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

Patrik Palacka 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute; Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia info_outline Patrik Palacka, Andrea Holickova, Jan Roska, Miroslava Vallova, Csaba Biro, Jan Slopovsky, Eveline Orasova, Jozef Mardiak, Karol Kajo, Miroslav Chovanec

Authors Patrik Palacka 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute; Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia info_outline Patrik Palacka, Andrea Holickova, Jan Roska, Miroslava Vallova, Csaba Biro, Jan Slopovsky, Eveline Orasova, Jozef Mardiak, Karol Kajo, Miroslav Chovanec Organizations 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute; Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia, Department of Pathology, St. Elisabeth Cancer Institute, Bratislava, Slovakia, 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Bratislava, Slovakia Abstract Disclosures Research Funding No funding received None. 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.