[-2]Proenzyme Prostate Specific Antigen for Prostate Cancer Detection: A National Cancer Institute Early Detection Research Network Validation Study

Departments of Pathology and Urology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
The Journal of urology (Impact Factor: 4.47). 09/2008; 180(2):539-43; discussion 543. DOI: 10.1016/j.juro.2008.04.015
Source: PubMed


This study evaluated the [-2]proenzyme prostate specific antigen serum marker using a blinded reference specimen set from 3 National Cancer Institute Early Detection Research Network centers from men with an indication for prostate biopsy.
Serum was collected before biopsy from 123 men with no prior biopsy or prostate cancer history. Specimens (cancer cases 51%, noncancer controls 49%) were selected equally from the 3 sites, and analyzed for prostate specific antigen, free prostate specific antigen, [-2]proenzyme prostate specific antigen, benign prostate specific antigen and testosterone (Beckman Coulter ACCESS(R) analyzer).
There was no difference in total prostate specific antigen concentrations (noncancer 6.80 +/- 5.20 ng/ml, cancer 6.94 +/- 5.12 ng/ml) among the groups. Overall %[-2]proenzyme prostate specific antigen had the greatest area under the curve (AUC 0.69) followed by percent free prostate specific antigen (AUC 0.61). For %[-2]proenzyme prostate specific antigen maximal sensitivity was 60% and specificity was 70%. A logistic regression model combining prostate specific antigen, benign prostate specific antigen, percent free prostate specific antigen, %[-2]proenzyme prostate specific antigen, [-2]proenzyme prostate specific antigen/benign prostate specific antigen and testosterone had an AUC of 0.73. In the 2 to 10 ng/ml prostate specific antigen range %[-2]proenzyme prostate specific antigen and the model had the largest AUC (0.73). The AUC for percent free prostate specific antigen was 0.53. Specificities for %[-2]proenzyme prostate specific antigen, the logistic regression model and percent free prostate specific antigen at 90% sensitivity were 41%, 32% and 18%, and at 95% sensitivity were 31%, 26% and 16%, respectively.
%[-2]proenzyme prostate specific antigen was the best predictor of prostate cancer detection compared to percent free prostate specific antigen, particularly in the 2 to 10 ng/ml total prostate specific antigen range. These findings provide a rationale for broader validation studies to determine whether %[-2]proenzyme prostate specific antigen alone can replace other molecular prostate specific antigen assays (such as percent free prostate specific antigen) for improving the accuracy of prostate cancer early detection. These findings also support the usefulness of well characterized, carefully collected reference sets to evaluate new biomarkers.

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    • "Table 1 shows studies investigating p2PSA validity and their main results. Sokoll et al. [24] evaluated the relationship between p2PSA and PCa by using serum samples of 123 men (51% PCa, 49% noncancer) enrolled in the Early Detection Research Network study. Overall, the %fPSA was significantly lower, whereas p2PSA and %p2PSA were higher, in PCa patients. "
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    ABSTRACT: Prostate-specific antigen (PSA) is recognized as an organ-specific marker with low specificity and sensitivity in discriminating prostate cancer (PCa) from other benign conditions, such as prostatic hyperplasia or chronic prostatitis. Thus, in the case of clinical suspicion, a PCa diagnosis cannot be made without a prostate biopsy. [-2]proPSA (p2PSA), a precursor of PSA, has been investigated as a new marker to accurately detect PCa. The aim of this systematic review was to discuss the available literature regarding the clinical validity and utility of p2PSA and its derivatives, p2PSA/fPSA (%p2PSA) and the Prostate Health Index (PHI). A systematic search of the PubMed and Scopus electronic databases was performed in accordance with the PRISMA statement (, considering the time period from January 1990 to January 2014 and using the following search terms: proprostate specific antigen, proenzyme PSA, proPSA, [-2]proPSA, p2PSA, Prostate Health Index, and PHI. To date, 115 studies have been published, but only 35 were considered for the qualitative analysis. These studies suggested that p2PSA is the most cancer-specific form of PSA, being preferentially expressed in PCa tissue and being significantly elevated in the serum of men with PCa. It is now evident that p2PSA, %p2PSA, and PHI measurements improve the specificity of the available tests (PSA and derivatives) in detecting PCa. Moreover, increasing PHI values seem to correlate with more aggressive disease. Some studies have compared p2PSA and its derivatives with other new biomarkers and found p2PSA to be significantly more accurate. Indeed, the implementation of these tests in clinical practice has the potential to significantly increase the physician's ability to detect PCa and avoid unnecessary biopsies, while also having an effective impact on costs. Further studies in large, multicenter, prospective trials are required to confirm these encouraging results on the clinical utility of these new biomarkers.
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