Prognostic value of DNA damage repair and tolerance factors in patients with muscle-infiltrating urothelial carcinoma.

Abstract

e16615 Background: Cisplatin (CDDP) is the key agent in treatment of muscle-infiltrating urothelial carcinomas (MIUCs). However, around a half of patients do not respond to combined chemotherapy based on this agent what might be caused by an increased capacity to repair CDDP-induced DNA damage. The objective of this study was to determine the levels of selected DNA repair and tolerance factors in patients with MIUC to reveal their potential prognostic value. Methods: We have evaluated the bladder tumors from 86 subjects reviewed by trained pathologists. Median age was 67 years (range 37-84 years), 75.6% were males. All patients had MIUCs. To detect the XPA, XPF, POLI, REV3L, and POLH levels in primary tumors, immunohistochemistry was used. Study population was divided into two groups by positivity defined as 76-100% (negative vs positive tumors). Overall survival (OS) was estimated by the Kaplan-Meier method and compared with the log-rank test. Results: At median follow-up of 20.6 months (1.0-212.5 months), 86.1% of patients died. Median OS of subjects with tumors stained negative for XPA, XPF, REV3L, and POLH did not differ significantly from patients with positive staining for these proteins, with hazard ratios (HRs) being 0.61, 0.62, 0.98, and 0.72, respectively. Patients with tumor negative for POLI expression had significantly ( p = 0.0334) better median OS of 23.5 months (range 17.3-47.3 months) compared to subjects with tumor stained positive for expression of this protein [median OS of 17.6 months (range 13.6-21.3 months)] (HR = 0.61, 95%, CI 0.39-0.97). Conclusions: In this study, we showed a clear correlation between higher POLI expression in primary tumor tissue and inferior outcome in MIUC patients. Hence, we believe that the expression level of POLI might represent a prognostic biomarker and potentially constitute promising therapeutic target.