Details

Autor(en) / Beteiligte

• Aggarwal, Rahul
• Huang, Jiaoti
• Alumkal, Joshi J
• Zhang, Li
• Feng, Felix Y
• Thomas, George V
• Weinstein, Alana S
• Friedl, Verena
• Zhang, Can
• Witte, Owen N
• Lloyd, Paul
• Gleave, Martin
• Evans, Christopher P
• Youngren, Jack
• Beer, Tomasz M
• Rettig, Matthew
• Wong, Christopher K
• True, Lawrence
• Foye, Adam
• Playdle, Denise
• Ryan, Charles J
• Lara, Primo
• Chi, Kim N
• Uzunangelov, Vlado
• Sokolov, Artem
• Newton, Yulia
• Beltran, Himisha
• Demichelis, Francesca
• Rubin, Mark A
• Stuart, Joshua M
• Small, Eric J

Titel

Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study

Ist Teil von

• Journal of clinical oncology, 2018-08, Vol.36 (24), p.2492-2503

Ort / Verlag

United States: American Society of Clinical Oncology

Erscheinungsjahr

2018

Link zum Volltext

Quelle

Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals

Beschreibungen/Notizen

• 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.