The majority of patients with bladder cancer are initially diagnosed with noninvasive or superficially invasive urothelial tumors. These tumors form a heterogeneous group, spanning from benign low grade Ta tumors that rarely progress to high grade T1 tumors with concomitant CIS that progress in up to 60% of cases. No biomarkers have yet been accepted in clinical routine for predicting the individual disease courses of these patients. Previously, we have identified gene expression signatures for prediction disease outcome for patients with non-muscle invasive bladder cancer. The aim of the present study was to validate key candidate markers from these signatures on the protein level. Five proteins were selected for investigation: Cathepsin E, Maspin, PLK-1, Survivin and TRIM29.

A total of 289 primary non-muscle invasive urothelial carcinomas (182 pTa, 101 pT1 and 6 CIS lesions) were chosen for tissue microarray (TMA) construction and protein expression was measured by immunohistochemistry (IHC). High resolution scans of the IHC stainings were scored dichotomized. The results were further validated using TMAs from Germany and Spain holding a total of 609 tumors from patients with stage pT1 bladder cancer.

We found significant correlations to progression to muscle invasive bladder cancer for Survivin (p<0.001), Maspin (p<0.001), PLK-1 (p<0.001) and Cathepsin E expression (p<0.001). TRIM29 expression was significantly associated with overall survival (p<0.04) but not with disease progression (p=0.16). Furthermore, multivariate Cox regression analysis showed that Cathepsin E (p=0.004), PLK-1 (p=0.021) and Survivin expression (p=0.001) were independent prognostic markers for progression to muscle invasive bladder cancer. We successfully validated Maspin as a prognostic marker for overall survival (p=0.045) in the Spanish patient cohort and PLK-1 as a marker for progression to muscle invasive disease (P=0.030) and overall survival (P=0.008) in the German patient cohort. In addition, both Maspin (p=0.022) and PLK-1 (p=0.002) were significantly associated with overall survival in multivariate Cox regression analysis when stratifying for other known risk factors for disease progression in these patient cohorts.

We conclude that Survivin, Maspin, PLK-1 and Cathepsin E have been successfully validated as strong prognostic markers for progression to muscle invasive bladder cancer. In addition, Maspin and PLK-1 expression was significantly associated with outcome in large German and Spanish patient cohorts. All four proteins may be clinically relevant markers for guiding optimal treatment of patients with non-muscle invasive urothelial carcinoma. Additional future prospective studies are needed for further validation of the clinical relevance of the marker panel.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4182. doi:10.1158/1538-7445.AM2011-4182