Identification of druggable targets in high-grade epithelial ovarian cancer (EOC) using next generation sequencing (NGS)–based molecular diagnostic

published in Journal of Clinical Oncology, 34(7-Suppl), 2016.; International audience; Background: Despite the great histological and molecular heterogeneity, the clinical management of EOC remains univocal. Additionally to conventional histological prognostic markers and oncogenetic investigations, molecular diagnostic was performed using NGS to identify "druggable" targets that could provide access to targeted therapy in high-grade EOC. Methods: This study was performed in 53 patients (pts) (mean age 58.9, range 25-87) with histologically proven high-grade EOC, mostly serous carcinomas (N = 45), 44 were treated by surgery, 9 received neo-adjuvant chemotherapy. BRCA1/2 germline mutations were screened in 19 pts with familial cancer history justifying oncogenetic investigations. P53 and PTEN expression was assessed on formalin fixed paraffin-embedded using immunohistochemistry. Somatic mutations of KRAS and NRAS (exons 2, 3 and 4), BRAF (exon 15), PIK3CA (exons 5, 10 and 21) and MET (exons 14, 16, 17, 18 and 19) were screened using NGS on DNA extracts from frozen tumor specimens taken at diagnosis. Sequences were aligned with reference sequences and variant calling was processed. At X1000 depth, NGS sensitivity was 1%. Mapping, sorting and indexing were performed twice using AVA, BWA and SAMtools. VarScan2 was finally used for variant calling. Results: With a median follow-up of 38.2 months (range 1.4-93.3), 24 pts are alive, 14 pts disease-free and15 progressed within 6 months after platinum-based therapy. All pts screened for BRCA mutations had serous EOC, mutations were detected in 7/19 pts. P53 overexpression was detected in 60% and PTEN loss in 41% of the pts. One KRAS (exon 2), 2 NRAS mutations (exon 3), 6 PIK3CA mutations (exon 5, 10 and 21) and 5 MET mutations (exons 14 and 18) were detected. All clear-cell EOC were mutated (N = 4). No mutation was found in endometrioid EOC (N = 3). All MET and NRAS mutations were found in serous EOC (N = 7). Conclusions: In high-grade EOC, NGS has adequate sensitivity and specificity to detect genetic abnormalities and provide molecular rationale for targeted therapies, potentially offering new therapeutic opportunities to the pts.