European Urology

1. Introduction

Messenger RNA (mRNA) of the prostate cancer antigen 3 (PCA3) gene, formerly known as DD3, was identified in 1999 and was found to be strongly overexpressed in >95% of primary prostate cancer (PCa) tissue specimens and PCa metastases [1] x M.J. Bussemakers, A. van Bokhoven, G.W. Verhaegh, et al. DD3: a new prostate-specific gene, highly overexpressed in prostate cancer. Cancer Res. 1999;59:5975-5979 . In the absence of a protein, a nucleic acid-based test was developed to investigate the potential of PCA3 mRNA as the basis for a diagnostic test [2] x D. Hessels, J.M.T. Klein Gunnewiek, I. van Oort, et al. DD3^PCA3-based molecular urine analysis for the diagnosis of prostate cancer. Eur Urol. 2003;44:8-16 discussion 15–6 Abstract, Full-text, PDF, Crossref. . In a cohort of 108 men admitted for prostate biopsies based on serum prostate-specific antigen (PSA) levels >3.0 ng/ml and/or an abnormal digital rectal examination (DRE), PCa was diagnosed in 24 of the 108 men (22.2%). Using a cut-off value of 200 × 10⁻³, this test has a sensitivity of 67% and a specificity of 83%. The relatively low sensitivity of 67% left doubts about the value of PCA3 as a first-line biopsy indicator [2] x D. Hessels, J.M.T. Klein Gunnewiek, I. van Oort, et al. DD3^PCA3-based molecular urine analysis for the diagnosis of prostate cancer. Eur Urol. 2003;44:8-16 discussion 15–6 Abstract, Full-text, PDF, Crossref. . The claimed PCa specificity was confirmed in another study [3] x J.B. De Kok, G.W. Verhaegh, R.W. Roelofs, et al. DD3(PCA3), a very sensitive and specific marker to detect prostate tumors. Cancer Res. 2002;62:2695-2698 , and diagnostic performance was validated in several studies using both urine and prostatic fluid as a substrate 4 x M. Tinzl, M. Marberger, S. Horvath, C. Chypre. DD3^PCA3 RNA analysis in urine – a new perspective for detecting prostate cancer. Eur Urol. 2004;46:182-187 discussion 187 Abstract, Full-text, PDF, Crossref. , and 5 x M.P. Van Gils, E.B. Cornel, D. Hessels, et al. Molecular PCA3 diagnostics on prostatic fluid. Prostate. 2007;67:881-887 Crossref. . Gen-Probe Inc. (San Diego, CA, USA) translated this quantitative PCA3-based test to the company's proprietary technology platform under the trade name Progensa PCA3 test [6] x J. Groskopf, S.M. Aubin, I.L. Deras, et al. APTIMA. PCA3 molecular urine test: development of a method to aid in the diagnosis of prostate cancer. Clin Chem. 2006;52:1089-1095 Crossref. . The first studies concentrated on the value of this test in men who had a previous negative biopsy [7] x L.S. Marks, Y. Fradet, I.L. Deras, et al. PCA3 molecular urine assay for prostate cancer in men undergoing repeat biopsy. Urology. 2007;69:532-535 Crossref. .

No single study to date has addressed the value of the PCA3 test as a primary indication for biopsy. All available studies primarily use the PSA test at different cut-off values with or without an abnormal DRE as a biopsy indication. Consequently, these studies are subject to assignment or attribution bias because any PSA cut-off value will miss many PCa cases, including aggressive ones, as has been shown 8 x I.M. Thompson, D.P. Ankerst, C. Chi, et al. Operating characteristics of prostate-specific antigen in men with an initial PSA level of 3.0 ng/ml or lower. JAMA. 2005;294:66-70 Crossref. , and 9 x I.L. Deras, S.M. Aubin, A. Blase, et al. PCA3: a molecular urine assay for predicting prostate biopsy outcome. J Urol. 2008;179:1587-1592 Crossref. .

The objective of the present study is to evaluate the performance characteristics of the PCA3 test with a cut-off score of ≥10 in comparison to a biopsy indication driven by PSA values of ≥3.0 ng/ml. Two issues of great clinical interest will also be addressed: (1) Is PCA3 helpful in improving the detection, specifically, of serious PCa in the low PSA ranges? (2) Is PCA3 helpful in improving the detection of PCa in men with a previous negative biopsy?

The evaluation is based on men presenting for rescreening within the ongoing European Randomised Study of Screening for Prostate Cancer (ERSPC), Rotterdam section [10] x M.J. Roobol, W.J. Kirkels, F.H. Schröder. Features and preliminary results of the Dutch centre of the ERSPC (Rotterdam, the Netherlands). BJU Int. 2003;92(Suppl 2):48-54 Crossref. .