Estrogen-Only HRT after Bilateral Oophorectomy Not Linked to Increased Breast Cancer Risk in BRCA Carriers: Study
Israel: In women with BRCA pathogenic variants after risk-reducing bilateral oophorectomy (RRBO), estrogen-only hormone replacement therapy (HRT) was not linked to increased breast cancer risk and may reduce risk in BRCA1 carriers. Combined estrogen-progestin HRT showed inconsistent effects. However, prior use of progestin-only contraception (e.g., LNG-IUD) was associated with increased breast cancer risk in BRCA1 carriers, possibly via the RANK/RANKL pathway.
A recent study published in JAMA Network Open provides important insights into the safety of hormone replacement therapy in women with inherited BRCA mutations following preventive oophorectomy. While RRBO is widely recommended to significantly lower ovarian cancer risk, concerns have persisted regarding the potential impact of post-surgical hormone therapy on breast cancer risk.
Conducted by Shira Regev-Sadeh and colleagues, this retrospective multicenter cohort study analyzed data from 919 women in Israel carrying BRCA1 or BRCA2 pathogenic variants. All participants were cancer-free at baseline, had not undergone prior mastectomy, and had at least one year of follow-up after undergoing RRBO between 2000 and 2024. The study evaluated the association between HRT use and the development of invasive breast cancer.
The researchers reported the following findings:
- During a mean follow-up of nearly nine years, 16% of participants developed breast cancer.
- Overall, 42% of women used hormone replacement therapy after surgery, while the rest did not.
- No overall increase in breast cancer risk was observed with HRT use.
- Estrogen-only HRT was associated with a reduced breast cancer risk, especially in women with BRCA1 mutations.
- Each additional year of estrogen-only therapy was linked to a modest but significant risk reduction.
- Combined estrogen-progestin HRT showed no clear association with breast cancer risk, suggesting inconsistent effects.
The findings also highlighted a notable association between prior exposure to progestin-only contraceptives, such as levonorgestrel-releasing intrauterine devices, and an elevated breast cancer risk among BRCA1 carriers. Researchers suggest this may be mediated through activation of the RANK/RANKL signaling pathway, which has been implicated in breast tissue proliferation and carcinogenesis.
Despite the reassuring findings regarding estrogen-only HRT, the authors acknowledged several limitations. The observational design leaves room for residual confounding, even though statistical adjustments were applied. The timing of HRT initiation varied, introducing potential bias, although this was addressed using time-dependent modeling. Additionally, reliance on self-reported data may have introduced recall bias, and missing data led to the exclusion of some participants, potentially affecting generalizability.
Overall, the study supports the relative safety of estrogen-only HRT in women with BRCA mutations after RRBO, particularly among BRCA1 carriers. These findings may help guide clinical decision-making and counseling for women undergoing risk-reducing surgery, balancing the benefits of symptom relief and quality of life with long-term cancer risk considerations.
Reference:
Regev-Sadeh S, Michaelson-Cohen R, Madorksy-Feldman D, et al. Hormone Therapy After Oophorectomy and Breast Cancer Risk in Women With BRCA Pathogenic Variant. JAMA Netw Open. 2026;9(4):e265648. doi:10.1001/jamanetworkopen.2026.5648
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