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

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. 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.

Characterization of transcriptomic signature of primary prostate cancer analogous to prostatic small cell neuroendocrine carcinoma

“…These 216 genes represented a set of candidate NE‐specific genes suitable for model development. Only 19 genes were in common with the 69 SC/NE signature presented by Aggarwal et al …”

Low‐serum prostate‐specific antigen level predicts poor outcomes in patients with primary neuroendocrine prostate cancer

“…However, further investigations are needed to confirm this association. Interestingly, recent large‐scale T‐SCNC‐related clinical studies conducted by Beltran et al and Aggarwal et al reported on two small‐cell NE carcinoma cohorts with median PSA levels of 0.38 and 64.8 with median survival times of approximately 10 and 36.7 months, respectively. The prognostic role of low PSA levels in patients with T‐SCNC thus needs further investigation.…”

“…Primary NEPC is a rare, highly malignant disease, accounting for only 1% of all newly diagnosed prostate cancers . It is not yet clear if primary NEPC and treatment‐induced small‐cell neuroendocrine prostate cancer (T‐SCNC) represent the same disease entity . However, a recent study suggested that primary small‐cell prostate cancer shared similar characteristics with T‐SCNC at the DNA and RNA levels, suggesting that the study of primary NEPC may provide clues relevant to T‐SCNC.…”

The influence of treatment sequence in the prognostic value of TMPRSS2‐ERG as biomarker of taxane resistance in castration‐resistant prostate cancer

“…This may explain, at least in part, the more adverse clinical outcome of patients treated with docetaxel after A/E and the lack of association between TMPRSS2‐ERG and resistance to therapy. In a recently published study by Aggarwal et al ., the acquisition of NE phenotype was observed in 17% patients who progressed to abiraterone, and this was associated with adverse clinical outcome, but no data regarding to response to chemotherapy were reported . Other genetic markers such as RB1 and TP53 lost have been related to antiandrogen resistance therapy but no conclusive data have been reported in association with taxanes either .…”

“…In a recently published study by Aggarwal et al, the acquisition of NE phenotype was observed in 17% patients who progressed to abiraterone, and this was associated with adverse clinical outcome, but no data regarding to response to chemotherapy were reported. 22 Other genetic markers such as RB1 and TP53 lost have been related to antiandrogen resistance therapy but no conclusive data have been reported in association with taxanes either. 23 The predictive value of NE markers and other common genetic alterations in taxane-resistance have to be further defined.…”