JAMA Netw Open. 2026 Apr 1;9(4):e265648. doi: 10.1001/jamanetworkopen.2026.5648.
ABSTRACT
IMPORTANCE: Risk-reducing bilateral salpingo-oophorectomy is recommended to substantially lower ovarian cancer risk in women carrying BRCA1 or BRCA2 pathogenic variant (PV). The use of hormone replacement therapy (HRT) after risk-reducing bilateral oophorectomy (RRBO), although generally recommended, remains debated due to concerns about its possible role in breast cancer (BC) risk.
OBJECTIVE: To assess the possible association between HRT use and BC incidence after RRBO in women harboring a limited range of germline BRCA PVs.
DESIGN, SETTING, AND PARTICIPANTS: This retrospective multicenter cohort study was conducted at 3 medical centers, including both referral and primary care facilities, in Israel. Cancer-free women (aged ≥18 years) with BRCA1 PV or BRCA2 PV, with no prior mastectomy, who underwent RRBO between January 1, 2000, and December 31, 2024, and who had at least 1 year of follow-up after RRBO were included.
EXPOSURES: HRT use after RRBO.
MAIN OUTCOMES AND MEASURES: First diagnosis or incidence of invasive BC. BC diagnoses were ascertained through pathology reports and diagnostic codes used in the electronic health records; some were confirmed via participant interviews. HRT use was assessed through medical records, pharmacy dispensing data, clinic visits, and telephone interviews. Cox proportional hazards regression models, with HRT modeled as a time-varying covariate, evaluated the associations with BC risk while adjusting for potential confounders.
RESULTS: A total of 919 women (mean [SD] age at RRBO, 47.6 [8.9] years) were included, of whom 496 had BRCA1 PV and 423 had BRCA2 PV. During a mean (SD) follow-up of 8.8 (6.2) years, 144 women (16%) were diagnosed with invasive BC. Overall, 381 participants (42%) had ever used and 538 (58%) had never used HRT following RRBO. Ever use of HRT was not associated with increased BC risk (combined estrogen-progestin: hazard ratio [HR], 1.06 [95% CI, 0.67-1.68]; estrogen only: HR, 0.89 [95% CI, 0.48-1.63]). In duration of use analyses, each year of estrogen-only HRT was associated with a reduction in BC risk overall (HR, 0.90; 95% CI, 0.81-0.99) and a reduction among participants with BRCA1 PV (HR, 0.87; 95% CI, 0.77-0.98).
CONCLUSIONS AND RELEVANCE: In this cohort study of women with BRCA PV who received HRT after RRBO, estrogen-only HRT was not associated with an increased risk of BC and was associated with a lower risk of BC among women with BRCA1 PV. Combined estrogen-progestin HRT was not associated with BC risk modification.
PMID:41949865 | DOI:10.1001/jamanetworkopen.2026.5648
