BERKELEY, CA (UroToday.com) - Despite the overall success of PSA, its use as a serum marker for prostate cancer leaves much to be desired. The primary limitation of PSA has been its inability to accurately distinguish between a benign and malignant pathology. This is especially true in the total PSA (tPSA) range of 2–10 ng/mL where benign and malignant prostatic conditions frequently co-exist (the so called diagnostic ‘grey zone’). However, preoperative tools (such as PSA and DRE) lack accuracy to avoid many negative biopsies and to predict confined PCa at radical prostatectomy (RP).[1] To supplement the information from PSA analysis, several biomarkers have been proposed such as phi index and PCA3 score.[2, 3, 4, 5, 6, 7]
In 2012, PCA3 was approved by the U.S. Food and Drug Administration (FDA) for the use in men scheduled for repeat biopsy and [-2]proPSA for initial biopsy decisions in men with PSA concentrations in the range of 4-10 ng/ml and negative DRE. To date, a direct comparison of phi and PCA3 in a single centre study in subjects undergoing first biopsy with PSA values comprised in the “grey” zone 2-10 ng/ml has not been available.
Our study was designed in an effort to compare the diagnostic ability of PCA3 and phi in men who had undergone initial biopsies. Moreover, we stratified patient risk before treatment, according to PRIAS criteria,[8] thus we evaluated not only the ability of the two biomarkers to detect PCa, but also their correlation with active surveillance (AS) eligibility. Therefore, 332 subjects were enrolled before prostate biopsy (minimum 16 cores) in a prospective observational study, approved by the hospital ethics committee. Among these, only those meeting eligibility criteria (n=300) according to the study protocol were ultimately enrolled: age over 50 years, no prior prostate surgery and biopsy, no bacterial acute or chronic prostatitis, no use of 5-α reductase inhibitors, PSA values included between 2 and 10 ng/ml, availability of serum samples and corresponding clinical data, and completion of at least a 16-core template biopsy after enrollment. The final study cohort included 108 PCa patients (36%) and 192 (64%) with no evidence of malignancy (NEM). The primary aim of the study was to compare the identifying ability of PCa-negative and PCa-positive of Beckman Coulter phi [(p2PSA/fPSA)x √tPSA] and PCA3 score [(PCA3 mRNA/PSA mRNA) x 1000].
We found that the largest AUCs were obtained with phi, %p2PSA and PCA3 with no significant differences in pairwise comparison. All of them outperformed fPSA and %fPSA even after Bonferroni correction for multiple comparisons. Phi, %p2PSA and PCA3 also showed comparable levels of specificity at 90% level of sensitivity. Secondly, we performed multivariable analysis to evaluate the effect of the addition of phi and PCA3 to a base model including currently used PCa predictors (age, PSA, %fPSA, DRE, prostate volume), and we found an increase of predictive accuracy. Of note, no model improved single biomarker performance. Our findings open the discussion about whether phi or PCA3 could be recommended as the best single parameter in addition to PSA “grey” values as first-line diagnostic test for PCa detection.
Recently two different prospective multicenter studies suggested that phi and %p2PSA provided significantly better clinical performance than other PSA molecular forms assays in detecting PCa in 2-10 ng/ml tPSA range.[7, 9] Hansen. et al.[10] demonstrated that PCA3 achieved independent predictor status of PCa in subjects undergoing first prostate biopsy. In studies comparing phi and PCA3 performance in mixed biopsy patient cohort,[8] PCA3 score was more accurate than phi in the repeat biopsy setting. However, owing to its easier and economical technology, its lower discomfort for patients, and its better ability to reduce unnecessary biopsies (as shown by DCA), phi should probably be recommended as the best assay, in addition to PSA, as first-line diagnostic test for PCa detection.
Finally we investigated the performance of phi and PCA3 in the selection of active surveillance (AS) compatible cancer, and we found that the two biomarkers inversely correlate with AS criteria compatibility. Our encouraging results may help to improve the selection of patients eligible for active surveillance according to PRIAS criteria or for neurovascular bundle-sparing surgery.
The strength of our study resides in a single centre dataset, including subjects at first biopsy, allowing us to assess the net clinical benefit of one marker over the other and to define cut-offs calculated on a large population. Unfortunately the number of PCa patients is not enough to evaluate the ability of phi and PCA3, alone or in combination, to predict clinically localized cancer compatible with watchful waiting.
References:
- Loeb S, Gonzalez CM, Roehl KA, Han M, Antenor JA, et al. (2006) Pathological characteristics of prostate cancer detected through prostate specific antigen based screening. J Urol 175: 902-906.
- Auprich M, Bjartell A, Chun FK, de la Taille A, Freedland SJ, et al. (2011) Contemporary role of prostate cancer antigen 3 in the management of prostate cancer. Eur Urol 60: 1045-1054.
- Auprich M, Haese A, Walz J, Pummer K, de la Taille A, et al. (2010) External validation of urinary PCA3-based nomograms to individually predict prostate biopsy outcome. Eur Urol 58: 727-732.
- Catalona WJ, Partin AW, Sanda MG, Wei JT, Klee GG, et al. (2011) A multicenter study of [-2]pro-prostate specific antigen combined with prostate specific antigen and free prostate specific antigen for prostate cancer detection in the 2.0 to 10.0 ng/ml prostate specific antigen range. J Urol 185: 1650-1655.
- Ferro M, Bruzzese D, Perdona S, Mazzarella C, Marino A, et al. (2012) Predicting prostate biopsy outcome: Prostate health index (phi) and prostate cancer antigen 3 (PCA3) are useful biomarkers. Clin Chim Acta 413: 1274-1278.
- Guazzoni G, Nava L, Lazzeri M, Scattoni V, Lughezzani G, et al. (2011) Prostate-Specific Antigen (PSA) Isoform p2PSA Significantly Improves the Prediction of Prostate Cancer at Initial Extended Prostate Biopsies in Patients with Total PSA Between 2.0 and 10 ng/ml: Results of a Prospective Study in a Clinical Setting. Eur Urol 60: 214-222.
- Lazzeri M, Haese A, de la Taille A, Palou Redorta J, McNicholas T, et al. (2013) Serum Isoform [-2]proPSA Derivatives Significantly Improve Prediction of Prostate Cancer at Initial Biopsy in a Total PSA Range of 2-10 ng/ml: A Multicentric European Study. Eur Urol 63: 986-994.
- van den Bergh RC, Vasarainen H, van der Poel HG, Vis-Maters JJ, Rietbergen JB, et al. (2010) Short-term outcomes of the prospective multicentre 'Prostate Cancer Research International: Active Surveillance' study. BJU Int 105: 956-962.
- Stephan C, Jung K, Semjonow A, Schulze-Forster K, Cammann H, et al. (2013) Comparative Assessment of Urinary Prostate Cancer Antigen 3 and TMPRSS2:ERG Gene Fusion with the Serum [-2]Proprostate-Specific Antigen-Based Prostate Health Index for Detection of Prostate Cancer. Clin Chem 59: 280-288.
- Hansen J, Auprich M, Ahyai SA, de la Taille A, van Poppel H, et al. (2013) Initial prostate biopsy: development and internal validation of a biopsy-specific nomogram based on the prostate cancer antigen 3 assay. Eur Urol 63: 201-209.
Written by:
Matteo Ferro,c, e Dario Bruzzese,b Claudia Mazzarella,d Sisto Perdonà,a and Daniela Terraccianod as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
aUrology Unit, Fondazione G. Pascale, Napoli, Italy; bDepartment of Preventive Medical Sciences, University “Federico II”, Naples, Italy; cUrology Unit, University “Federico II”, Naples, Italy; dDepartment of Translational Medical Sciences, University “Federico II”, Naples, Italy; eDivision of Urology, European Institute of Oncology, Milan, Italy
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