Clinical and genomic characterization of treatment-emergent small-cell neuroendocrine prostate cancer: A multi-institutional prospective study

Rahul Aggarwal, Jiaoti Huang, Joshi J. Alumkal, Li Zhang, Felix Y. Feng, George V. Thomas, Alana S. Weinstein, Verena Friedl, Can Zhang, Owen N. Witte, Paul Lloyd, Martin Gleave, Christopher P Evans, Jack Youngren, Tomasz M. Beer, Matthew Rettig, Christopher K. Wong, Lawrence True, Adam Foye, Denise PlaydleCharles J. Ryan, Primo N Lara, Kim N. Chi, Vlado Uzunangelov, Artem Sokolov, Yulia Newton, Himisha Beltran, Francesca Demichelis, Mark A. Rubin, Joshua M. Stuart, Eric J. Small

Research output: Contribution to journalArticle

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Abstract

Purpose The prevalence and features of treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC) are not well characterized in the era of modern androgen receptor (AR)-targeting therapy. We sought to characterize the clinical and genomic features of t-SCNC in a multi-institutional prospective study. Methods Patients with progressive, metastatic castration-resistant prostate cancer (mCRPC) underwent metastatic tumor biopsy and were followed for survival. Metastatic biopsy specimens underwent independent, blinded pathology review along with RNA/DNA sequencing. Results A total of 202 consecutive patients were enrolled. One hundred forty-eight (73%) had prior disease progression on abiraterone and/or enzalutamide. The biopsy evaluable rate was 79%. The overall incidence of t-SCNC detection was 17%. AR amplification and protein expression were present in 67% and 75%, respectively, of t-SCNC biopsy specimens. t-SCNC was detected at similar proportions in bone, node, and visceral organ biopsy specimens. Genomic alterations in the DNA repair pathway were nearly mutually exclusive with t-SCNC differentiation (P = .035). Detection of t-SCNC was associated with shortened overall survival among patients with prior AR-targeting therapy for mCRPC (hazard ratio, 2.02; 95% CI, 1.07 to 3.82). Unsupervised hierarchical clustering of the transcriptome identified a small-cell-like cluster that further enriched for adverse survival outcomes (hazard ratio, 3.00; 95% CI, 1.25 to 7.19). A t-SCNC transcriptional signature was developed and validated in multiple external data sets with . 90% accuracy. Multiple transcriptional regulators of t-SCNC were identified, including the pancreatic neuroendocrine marker PDX1. Conclusion t-SCNC is present in nearly one fifth of patients with mCRPC and is associated with shortened survival. The near-mutual exclusivity with DNA repair alterations suggests t-SCNC may be a distinct subset of mCRPC. Transcriptional profiling facilitates the identification of t-SCNC and novel therapeutic targets.

Original languageEnglish (US)
Pages (from-to)2492-2503
Number of pages12
JournalJournal of Clinical Oncology
Volume36
Issue number24
DOIs
StatePublished - Aug 20 2018

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Neuroendocrine Cells
Prostatic Neoplasms
Prospective Studies
Castration
Therapeutics
Biopsy
Androgen Receptors
Survival
DNA Repair
RNA Sequence Analysis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Clinical and genomic characterization of treatment-emergent small-cell neuroendocrine prostate cancer : A multi-institutional prospective study. / Aggarwal, Rahul; Huang, Jiaoti; Alumkal, Joshi J.; Zhang, Li; Feng, Felix Y.; Thomas, George V.; Weinstein, Alana S.; Friedl, Verena; Zhang, Can; Witte, Owen N.; Lloyd, Paul; Gleave, Martin; Evans, Christopher P; Youngren, Jack; Beer, Tomasz M.; Rettig, Matthew; Wong, Christopher K.; True, Lawrence; Foye, Adam; Playdle, Denise; Ryan, Charles J.; Lara, Primo N; Chi, Kim N.; Uzunangelov, Vlado; Sokolov, Artem; Newton, Yulia; Beltran, Himisha; Demichelis, Francesca; Rubin, Mark A.; Stuart, Joshua M.; Small, Eric J.

In: Journal of Clinical Oncology, Vol. 36, No. 24, 20.08.2018, p. 2492-2503.

Research output: Contribution to journalArticle

Aggarwal, R, Huang, J, Alumkal, JJ, Zhang, L, Feng, FY, Thomas, GV, Weinstein, AS, Friedl, V, Zhang, C, Witte, ON, Lloyd, P, Gleave, M, Evans, CP, Youngren, J, Beer, TM, Rettig, M, Wong, CK, True, L, Foye, A, Playdle, D, Ryan, CJ, Lara, PN, Chi, KN, Uzunangelov, V, Sokolov, A, Newton, Y, Beltran, H, Demichelis, F, Rubin, MA, Stuart, JM & Small, EJ 2018, 'Clinical and genomic characterization of treatment-emergent small-cell neuroendocrine prostate cancer: A multi-institutional prospective study', Journal of Clinical Oncology, vol. 36, no. 24, pp. 2492-2503. https://doi.org/10.1200/JCO.2017.77.6880
Aggarwal, Rahul ; Huang, Jiaoti ; Alumkal, Joshi J. ; Zhang, Li ; Feng, Felix Y. ; Thomas, George V. ; Weinstein, Alana S. ; Friedl, Verena ; Zhang, Can ; Witte, Owen N. ; Lloyd, Paul ; Gleave, Martin ; Evans, Christopher P ; Youngren, Jack ; Beer, Tomasz M. ; Rettig, Matthew ; Wong, Christopher K. ; True, Lawrence ; Foye, Adam ; Playdle, Denise ; Ryan, Charles J. ; Lara, Primo N ; Chi, Kim N. ; Uzunangelov, Vlado ; Sokolov, Artem ; Newton, Yulia ; Beltran, Himisha ; Demichelis, Francesca ; Rubin, Mark A. ; Stuart, Joshua M. ; Small, Eric J. / Clinical and genomic characterization of treatment-emergent small-cell neuroendocrine prostate cancer : A multi-institutional prospective study. In: Journal of Clinical Oncology. 2018 ; Vol. 36, No. 24. pp. 2492-2503.
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title = "Clinical and genomic characterization of treatment-emergent small-cell neuroendocrine prostate cancer: A multi-institutional prospective study",
abstract = "Purpose The prevalence and features of treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC) are not well characterized in the era of modern androgen receptor (AR)-targeting therapy. We sought to characterize the clinical and genomic features of t-SCNC in a multi-institutional prospective study. Methods Patients with progressive, metastatic castration-resistant prostate cancer (mCRPC) underwent metastatic tumor biopsy and were followed for survival. Metastatic biopsy specimens underwent independent, blinded pathology review along with RNA/DNA sequencing. Results A total of 202 consecutive patients were enrolled. One hundred forty-eight (73{\%}) had prior disease progression on abiraterone and/or enzalutamide. The biopsy evaluable rate was 79{\%}. The overall incidence of t-SCNC detection was 17{\%}. AR amplification and protein expression were present in 67{\%} and 75{\%}, respectively, of t-SCNC biopsy specimens. t-SCNC was detected at similar proportions in bone, node, and visceral organ biopsy specimens. Genomic alterations in the DNA repair pathway were nearly mutually exclusive with t-SCNC differentiation (P = .035). Detection of t-SCNC was associated with shortened overall survival among patients with prior AR-targeting therapy for mCRPC (hazard ratio, 2.02; 95{\%} CI, 1.07 to 3.82). Unsupervised hierarchical clustering of the transcriptome identified a small-cell-like cluster that further enriched for adverse survival outcomes (hazard ratio, 3.00; 95{\%} CI, 1.25 to 7.19). A t-SCNC transcriptional signature was developed and validated in multiple external data sets with . 90{\%} accuracy. Multiple transcriptional regulators of t-SCNC were identified, including the pancreatic neuroendocrine marker PDX1. Conclusion t-SCNC is present in nearly one fifth of patients with mCRPC and is associated with shortened survival. The near-mutual exclusivity with DNA repair alterations suggests t-SCNC may be a distinct subset of mCRPC. Transcriptional profiling facilitates the identification of t-SCNC and novel therapeutic targets.",
author = "Rahul Aggarwal and Jiaoti Huang and Alumkal, {Joshi J.} and Li Zhang and Feng, {Felix Y.} and Thomas, {George V.} and Weinstein, {Alana S.} and Verena Friedl and Can Zhang and Witte, {Owen N.} and Paul Lloyd and Martin Gleave and Evans, {Christopher P} and Jack Youngren and Beer, {Tomasz M.} and Matthew Rettig and Wong, {Christopher K.} and Lawrence True and Adam Foye and Denise Playdle and Ryan, {Charles J.} and Lara, {Primo N} and Chi, {Kim N.} and Vlado Uzunangelov and Artem Sokolov and Yulia Newton and Himisha Beltran and Francesca Demichelis and Rubin, {Mark A.} and Stuart, {Joshua M.} and Small, {Eric J.}",
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TY - JOUR

T1 - Clinical and genomic characterization of treatment-emergent small-cell neuroendocrine prostate cancer

T2 - A multi-institutional prospective study

AU - Aggarwal, Rahul

AU - Huang, Jiaoti

AU - Alumkal, Joshi J.

AU - Zhang, Li

AU - Feng, Felix Y.

AU - Thomas, George V.

AU - Weinstein, Alana S.

AU - Friedl, Verena

AU - Zhang, Can

AU - Witte, Owen N.

AU - Lloyd, Paul

AU - Gleave, Martin

AU - Evans, Christopher P

AU - Youngren, Jack

AU - Beer, Tomasz M.

AU - Rettig, Matthew

AU - Wong, Christopher K.

AU - True, Lawrence

AU - Foye, Adam

AU - Playdle, Denise

AU - Ryan, Charles J.

AU - Lara, Primo N

AU - Chi, Kim N.

AU - Uzunangelov, Vlado

AU - Sokolov, Artem

AU - Newton, Yulia

AU - Beltran, Himisha

AU - Demichelis, Francesca

AU - Rubin, Mark A.

AU - Stuart, Joshua M.

AU - Small, Eric J.

PY - 2018/8/20

Y1 - 2018/8/20

N2 - Purpose The prevalence and features of treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC) are not well characterized in the era of modern androgen receptor (AR)-targeting therapy. We sought to characterize the clinical and genomic features of t-SCNC in a multi-institutional prospective study. Methods Patients with progressive, metastatic castration-resistant prostate cancer (mCRPC) underwent metastatic tumor biopsy and were followed for survival. Metastatic biopsy specimens underwent independent, blinded pathology review along with RNA/DNA sequencing. Results A total of 202 consecutive patients were enrolled. One hundred forty-eight (73%) had prior disease progression on abiraterone and/or enzalutamide. The biopsy evaluable rate was 79%. The overall incidence of t-SCNC detection was 17%. AR amplification and protein expression were present in 67% and 75%, respectively, of t-SCNC biopsy specimens. t-SCNC was detected at similar proportions in bone, node, and visceral organ biopsy specimens. Genomic alterations in the DNA repair pathway were nearly mutually exclusive with t-SCNC differentiation (P = .035). Detection of t-SCNC was associated with shortened overall survival among patients with prior AR-targeting therapy for mCRPC (hazard ratio, 2.02; 95% CI, 1.07 to 3.82). Unsupervised hierarchical clustering of the transcriptome identified a small-cell-like cluster that further enriched for adverse survival outcomes (hazard ratio, 3.00; 95% CI, 1.25 to 7.19). A t-SCNC transcriptional signature was developed and validated in multiple external data sets with . 90% accuracy. Multiple transcriptional regulators of t-SCNC were identified, including the pancreatic neuroendocrine marker PDX1. Conclusion t-SCNC is present in nearly one fifth of patients with mCRPC and is associated with shortened survival. The near-mutual exclusivity with DNA repair alterations suggests t-SCNC may be a distinct subset of mCRPC. Transcriptional profiling facilitates the identification of t-SCNC and novel therapeutic targets.

AB - Purpose The prevalence and features of treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC) are not well characterized in the era of modern androgen receptor (AR)-targeting therapy. We sought to characterize the clinical and genomic features of t-SCNC in a multi-institutional prospective study. Methods Patients with progressive, metastatic castration-resistant prostate cancer (mCRPC) underwent metastatic tumor biopsy and were followed for survival. Metastatic biopsy specimens underwent independent, blinded pathology review along with RNA/DNA sequencing. Results A total of 202 consecutive patients were enrolled. One hundred forty-eight (73%) had prior disease progression on abiraterone and/or enzalutamide. The biopsy evaluable rate was 79%. The overall incidence of t-SCNC detection was 17%. AR amplification and protein expression were present in 67% and 75%, respectively, of t-SCNC biopsy specimens. t-SCNC was detected at similar proportions in bone, node, and visceral organ biopsy specimens. Genomic alterations in the DNA repair pathway were nearly mutually exclusive with t-SCNC differentiation (P = .035). Detection of t-SCNC was associated with shortened overall survival among patients with prior AR-targeting therapy for mCRPC (hazard ratio, 2.02; 95% CI, 1.07 to 3.82). Unsupervised hierarchical clustering of the transcriptome identified a small-cell-like cluster that further enriched for adverse survival outcomes (hazard ratio, 3.00; 95% CI, 1.25 to 7.19). A t-SCNC transcriptional signature was developed and validated in multiple external data sets with . 90% accuracy. Multiple transcriptional regulators of t-SCNC were identified, including the pancreatic neuroendocrine marker PDX1. Conclusion t-SCNC is present in nearly one fifth of patients with mCRPC and is associated with shortened survival. The near-mutual exclusivity with DNA repair alterations suggests t-SCNC may be a distinct subset of mCRPC. Transcriptional profiling facilitates the identification of t-SCNC and novel therapeutic targets.

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