Association of Molecular Subtypes with Pathologic Response, PFS, and OS in a Phase II Study of COXEN with Neoadjuvant Chemotherapy for Muscle-invasive Bladder Cancer

Abstract Purpose: The Coexpression Extrapolation (COXEN) gene expression model with chemotherapy-specific scores [for methotrexate, vinblastine, adriamycin, cisplatin (ddMVAC) and gemcitabine/cisplatin (GC)] was developed to identify responders to neoadjuvant chemotherapy (NAC). We investigated RNA-based molecular subtypes as additional predictive biomarkers for NAC response, progression-free survival (PFS), and overall survival (OS) in patients treated in S1314. Experimental Design: A total of 237 patients were randomized between four cycles of ddMVAC (51%) and GC (49%). On the basis of Affymetrix transcriptomic data, we determined subtypes using three classifiers: TCGA (k = 5), Consensus (k = 6), and MD Anderson (MDA; k = 3) and assessed subtype association with path response to NAC and determined associations with COXEN. We also tested whether each classifier contributed additional predictive power when added to a model based on predefined stratification (strat) factors (PS 0 vs. 1; T2 vs. T3, T4a). Results: A total of 155 patients had gene expression results, received at least three of four cycles of NAC, and had pT-N response based on radical cystectomy. TCGA three-group classifier basal-squamous (BS)/neuronal, luminal (Lum), Lum infiltrated, and GC COXEN score yielded the largest AUCs for pT0 (0.59, P = 0.28; 0.60, P = 0.18, respectively). For downstaging (<pT2), the three-category Consensus classifier [BS/neuroendocrine (NE)-like, Lum, stroma-rich] increased the AUC from 0.57 (strat factors alone) to 0.61 (P = 0.10). The MDA classifier AUC was 0.63 (P = 0.18) and the GC COXEN score AUC was 0.62 (P = 0.23), but neither significantly improved the AUC. There was no statistically significant association of stratification factors and subtypes with PFS or OS. Conclusions: The Consensus classifier, based in part on the TCGA and MDA classifiers, modestly improved prediction for pathologic downstaging but subtypes were not associated with PFS or OS.