Abstract 2057: CG>TG mutation frequency as negative predictor of homologous recombination deficiency in ovarian and breast cancer

Abstract Homologous recombination deficiency (HRD) is a predictive biomarker for PARP inhibition and platinum-based chemotherapy. Copy number alteration-based scores such as HRDsum =LST+TAI+LOH are included in therapy approvals of PARP inhibition, but have limited sensitivity for HRD detection in samples of low tumor purity. Biomarkers based on single base substitutions (SBS) beyond Mutational Signatures are underinvestigated as predictors of HRD. WES data of the TCGA pan-cancer cohort and an in-house ovarian cancer cohort were annotated by genetic and epigenetic alterations of BRCA1/2 and additional genes causative of HRD. Using this reference, the new biomarker fdeam defined as frequency of C>T transitions at CpG sites in relation to all SBS and HRDsum were compared for the detection of HRD. In the TCGA ovarian cancer, the in-house ovarian cancer, and the TCGA breast cancer cohorts, fdeam performed non-inferior to HRDsum (AUC=0.84, AUC=0.85, and AUC=0.88). The cutpoint fdeam=13.1% maximized the balanced accuracy in the TCGA ovarian cancer cohort and resulted in sensitivity=89% and specificity=77% in the in-house cohort. In a simulation study, fdeam retained high sensitivity for HRD detection and outperformed HRDsum for tumor purity 40%, 20%, and 10%. Thus, the new biomarker overcomes the limited robustness of copy number alteration-based biomarkers against low tumor purity and offers the opportunity of a more sensitive HRD detection in clinical tumor samples. Further studies are warranted to confirm its clinical validity and utility and explore its potential for liquid biopsies. Citation Format: Jan Budczies, Eva Romanovsky, Michael Menzel, Klaus Kluck, Susanne Beck, Markus Ball, Peter Schirmacher, Daniel Kazdal, Albrecht Stenzinger. CG>TG mutation frequency as negative predictor of homologous recombination deficiency in ovarian and breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2057.