Abstract 995: Impact of molecular subtypes on predicting chemotherapy response and survival in muscle invasive bladder cancer
Authors: Choi Woonyoung , Sundi Debasish , Metcalfe Michael , Lee i-ling , Pretzsch Shanna , Bondaruk Jolanta , Plimack Elizabeth , Siefker-Radtke Arlene Odelia , CzerniaK Bogdan , Dinney Colin , McConkey Daivd 
Published: July 2017

Abstract
Using whole genome mRNA expression profiling we reported the existence of molecular subtypes (basal, p53-like and luminal) characterized by distinct gene expression patterns and clinical outcomes in muscle invasive bladder cancer (MIBC). To further explore the potential clinical significance of the molecular subtypes, we measured the relative clinical impact of neoadjuvant chemotherapy (NAC) in each of the subtypes. We created a meta-dataset using 148 transurethral resection (TUR) specimens from patients who received NAC followed by radical cystectomy (RC) within the context of 5 separate Phase II clinical trials and another consisting of 127 TURs from patients who were treated with RC without NAC. We used TCGA’s complete MIBC dataset as a validation cohort. We assigned the tumors to subtypes using a published one nearest neighbor (oneNN) classifier, and the relationship between subtype assignment and overall survival (OS) was assessed by Kaplan-Meier analysis with log-rank test. In the NAC cohort, chemotherapy was active as measured by an overall pathological downstaging rate (≤pT1 at cystectomy) of 47 % (70/148). Based on pathological downstaging, p53-like tumors were resistant to chemotherapy (response rate; 28%, p=0.009). Patients with basal tumors had the best survival (median OS: 211 months, p= 0.033) compared to p53-like (45 months) and luminal tumors (85 months). In contrast, in the RC without NAC cohort, patients with basal tumors had the shortest survival (17 months, p&lt;0.001) compared to p53-like (110 months) and luminal tumors (108 months). When we compared the impact of NAC on OS within each subtype, patients with basal tumors obtained substantial clinical benefit (p&lt;0.0001), whereas NAC produced no significant differences in OS in patients with p53-like or luminal tumors. These results were confirmed in independent analyses of TCGA’s dataset, where patients with basal tumors were the only ones who received significant survival benefit from chemotherapy (median OS with chemotherapy-undefined; without chemotherapy -17 months, p=0.027). Our results demonstrate that the molecular subtypes of MIBC are associated with differential benefit from chemotherapy. If validated prospectively, the data suggest that basal tumors should be identified at diagnosis so that patients with these tumors can be aggressively managed with neoadjuvant chemotherapy. The molecular mechanisms that probably underlie the preferential impact of chemotherapy in basal tumors will be discussed.
Citation Format: Woonyoung Choi, Debasish Sundi, Michael Metcalfe, i-ling Lee, Shanna Pretzsch, Jolanta Bondaruk, Elizabeth Plimack, Arlene Odelia Siefker-Radtke, Bogdan CzerniaK, Colin Dinney, Daivd McConkey. Impact of molecular subtypes on predicting chemotherapy response and survival in muscle invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 995. doi:10.1158/1538-7445.AM2017-995