Abstract B004: Evaluating spatial inter-tumor heterogeneity in whole genome duplication states and homologous recombination deficiency status in advanced ovarian high grade serous carcinoma

Abstract The genomic landscape of ovarian high grade serous carcinoma (HGSC) is typified by extensive genomic instability and heterogeneity, near-ubiquitous TP53 mutations, copy number aberrations, and defects in homologous recombination (HR) repair in approximately 50% of patients. Due to different mechanisms underlying therapy resistance and a lack of predictive biomarkers, matching best treatment modalities to patients with HGSC is challenging. Assessing genomic instability scores to indicate HR-deficiency (HRD) status is used clinically to guide optimal maintenance regimens including PARP-inhibitor treatment. Recently, we demonstrated the degree of phenotypic and genomic heterogeneity in advanced, high tumor burden HGSC patients. Here, we aim to show that the spatial inter-tumoral heterogeneity in HGSC expands to variability in whole genome duplication (WGD) states and timing, and in HRD-score derivation. Systematic mapping of tumor dissemination patterns was performed in chemotherapy-naïve advanced HGSC patients (n=22) following maximal-effort cytoreduction. Multi-site biopsies from 4-15 different anatomical sites were collected, and paired relapse samples were collected where possible (n=10). Germline and Tumor DNA was extracted (5 tumors per case, plus all relapse samples) and underwent whole genome sequencing (WGS, ∼30x depth). We observed spatial and temporal genomic heterogeneity for common HGSC features including mutations, gene amplifications (e.g. CCNE1 and MYC), and copy number and mutational signatures. Somatic, pathogenic loss-of-function TP53 mutations were observed in all tumors in the cohort. We observed discordance in HRDsum classification measures, with 4/22 patients presenting with mixed-HRD scores, i.e. both HRD-positive and HRD-negative scores in their tumors. In each case, the HRDsum scores had a mean value close to the threshold of 42 (range 35.8-45.8). HRD-negative or mixed-HRD status patients had poorer progression free (p=0.0026) and overall survival (p=0.0015) than HRD-positive patients. Cases with mixed states for WGD (no WGD, one WGD or second sub-clonal WGD) were observed in 41% of the cohort with variable timings (early vs late) within disseminated tumors across the cohort, in patients with HRD-negative and mixed HRD-status. The significant inter-tumoral genomic diversity observed in our analysis in measures of HRD and WGD status across the various tumor sites in our cohort of advanced HGSC patients highlights the challenges facing clinicians to derive accurate clinically actionable or prognostic information from a single tumor biopsy alone to direct patient treatment. Citation Format: Paula Cunnea, Nikki Burdett, Marc Lorentzen, Ahwan Pandey, James Clark, Katherine Nixon, Jennifer Ploski, Shirya Varghese, David Bowtell, Jonathan Krell, Elizabeth Christie2, Christina Fotopoulou. Evaluating spatial inter-tumor heterogeneity in whole genome duplication states and homologous recombination deficiency status in advanced ovarian high grade serous carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr B004.