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Updated: Feb 8, 2026
miRNA Expression Analyses in Prostate Cancer Clinical Tissues
Published on: September 8, 2015
Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A
Rahul Aggarwal1, Jiaoti Huang1, Joshi J Alumkal1
1Rahul Aggarwal, Li Zhang, Felix Y. Feng, Paul Lloyd, Jack Youngren, Adam Foye, Denise Playdle, Charles J. Ryan, and Eric J. Small, University of California San Francisco, San Francisco; Alana S. Weinstein, Verena Friedl, Can Zhang, Christopher K. Wong, Vlado Uzunangelov, Artem Sokolov, Yulia Newton, and Joshua M. Stuart, University of California Santa Cruz, Santa Cruz; Owen N. Witte and Matthew Rettig, University of California Los Angeles, Los Angeles; Christopher P. Evans and Primo Lara, University of California Davis, Davis, CA; Jiaoti Huang, Duke University, Durham, NC; Joshi J. Alumkal, George V. Thomas, and Tomasz M. Beer, Oregon Health Sciences University, Portland, OR; Martin Gleave and Kim N. Chi, University of British Columbia, Vancouver, British Columbia, Canada; Lawrence True, University of Washington, Seattle, WA; Himisha Beltran and Mark A. Rubin, Weill Cornell Medicine, New York, NY; and Francesca Demichelis, University of Trento, Trento, Italy.
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.
Insights
Treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC) affects nearly one-fifth of patients with metastatic castration-resistant prostate cancer (mCRPC). This aggressive subtype is linked to poorer survival and distinct genomic features, offering new therapeutic targets.
Area of Science:
- Oncology
- Prostate Cancer Research
- Genitourinary Pathology
Background:
- Modern androgen receptor (AR)-targeting therapies have changed metastatic castration-resistant prostate cancer (mCRPC) treatment.
- The prevalence and characteristics of treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC) under these therapies remain unclear.
Purpose of the Study:
- To investigate the clinical and genomic features of t-SCNC in patients with mCRPC receiving contemporary AR-targeting agents.
- To determine the incidence and prognostic significance of t-SCNC.
Main Methods:
- Prospective multi-institutional study of 202 patients with progressive mCRPC.
- Metastatic tumor biopsies with subsequent pathology review and RNA/DNA sequencing.
- Survival analysis and transcriptional profiling for t-SCNC identification and characterization.
Main Results:
- t-SCNC was detected in 17% of evaluable biopsies, often after progression on abiraterone/enzalutamide.
- t-SCNC showed frequent AR amplification (67%) and expression (75%), but was nearly mutually exclusive with DNA repair alterations (P = .035).
- t-SCNC detection was associated with significantly shortened overall survival (HR, 2.02) and a distinct small-cell-like transcriptional signature.
Conclusions:
- t-SCNC is a prevalent subtype in mCRPC, associated with aggressive disease and poor outcomes.
- Its genomic profile, particularly the exclusion of DNA repair alterations, suggests t-SCNC is a distinct mCRPC subset.
- Transcriptional profiling accurately identifies t-SCNC and reveals potential therapeutic targets, including PDX1.
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