Frequent discordance between ERG gene rearrangement and ERG protein expression in a rapid autopsy cohort of patients with lethal, metastatic, castration-resistant prostate cancer

BACKGROUND. ERG rearrangements in localized prostate cancer can be detected with high sensitivity and specificity by immunohistochemistry (IHC). However, recent data suggest that ERG IHC may be less sensitive for ERG rearrangements in castration-resistant prostate cancer (CRPC). Thus, we sought to examine ERG protein expression in a cohort of rapid autopsy patients with lethal metastatic CRPC (mCRPC). METHODS. A tissue microarray (TMA) of tumor sites from these patients was evaluated for ERG, prostate-specific antigen (PSA), and androgen receptor (AR) expression by IHC and correlated with ERG rearrangement status by fluorescent in situ hybridization (FISH). IHC was scored as the product of tumor cell staining intensity (0-3) and percentage of cells positive (0-100) (overall product score range = 0-300). RESULTS. All 16 (100%) ERG rearrangement negative (ERG^neg) patients were also negative for ERG tumor cell expression (i.e., IHC product score = 0). Of the 10 ERG rearrangement positive (ERG ^pos) patients, two (20%) were completely negative for ERG tumor cell expression, while eight (80%) had weak ERG expression (median IHC product score = 5-110). Of these eight ERG^pos patients, five (63%) had at least one tumor site without any detectable ERG expression. For a given ERG^pos patient, ERG expression varied both between and within tumor sites; AR and PSA expression also varied between tumor sites, and there was no significant correlation between ERG and AR or PSA expression. CONCLUSIONS. These data reveal frequent discordance between ERG IHC and ERG FISH in ERG^pos patients from this unique cohort of heavily treated lethal mCRPC.