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

Abstract

AbstractPurposeTo determine whether germline BRCA pathogenic variants (gBRCA) are associated with decreased ovarian reserve.Materials and MethodsAn 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.ResultsMean ages of women with vs. without gBRCA1/2 (34.1± 4.9 vs. 34.3± 4.8 years; p=0.48), and with gBRCA1 vs gBRCA2 (33.7± 4.9 vs. 34.6± 4.8 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).ConclusionsYoung 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.ContextKey objectiveDNA repair deficiency is emerging as a joint mechanism for breast cancer and reproductive aging. Recent studies showed that ovarian reserve maybe lower in women with BRCA pathogenic variants (gBRCA) due to DNA repair deficiency. However, clinical studies using the most sensitive serum ovarian reserve marker Anti-Mullerian-Hormone (AMH) provided mixed results. Given the heterogeneity of the data from clinical studies, we performed an individual patient data (IPD) meta-analysis to determine if gBRCA are associated with lower ovarian reserve.Knowledge generatedgBRCA are associated with diminished ovarian reserve, as determined by serum AMH and this association is restricted to gBRCA1. This finding is firmer for affected women as this IPD meta-analysis predominantly studied those with breast cancer.RelevanceWomen with gBRCA may have shortened reproductive life span due to diminished ovarian reserve and should be proactively counseled for fertility preservation especially if faced with chemotherapy or delaying childbearing.