Decoding HRD: A Genomic LOH-Based Assay Associated With Platinum Response and Survival in High-Grade Serous Ovarian Cancer

Homologous recombination deficiency (HRD) is a clinically relevant biomarker associated with therapeutic response to platinum-based chemotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors in high-grade serous ovarian cancer (HGSOC). We evaluated an NGS-based HRD assay integrating BRCA1/2 mutation detection with genomic loss of heterozygosity (gLOH) using 90 HGSOC tumor samples from the Friends of Cancer Research HRD Harmonization clinical cohort. HRD positivity was defined as pathogenic BRCA1/2 alterations and/or gLOH ≥ 0.4. Integrated HRD assessment classified 70% of tumors as HRD-positive and demonstrated improved prediction of platinum response compared with BRCA mutation status alone, including in tumors with low inter-assay consensus. Notably, a substantial proportion of platinum responders were identified among BRCA–wild-type tumors, including the majority of super-responders. HRD-positive status was associated with longer relapse-free survival and overall survival, whereas BRCA1/2 mutation status alone was not significantly associated with either outcome. These findings support BRCA/gLOH-integrated HRD assessment as a clinically relevant approach for identifying platinum-sensitive HGSOC and suggest its potential value in ovarian cancer patient stratification, particularly among BRCA–wild-type tumors.