title: A DNA repair pathway-focused score for prediction of outcomes in ovarian cancer treated with platinum-based chemotherapy.
abstract: BACKGROUND
  New tools are needed to predict outcomes of ovarian cancer patients treated with platinum-based chemotherapy. We hypothesized that a molecular score based on expression of genes that are involved in platinum-induced DNA damage repair could provide such prognostic information.
  
  
  METHODS
  Gene expression data was extracted from The Cancer Genome Atlas (TCGA) database for 151 DNA repair genes from tumors of serous ovarian cystadenocarcinoma patients (n = 511). A molecular score was generated based on the expression of 23 genes involved in platinum-induced DNA damage repair pathways. Patients were divided into low (scores 0-10) and high (scores 11-20) score groups, and overall survival (OS) was analyzed by Kaplan-Meier method. Results were validated in two gene expression microarray datasets. Association of the score with OS was compared with known clinical factors (age, stage, grade, and extent of surgical debulking) using univariate and multivariable Cox proportional hazards models. Score performance was evaluated by receiver operating characteristic (ROC) curve analysis. Correlations between the score and likelihood of complete response, recurrence-free survival, and progression-free survival were assessed. Statistical tests were two-sided.
  
  
  RESULTS
  Improved survival was associated with being in the high-scoring group (high vs low scores: 5-year OS, 40% vs 17%, P < .001), and results were reproduced in the validation datasets (P < .05). The score was the only pretreatment factor that showed a statistically significant association with OS (high vs low scores, hazard ratio of death = 0.40, 95% confidence interval = 0.32 to 0.66, P < .001). ROC curves indicated that the score outperformed the known clinical factors (score in a validation dataset vs clinical factors, area under the curve = 0.65 vs 0.52). The score positively correlated with complete response rate, recurrence-free survival, and progression-free survival (Pearson correlation coefficient [r(2)] = 0.60, 0.84, and 0.80, respectively; P < .001 for all).
  
  
  CONCLUSIONS
  The DNA repair pathway-focused score can be used to predict outcomes and response to platinum therapy in ovarian cancer patients.
authors.affiliation: Harvard Radiation Oncology Program, Boston, MA, USA.
authors.forename: Josephine
authors.initials: J
authors.lastname: Kang
authors.forename: Alan D
authors.initials: AD
authors.lastname: D'Andrea
authors.forename: David
authors.initials: D
authors.lastname: Kozono
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000032:analysis*; D000077216:Carcinoma, Ovarian Epithelial; D004260:DNA Repair / Q000187:drug effects* / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial / Q000737:chemistry / Q000235:genetics; D010051:Ovarian Neoplasms / Q000737:chemistry* / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D017671:Platinum Compounds / Q000008:administration & dosage; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models
chemical_list: D014408:Biomarkers, Tumor; D017671:Platinum Compounds