Elsevier

European Urology

Volume 57, Issue 6, June 2010, Pages 921-927
European Urology

Platinum Priority – Prostate Cancer
Editorial by Bob Djavan on pp. 928–929 of this issue
Prostate-Specific Antigen (PSA) Isoform p2PSA in Combination with Total PSA and Free PSA Improves Diagnostic Accuracy in Prostate Cancer Detection

https://doi.org/10.1016/j.eururo.2010.02.003Get rights and content

Abstract

Background

Novel markers for prostate cancer (PCa) detection are needed. Total prostate-specific antigen (tPSA) and percent free prostate-specific antigen (%fPSA = tPSA/fPSA) lack diagnostic specificity.

Objective

To evaluate the use of prostate-specific antigen (PSA) isoforms p2PSA and benign prostatic hyperplasia–associated PSA (BPHA).

Design, setting, and participants

Our study included 405 serum samples from the Rotterdam arm of the European Randomised Study of Screening for Prostate Cancer and 351 samples from the Urology Department of Innsbruck Medical University.

Measurements

BPHA, tPSA, fPSA, and p2PSA levels were measured by Beckman-Coulter Access Immunoassay. In addition, the Beckman Coulter Prostate Health Index was calculated: phi = (p2PSA/fPSA) × √(tPSA).

Results and limitations

The p2PSA and phi levels differed significantly between men with and without PCa. No difference in BPHA levels was observed. The highest PCa predictive value in both cohorts was achieved by phi with areas under the curve (AUCs) of 0.750 and 0.709, a significant increase compared to tPSA (AUC: 0.585 and 0.534) and %fPSA (AUC: 0.675 and 0.576). Also, %p2PSA (p2PSA/fPSA) showed significantly higher AUCs compared to tPSA and %fPSA (AUC: 0.716 and 0.695, respectively). At 95% and 90% sensitivity, the specificities of phi were 23% and 31% compared to 10% and 8% for tPSA, respectively. In both cohorts, multivariate analysis showed a significant increase in PCa predictive value after addition of p2PSA to a model consisting of tPSA and fPSA (increase in AUC from 0.675 to 0.755 and from 0.581 to 0.697, respectively). Additionally, the specificity at 95% sensitivity increased from 8% to 24% and 7% to 23%, respectively. Furthermore, %p2PSA, phi, and the model consisting of tPSA and fPSA with or without the addition of p2PSA missed the least of the tumours with a biopsy or pathologic Gleason score ≥7 at 95% and 90% sensitivity.

Conclusions

This study shows significant increases in PCa predictive value and specificity of phi and %p2PSA compared to tPSA and %fPSA. p2PSA has limited additional value in identifying aggressive PCa (Gleason score ≥7).

Introduction

Because serum total prostate-specific antigen (tPSA) and percent free prostate-specific antigen (%fPSA) lack clear thresholds balancing specificity and sensitivity for the early detection of prostate cancer (PCa), continuous efforts are being made to discover new PCa markers. Detailed examination of the free prostate-specific antigen (fPSA) fraction resulted in the identification of several distinctive fPSA forms, among which a mixture of precursor isoforms of prostate-specific antigen (pPSA or proPSA) and a form designated “benign” PSA (ie, benign prostatic hyperplasia–associated PSA [BPHA]) [1], [2], [3], [4], [5], [6]. A study specifically concentrating on the precursor isoform of PSA containing two amino acids in the propeptide leader confirmed the presence of [-2]proPSA in serum of men with PCa, in which [-2]proPSA formed 25–95% of the fPSA fraction, in contrast with 6–19% in biopsy-negative men [2]. Initial reports investigating the clinical value of [-2]proPSA in screening for PCa showed that [-2]proPSA serum concentrations were in general higher in men with PCa compared to men without cancer [7], [8], [9], [10]. Recently, reports by Sokoll et al [11] and Stephan et al [12] showed that [-2]proPSA is able to significantly improve PCa detection.

Characterisation of BPHA showed that it contains 237 amino acids like PSA but is clipped at several specific amino acid residues [5]. Measurement of BPHA concentrations in serum demonstrated that BPHA represented 25% of the fPSA in biopsy-negative men and was significantly higher in benign compared to PCa serum [1]. Furthermore, BPHA outperformed fPSA as well as tPSA in the prediction of transition zone enlargement [13]. A recent study evaluating the use of BPHA in discriminating PCa patients from patients without evidence of PCa showed that BPHA might improve PCa detection [14]. Results on a possible prognostic role for BPHA as well as [-2]proPSA have proven inconclusive [12], [14], [15], [16].

In this two-centre study, both p2PSA and BPHA serum concentrations were measured in men with and without PCa to evaluate the additional clinical utility of p2PSA and BPHA next to tPSA and fPSA in a screening setting for PCa. (Note that the analyte is referred to as [-2]proPSA and the assay as p2PSA; for simplicity, p2PSA is used throughout the remainder of this report.) Also, several calculated derivatives, among which the Beckman Coulter Prostate Health Index (phi), a mathematical combination of PSA, fPSA, and p2PSA, were assessed. In addition, all analysed variables were assessed with respect to biopsy and pathologic Gleason scores and their ability to detect cancers with a Gleason score of ≥7.

Section snippets

Patient selection

Serum samples from site 1 were obtained from the biorepository of the Rotterdam arm of the European Study of Screening for Prostate Cancer. From 1994 to February 1997, indications for a prostate biopsy consisted of a tPSA level >4.0 ng/ml, abnormal digital rectal examination (DRE), or abnormal transrectal ultrasound (TRUS). In 1997, this combination was replaced by PSA testing only [17]. Serum samples from site 2 were enrolled from the PCa screening study at the Urology Department of the

Results

Patient characteristics are depicted in Table 1. Overall characteristics did not differ significantly except for the number of unknown pathologic Gleason scores and the number of men who underwent prostatectomy. In both cohorts, the percentage of tumours with a pathologic Gleason score ≥7 was higher than at the initial biopsy because of upgrading based on the prostatectomy specimen.

At site 1, median levels of all assayed and calculated variables except BPHA differed significantly between men

Discussion

The present two-centre study was initiated to assess the performance in PCa detection of the PSA isoforms p2PSA and BPHA in addition to tPSA and fPSA. Furthermore, the relationship between p2PSA and BPHA as well as biopsy and pathologic Gleason score and their ability to specifically detect cancers with a Gleason score ≥7 was assessed.

In short, BPHA had no additional PCa predictive value over tPSA and %fPSA, whereas phi and %p2PSA showed significantly higher PCa predictive values combined with

Conclusions

The present study shows that p2PSA and, moreover, %p2PSA and phi could have additional value with respect to tPSA and %fPSA in PCa detection within the tPSA range of 2–10 ng/ml by significantly increasing the predictive value and specificity for PCa. By increasing the clinical specificity of phi and p2PSA relative to tPSA and fPSA, the use of phi and p2PSA could potentially modify the number of men receiving a recommendation for biopsy. In addition, p2PSA has limited additional value in

References (23)

Cited by (223)

  • Biosensors for prostate cancer detection

    2023, Trends in Biotechnology
  • PSA: role in screening and monitoring patients with prostate cancer

    2022, Cancer Biomarkers: Clinical Aspects and Laboratory Determination
View all citing articles on Scopus

Please visit www.eu-acme.org/europeanurology to read and answer questions on-line. The EU-ACME credits will then be attributed automatically.

View full text