title: Paclitaxel is necessary for improved survival in epithelial ovarian cancers with homologous recombination gene mutations.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Jean
authors.affiliation: Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Surgical Sciences, Gynecologic Oncology, Azienda Ospedaliero-Universitaria Città della Salute, Turin, Italy.
authors.forename: Dionyssios
authors.initials: D
authors.lastname: Katsaros
authors.affiliation: Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Bradley
authors.initials: B
authors.lastname: Wubbenhorst
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Kara N
authors.initials: KN
authors.lastname: Maxwell
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Fishbein
authors.affiliation: Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: McLane
authors.affiliation: Department of Surgical Sciences, Gynecologic Oncology, Azienda Ospedaliero-Universitaria Città della Salute, Turin, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Benedetto
authors.affiliation: Department of Surgical Sciences, Gynecologic Oncology, Azienda Ospedaliero-Universitaria Città della Salute, Turin, Italy.
authors.forename: Emilie Marion
authors.initials: EM
authors.lastname: Canuto
authors.affiliation: Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Nandita
authors.initials: N
authors.lastname: Mitra
authors.affiliation: Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Janos L
authors.initials: JL
authors.lastname: Tanyi
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000077216:Carcinoma, Ovarian Epithelial; D017024:Chemotherapy, Adjuvant; D015331:Cohort Studies; D003520:Cyclophosphamide / Q000627:therapeutic use; D056915:DNA Copy Number Variations; D005260:Female; D005500:Follow-Up Studies; D059014:High-Throughput Nucleotide Sequencing; D059765:Homologous Recombination / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D017239:Paclitaxel / Q000627:therapeutic use*; D017671:Platinum Compounds / Q000627:therapeutic use; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D017671:Platinum Compounds; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D003520:Cyclophosphamide; D017239:Paclitaxel
keywords: clinical molecular genetics; homologous recombination; massively parallel sequencing; ovarian cancer; paclitaxel