Expression Levels of DNA Damage Repair Proteins Are Associated With Overall Survival in Platinum-Treated Advanced Urothelial Carcinoma.
BACKGROUND
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.


PATIENTS AND METHODS
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.


RESULTS
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).


CONCLUSION
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.
['Mullane|Stephanie A|SA|', 'Werner|Lillian|L|', 'Guancial|Elizabeth A|EA|', 'Lis|Rosina T|RT|', 'Stack|Edward C|EC|', 'Loda|Massimo|M|', 'Kantoff|Philip W|PW|', 'Choueiri|Toni K|TK|', 'Rosenberg|Jonathan|J|', 'Bellmunt|Joaquim|J|']
D019313:BRCA1 Protein D024682:BRCA2 Protein D002295:Carcinoma, Transitional Cell D004260:DNA Repair D004268:DNA-Binding Proteins D004720:Endonucleases D051856:Fanconi Anemia Complementation Group Proteins D005260:Female D006801:Humans D008297:Male D008565:Membrane Proteins D009362:Neoplasm Metastasis D009363:Neoplasm Proteins D010984:Platinum D000071137:Poly (ADP-Ribose) Polymerase-1 D011446:Prospective Studies D051135:Rad51 Recombinase D016019:Survival Analysis D016896:Treatment Outcome D014571:Urologic Neoplasms
DNA damage Platinum chemotherapy Immunohistochemistry Bladder cancer