Clinical relevance of homologous recombination repair gene alterations in endometrial cancer patients in the era of molecular classification.

Endometrial carcinoma (EC) is a biologically heterogeneous malignancy, and molecular classification has improved prognostic stratification. Recently, homologous recombination deficiency (HRD) has gained attention in the context of emerging therapeutic strategies based on PARP inhibitors, highlighting the need to better define its prevalence and define its clinical relevance in EC. Retrospective observational cohort study of 298 consecutive patients with EC treated at a tertiary cancer centre. Molecular profiling was performed and patients were classified in risk groups according to the 2025 ESGO-ESTRO-ESP guidelines. HRD was defined by the presence of pathogenic/likely pathogenic variants in homologous recombination repair genes. We assessed associations between HRD status and clinicopathological characteristics using exact tests. Overall survival (OS), disease-free survival (DFS) and progression-free survival (PFS) were analysed using the Kaplan-Meier method. Eighteen tumours (6.0%) were HRD-positive, most frequently involving BRCA1/2 and ATM. HRD-positive tumours were more common among non-endometrioid histologies, high-grade disease, and poor-prognosis molecular subgroups. However, HRD status was not associated with differences in OS (median 115.9 months vs not reached; p = 0.355), DFS (41.6 vs 31.3 months; p = 0.689), PFS (8.0 vs 13.8 months; p = 0.252) or platinum sensitivity (p = 0.234). HRD was rare and associated with aggressive biological features, but it did not have a prognostic value. These findings suggest that integrated molecular classification is paramount for risk stratification in EC, and that HRD, as currently defined, should not be used as an isolated biomarker for clinical decision-making.