Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study.
Journal Article (Clinical Trial;Multicenter Study;Journal Article)
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.
Full Text
Duke Authors
Cited Authors
- 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, P; Chi, KN; Uzunangelov, V; Sokolov, A; Newton, Y; Beltran, H; Demichelis, F; Rubin, MA; Stuart, JM; Small, EJ
Published Date
- August 2018
Published In
Volume / Issue
- 36 / 24
Start / End Page
- 2492 - 2503
PubMed ID
- 29985747
Pubmed Central ID
- PMC6366813
Electronic International Standard Serial Number (EISSN)
- 1527-7755
International Standard Serial Number (ISSN)
- 0732-183X
Digital Object Identifier (DOI)
- 10.1200/jco.2017.77.6880
Language
- eng