Using micro-RNA expression to predict response to neoadjuvant chemotherapy in urothelial carcinoma of the bladder.

Abstract

299 Background: Urothelial carcinoma of the bladder is among the 5 most common cancers in the US. Despite several clinical trials attempting to determine the best approach to muscle-invasive disease, the optimal treatment modalities and their sequence have not been established. Specifically, the decision to administer neo-adjuvant chemotherapy is currently based solely on clinical parameters, with no validated biomarkers. Micro-RNAs (miRNAs) are short RNA molecules that have roles in post-transcriptional gene expression regulation by binding to mRNAs. They were shown to have cardinal roles in many cancers, and their potential to serve as biomarkers is extensively studied. Our goal was to study whether miRNAs can serve as predictive biomarkers for response to neo-adjuvant chemotherapy in urothelial carcinoma. Methods: miRNAs were extracted from paraffin-embedded pre-operative muscle-invasive tumor biopsies of patients diagnosed with urothelial carcinoma, whose pathological surgical specimen was later found to either show complete or no-response to neo-adjuvant chemotherapy (termed 'responders' and 'non-responders', respectively). The expression pattern of approximately 900 miRNAs was compared using a commercial miRNA array, and the levels of candidate miRNAs was further assessed by quantitative real-time PCR (qRT-PCR). Results: The vast majority of miRNAs exhibited a similar expression pattern in the two patient groups, but two miRNAs were significantly lower in the responders (p <0.001 and q<0.1 using the false detection rate (FDR) method). Interestingly, both miRNAs can potentially target the mRNA of PTCH1 and SP5, two genes with known tumor-suppressor functions. qRT-PCR showed that high levels of one of the miRNAs correlated with lack of response to chemotherapy. Conclusions: This retrospective analysis identified two miRNAs that are differentially expressed between chemotherapy responders and non-responders. One of these miRNAs was confirmed to correlate with lack of response to neo-adjuvant chemotherapy. A prospective trial assessing the predictive values of these miRNAs is currently underway. Future research directions and potential implications will be discussed.