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 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

100 Scopus citations

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Aggarwal, R., Huang, J., Alumkal, J. J., Zhang, L., Feng, F. Y., Thomas, G. V., Weinstein, A. S., Friedl, V., Zhang, C., Witte, O. N., Lloyd, P., Gleave, M., Evans, C. P., Youngren, J., Beer, T. M., Rettig, M., Wong, C. K., True, L., Foye, A., ... Small, E. J. (2018). Clinical and genomic characterization of treatment-emergent small-cell neuroendocrine prostate cancer: A multi-institutional prospective study. Journal of Clinical Oncology, 36(24), 2492-2503. https://doi.org/10.1200/JCO.2017.77.6880