774P CCNE1 amplification defines a good prognostic subgroup among BRCAwt/HRDneg advanced high-grade ovarian cancer (HGOC)

Around 50% of HGOC is characterized as negative for homologous recombination deficiency (HRDneg) based on lack of BRCA mutation and low genomic instability score (GIS). ∼15% of HGOC patients harbor CCNE1 amplification (CCNE1amp) which has been presumed to be associated with chemoresistance, HRDneg and poor prognosis. We aimed to determine the genomic profiles and outcome of CCNE1amp HGOC in comparison to non-CCNE1amp HRDneg HGOC. We conducted a retrospective analysis of patients (pts) with advanced HGOC (excluding clear-cell and mucinous histology) with available genomic data from Institut Gustave Roussy, France and National University Cancer Institute, Singapore. CCNE1amp BRCA1/2 and RAD51C/D mutations were detected by next-generation sequencing on tumor samples. GIS was evaluated by Myriad MyChoice or Foundation Medicine LOH. Progression free survival (PFS) (date of diagnosis to first progression) and pathological response to neoadjuvant chemotherapy by chemotherapy response score (CRS) were collected. We identified 55 CCNE1amp and 104 HRDneg non-CCNE1amp tumors. Pts with CCNE1amp tumor were significantly older (64 versus 61.5 years, p<0.01). Overall, 81% were high-grade serous, 8% carcinosarcomas, and 62% benefited from complete cytoreductive surgery. As expected, no BRCA1/2 or RAD51C/D mutations were detected in the CCNE1amp cohort. 19% of CCNE1amp tumors were classified HRD positive and 81% HRDneg. Among CCNE1amp, 31% of patients experienced a good pathological response (CRS3) versus 18% in the HRDneg cohort (p=0.26). Median PFS was 21.1 months in the CCNE1amp cohort versus 14.2 months in the HRDneg cohort (p=0.008) and median overall survival was 55.3 months versus 42.9 months (p=0.044). In multivariate analysis including completeness of surgery, CCNE1amp was statistically associated with better PFS, HR=1.6 (95%CI 1.06-2.5). We report clinical and molecular features associated with CCNE1 amplification in advanced HGOC. As expected CCNE1 amplifications are mutually exclusive from BRCA mutations, however 20% were HRD according to GIS. We observed unexpected high rates of CRS3, and significantly improved outcomes compared to non-CCNE1amp HRDneg tumors.