A multicenter retrospective cohort of 919 women with BRCA1/2 pathogenic variants undergoing prophylactic bilateral salpingo-oopharectomy (BSO) reports hormone replacement therapy, as was used in 42% for a median duration of 5 years, had no association with increased risk for breast cancer at a median follow-up of nearly 9 years. Roughly two-thirds received a combo estrogen-progestin and the remaining third estrogen-only therapy, and neither formulation appeared to increase cancer risk. In fact, estrogen-only therapy was linked to a 10% relative reduction in breast cancer risk for every year it was used, with even stronger protection for BRCA1 variants. On the other hand, a signal emerged for increased breast cancer risk with levonorgestrel-releasing intrauterine devices among those with BRCA1 variants (HR 2.0). The authors explain: “BRCA1-related breast cancers are predominantly triple-negative and are believed to be promoted by progestin-driven activation of the RANK/RANKL pathway, which stimulates mammary epithelial proliferation. Estrogen-only therapy avoids this protumorigenic pathway and may exert protection through proapoptotic and antiproliferative properties.” Practically speaking, as estrogen-only therapy is appropriate only for women without a uterus, women opting for prophylactic BSO for BRCA reasons may want to throw-in a hysterectomy in order to safely reap the benefits of estrogen-only hormone replacement therapy for years to follow. | Regev-Sadeh, JAMA Netw Open 2026
