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 pathogenic variants (gBRCA) are associated with decreased ovarian reserve. Materials and Methods: An individual patient-data meta-analysis was performed using 5 datasets on 828 evaluable women who were tested for gBRCA. Of those, 250 carried gBRCA while 578 had tested negative and served as controls. Of the women with gBRCA, 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-mullerian hormone (AMH) levels in affected women were drawn before pre-systemic therapy. Results: Mean ages of women with vs. without gBRCA1/2 (34.1 vs. 34.3 years; p=0.48), and with gBRCA1 vs gBRCA2 (33.7 vs. 34.6 years; p=0.16) were similar. After the adjustments, women with gBRCA1/2 had significantly lower AMH levels compared to controls (23% lower; 95% CI: 4-38%, p=0.02). When the adjusted analysis was limited to affected women (157 with gBRCA vs. 524 without, after exclusions), the difference persisted (25% lower; CI: 9-38%, p=0.003). The serum AMH levels were lower in women with gBRCA1 (33% lower; CI: 12-49%, p=0.004) but not gBRCA2 compared to controls (7% lower; CI: 31% lower to 26% higher, p=0.64). Conclusions: Young women with gBRCA pathogenic variants, particularly of those affected and with gBRCA1, have lower serum AMH levels compared to controls. They may need to be preferentially counselled about the possibility of shortened reproductive lifespan due to diminished ovarian reserve.