Paclitaxel is necessary for improved survival in epithelial ovarian cancers with homologous recombination gene mutations

// Stephanie Jean 1 , Jiaqi Li 2 , Dionyssios Katsaros 3 , Bradley Wubbenhorst 4 , Kara N. Maxwell 5 , Lauren Fishbein 6 , Michael W. McLane 7 , Chiara Benedetto 3 , Emilie Marion Canuto 3 , Nandita Mitra 2 , Lin Zhang 7,8 , Katherine L. Nathanson 4,8,* and Janos L. Tanyi 1,7,* 1 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA 2 Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA 3 Department of Surgical Sciences, Gynecologic Oncology, Azienda Ospedaliero-Universitaria Citta della Salute, Turin, Italy 4 Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA 5 Division of Hematology and Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA 6 Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA 7 Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA 8 Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA * These authors co-directed these studies Correspondence to: Katherine L. Nathanson, email: // Keywords : ovarian cancer, massively parallel sequencing, clinical molecular genetics, homologous recombination, paclitaxel Received : September 16, 2015 Accepted : April 29, 2016 Published : May 14, 2016 Abstract PURPOSE: To investigate the impact of somatic mutations in homologous recombination (HR) genes on the chemotherapeutic response and survival of patients with epithelial ovarian cancer (EOC). EXPERIMENTAL DESIGN: We performed targeted massively parallel sequencing of tumor DNA from 158 patients with EOC. We associated adjuvant chemotherapy and clinical outcome with mutations in selected genes, focusing on those encoding HR proteins. RESULTS: HR mutations were found in 47 (30%) tumors. We did not detect an overall survival (OS) difference in advanced stage patients whose tumors had HR mutations compared to those without (median OS of 49.6 months (95% CI 29.9-57.7) vs . 43.3 months (95% CI 31.9-75.47), p = 0.87). However, when stratified by chemotherapy regimen, patients whose tumors had TP53 and HR mutations demonstrated a marked survival advantage when treated with platinum and paclitaxel vs . platinum +/- cyclophosphamide (median OS of 90 months (95% CI 50-NA) vs . 29.5 months (95% CI 17.7-50.5), p = 0.0005). CONCLUSIONS: Previous studies demonstrating a survival advantage for EOC patients with somatic HR mutations have been conducted with almost universal use of both platinum and paclitaxel. Our study is the first to our knowledge to compare cohorts with somatic HR gene mutations treated with and without paclitaxel containing platinum regimens. The survival benefit attributed to the platinum sensitivity of HR deficient ovarian cancers may depend upon the combined use of paclitaxel.