Original article
Clinical–prostate
Combining urinary detection of TMPRSS2:ERG and PCA3 with serum PSA to predict diagnosis of prostate cancer

https://doi.org/10.1016/j.urolonc.2011.04.001Get rights and content

Abstract

Objectives

We sought to develop a clinical algorithm combining serum PSA with detection of TMPRSS2:ERG fusion and PCA3 in urine collected after digital rectal exam (post-DRE urine) to predict prostate cancer on subsequent biopsy.

Materials and methods

Post-DRE urine was collected in 48 consecutive patients before prostate biopsy at 2 centers; quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to detect PCA3 and TMPRSS2:ERG fusion transcript expression. Serum PSA was measured by clinical assay. The performance of TMPRSS2:ERG fusion, PCA3, and serum PSA as biomarkers predicting prostate cancer at biopsy was measured; a clinically practical algorithm combining serum PSA with TMPRSS2:ERG and PCA3 in post-DRE urine to predict prostate cancer was developed.

Results

Post-DRE urine sediment provided informative RNA in 45 patients; prostate cancer was present on subsequent biopsy in 15. TMPRSS2:ERG in post-DRE urine was associated with prostate cancer (OR = 12.02; P < 0.001). PCA3 had the highest sensitivity in predicting prostate cancer diagnosis (93%), whereas TMPRSS2:ERG had the highest specificity (87%). TMPRSS2:ERG had the greatest discriminatory value in predicting prostate cancer (AUC = 0.77 compared with 0.65 for PCA3 and 0.72 for serum PSA alone). Combining serum PSA, PCA3, and TMPRSS2:ERG in a multivariable algorithm optimized for clinical utility improved cancer prediction (AUC = 0.88; specificity = 90% at 80% sensitivity).

Conclusions

A clinical algorithm specifying biopsy for all patients with PSA ≥ 10 ng/ml, while restricting biopsy among those with PSA <10 ng/ml to only those with detectable PCA3 or TMPRSS2:ERG in post-DRE urine, performed better than the individual biomarkers alone in predicting prostate cancer.

Introduction

More than 20 years after introduction of PSA into clinical practice, substantial gains in prostate cancer mortality reduction have been realized, but concurrent limitations in the performance of PSA in selecting patients for prostate biopsy have persisted. These limitations have been further underscored by recently reported results from the European Randomized Study of Screening for Prostate Cancer (ERSPC) and Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO), which together indicate a continued need to improve upon serum PSA as our leading tool for prostate cancer early detection [1], [2], [3], [4], [5], [6].

The need for additional biomarkers that supplement PSA is reflected by the number of ongoing studies in this field. Amongst numerous experimental biomarkers for prostate cancer early detection, prostate cancer gene 3 (PCA3) [7] and recurrent gene fusions involving TMPRSS2 and ETS family members (such as TMPRSS2:ERG) [8] have shown promising results in preliminary studies and can be detected in post-DRE [9], [10], [11] urine specimens that are suitable for possible use in clinical diagnostic strategies. One possible drawback of new molecular targets for early detection such as PCA3 or TMPRSS2:ERG fusion could be that they may only identify certain subgroups of cancer cases. In this context, one approach for optimizing performance of such biomarkers in predicting prostate cancer diagnosis is to develop models that combine different biomarkers to generate clinically useful, ‘multiplex’ algorithms for identifying candidates for prostate biopsy based on results of multiple biomarker assays combined with PSA test results.

In this study, we sought to verify the association of prostate cancer with detection in urine of TMPRSS2:ERG gene fusion, PCA3, and investigated how these biomarkers may be combined with serum PSA levels to develop clinically practical algorithms for predicting prostate cancer diagnosis.

Section snippets

Materials and methods

Urine samples were collected after attentive digital rectal exam (DRE) from 48 men undergoing prostate biopsy at 2 clinical practice sites participating in the National Cancer Institute/Early Detection Research Network biopsy cohort. Institutional Review Board approval was obtained at the collaborating institutions and informed consent was obtained from these men. Demographic and pre-biopsy clinical parameters, including age, race, history of smoking, height, weight, family history of prostate

Results

The demographic and pre-biopsy clinical parameters of 45 men from whom post-DRE urine samples were collected before prostate biopsy for these analyses and informative RNA was obtained are presented in Table 1. Fifteen (33%) men had a diagnosis of prostate cancer on biopsy of whom 7 (47%) have a Gleason 7 or higher. Of the 30 (67%) men without prostate cancer on biopsy, 5 (17%) had either atypia or prostatic intraepithelial neoplasia (PIN) or both identified on histology.

In the univariate

Comment

The performance of serum PSA as a biomarker for prostate cancer early detection is undermined by several limitations, including substantial false positive and false negative tests results because PSA is produced in benign as well as malignant prostate tissue. Hence, there is a need to identify biomarkers that are more specific for prostate cancer and that may thereby improve prospects for prostate cancer screening and early detection [5].

Recent advancements in high throughput technologies have

Conclusions

Early detection of prostate cancer is crucial in providing an effective therapy to patients. These new biomarkers can potentially fulfill this task more effectively than serum PSA alone, when used in combination. We have shown in this pilot study that TMPRSS2:ERG gene fusion and PCA3, especially in combination with serum PSA, are very attractive targets with respect to early detection of prostate cancer. Both markers can be detected in patients' urine after attentive digital rectal examination,

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    Funding was provided by NCI-EDRN CEVC U01 CA113913. SAT, AC, and MAR are listed as inventors in a patent related to diagnostic use of TMPRSS2:ERG.

    1

    These authors share first authorship.

    2

    These authors share senior authorship.

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