Impact of BRCA pathogenic variants and novel targeted agents on ovarian reserve measured by anti-Müllerian hormone levels in young women with early breast cancer: A biomarker analysis of the PREFER study.

526 Background: The impact of germline BRCA (g BRCA ) pathogenic variants (PVs) and of novel targeted agents (anti-HER2 therapy, CDK4/6 inhibitors, or immunotherapy) on ovarian reserve in young women treated with chemotherapy (CT) for early breast cancer (BC) remains limited. This biomarker analysis of the PREFER study prospectively evaluated ovarian reserve using anti-Müllerian hormone (AMH) according to main patient and treatment characteristics. Methods: We included premenopausal women enrolled in the prospective PREFER study (NCT02895165) and candidates to (neo)adjuvant CT at the coordinating centre, the IRCCS San Martino Policlinic Hospital, Genoa, Italy. Serial serum AMH measurements were performed at baseline (prior to any CT initiation), during, and after systemic treatment. Longitudinal changes in centrally measured AMH were analysed using mixed-effects models on log-transformed values. Analyses explored the impact of patient (including age and gBRCA status) and treatment (CT alone or with anti-HER2 therapy, CDK4/6 inhibitors, or immunotherapy) characteristics on AMH levels over time. Results: Between 2012 and 2025, 309 premenopausal patients were enrolled at the coordinating centre, of whom 194 were included in the present analysis. Median age at diagnosis was 37 (IQR 33-40) years, with 146 patients (75.3%) aged ≤40 years and 48 (24.7%) 41-45 years. Overall, 85 patients (43.8%) had hormone receptor-positive/HER2-negative, 62 (32.0%) HER2-positive, and 47 (24.2%) triple-negative BC. In the entire cohort, AMH levels showed a marked decline during CT, followed by partial recovery during follow-up (p<0.001), irrespective of patient and treatment characteristics. Younger women showed higher baseline values (2.31 vs 1.11 µg/L for ≤40 years and 41-45 years) and greater post-treatment recovery (p<0.001). Among patients with known gBRCA status (n=147), patients harbouring gBRCA PVs (n=29, 19.7%) showed lower baseline levels (1.60 vs 2.18 µg/L for gBRCA carriers vs non-carriers) and a lower post-treatment recovery compared to non-carriers (n=118, 80.3%) (p=0.01). Regarding treatment exposure, 106 patients (54.6%) received CT alone, 62 (32.0%) CT plus anti-HER2 agents, 10 (5.2%) CT plus immunotherapy, and 16 (8.2%) CT followed by CDK4/6 inhibitors. No significant differences over time were observed according to treatment exposure (p=0.41); however, numerically lower mean AMH values after end of CT were observed among patients treated with CDK4/6 inhibitors and immunotherapy. Conclusions: In this PREFER biomarker analysis, older age and gBRCA PVs were associated with reduced ovarian recovery after treatment. Limited sample size precludes definitive conclusions on the gonadal impact of immunotherapy or CDK4/6 inhibitors; further analyses are urgently needed in this field.