552 ANTI-IL10-R1 MONOCLONAL ANTIBODY WITH CONCOMITANT BACILLUS CALMETTE-GUERIN (BCG) PREVENTS METASTATIC BLADDER CANCER IN AN IN VIVO MOUSE MODEL

Abstract

INTRODUCTION AND OBJECTIVES: Heat shock proteins (HSPs) are overexpressed in a wide range of human cancers and are implicated in tumor cell proliferation, differentiation, invasion, metastasis, death, and recognition by the immune system. Furthermore, several HSPs are implicated with the prognosis of specific cancers. HSP60 and HSP90 have been proposed as prognostic factors for bladder cancer (BC). Since HSPs proteins are among the most immunogenic reported molecules and BCG therapy is immune dependent, the role of HSPs in patients with BC treated with BCG warrants investigation. Previously, our group showed that in primary T1 BC treated with BCG, FGRF3 mutation and protein overexpression were associated with a decreased risk of tumor progression. Here, we evaluated HSP70 expression levels and its relationship to pathological and clinical parameters in the same group of previously untreated primary T1 BC treated with BCG. We chose this patient specific BC population to minimize the influence of other factors such as previous treatments. METHODS: 69 patients diagnosed with primary T1 BC (confirmed by pathological review) treated at the University Health Network, Toronto were included in the study. Microarrays were built and HSP70 protein expression was determined by standard immunohistochemistry (HSP70 Antibody, StressMarq Biosciences Inc, Victoria, BC, Canada). Slides were co-reviewed with an experienced uro-pathologist with staining scores dependent on the expression and intensity of the marker. HSPs expression was correlated with pathological, clinical outcomes and with the expression of FGFR3. FGFR3 mutation status was examined by multiplex PCR-SNaPshot analysis. Kaplan-Meier method and multivariate Cox-regression analysis were used for data analysis. RESULTS: Mean age of patients was 71.1 years ( 8.5). HSP70 was found to be expressed in 29/53 (55%) high-grade tumors and in 9/14 (64%) low-grade tumors. Kaplan-Meier survival analysis demonstrated that the lack of HSP70 expression was a significant predictor for disease recurrence (p 0.05) but did not affect progression. In a multivariate model adjusting for grade, size and concomitant CIS, lack of HSP70 expression remained a significant predictor for recurrence (HR of 1.952, 95% CI 1.02-3.75; p 0.045). HSP70 was shown to correlate with FGFR3 expression and mutation (p 0.05). CONCLUSIONS: HSP70 is a promising marker in T1 BC treated with BCG. Both HSP70 and FGFR3 may play an important prognostic role in T1 BC identifying a group at lower risk of recurrence.