Homologous Recombination Deficiency (HRD) and BRCA oncogenic variants in newly diagnosed advanced Epithelial Ovarian Cancer (EOC): first report among multi-ethnic patients

Abstract

Ovarian cancer patients with homologous recombination deficiencies (HRD) exhibit specific clinical behaviours and improved responses to platinum-based chemotherapy and poly (ADP-ribose) polymerase treatment. HRD-positive patients are characterised by having genomic scar score (GSS), BRCA1 and/or BRCA2 oncogenic variants (OV). As the variant spectrum for ovarian cancer is unclear among the understudied Southeast Asian population and no data has been reported in Malaysia, the objective of this study is to report on the distribution of HRD and BRCA variants among multi-ethnic patients in Malaysia with newly diagnosed advanced epithelial ovarian cancer. A total of 61 formalin-fixed paraffin-embedded (FFPE) tumour tissues from epithelial ovarian cancer (EOC) were subjected to targeted DNA sequencing. The results were analysed using the AmoyDx NGS Data Analysis System (ANDAS), and positive HRD status is defined by either the presence of an OV in BRCA1 and/or BRCA2 genes or a positive GSS (defined by GSS score ≥ 50). Of the 61 EOC cases, 8 (13.1%) were clear cell variants, 10 (16.4%) were endometrioid, 29 (47.5%) were high-grade serous, two (3.3%) were low-grade serous and 12 (19.7%) were categorised as others. Twenty-six (42.6%) cases had HRD-positive tumours, and 35 (57.4%) showed negative HRD results. Nine cases (14.8%) had BRCA1 OV, two (3.3%) were BRCA2 OV, and 15 (24.6%) were GSS greater than or equal to 50. The median age at diagnosis was 51.2, albeit older age in the BRCA1 OV group (median age 53.6) and the BRCA2 OV group (median age 61). 72.4% of the high-grade serous carcinoma (HGSC) cases were HRD-positive, whereas 44.8% (13/29) of the HRD-positive cases were without BRCA1 /2 OVs. Only 20% of the endometrioid ovarian cancers were HRD-positive. HRD was commonly found in older people and mostly in HGSC patients, while BRCA1 /2 variants are present in a smaller subset of HRD cases. These identified factors warrant further validation to help clinicians improve their prediction of patients’ response to PARP inhibitor therapy.