Molecular Characterization of Neuroendocrine-like Bladder Cancer

Purpose: Neuroendocrine (NE) bladder carcinoma is a rare and aggressive variant. Molecular subtyping studies have found that 5-15% of muscle-invasive bladder cancer (MIBC) have transcriptomic patterns consistent with NE bladder cancer in the absence of NE histology. The clinical implications of this NE-like subtype have not been explored in depth. Experimental design: Transcriptome-wide expression profiles were generated for MIBC collected from seven institutions and clinical-use of Decipher Bladder. Using unsupervised clustering, we generated a clustering solution on a prospective training cohort (PTC; n=175), developed single-sample classifiers to predict NE tumors, and evaluated the resultant models on a testing radical cystectomy (RC) cohort (n=225). A random forest model was finalized and applied to five validation cohorts (n=1302). Uni- and multivariable survival analyses were used to characterize clinical outcomes. Results: In the training cohort (PTC), hierarchical clustering using an 84 gene panel showed a cluster of eight patients (4.6%) with highly heterogeneous expression of NE markers in the absence of basal or luminal marker expression. NE-like tumors were identified in 1% to 7.1% of cases in validation cohorts. Patients with NE-like tumors had significantly worse 1-year progression free survival (65% NE-like vs 82% overall; p=0.046) and, after adjusting for clinical and pathological factors, had a 6.4-fold increased risk of all-cause mortality (p=0.001). IHC confirmed the neuronal character of these tumors. Conclusion: A single patient classifier was developed that identifies patients with histological urothelial cancer harboring a NE transcriptomic profile. These tumors represent a high-risk subgroup of MIBC which may require different treatment.