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Clinical and genomic characterization of treatment-emergent small-cell neuroendocrine prostate cancer: A multi-institutional prospective study
Aggarwal R.8; Huang J.6; Alumkal J.J.9; Zhang L.8; Feng F.Y.8; Thomas G.V.9; Weinstein A.S.10; Friedl V.10; Zhang C.10; Witte O.N.3; Lloyd P.8; Gleave M.4; Evans C.P.5; Youngren J.8; Beer T.M.9; Rettig M.3; Wong C.K.10; True L.7; Foye A.8; Playdle D.8; Ryan C.J.8; Lara P.5; Chi K.N.4; Uzunangelov V.10; Sokolov A.10; Newton Y.10; Beltran H.1; Demichelis F.2; Rubin M.A.1; Stuart J.M.10; Small E.J.8
2018-08-20
Source PublicationJournal of Clinical Oncology
ISSN15277755 0732183X
Volume36Issue:24Pages:2492-2503
AbstractPurpose 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.
DOI10.1200/JCO.2017.77.6880
URLView the original
Language英語
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Cited Times [WOS]:51   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionUniversity of Macau
Affiliation1.Weill Cornell Medicine
2.Università degli Studi di Trento
3.University of California, Los Angeles
4.The University of British Columbia
5.University of California, Davis
6.Duke University
7.University of Washington, Seattle
8.University of California, San Francisco
9.Oregon Health and Science University
10.University of California, Santa Cruz
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Aggarwal R.,Huang J.,Alumkal J.J.,et al. Clinical and genomic characterization of treatment-emergent small-cell neuroendocrine prostate cancer: A multi-institutional prospective study[J]. Journal of Clinical Oncology,2018,36(24):2492-2503.
APA Aggarwal R..,Huang J..,Alumkal J.J..,Zhang L..,Feng F.Y..,...&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.
MLA Aggarwal R.,et al."Clinical and genomic characterization of treatment-emergent small-cell neuroendocrine prostate cancer: A multi-institutional prospective study".Journal of Clinical Oncology 36.24(2018):2492-2503.
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