Increased chemotherapy-induced ovarian reserve loss in women with germline BRCA mutations due to oocyte deoxyribonucleic acid double strand break repair deficiency.

ABSTRACT

OBJECTIVE: To assess whether woman who have BRCA mutations (WBM) experience more declines in ovarian reserve after chemotherapy treatment, as it induces oocyte death by deoxyribonucleic acid (DNA) damage, and BRCA mutations result in DNA damage repair deficiency. DESIGN: Longitudinal cohort study. SETTING: Academic centers. PATIENT(S) The 108 evaluable women with breast cancer were stratified into those never tested (negative family history; n = 35) and those negative (n = 59) or positive (n = 14) for a pathogenic BRCA mutation. INTERVENTION(S) Sera were longitudinally obtained before and 12-24 months after chemotherapy treatment, assayed for antimüllerian hormone (AMH), and adjusted for age at sample collection. MAIN OUTCOME MEASURE(S) Ovarian recovery, defined as the geometric mean of the after chemotherapy age-adjusted AMH levels compared with baseline levels. RESULT(S) Compared with the controls, the before chemotherapy treatment AMH levels were 24% and 34% lower in those negative or positive for BRCA mutations, consistent with accelerated ovarian aging in WBM. The WBM had a threefold difference in AMH recovery after chemotherapy treatment (1.6%), when compared with BRCA negative (3.7%) and untested/low risk controls (5.2%). Limiting the analysis to the most common regimen, doxorubicin and cyclophosphamide followed by paclitaxel, showed similar results. These findings were mechanistically confirmed in an in vitro mouse oocyte BRCA knockdown bioassay, which showed that BRCA deficiency results in increased oocyte susceptibility to doxorubicin. CONCLUSION(S) Women who have pathogenic BRCA mutations are more likely to lose ovarian reserve after chemotherapy treatment, suggesting an emphasis on fertility preservation. Furthermore, our findings generate the hypothesis that DNA repair deficiency is a shared mechanism between aging, infertility, and cancer. CLINICAL TRIAL REGISTRATION NUMBER NCT00823654.