TY - JOUR
T1 - Molecular characterization of neuroendocrinelike bladder cancer
AU - Da Costa, José Batista
AU - Gibb, Ewan A.
AU - Bivalacqua, Trinity J.
AU - Liu, Yang
AU - Zarni Oo, Htoo
AU - Miyamoto, David T.
AU - Alshalalfa, Mohammed
AU - Davicioni, Elai
AU - Wright, Jonathan
AU - Dall'Era, Marc A.
AU - Douglas, James
AU - Boormans, Joost L.
AU - Van Der Heijden, Michiel S.
AU - Wu, Chin Lee
AU - Van Rhijn, Bas W.G.
AU - Gupta, Shilpa
AU - Grivas, Petros
AU - Mouw, Kent W.
AU - Murugan, Paari
AU - Fazli, Ladan
AU - Ra, Seong
AU - Konety, Badrinath R.
AU - Seiler, Roland
AU - Daneshmand, Siamak
AU - Mian, Omar Y.
AU - Efstathiou, Jason A.
AU - Lotan, Yair
AU - Black, Peter C.
N1 - Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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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U2 - 10.1158/1078-0432.CCR-18-3558
DO - 10.1158/1078-0432.CCR-18-3558
M3 - Article
C2 - 30952638
AN - SCOPUS:85068530739
SN - 1078-0432
VL - 25
SP - 3908
EP - 3920
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 13
ER -