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

Abstract

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.

Keywords: Early detection; Gene fusions; PCA3; Prostate cancer; Urine biomarkers.

Fig. 1

Flow diagram of specimens in the training and validation cohort. Specimen cohorts for all urine samples assessed for TMPRSS2:ERG (T2:ERG) and PCA3 are shown. Samples excluded from various analyses (indicated by legend and described in the text) are indicated in red. Samples assessed using version 2 or version 3 (final assay) T2:ERG transcription-mediated amplification assays are indicated. AS= active surveillance; EDRN = Early Detection Research Network; PCPTrc = Prostate Cancer Prevention Trial risk calculator; PCPThg = PCPT high grade cancer risk calculator; PSA = prostate-specific antigen; ROC = receiver operating characteristic; T2:ERG = TMPRSS2:ERG;UMHS = University of Michigan Health System; v3 = version 3.

Fig. 2

Calibration plots and decision curve analysis (DCA) demonstrate enhanced risk stratification and net clinical benefit of Mi-Prostate Score (MiPS) models compared with Prostate Cancer Prevention Trial risk calculators for predicting prostate cancer (PCPTrc) or high-grade cancer (PCPThg) on biopsy. Logistic regression models incorporating serum prostate-specific antigen (or PCPT risk calculators), urine TMPRSS2:ERG (T2:ERG) score, and urine PCA3 scores were trained on a cohort of 711 evaluable patients for predicting prostate cancer on biopsy. Trained models were then evaluated in a separate validation cohort of 1225 evaluable patients. (a) Calibration plot (observed vs predicted risks of prostate cancer on biopsy) using predicted probabilities from the PCPTrc version 1.0 (PCPTrc, red points) and the trained MiPS_PCPT model (PCPTrc plus T2:ERG plus PCA3, black points) in the validation cohort. Plots from groups of n = 10 are shown (Supplementary Fig. 1 shows plots from group of n = 5 and n = 15). Perfect calibration is indicated by the dashed 45° line. (b) As in panel (a) but predicting high-grade cancer (Gleason score >6) on biopsy and using the PCPThg (red points) and the trained MiPS_PCPThg model (PCPThg plus T2:ERG plus PCA3, black points). (c–f) Decision curve analysis (DCA) demonstrated net clinical benefit of biopsying patients in the validation cohort based on MiPS- versus PCPT-based models across a range of clinically relevant threshold probabilities (the risk of cancer [or high-grade cancer] on biopsy that a patient would choose to undergo biopsy based on their weight of relative harms of false-positive and false-negative predictions). (c) Net clinical benefit of the PCPTrc (red line) and the MiPS_PCPT model (black line) are shown (using 5% increments) compared with strategies of biopsying everyone (gray line) and biopsying no one (x-axis). The MiPS_PCPT-based strategy shows net clinical benefit compared with PCPTrc across a range of relevant threshold probabilities. (d) As in panel (c) but comparing the PCPThg (red line) and the MiPS_PCPThg model (black line). (e, f) DCA can also be used to visualize the percentage of biopsies avoided (compared with biopsying all patients) without missing any events across threshold probabilities. (e) Percentage of biopsies avoided without missing any cancers using the PCPTrc (red line) and the MiPS_PCPT model (black line) in the validation cohort. (f) Percentage of biopsies avoided without missing any high-grade cancers using the PCPThg (red line) and the MiPS_PCPThg model (black line). As an example, at a threshold probability of 10% chance of high-grade cancer on biopsy, biopsying patients on the basis of MIPS_PCPThg would result in an 18.5% reduction in biopsies without missing any high-grade cancers compared to only 3.2% for PCPThg. MiPS = Mi-Prostate Score; PCPTrc = Prostate Cancer Prevention Trial risk calculator; PCPThg = PCPT high grade cancer risk calculator.