Molecular characterization of neuroendocrinelike bladder cancer
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.
|Persistent URL||dx.doi.org/10.1158/1078-0432.CCR-18-3558, hdl.handle.net/1765/117946|
|Journal||Clinical Cancer Research|
Da Costa, J. (José Batista), Gibb, E.A. (Ewan A.), Bivalacqua, T.J. (Trinity J.), Liu, Y. (Yang), Zarni Oo, H. (Htoo), Miyamoto, D.T. (David T.), … Black, P.C. (Peter C.). (2019). Molecular characterization of neuroendocrinelike bladder cancer. Clinical Cancer Research, 25(13), 3908–3920. doi:10.1158/1078-0432.CCR-18-3558