Background TMPRSS2:ERG (T2:ERG) and prostate cancer antigen 3 (PCA3) are the most advanced urine-based prostate cancer (PCa) early detection biomarkers. Objective Validate logistic regression models, termed Mi-Prostate Score (MiPS), that incorporate serum prostate-specific antigen (PSA; or the multivariate Prostate Cancer Prevention Trial risk calculator version 1.0 [PCPTrc]) and urine T2:ERG and PCA3 scores for predicting PCa and high-grade PCa on biopsy. Design, setting, and participants T2:ERG and PCA3 scores were generated using clinical-grade transcription-mediated amplification assays. Pretrained MiPS models were applied to a validation cohort of whole urine samples prospectively collected after digital rectal examination from 1244 men presenting for biopsy. Outcome measurements and statistical analysis Area under the curve (AUC) was used to compare the performance of serum PSA (or the PCPTrc) alone and MiPS models. Decision curve analysis (DCA) was used to assess clinical benefit. Results and limitations Among informative validation cohort samples (n = 1225 [98%], 80% from patients presenting for initial biopsy), models incorporating T2:ERG had significantly greater AUC than PSA (or PCPTrc) for predicting PCa (PSA: 0.693 vs 0.585; PCPTrc: 0.718 vs 0.639; both p < 0.001) or high-grade (Gleason score >6) PCa on biopsy (PSA: 0.729 vs 0.651, p < 0.001; PCPTrc: 0.754 vs 0.707, p = 0.006). MiPS models incorporating T2:ERG score had significantly greater AUC (all p < 0.001) than models incorporating only PCA3 plus PSA (or PCPTrc or high-grade cancer PCPTrc [PCPThg]). DCA demonstrated net benefit of the MiPS_PCPTrc (or MiPS_PCPThg) model compared with the PCPTrc (or PCPThg) across relevant threshold probabilities. Conclusions Incorporating urine T2:ERG and PCA3 scores improves the performance of serum PSA (or PCPTrc) for predicting PCa and high-grade PCa on biopsy. Patient summary Incorporation of two prostate cancer (PCa)-specific biomarkers (TMPRSS2:ERG and PCA3) measured in the urine improved on serum prostate-specific antigen (or a multivariate risk calculator) for predicting the presence of PCa and high-grade PCa on biopsy. A combined test, Mi-Prostate Score, uses models validated in this study and is clinically available to provide individualized risk estimates.
INTRODUCTION AND OBJECTIVES: There has been no consensus on the prostatic tissue and blood androgen concentrations in men with different stages and pathological grades of prostate cancer. In this study, testosterone (T) and dihydrotestosterone (DHT) concentrations in blood and needle biopsy specimens of prostate were examined by newly developed ultra sensitive LC-MS/MS method.METHODS: We analyzed 196 men (mean age 70.6 years) diagnosed as prostate cancer from November 2005 to July 2007. Those patients received systematic needle biopsy, and additionally one needle biopsy from proximal zone was conducted for the purpose of simultaneous determination of T and DHT. T and DHT concentrations in prostate tissues and blood were determined by LC-MS/MS method. Determination limit of this method was 0.5 pg/shot for T and 1 pg/shot for DHT. Concentration of T and DHT were expressed in pg/mg. T and DHT levels in tissue and blood were compared with Gleason score, clinical stage, and percentage of positive biopsy cores (% positive cores) by multivariate analyses.RESULTS: Median value of PSA and prostate volume measured by ultrasound were 11.5 ng/mL and 27.7 cc, respectively. Median values of T and DHT in blood were 3551.0 pg/mL and 330.5 pg/mL, respectively. There was a strong correlation between serum T and DHT. Median values of T and DHT in tissue were 0.566 pg/mg and 7.062 pg/mg, respectively. In multivariate analysis, serum PSA and tissue T levels were significantly associated with poor prognosis factors in men with prostate cancer. High testosterone levels in prostate tissue were related to high Gleason score (pϭ0.041), advanced clinical stage (pϭ0.002), and high proportion of % positive cores (pϭ0.001).CONCLUSIONS: Testosterone and dihydrotestosterone concentrations in blood or prostate tissue of needle biopsy were simultaneously examined by newly developed ultra sensitive quantifying method, LC-MS/MS. We confirmed that high testosterone levels in prostate tissue were related to high Gleason score, advanced clinical stage, and high proportion of % positive cores. These results suggest that testosterone level of needle biopsy specimens may be useful as a predictive factor in prostate cancer patients.
Objective: In men diagnosed with prostate cancer (PCa) at biopsy, a major challenge is correctly stratifying those with indolent versus significant PCa for treatment selection. The extent and grade of PCa is assessed in part based on standard risk factors, biopsy Gleason score (bx GS) and the number of positive biopsy cores. However, due to under-sampling at biopsy, upgrading in Gleason score is often seen from biopsy to prostatectomy. In this study we evaluated a TMPRSS2:ERG (T2:ERG) urine test for its ability to identify significant cancer and upgrading at prostatectomy. Methods: Post-DRE urine specimens were prospectively collected from 218 men referred for prostatectomy. T2:ERG mRNA copies were quantified using a transcription-mediated amplification assay and normalized to PSA mRNA copies to calculate a T2:ERG score. The prototype T2:ERG urine assay detects the gene fusion mRNA isoform TMPRSS2 exon 1 to ERG exon 4. T2:ERG score was correlated to prostatectomy Gleason score (px GS) and significant cancer as defined by the Epstein criteria at prostatectomy. Results: Of 185 men scheduled for radical prostatectomy, 61 had low risk of significant cancer based on having bx GS<6 and % positive biopsy cores<33%, yet upon prostatectomy, 57% of these men were found to harbor a significant PCa. The T2:ERG assay identified an additional 31% prostatectomy significant cancer in the biopsy low-risk disease cancer group. In a multivariate model, adding T2:ERG to bx GS and % positive cores significantly increased the accuracy for predicting significant PCa at prostatectomy from 0.84 to 0.89 (p=0.0002). Sensitivity increased by 8% for detecting prostatectomy significant cancer when T2:ERG was added to these biopsy criteria (sens/spec=85%/87% vs 77%/87%). T2:ERG also significantly correlated with Gleason score upgrading from biopsy to prostatectomy (bx GS/px GS = 6/ 6 vs bx GS/px GS = 6/>7, p = 0.0076). At biopsy, 70 men were found to have low-grade cancer (bx GS<6), but upon prostatectomy, upgrading was seen in 50% of these men. T2:ERG was able to identify 40% of men with bx GS<6 that were later upgraded. Conclusions: A T2:ERG urine test may help identify significant cancers and Gleason score upgrading, and increase predictive accuracy when used in combination with currently available methods. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 899. doi:10.1158/1538-7445.AM2011-899
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