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

Abstract

To determine whether germline <i>BRCA</i> (g<i>BRCA</i>) pathogenic variants are associated with decreased ovarian reserve. An individual patient-level data meta-analysis was performed using five data sets on 828 evaluable women who were tested for g<i>BRCA</i>. Of those, 250 carried g<i>BRCA</i>, whereas 578 had tested negative and served as controls. Of the women with g<i>BRCA,</i> 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. The mean age of women with versus without g<i>BRCA1/2</i> (34.1 ± 4.9 <i>v</i> 34.3 ± 4.8 years; <i>P</i> = .48) and with g<i>BRCA1</i> versus g<i>BRCA2</i> (33.7 ± 4.9 <i>v</i> 34.6 ± 4.8 years; <i>P</i> = .16) was similar. After the adjustments, women with g<i>BRCA1/2</i> had significantly lower AMH levels compared with controls (23% lower; 95% CI, 4 to 38; <i>P</i> = .02). When the adjusted analysis was limited to affected women (157 with g<i>BRCA v</i> 524 without, after exclusions), the difference persisted (25% lower; 95% CI, 9 to 38; <i>P</i> = .003). The serum AMH levels were lower in women with g<i>BRCA1</i> (33% lower; 95% CI, 12 to 49; <i>P</i> = .004) but not g<i>BRCA2</i> compared with controls (7% lower; 95% CI, 31% lower to 26% higher; <i>P</i> = .64). Young women with g<i>BRCA</i> pathogenic variants, particularly those affected and with g<i>BRCA1</i>, 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.