Molecular characterization of neuroendocrinelike bladder cancer

Da Costa, José Batista, Gibb, Ewan A., Bivalacqua, Trinity J., Liu, Yang, Zarni Oo, Htoo, Miyamoto, David T., Alshalalfa, Mohammed, Davicioni, Elai, Wright, Jonathan, Dall'Era, Marc A., Douglas, James, Boormans, Joost L., Van Der Heijden, Michiel S., Wu, Chin Lee, Van Rhijn, Bas W.G., Gupta, Shilpa, Grivas, Petros, Mouw, Kent W., Murugan, Paari, Fazli, Ladan, Ra, Seong, Konety, Badrinath R., Seiler, Roland, Daneshmand, Siamak, Mian, Omar Y., Efstathiou, Jason A., Lotan, Yair and Black, Peter C. (2019) Molecular characterization of neuroendocrinelike bladder cancer. Clinical Cancer Research, 25 (13), 3908-3920. (doi:10.1158/1078-0432.CCR-18-3558).

Abstract

Purpose: neuroendocrine (NE) bladder carcinoma is a rare and aggressive variant. Molecular subtyping studies have found that 5% to 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 7 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 5 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 8 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 6.6% 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 pathologic factors, had a 6.4-fold increased risk of all-cause mortality (P = 0.001). IHC confirmed the neuronal character of these tumors. 

Conclusions: a single-patient classifier was developed that identifies patients with histologic urothelial cancer harboring a NE transcriptomic profile. These tumors represent a high-risk subgroup of MIBC, which may require different treatment.

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