Homologous Recombination Deficiency in Ovarian and Breast Cancers: Biomarkers, Diagnosis, and Treatment

Homologous recombination deficiency (HRD) is a pivotal biomarker in precision oncology, driving therapeutic strategies for ovarian and breast cancers through impaired DNA double-strand break repair. This narrative review synthesizes recent advances (2021–2025) in HRD’s biological basis, prevalence, detection methods, and clinical implications, focusing on high-grade serous ovarian carcinoma (HGSOC; ~50% HRD prevalence) and triple-negative breast cancer (TNBC; 50–70% prevalence). HRD arises from genetic (BRCA1/2, RAD51C/D, PALB2) and epigenetic alterations (e.g., BRCA1 methylation), leading to genomic instability detectable via scars (LOH, TAI, LST) and mutational signatures (e.g., COSMIC SBS3). Advanced detection integrates genomic assays (Myriad myChoice CDx, Caris HRD, FoundationOne CDx), functional assays (RAD51 foci), and epigenetic profiling, with tools like HRProfiler and GIScar achieving >90% sensitivity. HRD predicts robust responses to PARP inhibitors (PARPi) and platinum therapies, extending progression-free survival by 12–36 months in HGSOC. However, resistance mechanisms (BRCA reversion, SETD1A/EME1, SOX5) and assay variability (60–70% non-BRCA concordance) pose challenges. We propose a conceptual framework in Section 10, integrating multi-omics, methylation analysis, and biallelic reporting to enhance detection and therapeutic stratification. Regional variations (e.g., Asian cohorts) and disparities in access underscore the need for standardized, cost-effective diagnostics. Future priorities include validating novel biomarkers (SBS39, miR-622) and combination therapies (PARPi with ATR inhibitors) to overcome resistance and broaden HRD’s applicability across cancers.