Elsevier

European Urology

Volume 58, Issue 6, December 2010, Pages 893-899
European Urology

Prostate Cancer
Performance of Prostate Cancer Antigen 3 (PCA3) and Prostate-Specific Antigen in Prescreened Men: Reproducibility and Detection Characteristics for Prostate Cancer Patients with High PCA3 Scores (≥100)

https://doi.org/10.1016/j.eururo.2010.09.030Get rights and content

Abstract

Background

Prostate cancer antigen 3 (PCA3) is considered to be prostate cancer (PCa) specific and highly overexpressed in cancer. Therefore a high PCA3 score should result in a high positive predictive value (PPV) and specificity for a positive biopsy.

Objective

Our aim was to reevaluate, retest PCA3, and rebiopsy men with an initial PCA3 ≥100 and no PCa detected and compare the results with a random cohort of men with an initial PCA3 < 100.

Design, setting, and participants

We invited men 63–75 yr of age with a PCA3 ≥100 for retesting and a control group with an initial PCA3 < 100 to participate in the European Randomized Study of Screening for Prostate Cancer, section Rotterdam.

Interventions

Blood and urine sampling were used to determine prostate-specific antigen (PSA) and PCA3. Prostate biopsies were performed if the PSA was ≥2.5 ng/ml and/or the PCA3 score was ≥35.

Measurements

We correlated the initial and reevaluated PCA3 scores. Our assessment of the PPV after rebiopsy was based on the newly determined PCA3 score.

Results and limitations

After a mean study period of 19 mo, more cases of PCa were detected in rebiopsied men with initial PCA3 scores ≥100 than in the controls with PCA3 scores <100 (30.0% vs 18.8%). Combining initial and rebiopsy data resulted in a PPV of 52.2% in men with PCA3 ≥100. Over time, changes in PSA and PCA3 levels were quite different.

Conclusions

In spite of our rescreened population, PPV and specificity were comparable with all reported studies of men with PCA3 scores ≥100. These findings do not explain why these PCA3 scores were excessively high in spite of the absence of biopsy-detectable PCa.

Introduction

The prostate cancer gene 3 (DD3), now known as prostate cancer antigen 3 (PCA3), was identified in 1999. A DD3-based quantitative reverse transcriptase-polymerase chain reaction assay was developed to determine PCA3 in prostate cells shed into the urine after rectal examination [1], [2], [3], [4].

The difference in expression of PCA3 between normal prostate cells and prostate cancer (PCa) cells is large, qualifying the test as more specific for PCa than serum prostate-specific antigen (PSA). Such a test is obviously needed to improve on PSA, which is prostate specific but not cancer specific [5].

The high level of specificity of PCA3 in prostate tissues created an expectation for PCA3 in cells shed into urine, and thus the positive predictive value (PPV) after biopsy should be high. A rebiopsy should be considered in men who have a high PCA3 score and a negative biopsy result. In our previous publication [6] on 721 men who were all biopsied, only 28 of 90 men with a PCA3 score ≥100 had a positive lateralized sextant biopsy (PPV: 31.1%), although the specificity was 90%. This warranted further research, which is described in this paper.

Section snippets

Material and methods

We further assessed men with high PCA3 scores and negative biopsy results in the PCA3 study within the European Randomized Study of Screening for Prostate Cancer (ERSPC), section Rotterdam, performed earlier [6]. Repeat PCA3 testing and biopsy were performed in men with a PCA3 score ≥100 as well as in a randomly assigned control population of men with PCA3 scores <100. The study had three objectives: (1) to compare PCA3 scores obtained from retesting of archived urine specimens with the value

Part 1: Reevaluation of prostate cancer antigen 3 on original urine samples

The stored urine samples of 83 men (PCA3 score ≥100) and 117 men (PCA3 score <100) were retested in San Diego in January 2009 (Fig. 1). The PCA3 scores <100 were confirmed in 96.5% and the original PCA3 scores ≥100 in 50.6% of cases. This discrepancy was attributed to gel formation in the urine specimens in San Diego. Investigation performed by Gen-Probe indicated that overnight thawing caused the gelling, resulting in nonhomogeneous specimens, and the automated pipetter did not obtain an

Discussion

Part 1 of our evaluation described the retesting of archived frozen urine specimens. During this analysis, it became obvious that specimen thawing/handling can affect assay results, especially when using the Tecan automated pipette (Tecan Group, Männedorf, Switzerland). This problem is addressed in the manufacturer’s labeling. Discrepancy between the original and retest PCA3 scores due to assay variability seems unlikely. High concordance was shown when separate laboratories tested the same

Conclusions

Our data reveal an increase of the PPV to a level similar to those reported from other studies of men with PCA3 scores ≥100, which average 59%. PCA3 specificity is consistent with previous reports. These findings do not offer a direct explanation why PCA3 scores can be excessively high in spite of the absence of biopsy-detectable PCa. Longer follow-up of these men might provide more information. Changes over time of PSA and PCA3 are different with considerably more decreasing PCA3 values.

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