Prostate Health Index Literature

Prostate Health Index Literature Update June 2013 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 Guazzoni et al. European Urology 2012; 61: 455-466 2 Association of [-2]proPSA with Biopsy Reclassification During Active Surveillance for Prostate Cancer Radical Tosoian et al. The Journal of Urology 2012; 188: 1131-1136 3 Serum Index Test %[-2]proPSA and Prostate Health Index are More Accurate than Prostate Specific Antigen and %fpsa in Predicting a Positive Repeat Prostate Biopsy Lazzeri et al. The Journal of Urology 2012; 188: 1137-1143 4 Development and Internal Validation of a Prostate Health Index Based Nomogram for Predicting Prostate Cancer at Extended Biopsy Lughezzani et al. The Journal of Urology 2012; 188: 1144-1150 5 Diagnostic significance of [ 2]pro-PSA and prostate dimension-adjusted PSA-related indices in men with total PSA in the 2.0 10.0 ng/ml range Ito et al. World Journal of Urology 2012; 18: [Epub ahead of print] 6 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 Catalona et al. The Journal of Urology 2011; 185: 1650-1655 7 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 Guazzoni et al. European Urology 2011; 60: 214-222 8 Prostate-Specific Antigen (PSA) Isoform p2psa in Combination with Total PSA and Free PSA Improves Diagnostic Accuracy in Prostate Cancer Detection Jansen et al. European Urology 2010; 57: 921-927 9 1

Serum Isoform [S2]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 Lazzeri et al. European Urology 2013; 63: 986-994 11 Multicenter Evaluation of [-2]Proprostate-Specific Antigen and the Prostate Health Index for Detecting Prostate Cancer Stephan et al. Clinical Chemistry 2013; 59:1 306-314 12 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 Stephan et al. Clinical Chemistry 2013; 59:1 280-288 13 Prospective Multicenter Evaluation of the Beckman Coulter Prostate Health Index Using WHO Calibration Loeb et al. Journal of Urology 2013; 189: 1702-1706 14 2

European Urology 2012; 61: 455-466 Background: Currently available predictive models fail to assist clinical decision making in prostate cancer (PCa) patients who are possible candidates for radical prostatectomy (RP). New biomarkers would be welcome. Objective: Test the hypothesis that prostate-specific antigen (PSA) isoform p2psa and its derivates, percentage of p2psa to free PSA (%p2psa) and the Prostate Health Index (PHI), predict PCa characteristics at final pathology after RP. Design, setting, and participants: An observational prospective study was performed in 350 consecutive men diagnosed with clinically localised PCa who underwent RP. Measurements: We determined the predictive accuracy of serum total PSA (tpsa), free PSA (fpsa), fpsa-to-tpsa ratio (%fpsa), p2psa, %p2psa, and PHI. The primary end point was to determine the accuracy of these biomarkers in predicting the presence of pt3 disease, pathologic Gleason sum 7, Gleason sumupgrading, and tumour volume<0.5 ml. Intervention: Open retropubic and robot-assisted laparoscopic RP was performed. Pelvic lymphadenectomy was performed according to baseline oncologic parameters and the surgeon s judgement. Results and limitations: The %p2psa and PHI levels were significantly higher in patients with pt3 disease, pathologic Gleason sum 7, and Gleason sum upgrading (all p values <0.001). Conversely, %p2psa and PHI levels were significantly lower in patients with tumour volume <0.5 ml ( p < 0.001). By univariate analysis, both %p2psa and PHI were accurate predictors of pt3 disease, pathologic Gleason sum 7, Gleason sum upgrading, and tumour volume <0.5 ml. By multivariate analyses, the inclusion of both %p2psa and PHI significantly increased the predictive accuracy of a base multivariate model (excluding the tumour volume prediction for both variables, and Gleason sum upgrading for the model including %p2psa) that included patient age, tpsa, fpsa, f/tpsa, clinical stage, and biopsy Gleason sum. Conclusions: We found that p2psa and its derivatives are predictors of PCa characteristics at final pathology after RP and are more accurate than currently available markers. 3

The Journal of Urology 2012; 188: 1131-1136 4

World Journal of Urology 2012; 18: [Epub ahead of print] Kazuto Ito, Mai Miyakubo, Yoshitaka Sekine, Hidekazu Koike, Hiroshi Matsui, Yasuhiro Shibata, Kazuhiro Suzuki From the department of Urology, Gunma University Graduate School of Medicine, Showa-machi, Maebashi, Gunma, Japan Purpose: One of the most important issues to address when developing an optimal screening system for prostate cancer is investigating appropriate biopsy indications following serum prostate-specific antigen (PSA) measurements in order to maintain high sensitivity and avoid unnecessary biopsy. Methods: Between April 2004 and December 2007, 239 consecutive men with total PSA levels of 2.0 10.0 ng/ml underwent measurements of PSA, free PSA, and [- 2]pro-PSA. We assessed the significance of laboratory-based PSA-related indices including free PSA/total PSA (%f-psa), p2psa/free PSA (%p2psa), p2psa/%f- PSA, Prostate Health Index (phi, an index combining PSA, free PSA, and p2psa), total prostate volume (TPV)-adjusted PSA-related indices, including PSA density, %p2psa density, p2psa/%f-psa density, and phi density, and transition zone (TZ) prostate volume-adjusted PSA-related indices such as PSA TZ density (PSATZD), %p2psa TZD, p2psa/%fpsa TZD, and phi TZD. Results: The positive biopsy rate was 22.2 %. When sensitivity was fixed at 95 %, unnecessary biopsies could be avoided in 28 % of men when phi was used as a biopsy indication. In cases where total and transition zone prostate volumes were available, the use of %p2psa density, phi density, p2psa/%f-psa TZD, and phi TZD resulted in the avoidance of 48, 47, 54, and 54 % of unnecessary biopsies, respectively, while maintaining a high sensitivity of 90 %. Conclusions: At 90 and 95 % sensitivity, laboratory-based indices containing p2psa, particularly phi, showed significantly greater specificity for prostate cancer as compared with %f-psa. The diagnostic accuracy of prostate volume-adjusted p2psa-related indices could be excellent, particularly the transition zone volumeadjusted indices at fixed sensitivities of 95 and 90 %. 7

European Urology 2011; 60: 214-222 Background: Total prostate-specific antigen (tpsa), ratio of free PSA (fpsa) to tpsa (%fpsa), and PSA density (PSAD) testing have a very low accuracy in the detection of prostate cancer (PCa). There is an urgent need for more accurate biomarkers. Objective: To compare the diagnostic accuracy of PSA isoform p2psa and its derivatives in determining the presence of PCa at initial biopsy with the accuracy of other predictors in patients with tpsa 2.0 10 ng/ml. Design, setting, and participants: We conducted an observational prospective study in a real clinical setting of consecutive men with tpsa 2.0 10 ng/ml and negative digital rectal examination who were scheduled for prostate biopsy at a tertiary academic center. Intervention: Outpatient transrectal ultrasound-guided prostate biopsies were performed according to a standardized institutional saturation scheme (18 22 cores). Measurements: We determined the diagnostic accuracy of serum tpsa, %fpsa, PSAD, p2psa, %p2psa [(p2psa/fpsa) x 100] and the Beckman Coulter Prostate Health Index (phi; [p2psa/fpsa x PSA]). Results and limitations: Overall, 107 of 268 patients (39.9%) were diagnosed with PCa at extended prostate biopsies. Statistically significant differences between patients with and without PCa were observed for age, prostate and transition zone volume, PSAD, %p2psa, and phi (all p values < 0.05). In univariate accuracy analysis, phi and %p2psa were the most accurate predictors of PCa (area under the curve: 75.6% and 75.7%, respectively), followed by transition zone volume (66%), prostate volume (65%), patient age (63%), PSAD (61%), %fpsa (58%), and tpsa (53%). In multivariate accuracy analyses, both phi (+11%) and %p2psa (+10%) significantly improved the accuracy of established predictors in determining the presence of PCa at biopsy ( p < 0.001). Although %p2psa and phi were significantly associated with Gleason score (Spearman r: 0.303 and 0.387, respectively; p 0.002), they did not improve the prediction of Gleason score 7 PCa in multivariable accuracy analyses ( p > 0.05). Conclusions: In patients with a tpsa between 2.0 and 10 ng/ml, %p2psa and phi are the strongest predictors of PCa at initial extended biopsies and are significantly more accurate than the currently used tests (tpsa, %fpsa, and PSAD) in determining the presence of PCa at biopsy. 9

European Urology 2010; 57: 921-927 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) x 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). 10

European Urology 2013; 63: 986-994 Background: Strategies to reduce prostate-specific antigen (PSA) driven prostate cancer (PCa) overdiagnosis and overtreatment seem to be necessary. Objective: To test the accuracy of serum isoform [-2]proPSA (p2psa) and its derivatives, percentage of p2psa to free PSA (fpsa; %p2psa) and the Prostate Health Index (PHI) called index tests in discriminating between patients with and without PCa. Design, setting, and participants: This was an observational, prospective cohort study of patients from five European urologic centers with a total PSA (tpsa) range of 2 10 ng/ml who were subjected to initial prostate biopsy for suspected PCa. Outcome measurements and statistical analysis: The primary end point was to evaluate the specificity, sensitivity, and diagnostic accuracy of index tests in determining the presence of PCa at prostate biopsy in comparison to tpsa, fpsa, and percentage of fpsa to tpsa (%fpsa) (standard tests) and the number of prostate biopsies that could be spared using these tests. Multivariable logistic regression models were complemented by predictive accuracy analysis and decision curve analysis. Results and limitations: Of >646 patients, PCa was diagnosed in 264 (40.1%). Median tpsa (5.7 vs 5.8 ng/ml; p = 0.942) and p2psa (15.0 vs 14.7 pg/ml) did not differ between groups; conversely,median fpsa (0.7 vs 1 ng/ml; p < 0.001), %fpsa (0.14 vs 0.17; p < 0.001), %p2psa (2.1 vs 1.6; p < 0.001), and PHI (48.2 vs 38; p < 0.001) did differ significantly between menwith and without PCa. In multivariable logistic regression models, p2psa, %p2psa, and PHI significantly increased the accuracy of the base multivariable model by 6.4%, 5.6%, and 6.4%, respectively (all p < 0.001). At a PHI cut-off of 27.6, a total of 100 (15.5%) biopsies could have been avoided. The main limitation is that cases were selected on the basis of their initial tpsa values. Conclusions: In patients with a tpsa range of 2 10 ng/ml, %p2psa and PHI are the strongest predictors of PCa at initial biopsy and are significantly more accurate than tpsa and %fpsa. Trial registration: The study is registered at http://www.controlled-trials.com, ref. ISRCTN04707454. 11

Clinical Chemistry 2013; 59:1 306-314 Multicenter Evaluation of [-2]Proprostate-Specific Antigen and the Prostate Health Index for Detecting Prostate Cancer Carsten Stephan, 1,2* Sébastien Vincendeau, 3 Alain Houlgatte, 4 Henning Cammann, 5 Klaus Jung, 1,2 and Axel Semjonow 6 1 Department of Urology, Charité -Universitätsmedizin Berlin, Berlin, Germany; 2 Berlin Institute for Urologic Research, Berlin, Germany; 3 Department of Urology, Hospital Pontchaillou, Rennes, France; 4 Department of Urology, HIA du Val de Grâce, Paris, France; 5 Institute of Medical Informatics, Charité- Universitätsmedizin Berlin, Germany; 6 Prostate Center, Department of Urology, University Hospital Münster, Germany. Background: Total prostate-specific antigen (tpsa) is flawed for prostate cancer (PCa) detection. [-2]proprostate-specific antigen (p2psa), a molecular isoform of free PSA (fpsa), shows higher specificity compared with tpsa or percentage of free PSA (%fpsa). The prostate health index (Phi), a measure based on p2psa and calculated as p2psa/fpsa x tpsa, was evaluated in a multicenter study for detecting PCa. Method: A total of 1362 patients from 4 different study sites who had tpsa values of 1.6 8.0 µg/l (668 patients with PCa, 694 without PCa) underwent >10 core biopsies. Serum concentrations of tpsa, fpsa (both calibrated against a WHO reference material), and p2psa were measured on Access2 or DxI800 analyzers (Beckman Coulter). Results: The percentage ratio of p2psa to fpsa (%p2psa) and Phi were significantly higher in all PCa subcohorts (positive initial or repeat biopsy result or negative digital rectal examination) (P < 0.0001) compared with patients without PCa. Phi had the largest area under the ROC curve (AUC) (AUC = 0.74) and provided significantly better clinical performance for predicting PCa compared with %p2psa (AUC = 0.72, P < 0.018), p2psa (AUC = 0.63, P < 0.0001), %fpsa (AUC = 0.61) or tpsa (AUC = 0.56). Significantly higher median values of Phi were observed for patients with a Gleason score 7 (Phi = 60) compared with a Gleason score 7 (Phi = 53; P < 0.0018). The proportion of aggressive PCa (Gleason score 7) increased with the Phi score. Conclusions: The results of this multicenter study show that Phi, compared with tpsa or %fpsa, demonstrated superior clinical performance in detecting PCa at tpsa 1.6 8.0 µg/l (i.e., approximately 2 10 µg/l in traditional calibration) and is better able to detect aggressive PCa. 12

Clinical Chemistry 2013; 59:1 280-288 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 Carsten Stephan, 1,2* Klaus Jung, 1,2 Axel Semjonow, 3 Kai Schulze-Forster, 4 Henning Cammann, 5 Xinhai Hu, 1 Hellmuth-A. Meyer, 1 Martin Bögemann, 3 Kurt Miller, 1 and Frank Friedersdorff 1 1 Department of Urology, Charité -Universitätsmedizin Berlin, Germany; 2 Berlin Institute for Urologic Research, Berlin, Germany; 3 Prostate Center, University Clinic Münster, Münster, Germany; 4 Zentrum fü r molekulare Onkologie GmbH, Luckenwalde, Germany; 5 Institute of Medical Informatics, Charité - Universitätsmedizin Berlin, Berlin, Germany. Background: We compared urinary prostate cancer antigen 3 (PCA3), transmembrane protease, serine 2 (TMPRSS2):v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) gene fusion (T2:ERG), and the serum [-2]proprostate-specific antigen ([-2]proPSA)-based prostate health index (Phi) for predicting biopsy outcome. Method: Serum samples and first-catch urine samples were collected after digital rectal examination (DRE) from consented outpatients with PSA 0.5 20 µg/l who were scheduled for prostate biopsy. The PCA3 score (PROGENSA PCA3, Hologic Gen-Probe) and T2:ERG score (Hologic Gen-Probe) were determined. Measurements of serum PSA, free PSA, and [-2]proPSA (Beckman Coulter) were performed, and the percentages of free PSA (%fpsa) and Phi ([- 2]proPSA / fpsa x PSA) were determined. Results: Of 246 enrolled men, prostate cancer (PCa) was diagnosed in 110 (45%) and there was no evidence of malignancy (NEM) in 136 (55%). A first set of biopsies was performed in 136 (55%) of all men, and 110 (45%) had 1 repeat biopsies. PCA3, Phi, and T2:ERG differed significantly between men with PCa and NEM, and these markers showed the largest areas under the ROC curve (AUCs) (0.74, 0.68, and 0.63, respectively). PCA3 had the largest AUC of all parameters, albeit not statistically different from Phi. Phi showed somewhat lower specificities than PCA3 at 90% sensitivity. Combination of both markers enhanced diagnostic power with modest AUC gains of 0.01 0.04. Although PCA3 had the highest AUC in the repeat-biopsy cohort, the highest AUC for Phi was observed in DRE-negative patients with PSA in the 2 10 µg/l range. Conclusions: PCA3 and Phi were superior to the other evaluated parameters but their combination gave only moderate enhancements in diagnostic accuracy for PCa at first or repeat prostate biopsy. 13

Journal of Urology 2013; 189: 1702-1706 Prospective Multicenter Evaluation of the Beckman Coulter Prostate Health Index Using WHO Calibration Purpose: Reported prostate specific antigen values may differ substantially among assays using Hybritech or WHO standardization. The Beckman Coulter Prostate Health Index and [ 2]proPSA are newly approved serum markers associated with prostate cancer risk and aggressiveness. We studied the influence of assay standardization on these markers. Matetial and Method: Prostate specific antigen, percent free prostate specific antigen and [ 2]proPSA were measured using Hybritech calibration in 892 men from a prospective, multicenter study undergoing prostate biopsy. We calculated the Prostate Health Index using the equation, ([ 2]proPSA / free prostate specific antigen) x SA. Index performance characteristics for prostate cancer detection were then determined using recalculated WHO calibration prostate specific antigen values. Results: The median Prostate Health Index was significantly higher in men with prostate cancer than in those with negative biopsies using WHO values (47.4 vs 39.8, p > 0.001). The index offered improved discrimination of prostate cancer detection on biopsy (AUC 0.704) compared to percent free or total prostate specific antigen using the WHO calibration. Conclusions: The Prostate Health Index can be calculated using Hybritech or WHO standardized assays. It significantly improved prediction of the biopsy outcome over that of percent free or prostate specific antigen alone. 14

Jean-Sébastien BLANCHET, PhD Scientific Affairs Immunodiagnostics EMEAI Beckman Coulter Eurocenter S.A. 22, rue Juste-Olivier Case Postale 1044 CH - 1260 Nyon 1, Switzerland Tel: +33 (0)563 558 959 Mobile: +33 (0)632 441 646 E-mail : jblanchet@beckman.com www.beckmancoulter.com 15