HRDetect in Tubo-ovarian Carcinoma: Stratification and Therapeutic Implications

PURPOSE: To evaluate HRDetect, a mutational-signature-based algorithm, for prognostic utility in tubo-ovarian carcinoma (OC), and to determine if whole-genome sequencing (WGS) with rearrangement signature (RS) analysis can refine genomic classification beyond the traditional homologous recombination deficient (HRD) versus proficient (HRP) framework. EXPERIMENTAL DESIGN: WGS was performed on matched tumor-normal pairs from 185 patients with advanced-stage OC from the University of Washington (UW) cohort. HRDetect scores were calculated using substitution signatures, rearrangement signatures, microhomology-mediated deletions, and global loss of heterozygosity. An independent validation cohort (ARIEL2, n = 77) of platinum-sensitive OC treated with rucaparib, was analyzed to correlate HRDetect with PARP inhibitor (PARPi) response. RS analysis and unsupervised hierarchical clustering were employed to delineate genomic subgroups. RESULTS: In the UW cohort, 51.4% of cases were classified as HRDetect-high and had significantly prolonged median overall survival versus others (6.2 vs 4.1 years; HR=0.6; 95% CI=0.41-0.87; p=0.007). 48.4% of HRDetect-high tumors harbored BRCA1/2 mutations or BRCA1 promoter methylation, while 22.1% lacked BRCA1/2 alterations. A substantial fraction (23.2%) fell into an HRDetect-intermediate category, highlighting greater genomic heterogeneity than currently appreciated. RS profiling uncovered eleven genomic clusters, with specific RS profiles (RS1, RS14, RS18) correlating with poor survival. In ARIEL2, HRDetect-high tumors showed better PARPi responses, with improved progression-free survival (11.1 vs 7.1 months; HR=0.44; 95% CI=0.26-0.74; p=0.03) and response rates (54% vs 22.5%). CONCLUSIONS: HRDetect predicts survival and sensitivity to PARPi in OC. Combined with RS-based clustering, it reveals unappreciated genomic heterogeneity, and supports a nuanced stratification framework to improve precision oncology in OC.