Abstract 406: Characterizing the molecular features of the neuroendocrine phenotype in castration resistant prostate cancer.
Authors: Zhang Xiaotun , Coleman Ilsa , Coleman Roger , Doan Khanhthy , Roudier Martine , Chéry Lisly , Noteboom Jennifer , Higano Celestia , True Lawrence D. , Lange Paul H. , Nelson Peter S. , Vessella Robert L. , Morrissey Colm 
Published: August 2014

Metastatic castration-resistant prostate cancer (CRPC) has a poor prognosis and remains a significant therapeutic challenge. Understanding the conversion from hormone sensitive to castration resistance may promote the development of more effective therapies. Recent findings suggest that neuroendocrine (NE) differentiation may be associated with the development of CRPC. Our objective was to characterize the NE phenotype in CRPC.

Using specimens obtained at radical prostatectomy and rapid autopsy at the University of Washington, 2 sets of tissue microarrays were made from 50 radical prostatectomies and 155 metastatic sites from 50 autopsy patients who died from CRPC (with up to 4 metastatic sites from each patient). NE markers, including Chromogranin A (CHGA), Neuron specific enolase (NSE) and Synaptophysin (SYN), as well as androgen receptor (AR) and prostate specific antigen (PSA) were analyzed by immunohistochemistry (IHC). To characterize the molecular features of the NE phenotype in CRPC, 78 corresponding metastatic sites were also assessed by Agilent gene expression analysis.

IHC revealed that only 2 of 50 primary prostate cancers had &gt;10% CHGA positive cells whereas 7 of 50 primary prostate cancers 1-10% of cells expressed CHGA and all 50 were AR positive. By contrast, 29 of 50 CRPC autopsy patients had at least 1 CHGA+ metastasis; 53 of 155 metastatic sites had &gt;10% CHGA positive cells (11 sites were AR negative), and 7 had 1-10% CHGA positive cells. Compared to primary prostate carcinomas, CRPC metastases had an increase in the frequency of CHGA+ expression (4% vs. 58%, p&lt;0.001). Two other NE markers were also highly expressed by &gt;10% of cells in each of the CRPC metastases. Of 155 CRPC metastases: 28 were positive for SYN and 47 were positive for NSE. Co-expression of CHGA and SYN was observed in 22 sites from 10 patients (10 sites did not express AR) and co-expression of CHGA, SYN and NSE was observed in 12 sites from 6 patients (6 sites did not express AR). PSA, a surrogate of AR activity, was absent in all NE CRPC tumors that did not express AR. All AR negative sites (12/155) expressed at least one NE marker. Gene expression data were generated from 78 laser captured metastases, which were grouped into 4 categories: 21 CHGA+ sites, 6 CHGA+, SYN+ and AR- sites, 5 CHGA+, SYN+ and AR+ sites, and 40 CHGA-, SYN-, NSE- and AR+ sites.

This study is the first extensive analysis of the NE features of CRPC. Our data suggest that a) the NE phenotype (as defined by CHGA expression) is significantly more common in CRPC than in hormone sensitive primary disease, b) NE status from different sites in the same patient can be heterogeneous, and c) the NE phenotype is not necessarily associated with the loss of AR. These molecular studies suggest that evolution from hormone sensitive to castration resistant disease involves emergence of NE characteristics over time that may explain the behavior of true “androgen independent” disease.

Citation Format: Xiaotun Zhang, Ilsa Coleman, Roger Coleman, Khanhthy Doan, Martine Roudier, Lisly Chéry, Jennifer Noteboom, Celestia Higano, Lawrence D. True, Paul H. Lange, Peter S. Nelson, Robert L. Vessella, Colm Morrissey. Characterizing the molecular features of the neuroendocrine phenotype in castration resistant prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 406. doi:10.1158/1538-7445.AM2013-406