Validation of a neuroendocrine-like classifier confirms poor outcomes in patients with bladder cancer treated with cisplatin-based neoadjuvant chemotherapy

Petros Grivas, Tarek A. Bismar, Aijai S. Alva, Huei Chung Huang, Yang Liu, Roland Seiler, Nimira Alimohamed, Liang Cheng, M. Eric Hyndman, Bashar Dabbas, Peter C. Black, Elai Davicioni, Jonathan L. Wright, Moshe C. Ornstein, Omar Y. Mian, Hristos Z. Kaimakliotis, Ewan A. Gibb, Yair Lotan

Research output: Contribution to journalArticle

Abstract

Purpose: Neuroendocrine (NE)-like carcinoma is a newly recognized molecular subtype of conventional urothelial carcinoma of the bladder with transcriptomic profiles and clinical outcomes highly similar to histological NE carcinoma. The identification of NE-like tumors is challenging, as these tumors often appear histologically like urothelial carcinoma and can be missed by routine morphological criteria. We previously developed a single-sample classifier to identify NE-like tumors, which we aimed to validate in an independent cohort. Materials and methods: A single-sample genomic classifier was performed on transurethral specimens from a retrospective multicenter cohort of 234 patients who underwent cisplatin-based neoadjuvant chemotherapy and subsequent radical cystectomy. Outcomes were compared for NE-like vs. non-NE-like. Results: We identified 10 patients with urothelial tumors of the NE-like subtype, all of which had robust gene expression of neuronal markers, but did not express markers associated with basal or luminal tumors. The cancer-specific mortality rates were significantly higher compared to non-NE-like tumors (P < 0.001), with 5 of the 10 patients dying within 12 months from surgery. Conclusions: The single-sample classifier was able to identify urothelial carcinomas with NE-like subtype. These NE-like tumors have demonstrated transcriptomic profiles and clinical behavior similar to histological NE tumors across multiple patient cohorts. We propose that NE-like tumors should be managed similarly to histological NE tumors, and that standard treatments for small cell lung cancer as well as novel strategies may be evaluated in these patients.

Original languageEnglish (US)
JournalUrologic Oncology: Seminars and Original Investigations
DOIs
StateAccepted/In press - Jan 1 2019

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Neuroendocrine Tumors
Urinary Bladder Neoplasms
Cisplatin
Drug Therapy
Neuroendocrine Carcinoma
Neoplasms
Carcinoma
Cystectomy
Small Cell Lung Carcinoma
Urinary Bladder
Gene Expression
Mortality

Keywords

  • Bladder cancer
  • Gene expression analysis
  • Molecular subtypes
  • Neuroendocrine
  • Urothelial carcinoma

ASJC Scopus subject areas

  • Oncology
  • Urology

Cite this

Validation of a neuroendocrine-like classifier confirms poor outcomes in patients with bladder cancer treated with cisplatin-based neoadjuvant chemotherapy. / Grivas, Petros; Bismar, Tarek A.; Alva, Aijai S.; Huang, Huei Chung; Liu, Yang; Seiler, Roland; Alimohamed, Nimira; Cheng, Liang; Hyndman, M. Eric; Dabbas, Bashar; Black, Peter C.; Davicioni, Elai; Wright, Jonathan L.; Ornstein, Moshe C.; Mian, Omar Y.; Kaimakliotis, Hristos Z.; Gibb, Ewan A.; Lotan, Yair.

In: Urologic Oncology: Seminars and Original Investigations, 01.01.2019.

Research output: Contribution to journalArticle

Grivas, P, Bismar, TA, Alva, AS, Huang, HC, Liu, Y, Seiler, R, Alimohamed, N, Cheng, L, Hyndman, ME, Dabbas, B, Black, PC, Davicioni, E, Wright, JL, Ornstein, MC, Mian, OY, Kaimakliotis, HZ, Gibb, EA & Lotan, Y 2019, 'Validation of a neuroendocrine-like classifier confirms poor outcomes in patients with bladder cancer treated with cisplatin-based neoadjuvant chemotherapy', Urologic Oncology: Seminars and Original Investigations. https://doi.org/10.1016/j.urolonc.2019.11.004
Grivas, Petros ; Bismar, Tarek A. ; Alva, Aijai S. ; Huang, Huei Chung ; Liu, Yang ; Seiler, Roland ; Alimohamed, Nimira ; Cheng, Liang ; Hyndman, M. Eric ; Dabbas, Bashar ; Black, Peter C. ; Davicioni, Elai ; Wright, Jonathan L. ; Ornstein, Moshe C. ; Mian, Omar Y. ; Kaimakliotis, Hristos Z. ; Gibb, Ewan A. ; Lotan, Yair. / Validation of a neuroendocrine-like classifier confirms poor outcomes in patients with bladder cancer treated with cisplatin-based neoadjuvant chemotherapy. In: Urologic Oncology: Seminars and Original Investigations. 2019.
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abstract = "Purpose: Neuroendocrine (NE)-like carcinoma is a newly recognized molecular subtype of conventional urothelial carcinoma of the bladder with transcriptomic profiles and clinical outcomes highly similar to histological NE carcinoma. The identification of NE-like tumors is challenging, as these tumors often appear histologically like urothelial carcinoma and can be missed by routine morphological criteria. We previously developed a single-sample classifier to identify NE-like tumors, which we aimed to validate in an independent cohort. Materials and methods: A single-sample genomic classifier was performed on transurethral specimens from a retrospective multicenter cohort of 234 patients who underwent cisplatin-based neoadjuvant chemotherapy and subsequent radical cystectomy. Outcomes were compared for NE-like vs. non-NE-like. Results: We identified 10 patients with urothelial tumors of the NE-like subtype, all of which had robust gene expression of neuronal markers, but did not express markers associated with basal or luminal tumors. The cancer-specific mortality rates were significantly higher compared to non-NE-like tumors (P < 0.001), with 5 of the 10 patients dying within 12 months from surgery. Conclusions: The single-sample classifier was able to identify urothelial carcinomas with NE-like subtype. These NE-like tumors have demonstrated transcriptomic profiles and clinical behavior similar to histological NE tumors across multiple patient cohorts. We propose that NE-like tumors should be managed similarly to histological NE tumors, and that standard treatments for small cell lung cancer as well as novel strategies may be evaluated in these patients.",
keywords = "Bladder cancer, Gene expression analysis, Molecular subtypes, Neuroendocrine, Urothelial carcinoma",
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T1 - Validation of a neuroendocrine-like classifier confirms poor outcomes in patients with bladder cancer treated with cisplatin-based neoadjuvant chemotherapy

AU - Grivas, Petros

AU - Bismar, Tarek A.

AU - Alva, Aijai S.

AU - Huang, Huei Chung

AU - Liu, Yang

AU - Seiler, Roland

AU - Alimohamed, Nimira

AU - Cheng, Liang

AU - Hyndman, M. Eric

AU - Dabbas, Bashar

AU - Black, Peter C.

AU - Davicioni, Elai

AU - Wright, Jonathan L.

AU - Ornstein, Moshe C.

AU - Mian, Omar Y.

AU - Kaimakliotis, Hristos Z.

AU - Gibb, Ewan A.

AU - Lotan, Yair

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Purpose: Neuroendocrine (NE)-like carcinoma is a newly recognized molecular subtype of conventional urothelial carcinoma of the bladder with transcriptomic profiles and clinical outcomes highly similar to histological NE carcinoma. The identification of NE-like tumors is challenging, as these tumors often appear histologically like urothelial carcinoma and can be missed by routine morphological criteria. We previously developed a single-sample classifier to identify NE-like tumors, which we aimed to validate in an independent cohort. Materials and methods: A single-sample genomic classifier was performed on transurethral specimens from a retrospective multicenter cohort of 234 patients who underwent cisplatin-based neoadjuvant chemotherapy and subsequent radical cystectomy. Outcomes were compared for NE-like vs. non-NE-like. Results: We identified 10 patients with urothelial tumors of the NE-like subtype, all of which had robust gene expression of neuronal markers, but did not express markers associated with basal or luminal tumors. The cancer-specific mortality rates were significantly higher compared to non-NE-like tumors (P < 0.001), with 5 of the 10 patients dying within 12 months from surgery. Conclusions: The single-sample classifier was able to identify urothelial carcinomas with NE-like subtype. These NE-like tumors have demonstrated transcriptomic profiles and clinical behavior similar to histological NE tumors across multiple patient cohorts. We propose that NE-like tumors should be managed similarly to histological NE tumors, and that standard treatments for small cell lung cancer as well as novel strategies may be evaluated in these patients.

AB - Purpose: Neuroendocrine (NE)-like carcinoma is a newly recognized molecular subtype of conventional urothelial carcinoma of the bladder with transcriptomic profiles and clinical outcomes highly similar to histological NE carcinoma. The identification of NE-like tumors is challenging, as these tumors often appear histologically like urothelial carcinoma and can be missed by routine morphological criteria. We previously developed a single-sample classifier to identify NE-like tumors, which we aimed to validate in an independent cohort. Materials and methods: A single-sample genomic classifier was performed on transurethral specimens from a retrospective multicenter cohort of 234 patients who underwent cisplatin-based neoadjuvant chemotherapy and subsequent radical cystectomy. Outcomes were compared for NE-like vs. non-NE-like. Results: We identified 10 patients with urothelial tumors of the NE-like subtype, all of which had robust gene expression of neuronal markers, but did not express markers associated with basal or luminal tumors. The cancer-specific mortality rates were significantly higher compared to non-NE-like tumors (P < 0.001), with 5 of the 10 patients dying within 12 months from surgery. Conclusions: The single-sample classifier was able to identify urothelial carcinomas with NE-like subtype. These NE-like tumors have demonstrated transcriptomic profiles and clinical behavior similar to histological NE tumors across multiple patient cohorts. We propose that NE-like tumors should be managed similarly to histological NE tumors, and that standard treatments for small cell lung cancer as well as novel strategies may be evaluated in these patients.

KW - Bladder cancer

KW - Gene expression analysis

KW - Molecular subtypes

KW - Neuroendocrine

KW - Urothelial carcinoma

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