a confirmed diagnosis of breast cancer who had no history of other cancers and had not used menopausal HRT prior to their breast cancer diagnosis.

A matched-pair design was employed to control for confounding variables. Each menopausal HRT user was matched to a nonuser based on year of birth, age at breast cancer diagnosis, and treatments received. This resulted in a total study size of 676 matched pairs.

“To summarize, I think the overall conclusion is that we saw no adverse effect of [HRT] on BRCA breast cancer risk. Estrogen alone was associated with a lower risk, irrespective of route and type. We saw no increased risks with the combination therapy,” said Kotsopoulos.

Kotsopoulos also acknowledged the limitations of the study, including small strata, not stratifying by tumor receptor status, and the need for a longer follow-up.

References

1. Kotsopoulos J. Menopausal hormone therapy and the risk of breast cancer in women with pathogenic variant in BRCA1 or BRCA2. Press briefing. San Antonio Breast Cancer Symposium. December 12, 2025.
2. Kotsopoulos J, Seca M, Lubinski J, et al. Menopausal hormone therapy after a diagnosis of breast cancer in women with a BRCA pathogenic variant and risk of death. J Clin Oncol. 2025;43(suppl 16):10506. doi:10.1200/JCO.2025.43.16_suppl.10506.