Abstract C50: Molecular Segmentation of High-Risk Prostate Cancer by PTEN Loss, AR Upregulation, and TMPRSS2-ERG Gene Fusion.

Abstract Prostate cancer (PCa) is the most frequently diagnosed cancer in men accounting for 10% of all US cancer deaths and 33% of all cancer cases. Few options exist for patients that present with metastatic disease or fail anti-androgen therapy and develop hormone (castrate) resistant prostate cancer (HRPC). The definition of new molecular segments may offer therapeutic opportunities for high risk prostate cancer. In order to characterise high risk PCa segments at a molecular level a combination of immunohistochemistry (IHC, to detect nuclear AR, nuclear ERG and cytoplasmic PTEN protein expression) and fluorescent in situ hybridisation (FISH, to detect TMPRSS2-ERG fusion, translocation and PTEN gene loss) were employed to analyze archival prostate cancer specimens representing disease progression (n>500). After pathology scoring, correlations were performed between biomarkers and clinicopathological parameters. PCa-associated changes for each biomarker were defined using both normal prostate samples and benign glands within lesions as comparators and were identified as PTEN loss, TMPRSS2-ERG gene fusion, ERG positivity and AR up-regulation. PTEN loss was classified as a lack of cytoplasmic signal in malignant glands by IHC; FISH analysis of a subset confirmed this to be indicative of allelic deletion. TMPRSS2-ERG fusion was classed as a FISH green: red probe ratio score of <0.7 and in primary PCa, 95% concordance was observed between the fusion and nuclear expression of ERG protein (IHC score >0). AR up-regulation was defined by IHC as a strong (3+) nuclear signal in malignancy compared to a weak-medium signal (1–2+) in benign glands. Both PTEN loss (50%) and TMPRSS2-ERG fusion with concurrent nuclear ERG (43%), were found in hormone sensitive prostate cancer (HSPC) compared to normal prostate epithelium or prostatic intraepithelial neoplasia (PIN) suggesting that these are early events. PTEN loss increased during progression (60% HRPC; 70% metastases) and TMPRSS2-ERG fusions with ERG expression persisted in HRPC (39%). PTEN loss correlated with Gleason score (G4–7: 49%; G8–10: 62%), whereas TMPRSS2-ERG did not. Translocation of the TMPRSS2 locus to other chromosomes was found within a small subset of HRPC and metastatic lesions (10%). Up-regulation of nuclear AR was associated with HRPC (70%) but not HSPC (<5%), and was retained with progression to metastases (70%). AR up-regulation correlated with Gleason score (G4–7: 26%; G8–10: 50%). With respect to biomarker relationships, high nuclear AR correlated with TMPRSS2-ERG fusions during progression (HSPC (23%), HRPC (72%) and metastases (80%)). Although HSPC exhibited either PTEN loss or nuclear AR up-regulation both were rarely observed in the same tumor (2.5%) compared to HRPC and metastatic samples (>30%). The proportion of tumors exhibiting one or more PCa-related change (PTEN loss, AR up-regulation or TMPRSS2-ERG fusion) increased with disease progression (HSPC, 75%; HRPC, 85%; metastases, 95%). Taken together, these data provide evidence to suggest combination therapy targeting these three core molecular events may provide benefit to a significant number of high risk PCa patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C50.