Abstract 909: Defining molecular and laboratory predictive biomarkers of response to cisplatin-based neoadjuvant chemotherapy (NC) in muscle-invasive bladder cancer (MIBC) - preliminary results and future plans
Authors: Leibowitz-Amit Raya , Seah Jo-An , Berger Raanan , Sridhar Srikala S. 
Published: May 2015

Abstract
Background: MIBC is common, yet there has been little progress in its research, with no new therapeutic agents approved in years. The optimal therapeutic modalities and treatment sequence are not entirely well-defined. Cisplatin-based NC prior to definitive radical cystectomy (RC) increases overall survival (OS), yet is only active in a proportion of patients (pts). A pathological complete response (pCR) at RC is associated with improved OS, but there are currently no molecular biomarkers predicting which pts are likely to achieve pCR, and thus treatment decisions are currently based solely on clinical parameters.
Methods: Since micro-RNAs (miRNAs) are known to be key-players in cancer, we chose to study the differences in miRNA expression patterns between 7 pts who achieved pCR and 9 pts who did not respond (‘responders’ and ‘non-responders’, respectively), using commercial micro-arrays (Agilent ®) and quantitative RT-PCR. In a different cohort, we performed a retrospective chart review of 29 pts with MIBC receiving NC to find associations between clinical, biochemical or radiological characteristics and pCR. As the peripheral blood neutrophil-to-lymphocyte ratio (NLR) is thought to non-specifically correlate with systemic inflammatory burden, we analyzed its levels before and during NC as well as prior to RC.
Results: The trend of change in NLR was significantly different between responders and non-responders (p=0.039), the former exhibiting a sustained decrease in NLR throughout chemotherapy up until RC, and the latter exhibiting a transient decrease in NLR by mid-NC, followed by an increase to above baseline. One miRNA was significantly lower in responders than in non-responders (q value=0.048, corrected for multiple comparisons), and five miRNAs with the identical seed sequence (thus potentially targeting the same mRNAs) were also all lower in responders, one with borderline significance (q value=0.1, corrected).
Conclusions: These findings suggest that chemo-sensitivity of MIBC is determined by both inherent molecular characteristics as well as the immune/inflammatory system, and raises the question whether the response to NC could be enhanced by decreasing the systemic inflammatory burden. We will corroborate these results in larger pts cohorts and search for potential targets of these miRNAs. We also plan to initiate a prospective multi-center clinical trial in which both intra-tumoral and circulating miRNAs, as well as micro-environment/systemic inflammatory markers, will be monitored and assessed in order to establish predictive factors for pCR with NC.
Citation Format: Raya Leibowitz-Amit, Jo-An Seah, Raanan Berger, Srikala S. Sridhar. Defining molecular and laboratory predictive biomarkers of response to cisplatin-based neoadjuvant chemotherapy (NC) in muscle-invasive bladder cancer (MIBC) - preliminary results and future plans. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 909. doi:10.1158/1538-7445.AM2014-909