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

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.
Competing Interests: Matteo LambertiniConsulting or Advisory Role: Roche, Novartis, Lilly, AstraZenecaSpeakers' Bureau: Theramex, Takeda, Roche, Lilly, Novartis, Pfizer, Sandoz Erica WangConsulting or Advisory Role: OncoPepResearch Funding: Merck Florian ClatotHonoraria: Merck Serono, Bristol-Myers Squibb, AstraZenecaConsulting or Advisory Role: Lilly, Bristol-Myers Squibb, Roche, Merck SeronoResearch Funding: AstraZeneca, Roche DiagnosticsTravel, Accommodations, Expenses: Merck Serono, Roche, Bristol-Myers Squibb Beth Y. KarlanConsulting or Advisory Role: Roche Pharma AG, Merck, Mercy BioAnalyticsResearch Funding: VBL Therapeutics, AstraZenecaPatents, Royalties, Other Intellectual Property: US and EU patent on gene signatureOther Relationship: Elsevier Isabelle DemeestereConsulting or Advisory Role: RocheResearch Funding: Roche DiagnosticsTravel, Accommodations, Expenses: FerringNo other potential conflicts of interest were reported.