Abstract 3656: Cathepsin E, Maspin, PLK1, and Survivin are promising prognostic protein markers for progression in non-muscle invasive bladder cancer
Authors: Fristrup Niels , Ulhøi Benedicte Parm , Birkenkamp-Demtröder Karin , Mansilla Francisco , Sanchez-Carbayo Marta , Segersten Ulrika , Malmström Per-Uno , Hartmann Arndt , Palou Joan , Alvarez-Múgica Miguel , Zieger Karsten , Borre Michael , Ørntoft Torben F. , Dyrskjøt Lars 
Published: August 2012

Abstract
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. The histopathological parameters used in the clinic cannot precisely predict the individual disease course, and no molecular markers are currently in clinical use for predicting tumor recurrence or later progression. Previously, we have identified gene expression signatures for prediction of 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 at the protein level. Four proteins were selected for investigation: Cathepsin E, Maspin, PLK1, and Survivin. We used three different tissue-microarrays with a total of 693 non-muscle invasive urothelial carcinomas from Danish, Swedish, and Spanish patient cohorts. The Danish patient cohort was used for optimizing IHC cutoff values and the Swedish-Spanish cohort was used as independent validation. Protein expression was measured by IHC and antibody specificity was validated by Western blotting. In the Danish patient cohort, we found the expression of Cathepsin E, Maspin, PLK1, and Survivin to be significantly associated with progression to stage T2-4 bladder cancer (for each marker: log-rank test; p&lt;0.001). Multivariate Cox regression analysis identified Cathepsin E (p&lt;0.001), Maspin (p=0.001), PLK1 (p=0.021), and Survivin (p=0.001) as independent prognostic markers. Furthermore, Cathepsin E, Maspin and Survivin expression significantly sub-grouped patients already stratified by EORTC risk scores. Survivin expression (log-rank test; p=0.004) and Maspin expression (log-rank test; p&lt;0.001) significantly subgrouped the EORTC low risk patients. Cathepsin E expression subgrouped the EORTC high risk patients (log-rank test; p=0.001). Finally, we successfully validated the results in tumors from 410 patients from Sweden and Spain. Using univariate Cox regression analysis we identified Cathepsin E (p=0.002), Maspin (p&lt;0.001), PLK1 (p=0.003), and Survivin (p=0.002) to show significant association with disease progression to muscle invasive bladder cancer in the Spanish-Swedish validation cohort. Furthermore, in multivariate analysis Cathepsin E (p=0.019) and Survivin (p=0.014) were significantly associated with disease progression when adjusting for other known clinical and histopathological risk factors. We conclude that all four protein markers may have prognostic value in non-muscle invasive bladder cancer for guiding optimal treatment of patients. Additional 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 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3656. doi:1538-7445.AM2012-3656