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
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.
N1 - Publisher Copyright:
© 2018 by American Society of Clinical Oncology.
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.
UR - http://www.scopus.com/inward/record.url?scp=85052502863&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85052502863&partnerID=8YFLogxK
U2 - 10.1200/JCO.2017.77.6880
DO - 10.1200/JCO.2017.77.6880
M3 - Article
C2 - 29985747
AN - SCOPUS:85052502863
SN - 0732-183X
VL - 36
SP - 2492
EP - 2503
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 24
ER -