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 and to determine if whole-genome sequencing (WGS) with rearrangement signature (RS) analysis can refine genomic classification beyond the traditional homologous recombination-deficient versus homologous recombination-proficient framework.

EXPERIMENTAL

DESIGN

WGS was performed on matched tumor-normal pairs from 185 patients with advanced-stage tubo-ovarian carcinoma from the University of Washington (UW) cohort. HRDetect scores were calculated using substitution signatures, RS, microhomology-mediated deletions, and global loss of heterozygosity. An independent validation cohort (ARIEL2, n = 77) of platinum-sensitive tubo-ovarian carcinoma 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; hazard ratio (HR), 0.6; 95% confidence interval (CI), 0.41-0.87; P = 0.007]. Furthermore, 48.4% of HRDetect-high tumors harbored BRCA1/2 mutations or BRCA1 promoter methylation, whereas 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 11 genomic clusters, with specific RS profiles (RS1, RS14, and 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 tubo-ovarian carcinoma. Combined with RS-based clustering, it reveals unappreciated genomic heterogeneity and supports a nuanced stratification framework to improve precision oncology in tubo-ovarian carcinoma.