Thioredoxin Reductase Rna Levels In Expressed Prostatic Secretions As Prognostic Indicators Of Prostate Cancer.

4623 Background: Thioredoxin reductases (TXNRD1, TXNRD2 and TGR) are involved in multiple cell functions: protection from oxidative stress, control of apoptosis, and synthesis of DNA. Like TMPRSS2:ERG, the thioredoxin system has been shown to play a role in more advanced prostate cancer. We have used nanotechnology to demonstrate that TXNRD1 and TXNRD2 are strongly up regulated in intratumoral reactive stroma (Singer et al., In Press). Using expressed prostatic secretions (EPS) we evaluated TXNRD1, along with other biomarkers as predictors of positive surgical margins in patients undergoing radical prostatectomy. Methods: We collected EPS prior to surgery in a blinded prospective study from 82 men undergoing radical prostatectomy for prostate cancer. 200ng of RNA from each specimen was used to prepare cDNA for TaqMan qPCR analysis of RNA levels. Specimens were analyzed for expression of RNA from PSA, PCA3, TXNRD1, and Type III plus VI TMPRSS2:ERG gene fusions. The capacity of these biomarkers to improve characteristic performance for predicting positive surgical margins (PSM), over baseline pre-surgical parameters: age, pre-biopsy serum PSA, biopsy Gleason sum and digital rectal exam (DRE) was analyzed. Results: The addition of assays for TXNRD1, PSA, PCA3, and TMPRSS2:ERG (type III+VI) RNA to baseline presurgical parameters for positive surgical margin prediction improved the area under the curve (AUC) from 0.728 (95%CI 0.6313728-0.8240672) to 0.862 (95%CI 0.7870411-0.9364589). At 80% specificity for positive margins, the baseline sensitivity using only DRE,PSA and biopsy Gleason sum was 56%. However, when TXNRD1, PSA, PCA3, and TMPRSS2:ERG (type III+VI), were added as predictors, the sensitivity was increased to 80% at 80% specificity. Based on these data, this test provides an 81% negative predictive value, compared to 75% for PSA, DRE and biopsy Gleason sum alone. Conclusions: The combination of biopsy Gleason sum and PSA correlate strongly with positive surgical margins. The addition of TXNRD1, PSA, PCA3, and TMPRSS2:ERG(type III+VI), markers as predictors improves the sensitivity and negative predictive value in predicting positive surgical margins prior to surgery.