Impact of germline <i>BRCA</i> pathogenic or likely pathogenic variants on fertility potential and reproductive outcomes in young women with breast cancer: A systematic review and meta-analysis.

Abstract

10606 Background: In young women with a diagnosis of breast cancer (BC), the impact of germline BRCA ( gBRCA ) pathogenic or likely pathogenic variants (PVs) on their reproductive reserve and fertility outcomes remains uncertain. This systematic review and meta-analysis assessed the influence of harboring gBRCA PVs on ovarian reserve, efficacy of fertility preservation (FP) techniques, and pregnancies after BC diagnosis. Methods: A systematic PubMed/MEDLINE search was conducted with no date restrictions up to June 30 th , 2025 (CRD420251114990). Eligible studies included retrospective and prospective case-control or cohort studies and clinical trials, comparing at least one of the following outcomes between gBRCA carriers vs. non-carriers: ovarian reserve parameters [i.e., anti-Müllerian hormone (AMH) levels or antral follicle count (AFC)] at BC diagnosis (objective 1); efficacy of FP techniques (i.e., number of total and mature retrieved oocytes, and cryopreserved oocytes before chemotherapy) (objective 2); likelihood of conceiving after treatments (objective 3). Pooled mean differences and risk ratios (RRs) with 95% confidence intervals (CI) were calculated using a random-effects model. Results: Out of 5,325 screened records, 18 studies met the inclusion criteria and were included in the final analysis (2,631 patients, of whom 737 gBRCA carriers). Mean age of patients at BC diagnosis was 32.6 years for gBRCA carriers and 33.1 years for non-carriers. Among 12 studies (n=1,529 patients) reporting on objective 1, gBRCA carriers (n=399) showed significantly lower AMH levels compared with non-carriers, with a mean difference of -0.5 (95% CI -0.8; -0.2) ng/mL, and a numerically lower AFC count (-0.8; 95% CI -2.3; +0.8). Among the 11 studies (n=1,027 patients) addressing objective 2, gBRCA carriers (n=318) had a lower median number of total oocytes (-1.8; 95% CI -3.3; -0.3), retrieved mature oocytes (-1.6; 95% CI -2.8; -0.3), and numerically lower cryopreserved oocytes (-1.1; 95% CI -2.7; +0.6). Subgroup analyses showed that reductions in ovarian reserve and FP outcomes were mainly driven by BRCA1 carriers (n=184), whereas reproductive outcomes in BRCA2 carriers (n=125) were comparable to those of non-carriers. Regarding objective 3, only one study (n=75 patients) reported the likelihood of conceiving after BC using assisted reproductive technologies (ART) and showed no differences between gBRCA carriers (n=20) and non-carriers (RR 0.28; 95% CI 0.04; 2.04). Conclusions: Young patients with BC harboring gBRCA PVs showed reduced AMH levels and lower FP efficacy, while no differences were observed in pregnancy rates after BC through ART, although evidence remains limited. Prospective studies are needed to optimize oncofertility counselling young gBRCA carriers.