[HTML][HTML] Clinical and genomic characterization of treatment-emergent small-cell neuroendocrine prostate cancer: a multi-institutional prospective study

R Aggarwal, J Huang, JJ Alumkal, L Zhang… - Journal of Clinical …, 2018 - ncbi.nlm.nih.gov
R Aggarwal, J Huang, JJ Alumkal, L Zhang, FY Feng, GV Thomas, AS Weinstein, V Friedl
Journal of Clinical Oncology, 2018ncbi.nlm.nih.gov
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 …
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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