Cost-effectiveness of an urinary biomarker panel in combination with MRI for prostate cancer diagnosis.

PURPOSE: The health impact and cost-effectiveness of the biomarker test SelectMDx were evaluated when used in combination with MRI, in two US populations: biopsy naïve men and men with a previous negative biopsy. METHODS: Using a decision model, the current MRI strategy was compared with two SelectMDx strategies: SelectMDx used before MRI to select men for MRI and SelectMDx used after a negative MRI to select men for biopsy. Parameters were informed by the literature most relevant for both populations. Differences in quality-adjusted life years (QALYs) and costs between the current strategy and the SelectMDx strategies were calculated using two different assumptions regarding PCa-specific mortality (SPCG-4 and PIVOT). RESULTS: In biopsy naïve men, the use of SelectMDx before MRI results in a gain of 0.004 QALY per patient under the SPCG-4 scenario, and a gain of 0.030 QALY under the PIVOT scenario. The cost savings are $1650 per patient. When used after MRI, SelectMDx results in a QALY gain per patient of 0.004 (SPCG-4), and 0.006 (PIVOT) with $262 in cost savings. In the previous negative population, SelectMDx before MRI results in a QALY gain of 0.006 (SPCG-4) and 0.022 (PIVOT), with $1281 in cost savings per patient. SelectMDx after MRI results in a QALY gain of 0.003 (SPCG-4) and 0.004 (PIVOT) with $193 in cost savings. CONCLUSION: Application of SelectMDx results in better health outcomes and cost savings. The value of SelectMDx was highest when used before MRI to select patients for MRI and subsequent biopsy.

Epigenetic risk score improves prostate cancer risk assessment.

BACKGROUND: Early detection of aggressive prostate cancer (PCa) remains crucial for effective treatment of patients. However, PCa screening remains controversial due to a high rate of overdiagnosis and overtreatment. To better reconcile both objectives, more effective methods for assessing disease severity at the time of diagnosis are needed. METHODS: The relationship between DNA-methylation and high-grade PCa was examined in a cohort of 102 prospectively enrolled men who received standard 12-core prostate biopsies. EpiScore, an algorithm that quantifies the relative DNA methylation intensities of GSTP1, RASSF1, and APC in prostate biopsy tissue, was evaluated as a method to compensate for biopsy under-sampling and improve risk stratification at the time of diagnosis. RESULTS: DNA-methylation intensities of GSTP1, RASSF1, and APC were higher in biopsy cores from men diagnosed with GS ≥ 7 cancer compared to men with diagnosed GS 6 disease. This was confirmed by EpiScore, which was significantly higher for subjects with high-grade biopsies and higher NCCN risk categories (both P < 0.001). In patients diagnosed with GS ≥ 7, increased levels of DNA-methylation were present, not only in the high-grade biopsy cores, but also in other cores with no or low-grade disease (P < 0.001). By combining EpiScore with traditional clinical risk factors into a logistic regression model, the prediction of high GS reached an AUC of 0.82 (95%CI: 0.73-0.91) with EpiScore, DRE, and atypical histological findings as most important contributors. CONCLUSIONS: In men diagnosed with PCa, DNA-methylation profiling can detect under-sampled high-risk PCa in prostate biopsy specimens through a field effect. Predictive accuracy increased when EpiScore was combined with other clinical risk factors. These results suggest that EpiScore could aid in the detection of occult high-grade disease at the time of diagnosis, thereby improving the selection of candidates for Active Surveillance.

Association Between Combined TMPRSS2:ERG and PCA3 RNA Urinary Testing and Detection of Aggressive Prostate Cancer.

IMPORTANCE: Potential survival benefits from treating aggressive (Gleason score, ≥7) early-stage prostate cancer are undermined by harms from unnecessary prostate biopsy and overdiagnosis of indolent disease. OBJECTIVE: To evaluate the a priori primary hypothesis that combined measurement of PCA3 and TMPRSS2:ERG (T2:ERG) RNA in the urine after digital rectal examination would improve specificity over measurement of prostate-specific antigen alone for detecting cancer with Gleason score of 7 or higher. As a secondary objective, to evaluate the potential effect of such urine RNA testing on health care costs. DESIGN, SETTING, AND PARTICIPANTS: Prospective, multicenter diagnostic evaluation and validation in academic and community-based ambulatory urology clinics. Participants were a referred sample of men presenting for first-time prostate biopsy without preexisting prostate cancer: 516 eligible participants from among 748 prospective cohort participants in the developmental cohort and 561 eligible participants from 928 in the validation cohort. INTERVENTIONS/EXPOSURES: Urinary PCA3 and T2:ERG RNA measurement before prostate biopsy. MAIN OUTCOMES AND MEASURES: Presence of prostate cancer having Gleason score of 7 or higher on prostate biopsy. Pathology testing was blinded to urine assay results. In the developmental cohort, a multiplex decision algorithm was constructed using urine RNA assays to optimize specificity while maintaining 95% sensitivity for predicting aggressive prostate cancer at initial biopsy. Findings were validated in a separate multicenter cohort via prespecified analysis, blinded per prospective-specimen-collection, retrospective-blinded-evaluation (PRoBE) criteria. Cost effects of the urinary testing strategy were evaluated by modeling observed biopsy results and previously reported treatment outcomes. RESULTS: Among the 516 men in the developmental cohort (mean age, 62 years; range, 33-85 years) combining testing of urinary T2:ERG and PCA3 at thresholds that preserved 95% sensitivity for detecting aggressive prostate cancer improved specificity from 18% to 39%. Among the 561 men in the validation cohort (mean age, 62 years; range, 27-86 years), analysis confirmed improvement in specificity (from 17% to 33%; lower bound of 1-sided 95% CI, 0.73%; prespecified 1-sided P = .04), while high sensitivity (93%) was preserved for aggressive prostate cancer detection. Forty-two percent of unnecessary prostate biopsies would have been averted by using the urine assay results to select men for biopsy. Cost analysis suggested that this urinary testing algorithm to restrict prostate biopsy has greater potential cost-benefit in younger men. CONCLUSIONS AND RELEVANCE: Combined urinary testing for T2:ERG and PCA3 can avert unnecessary biopsy while retaining robust sensitivity for detecting aggressive prostate cancer with consequent potential health care cost savings.

Urine TMPRSS2:ERG Plus PCA3 for Individualized Prostate Cancer Risk Assessment.

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.

A comparative study of ERG status assessment on DNA, mRNA, and protein levels using unique samples from a Swedish biopsy cohort.

The ERG rearrangement is identified in approximately 50% of prostate cancer screened cohorts and is known to be highly specific. This genetic aberration, most commonly leading to the TMPRSS2-ERG fusion, but also SLC45A3-ERG or NDRG1-ERG fusions, all leading to an overexpression of a truncated ERG protein. Most studies have applied in situ hybridization (FISH) methods or mRNA-based assays to investigate the ERG status. Recently, studies showed that ERG protein levels assessed by ERG antibodies can be used as a surrogate marker for ERG rearrangement. In the current study, we investigate ERG status on a series of diagnostic biopsies using DNA-based, mRNA-based, and protein-based assays. We formally compared 3 assay results (ie, FISH, fusion mRNA, and immunohistochemistry) to identify which method could be most appropriate to use when having limited amount of tissue. ERG rearrangement was found in 56% of the cases. Comparing ERG rearrangement status by FISH with ERG overexpression and TMPRSS2-ERG fusion transcript we found 95.1% (154/162, Fisher exact test 9.50E-36) and 85.2% (138/162, Fisher exact test 7.26E-22) concordance, respectively. We show that the ERG antibody highly correlates with the ERG rearrangement with high sensitivity and specificity. We also identified the most common TMPRSS2-ERG isoform in the majority of ERG rearranged cases. These results provide compelling evidence that the ERG antibody can be used to further investigate the role of ERG in prostate cancer.