Association of DNA repair factors with overall survival in advanced urothelial carcinoma treated with platinum-based chemotherapy.
291 Background: DNA repair factors are hypothesized to mediate chemosensitivity to cytotoxic agents that produce DNA damage and may be predictive for response to platinum-based chemotherapeutic regimens. Primary urothelial carcinoma (UC) tumors of patients who developed metastatic disease were evaluated for expression of a panel of DNA repair factors by immunohistochemistry (IHC). Methods: A cohort of 132 clinically annotated, uniformly-treated (platinum-based combination chemotherapy) UC patients who subsequently developed distant metastases with FFPE primary tumor tissue available was identified. Tumor bearing areas were evaluated by a single urologic pathologist. Tissue arrays were constructed for IHC analysis of the following DNA repair factors: ERCC1, Rad 51, BRCA1/2, PAR and PARP1. Tumor was deparaffinized and specific antigen retrieval determined for individual antibodies. Pathologist supervised IHC analysis of nuclear versus cytoplasmic expression was performed using spectral imaging analysis. Overall survival (OS) was defined from start of chemotherapy for metastatic disease to death (N=67) or censored on the last known alive date. Percent of positive nuclear staining was categorized as quartiles or previously identified cut-points. Cox regression evaluated the associations of percent positive nuclear staining levels and OS in multivariable analysis (HRs and 95% CIs included) that controlled for known prognostic variables (performance status and visceral metastases). Results: Higher percentage of nuclear staining of ERCC1 [HR=2.7 (1.5, 4.9), p=0.0007]; Rad51 [HR=5.6 (1.7, 18.3), p=0.005]; and PAR [HR=2.2 (1.1, 4.4), p=0.026] in tumor tissue were associated with poor outcome; each was independent of the other two repair factors and known prognostic variables. Neither nuclear nor cytoplasmic staining for BRCA1/2 or PARP1 reached statistical significance for an association with OS. Conclusions: DNA damage repair factor levels measured by IHC impact outcomes in advanced UC. External validation is ongoing and will be presented. Further studies are required to determine whether these biomarkers are prognostic or predictive in this setting.