Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study
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- 20 August 2018
- journal article
- research article
- Published by American Society of Clinical Oncology (ASCO) in Journal of Clinical Oncology
- Vol. 36 (24), 2492-2503
- https://doi.org/10.1200/jco.2017.77.6880
Abstract
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. 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. 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. 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.Keywords
This publication has 33 references indexed in Scilit:
- Platinum-Based Chemotherapy for Variant Castrate-Resistant Prostate CancerClinical Cancer Research, 2013
- Abiraterone in Metastatic Prostate Cancer without Previous ChemotherapyNew England Journal of Medicine, 2013
- Challenges in Recognizing Treatment-Related Neuroendocrine Prostate CancerJournal of Clinical Oncology, 2012
- Molecular Characterization of Neuroendocrine Prostate Cancer and Identification of New Drug TargetsCancer Discovery, 2011
- A human B‐cell interactome identifies MYB and FOXM1 as master regulators of proliferation in germinal centersMolecular Systems Biology, 2010
- The diabetes gene Pdx1 regulates the transcriptional network of pancreatic endocrine progenitor cells in miceJCI Insight, 2009
- Genomic Strategy for Targeting Therapy in Castration-Resistant Prostate CancerJournal of Clinical Oncology, 2009
- Design and End Points of Clinical Trials for Patients With Progressive Prostate Cancer and Castrate Levels of Testosterone: Recommendations of the Prostate Cancer Clinical Trials Working GroupJournal of Clinical Oncology, 2008
- Linking Ligand-Induced Alterations in Androgen Receptor Structure to Differential Gene Expression: A First Step in the Rational Design of Selective Androgen Receptor ModulatorsMolecular Endocrinology, 2006
- Nonparametric Estimation from Incomplete ObservationsJournal of the American Statistical Association, 1958