Association of Germline BRCA Pathogenic Variants With Diminished Ovarian Reserve: A Meta-Analysis of Individual Patient-Level Data

Abstract

PURPOSE To determine whether germline BRCA (g BRCA) pathogenic variants are associated with decreased ovarian reserve. MATERIALS AND METHODS An individual patient-level data meta-analysis was performed using five data sets on 828 evaluable women who were tested for g BRCA. Of those, 250 carried g BRCA, whereas 578 had tested negative and served as controls. Of the women with g BRCA, four centers studied those affected with breast cancer (n = 161) and one studied unaffected individuals (n = 89). The data were adjusted for the center, age, body mass index, smoking, and oral contraceptive pill use before the final analysis. Anti-Müllerian hormone (AMH) levels in affected women were drawn before presystemic therapy. RESULTS The mean age of women with versus without g BRCA1/2 (34.1 ± 4.9 v 34.3 ± 4.8 years; P = .48) and with g BRCA1 versus g BRCA2 (33.7 ± 4.9 v 34.6 ± 4.8 years; P = .16) was similar. After the adjustments, women with g BRCA1/2 had significantly lower AMH levels compared with controls (23% lower; 95% CI, 4 to 38; P = .02). When the adjusted analysis was limited to affected women (157 with g BRCA v 524 without, after exclusions), the difference persisted (25% lower; 95% CI, 9 to 38; P = .003). The serum AMH levels were lower in women with g BRCA1 (33% lower; 95% CI, 12 to 49; P = .004) but not g BRCA2 compared with controls (7% lower; 95% CI, 31% lower to 26% higher; P = .64). CONCLUSION Young women with g BRCA pathogenic variants, particularly those affected and with g BRCA1, have lower serum AMH levels compared with controls. They may need to be preferentially counseled about the possibility of shortened reproductive lifespan because of diminished ovarian reserve.