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. MethodsPatients 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. ResultsA 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.J Clin Oncol 36.

While mutations affecting protein-coding regions have been examined across many cancers, structural variants at the genome-wide level are still poorly defined. Through integrative deep whole-genome and -transcriptome analysis of 101 castration-resistant prostate cancer metastases (109X tumor/38X normal coverage), we identified structural variants altering critical regulators of tumorigenesis and progression not detectable by exome approaches. Notably, we observed amplification of an intergenic enhancer region 624 kb upstream of the androgen receptor (AR) in 81% of patients, correlating with increased AR expression. Tandem duplication hotspots also occur near MYC, in lncRNAs associated with post-translational MYC regulation. Classes of structural variations were linked to distinct DNA repair deficiencies, suggesting their etiology, including associations of CDK12 mutation with tandem duplications, TP53 inactivation with inverted rearrangements and chromothripsis, and BRCA2 inactivation with deletions. Together, these observations provide a comprehensive view of how structural variations affect critical regulators in metastatic prostate cancer.

Prostate cancer induced in primary human prostate basal cells recapitulates disease initiation and progression in immunodeficient mice.Luminal cells are believed to be the cells-of-origin for human prostate cancer because the disease is characterized by luminal cell expansion and absence of basal cells. Yet functional studies addressing the origin of human prostate cancer have not previously been reported due to a lack of relevant in vivo human models. Here we show that basal cells, from primary benign human prostate tissue, can initiate prostate cancer in immunodeficient mice. The cooperative effects of AKT, ERG, and androgen receptor (AR) in basal cells recapitulated the histological and molecular features of human prostate cancer with loss of basal cells and expansion of luminal cells expressing prostate-specific antigen (PSA) and alpha-methylacylCoA racemase (AMACR). Our results demonstrate that histological characterization of cancers does not necessarily correlate with the cellular origins of the disease.Prostate cancer research has been hindered by an absence of model systems in which the disease is initiated from primary human prostate epithelial cells, precluding investigation of transforming alterations and cells-of-origin. Commonly used human prostate cancer cell lines and xenografts were derived from metastatic lesions. Murine prostate cancer models prohibit testing of species-specific therapies such as monoclonal antibodies against human proteins (1). An ideal model system would be human cell-derived and present as a multifocal disease to accurately represent the heterogeneity of prostate malignancy (2). The