Association Between Heat Shock Proteins 60 and 70 and Long-Term Outcomes of T1-Stage High-Grade Urothelial Tumors Treated with BCG - Beyond the Abstract

Patients with high-grade non-muscle invasive tumors of the bladder (NMIBC) who fail BCG intravesical treatment are at a substantially high risk for disease progression and may, therefore, benefit from early radical cystectomy. Identifying these patients before they progress could improve treatment outcomes. Heat shock proteins (HSP) are a group of molecular chaperons with low expression levels in normal physiological conditions, that are markedly upregulated after the cell is exposed to external stressors. Alteration in HSP levels are observed in many cancers, and HSP overexpression usually signals a poor prognosis. Previous studies have shown an association between HSP expression and outcome in bladder cancer, including in patients treated with BCG. Thus, in the search for additional biomarkers for this high-risk group of patients, we aimed to evaluate the association between HSP60, 70 and 90 expression and outcomes in a homogenous group of T1HG NMIBC patients treated with BCG.

The study cohort included a total of 54 patients who received at least an induction course of intravesical BCG, 37 of whom (69%) received partial or complete maintenance BCG treatment. All patients had a high EORTC risk score for progression. The median follow-up for this cohort was long, approaching 10 years. The estimated 5-year recurrence and progression-free survival rates were 59% and 81%, respectively. We found a significant association between elevated HSP60 staining and decreased HSP70 staining and the risk of disease progression. These findings remained significant when controlling for EORTC risk score for progression. Moreover, 4/5 patients who had both an increased HSP60 expression and decreased HSP70 expression progressed during follow-up. To further support our findings, we evaluated the differential expression of HSP-related genes in a previously-published cohort of 460 NMIBC patients who underwent comprehensive transcriptional analysis. We found that multiple genes corresponding to HSP60, HSP70, and HSP90 were highly expressed in the sub-group of patients that displayed luminal-like characteristics however we were unable to find a clear association with levels of tumor aggressiveness in this heterogeneous cohort of patients.

While we found a significant association between HSP expression and outcome in NMIBC, the mixed results regarding the direction of this association emphasize its complexity. The opposite effect of higher cellular expression levels of HSP60 and HSP70 may be the result of the different roles these HSPs have in the cell and their different cellular locations. We believe additional studies will shed light on the true association between HSP levels and outcome in this high-risk group of patients, enabling us to use these markers to better identify patients at the highest risk for progression who may benefit from early radical cystectomy. Furthermore, a better understanding of the mechanism underlying this association may lead to future studies evaluating whether manipulating cellular HSP levels may have a therapeutic effect, possibly discovering additional avenues for treatment of this disease.

Written by: Roy Mano MD, and David Margel MD, Ph.D., Department of Urology, Rabin Medical Center, Petach Tikva, Israel

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