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.

The COXEN gene expression model with chemotherapy-specific scores (for DD-MVAC and GC) was developed to identify responders to NAC. We investigated RNA-based molecular subtypes as additional predictive biomarkers for NAC response, PFS, and OS in patients treated in S1314. 237 patients were randomized between 4 cycles of ddMVAC (51%) and GC (49%). Based on Affymetrix transcriptomic data, we determined subtypes using 3 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 pre-defined stratification factors (PS 0 vs. 1; T2 vs. T3, T4a). 155 patients had gene expression results, received at least 3 of 4 cycles of NAC and had pT-N response based on RC. TCGA 3 group classifier BS/Neuronal, 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 3 category Consensus classifier (BS/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. 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.