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.
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Authors | 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 Playdle, Charles 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 |
Journal | Journal of clinical oncology : official journal of the American Society of Clinical Oncology
(J Clin Oncol)
Vol. 36
Issue 24
Pg. 2492-2503
(08 20 2018)
ISSN: 1527-7755 [Electronic] United States |
PMID | 29985747
(Publication Type: Clinical Trial, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
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Topics |
- Aged
- Aged, 80 and over
- Carcinoma, Neuroendocrine
(epidemiology, genetics, pathology)
- DNA Repair
(genetics)
- Humans
- Male
- Middle Aged
- Prospective Studies
- Prostatic Neoplasms, Castration-Resistant
(epidemiology, genetics, pathology)
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