936 Genomic features underlying spatial heterogeneity in homologous recombination deficiency scores in ovarian high grade serous cancer

Introduction/Background Extensive genomic instability and heterogeneity are characteristics of ovarian high-grade serous cancer (HGSC). Matching best treatment options for patients is difficult due to diverse resistance mechanisms and paucity of predictive biomarkers. Somatic HR-deficiency (HRD) testing is an approved clinical test to stratify patients for PARP-inhibitor treatment. Here, we investigate the effect of spatial and temporal heterogeneity on HRD status. Methodology Patients (n=59) at Hammersmith Hospital (HH) underwent primary cytoreductive surgery for advanced HGSC, with tumour biopsies collected (range 4–15) plus any paired relapse samples (n=11). Tumour DNA was extracted (n=5 tumours per case, plus relapse), genotyping performed for all cases with targeted sequencing (20 HR-related genes) performed for a subset. Multi-site CN data was also accessed from two cohorts (GSE38787, GSE40546). Tumours that failed QC or had an aberrant cell fraction Results We detected variation in HR scores in each cohort with approximately one-fifth of patients presenting with a mixed HR score, displaying both HRD and HR-Proficient tumour scores: HH (20%, 11/54 patients); GSE38787 (17%, 4/24 patients); and GSE40546 (28%, 4/14 patients). In the targeted sequencing cases, data was correlated with HR scores to delineate the underlying mutational status of each HR group (HRD, HRP and HR-mixed). Multiple repair-related mutations were flagged as possible causes for the mixed-HR scores (notably BARD1, FANCM), while also demonstrating the intra-patient heterogeneity, even in non-mixed patients. Conclusion Variability in HRD/HRP scores indicates that HR status for a subset of ovarian HGSC patients is not uniform across their disseminated tumour burden, thus suggesting that sampling a single tumour site may not accurately represent a patient's tumour biology, leading to incorrect treatment stratification. Disclosures N/A