Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study
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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.
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The vast majority of mCRPC samples from patients resistant to abiraterone and enzalutamide exhibit robust AR/nuclear AR staining.
“Recent analyses of clinical samples have demonstrated that the vast majority of mCRPC samples from patients resistant to ARSI agents abiraterone and enzalutamide exhibit robust AR/nuclear AR staining20,21.”
From Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer (2025) · cites this paper as [20]
The Results (page not provided) report strong nuclear AR staining in 90 of 106 tested biopsies (15 of 20 t-SCNC and 75 of 86 adenocarcinoma specimens). They also report that 73% of enrolled patients had progressed on abiraterone and/or enzalutamide, but do not give the staining rate specifically for those patients. The claim extends the overall staining finding to that resistant subgroup. (LLM, conf=0.85)
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“PTGES3 knockdown also decreased levels exhibit robust AR/nuclear AR staining 20,21 .”
Self-citation
- Authors
- Aggarwal, R., Huang, J., Alumkal, J. J., Zhang, L., Feng, F. Y., Thomas, G. V., Weinstein, A. S., Friedl, V., Zhang, C., Witte, O. N., Lloyd, P., Gleave, M., Evans, C. P., Youngren, J., Beer, T. M., Rettig, M., Wong, C. K., True, L., Foye, A., Playdle, D., Ryan, C. J., Lara, P., Chi, K. N., Uzunangelov, V., Sokolov, A., Newton, Y., Beltran, H., Demichelis, F., Rubin, M. A., Stuart, J. M., & Small, E. J.
- Affiliations
- University of California, Los Angeles (US)
- Rahul 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...
- ORCID
- 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
- Ryan, Charles J.
- Lara, Primo
- Chi, Kim N.
- Sokolov, Artem
- Newton, Yulia
- Beltran, Himisha
- Demichelis, Francesca
- Rubin, Mark A.
- Stuart, Joshua M.
- Small, Eric J.
- Venue
- Journal of Clinical Oncology
- Published
- 2018-08-20
- Volume
- 36
- Issue
- 24
- Pages
- 2492-2503
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC6366813
- OpenAlex
- W2841858285
- Cited by
- 810
- References
- 33
- Citations by year
- 2026: 95 · 2025: 99 · 2024: 117 · 2023: 116 · 2022: 98 · 2021: 114 · 2020: 85 · 2019: 66 · 2018: 17
- FWCI
- 53.12
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Oncology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Cancer Institute (R01CA205001)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Health Sciences › Medicine › Neurology › Neuroblastoma Research and Treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- castration-resistant prostate cancer, androgen receptor amplification, abiraterone, enzalutamide, gene expression signatures, PDX1, overall survival, genetic alterations
- MeSH terms
- Aged, Aged, 80 and over, DNA Repair, Humans, Male, Middle Aged, Prospective Studies, Carcinoma, Neuroendocrine, Prostatic Neoplasms, Castration-Resistant
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