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Precision Medicine and Imaging

Molecular Characterization of Neuroendocrine-like Bladder Cancer

José Batista da Costa, Ewan A. Gibb, Trinity J. Bivalacqua, Yang Liu, Htoo Zarni Oo, David T. Miyamoto, Mohammed Alshalalfa, Elai Davicioni, Jonathan Wright, Marc A. Dall’Era, James Douglas, Joost L. Boormans, Michiel S. Van der Heijden, Chin-Lee Wu, Bas W.G. 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 and Peter C. Black
José Batista da Costa
Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
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Ewan A. Gibb
GenomeDx Inc., Vancouver, British Columbia, Canada.
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Trinity J. Bivalacqua
Department of Urology, Johns Hopkins Medical Institution, Baltimore, Maryland.
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Yang Liu
GenomeDx Inc., Vancouver, British Columbia, Canada.
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Htoo Zarni Oo
Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
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David T. Miyamoto
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
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Mohammed Alshalalfa
GenomeDx Inc., Vancouver, British Columbia, Canada.
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Elai Davicioni
GenomeDx Inc., Vancouver, British Columbia, Canada.
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Jonathan Wright
Department of Urology, University of Washington School of Medicine, Seattle, Washington.
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Marc A. Dall’Era
Department of Urology, Urothelial Carcinoma Davis Comprehensive Cancer Center, Sacramento, California.
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James Douglas
Department of Urology, University Hospital of Southampton, Hampshire, United Kingdom.
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Joost L. Boormans
Department of Urology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, the Netherlands.
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Michiel S. Van der Heijden
Department of Medical Oncology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
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Chin-Lee Wu
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
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Bas W.G. van Rhijn
Department of Surgical Oncology (Urology), Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
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Shilpa Gupta
Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, Minnesota.
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Petros Grivas
Department of Oncology, University of Washington, Seattle, Washington.
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Kent W. Mouw
Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Paari Murugan
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota.
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Ladan Fazli
Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
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Seong Ra
San Diego Pathologist Medical Group, San Diego, California.
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Badrinath R. Konety
Department of Urology, University of Minnesota, Minneapolis, Minnesota.
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Roland Seiler
Department of Urology, University of Bern, Bern, Switzerland.
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Siamak Daneshmand
Urology Department, University of Southern California, Los Angeles, California.
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Omar Y. Mian
Department of Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, Ohio.
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Jason A. Efstathiou
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
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Yair Lotan
Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.
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Peter C. Black
Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
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  • For correspondence: pblack@mail.ubc.ca
DOI: 10.1158/1078-0432.CCR-18-3558 Published July 2019
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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.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Clin Cancer Res 2019;25:3908–20

  • Received October 31, 2018.
  • Revision received January 21, 2019.
  • Accepted March 26, 2019.
  • Published first April 5, 2019.
  • ©2019 American Association for Cancer Research.
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Clinical Cancer Research: 25 (13)
July 2019
Volume 25, Issue 13
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Molecular Characterization of Neuroendocrine-like Bladder Cancer
José Batista da Costa, Ewan A. Gibb, Trinity J. Bivalacqua, Yang Liu, Htoo Zarni Oo, David T. Miyamoto, Mohammed Alshalalfa, Elai Davicioni, Jonathan Wright, Marc A. Dall’Era, James Douglas, Joost L. Boormans, Michiel S. Van der Heijden, Chin-Lee Wu, Bas W.G. 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 and Peter C. Black
Clin Cancer Res July 1 2019 (25) (13) 3908-3920; DOI: 10.1158/1078-0432.CCR-18-3558

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Molecular Characterization of Neuroendocrine-like Bladder Cancer
José Batista da Costa, Ewan A. Gibb, Trinity J. Bivalacqua, Yang Liu, Htoo Zarni Oo, David T. Miyamoto, Mohammed Alshalalfa, Elai Davicioni, Jonathan Wright, Marc A. Dall’Era, James Douglas, Joost L. Boormans, Michiel S. Van der Heijden, Chin-Lee Wu, Bas W.G. 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 and Peter C. Black
Clin Cancer Res July 1 2019 (25) (13) 3908-3920; DOI: 10.1158/1078-0432.CCR-18-3558
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