Precision Oncology of High-Grade Ovarian Cancer Defined through Targeted Sequencing

SIMPLE SUMMARY: Ovarian cancer is a rare and deadly gynaecologic cancer, with a relatively large hereditary component. Genomic analysis of tumour material can potentially provide information regarding therapy and identify hereditary carriers and their families. The aim of our prospective study was to apply genomic characterization to tumour material from women with ovarian cancer to identify women that might benefit from PARP inhibitor therapy, as well as to detect and triage women to genetic counselling. We used next generation sequencing using a targeted panel to prospectively analyse 274 tumours and identified 50 with a BRCA1/2 pathogenic variant. Twenty patients received olaparib based on these results, and 16 previously unknown hereditary carriers were identified. In addition, in a subset examined by an extended sequencing panel, actionable mutations were found in 84/88 tumours. This study demonstrates that personalized medicine approaches can be useful for women with ovarian cancer and can help with therapy selection and identification of at risk families. ABSTRACT: Background: We examined whether molecular characterization of high-grade epithelial ovarian cancer can inform the diagnosis and/or identify potential actionable targets. Methods: All of the consecutively sequenced high-grade ovarian tumours with consent between 2014 until 2019 were included. A total of 274 tumours underwent next generation sequencing using a targeted panel. Results: Patients with high-grade ovarian epithelial cancer were consented to prospective molecular characterization. Clinical information was extracted from their medical record. Tumour DNA was subjected to sequencing, and selected patients received PARP inhibitor therapy. Conclusions: Tumours from 274 women were sequenced, including high-grade serous carcinoma (n = 252), clear cell carcinoma (n = 4), carcinosarcoma (n = 9), endometrioid carcinoma (n = 3), undifferentiated carcinoma (n = 1), and mixed tumours (n = 5). Genomic profiling did not influence histologic diagnosis. Mutations were identified in TP53, BRCA1, BRCA2, as well as additional homologous recombination repair pathway genes BARD1, ATR, CHEK2, PALB2, RAD51D, RAD50, SLX4, FANCA, RAD51C, and RAD54L. In addition, mutations in PTEN and CDKN2A were identified. Several somatic mutations with implications for germline testing were identified, including RMI1, STK11, and CDH1. Germline testing identified 16 previously unknown BRCA1/2 carriers. Finally, 20 patients were treated with the PARP inhibitor olaparib based on the sequencing results.