BERKELEY, CA (UroToday.com) - Clinical decision-making for men with suspected prostate cancer, especially for those who have had a previous negative biopsy, is increasingly being guided by predictive markers. Since the recognition of low specificity of total PSA (tPSA), newly introduced markers, such as free PSA, free/total PSA (%fPSA), and the more recently introduced Progensa PCA3 assay (Gen-Probe, San Diego, CA USA), have been playing an increasingly important role in selecting patients for prostate biopsy. As the number of available RNA-, or DNA-based markers and molecular signatures based on multiplex assays is expected to increase in the near future, there is a pressing need to perform critical analysis of the clinical utility of current markers. According to preliminary investigations and observational studies, [-2]proPSA, an isoform of PSA, and its derivatives, namely [-2]proPSA over fPSA (%[-2]proPSA) and the Hybritech Prostate Health Index (PHI) may, when used clinically, improve both discrimination between men with or without PCa and between cases of clinically significant and indolent cancer.(1,2,3) Recently we tested the hypothesis that serum isoform [-2]proPSA derivatives %p2PSA and PHI are accurate predictors of prostate cancer in men scheduled for repeat biopsy.(4) We found that %p2PSA and PHI were significantly higher in men with PCa at repeat biopsy and were the most accurate predictors of outcome, outperforming reference standard tests when included in multivariable regression analysis.
Recently the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) working group has designated three important and necessary steps in developing the clinical use of a new markers: analytic validity, clinical validity, and clinical utility.(5) Analytic validity refers to laboratoristic and analytic accuracy, reliability, and reproducibility. In our paper, we reported that all blood samples were centrally managed according to the methods suggested and investigated by Semjonow et al..(6) This is the first step in guaranteeing analytic validity of a marker. Past studies have used archived serum, which does not allow for a complete guarantee of the analytic validity. Clinical validity is the demonstration that the test has a suitably strong association with a clinical outcome of interest. We found that %p2PSA and PHI were the most accurate predictors of disease. Furthermore, in multivariable logistic regression models, %p2PSA and PHI achieved independent predictor status and significantly increased the accuracy of multivariable models including PSA and prostate volume with or without %fPSA and PSA density by 8% to 11%. However neither analytic nor clinical validity alone implies that %p2PSA and PHI should be used in clinical practice. Most importantly, we need to verify clinical utility. This implies that using the marker test in patient management results in a favourable balance of benefits to harm, leading to improved outcomes compared with non-use of the marker test. Our Italian team found that by implementing a PHI cut-off of 28.8, a total of 116 (52.25%) biopsies could have been avoided. Included in the avoided biopsied would be a total of 6 patients with PCa, but, importantly, no patient with PCa with a Gleason score of 7 or greater would have been missed. In other words, PHI could significantly spare a relevant number of unnecessary repeat biopsies, missing a negligible number of cancers. Taken together, the analytic validity, clinical validity, and clinical utility of [-2]proPSA derivatives indicate that the use of this serum could result in an improvement in the decision-making process regarding which patients should undergo a repeat biopsy. The next endeavour will be to conduct comparative effectiveness research to confirm these single centre findings.
- Guazzoni G, Nava L, Lazzeri M, et al. 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 2011; 60: 214
- Catalona WJ, Partin AW, Sanda MG, et al. 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 2011; 185:1650
- Guazzoni G, Lazzeri M, Nava L, et al. Preoperative prostate-specific antigen isoform p2PSA and its derivatives, %p2PSA and prostate health index, predict pathologic outcomes in patients undergoing radical prostatectomy for prostate cancer. Eur Urol. 2012; 61: 455
- Lazzeri M., Briganti A, Scattoni V et al. Serum index test %[-2]proPSA and PHI (prostate health index) are more accurate than PSA and %fPSA in predicting a positive repeat prostate biopsy J Urol 2012; 188:1137
- Teutsch SM, Bradley LA, Palomaki GE, et al.The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Initiative: Methods of the EGAPP Working Group. Genet Med 2009; 11:3
- Semjonow A, Köpke T, Eltze E, et al. Pre-analytical in-vitro stability of [-2]proPSA in blood and serum. Clin Biochem 2010; 47: 926
Massimo Lazzeri, MD, PhD and Giorgio Guazzoni, MD 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.
Department of Urology
San Raffaele Turro
Vita-Salute San Raffaele University
Via Stamira D’Ancona 20
20127 Milan, Italy