Effect of olaparib on cyclophosphamide-induced ovarian tissue damage in patients with Breast Cancer 1 germline mutation

Abstract

PARP inhibitors are now used as adjuvant targeted therapy for BRCA1-mutated breast cancer. Although prescribed to young women of reproductive age, their effects on fertility remain unknown, particularly when combined with highly gonadotoxic chemotherapy. This study therefore examined whether olaparib potentiates cyclophosphamide-induced gonadotoxicity in human ovarian tissue. Cryopreserved ovarian tissue from young (< 35 years) patients with breast cancer, with (n = 4) or without (n = 4) BRCA1 pathogenic variants, was exposed to anticancer drugs using two models: (i) a 3-days in vitro culture with 4-hydroperoxycyclophosphamide (10 µM) and/or olaparib (20 µM), and (ii) xenotransplantation in mice followed by one cyclophosphamide injection (75 mg/kg) and two weeks of daily oral olaparib (100 mg/kg). Across both models and regardless of BRCA1 status, the proportion of primordial follicles remained unchanged following exposure to the drugs. However, in vivo, follicle density significantly reduced with cyclophosphamide compared to controls in BRCA1-mutated xenografts. Olaparib did not exacerbate cyclophosphamide-induced follicle loss. 4HC induced DNA fragmentation and double-strand breaks in vitro in both groups, while olaparib alone caused minimal damage and did not appear to potentiate the effects of 4HC. In BRCA1-mutated xenografts, combined treatment resulted in a modest but significant reduction in RAD51 rates compared with controls, while 53BP1 expression tended to rise after cyclophosphamide alone or combined with olaparib, without reaching significance. Our findings suggest that olaparib does not exacerbate cyclophosphamide-induced gonadotoxicity, providing valuable information for reassuring patients regarding its reproductive safety.