title: Expression Levels of DNA Damage Repair Proteins Are Associated With Overall Survival in Platinum-Treated Advanced Urothelial Carcinoma.
abstract: Combination platinum chemotherapy is standard first-line therapy for metastatic urothelial carcinoma (mUC). Defining the platinum response biomarkers for patients with mUC could establish personalize medicine and provide insights into mUC biology. Although DNA repair mechanisms have been hypothesized to mediate the platinum response, we sought to analyze whether increased expression of DNA damage genes would correlate with worse overall survival (OS) in patients with mUC.
  
  
  
  We retrospectively identified a clinically annotated cohort of patients with mUC, who had been treated with first-line platinum combination chemotherapy. A tissue microarray was constructed from formalin-fixed paraffin-embedded tissue from the primary tumor before treatment. Immunohistochemical analysis of the following DNA repair proteins was performed: ERCC1, RAD51, BRCA1/2, PAR, and PARP-1. Nuclear and cytoplasmic expression was analyzed using multispectral imaging. Nuclear staining was used for the survival analysis. Cox regression analysis was used to evaluate the associations between the percentage of positive nuclear staining and OS in multivariable analysis, controlling for known prognostic variables.
  
  
  
  In a cohort of 104 patients with mUC, a greater percentage of nuclear staining of ERCC1 (hazard ratio [HR], 2.7; 95% confidence interval [CI], 1.5-4.9; P = .0007), RAD51 (HR, 5.6; 95% CI, 1.7-18.3; P = .005), and PAR (HR, 2.2; 95% CI, 1.1-4.4; P = .026) was associated with worse OS. BRCA1, BRCA2, and PARP-1 expression was not associated with OS (P = .76, P = .38, and P = .09, respectively). A greater percentage of combined ERCC1 and RAD51 nuclear staining was strongly associated with worse OS (P = .005).
  
  
  
  A high percentage of nuclear staining of ERCC1, RAD51, and PAR, assessed by immunohistochemistry, correlated with worse OS for patients with mUC treated with first-line platinum combination chemotherapy, supporting the evidence of the DNA repair pathways' role in the prognosis of mUC. We also report new evidence that RAD51 and PAR might play a role in the platinum response. Additional prospective studies are required to determine the prognostic or predictive nature of these biomarkers in mUC.
authors.affiliation: Bladder Cancer Center, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, MA.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Mullane
authors.affiliation: Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Lillian
authors.initials: L
authors.lastname: Werner
authors.affiliation: Department of Medicine, Wilmot Cancer Institute, University of Rochester, Rochester, NY.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Guancial
authors.affiliation: Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Rosina T
authors.initials: RT
authors.lastname: Lis
authors.affiliation: Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Stack
authors.affiliation: Department of Pathology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, MA; Harvard Medical School, Boston, MA.
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.affiliation: Bladder Cancer Center, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, MA; Harvard Medical School, Boston, MA.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Kantoff
authors.affiliation: Bladder Cancer Center, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, MA; Harvard Medical School, Boston, MA.
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rosenberg
authors.affiliation: Bladder Cancer Center, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, MA; Harvard Medical School, Boston, MA. Electronic address: joaquim_bellmunt@dfci.harvard.edu.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Bellmunt
mesh_terms: D019313:BRCA1 Protein / Q000378:metabolism; D024682:BRCA2 Protein / Q000378:metabolism; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004720:Endonucleases / Q000378:metabolism*; D051856:Fanconi Anemia Complementation Group Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000378:metabolism*; D010984:Platinum / Q000008:administration & dosage* / Q000627:therapeutic use; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism*; D011446:Prospective Studies; D051135:Rad51 Recombinase / Q000378:metabolism; D016019:Survival Analysis; D016896:Treatment Outcome; D014571:Urologic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D004268:DNA-Binding Proteins; D051856:Fanconi Anemia Complementation Group Proteins; C407989:JTB protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D010984:Platinum; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; C071447:ERCC1 protein, human; D004720:Endonucleases
keywords: Bladder cancer; DNA damage; Immunohistochemistry; Platinum chemotherapy