P-426 In vitro and in vivo toxicity of carboplatin and paclitaxel regimen on BRCA-mutated ovarian tissue fragments

Abstract Study question Does carboplatin and paclitaxel regimen have a toxic cumulative impact on the ovarian reserve of young breast cancer patients with germline Breast Cancer (BRCA) mutation? Summary answer Based follicle classification survival through apoptosis DNA repair mechanism recruitment analyses, gonadotoxic but no effect was observed in BRCA-mutated tissue. What is known already Ovarian function recovery fertility issues remain major concerns for diagnosed cancer. first among women under 40 years around 10% them are BRCA mutation carriers. Beside their predisposition to cancers, carriers might be more sensitive chemotherapy-induced gonadotoxicity due role mechanism. Current therapies often include paclitaxel, drugs that both considered as moderately gonadotoxic. However, combined therapy tissue unknown. design, size, duration cryopreserved preservation before chemotherapy donated research by or without BRCA1/2 (< 35 at diagnosis) were used this study. Two models investigated: 3 days vitro culture (10 µg/mL) and/or (1 µM) xenograft into mice followed weeks injections (50mg/kg/week) (10mg/kg every days). Control conditions performed each model. Participants/materials, setting, methods from non-mutated thawed exposed vivo chemotherapy. Follicle density (number follicles/mm²) well ratios quiescent/activated healthy/atretic follicles evaluated following haematoxylin-eosin staining. Apoptosis mechanisms analysed using TUNEL/GDF9 co-staining phosphorylated H2A histone family member X (γH2AX)/ZP-3 co-staining, respectively. Genes expression level will isolated assess activation process. Main results chance First, xenotransplantation counting classification. A decrease follicular (5 95% irrespective patient, model, nor condition) an increase activated atretic after experiments all conditions. slight quiescent pool control condition, difference between mutated fragments. Then, immunofluorescence staining evaluate damage. For quantification, 30 150 per patient counted within condition classified positive if least one cell stained. assessed co-staining. In models, ratio higher fragments treated (40-60%) compared (15-20%). Recruitment complex γH2AX/ZP3 (15-40%) (5-10%). Interestingly, lower (15-18%) than (25-40%) 3-days culture, treatment used. Limitations, reasons caution Reasons high inter-variations intra-variations regarding Moreover, included (27.67 ± 2.08) younger ones (33.67 1.53). Ongoing additional should support obtained. Wider implications findings Carboplatin exposure does not seem deleterious reserve. BRCA-mutation did appear exposure. Further investigations focusing models. Trial registration number Not applicable