Molecular characterization of neuroendocrine-like bladder cancer.

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.

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.

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.

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.

Clinical cancer research : an official journal of the American Association for Cancer Research. 2019 Apr 05 [Epub ahead of print]

José Batista da Costa, Ewan A Gibb, Trinity J Bivalacqua, Yang Liu, Htoo Zarni Oo, David T Miyamoto, Mohammed Alshalalfa, Elai Davicioni, Jonathan L Wright, Marc Dall'Era, James Douglas, Joost L Boormans, Michiel S van der Heijden, Chin-Lee Wu, Bas Wg van Rhijn, Shilpa Gupta, Petros Grivas, Kent W Mouw, Paari Murugan, Ladan Fazli, Seong Ra, Badrinath R Konety, Roland Seiler, Siamak Daneshmand, Omar Y Mian, Jason A Efstathiou, Yair Lotan, Peter C Black

Department of Urologic Sciences, University of British Columbia., R&D, GenomeDx Biosciences., The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins School of Medicine., Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia., Radiation Oncology, Massachusetts General Hospital, Harvard Medical School., GenomeDx Biosciences., Clinical Laboratory, Decipher Biosciences Inc., Urology, University of Washington., UC Davis Comprehensive Cancer Center., Cancer Sciences Unit, University of Southampton., Urology, Erasmus MC., Surgical Oncology, The Netherlands Cancer Institute., Massachusetts General Hospital Cancer Center, Harvard Medical School., Surgical Oncology, Urology, Netherlands Cancer Institute - Antoni van leeuwenhoek Hospital., Medicine, Masonic Cancer Center, University of Minnesota., Medicine (Division of Oncology), University of Washington., Radiation Oncology, Dana-Farber Cancer Institute/Brigham & Women's Hospital., Laboratory Medicine and Pathology, University of Minnesota., Pathology, Contra Costa Pathology Associates., Institute for Prostate and Urologic Cancers and Department of Urology, University of Minnesota., Department of Urology, University Hospital of Bern., Department of Urology, USC/Norris Comprehensive Cancer Center., Translational Hematology & Oncology Research (THOR) and Radiation Oncology, Cleveland Clinic., Department of Urology, University of Texas Southwestern., Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia .