The prostate health index selectively identifies clinically significant prostate cancer.

PURPOSE: The Prostate Health Index (phi) is a new test combining total, free and [-2]proPSA into a single score. It was recently approved by the FDA and is now commercially available in the U.S., Europe and Australia. We investigate whether phi improves specificity for detecting clinically significant prostate cancer and can help reduce prostate cancer over diagnosis. MATERIALS AND METHODS: From a multicenter prospective trial we identified 658 men age 50 years or older with prostate specific antigen 4 to 10 ng/ml and normal digital rectal examination who underwent prostate biopsy. In this population we compared the performance of prostate specific antigen, % free prostate specific antigen, [-2]proPSA and phi to predict biopsy results and, specifically, the presence of clinically significant prostate cancer using multiple criteria. RESULTS: The Prostate Health Index was significantly higher in men with Gleason 7 or greater and "Epstein significant" cancer. On receiver operating characteristic analysis phi had the highest AUC for overall prostate cancer (AUCs phi 0.708, percent free prostate specific antigen 0.648, [-2]proPSA 0.550 and prostate specific antigen 0.516), Gleason 7 or greater (AUCs phi 0.707, percent free prostate specific antigen 0.661, [-2]proPSA 0.558, prostate specific antigen 0.551) and significant prostate cancer (AUCs phi 0.698, percent free prostate specific antigen 0.654, [-2]proPSA 0.550, prostate specific antigen 0.549). At the 90% sensitivity cut point for phi (a score less than 28.6) 30.1% of patients could have been spared an unnecessary biopsy for benign disease or insignificant prostate cancer compared to 21.7% using percent free prostate specific antigen. CONCLUSIONS: The new phi test outperforms its individual components of total, free and [-2]proPSA for the identification of clinically significant prostate cancer. Phi may be useful as part of a multivariable approach to reduce prostate biopsies and over diagnosis.

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. MATERIALS AND METHODS: 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) × PSA. 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.

Multi-center analytical performance evaluation of the Access Hybritech® p2PSA immunoassay.

BACKGROUND: Total PSA assays measure both complexed and non-complexed forms of PSA while free PSA assays only measure non-complexed forms. Free PSA is a mixture of isoforms including immature PSA (proPSA) with retained portions of the leader sequence (e.g. [-7], [-4], and [-2]proPSA) and nicked forms (BPSA). ProPSA isoforms in male sera have been associated with prostate cancer. This study characterized the analytical performance of a chemiluminescent immunoassay for [-2]proPSA. METHODS: The Access Hybritech p2PSA assay is a sandwich immunoassay using an anti-[-2]proPSA monoclonal antibody attached to paramagnetic beads and an anti-PSA monoclonal antibody conjugated to alkaline phosphatase calibrated with recombinant [-2]proPSA. Analytical studies including sensitivity (CLSI EP17-A) and imprecision (CLSI EP5-A2) were performed. RESULTS: The Access Hybritech p2PSA assay for [-2]proPSA had a dynamic range of 0.5 to 5000 pg/ml. The total CV of the assay was <7% for [-2]proPSA concentrations between 20 and 1000 pg/ml. The LOB was 0.50 pg/ml, LOD 0.69 pg/ml, and LOQ 3.23 pg/ml (20% CV). There was no hook effect up to 15,000 pg/ml. There was a <5% difference between calibrator and reagent lots and no interference from normal serum constituents. CONCLUSIONS: The Access Hybritech p2PSA assay is a robust immunoassay for the measurement of serum [-2]proPSA.

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.

PURPOSE: Prostate specific antigen and free prostate specific antigen have limited specificity to detect clinically significant, curable prostate cancer, leading to unnecessary biopsy, and detection and treatment of some indolent tumors. Specificity to detect clinically significant prostate cancer may be improved by [-2]pro-prostate specific antigen. We evaluated [-2]pro-prostate specific antigen, free prostate specific antigen and prostate specific antigen using the formula, ([-2]pro-prostate specific antigen/free prostate specific antigen × prostate specific antigen(1/2)) to enhance specificity to detect overall and high grade prostate cancer. MATERIALS AND METHODS: We enrolled 892 men with no history of prostate cancer, normal rectal examination, prostate specific antigen 2 to 10 ng/ml and 6-core or greater prostate biopsy in a prospective multi-institutional trial. We examined the relationship of serum prostate specific antigen, free-to-total prostate specific antigen and the prostate health index with biopsy results. Primary end points were specificity and AUC using the prostate health index to detect overall and Gleason 7 or greater prostate cancer on biopsy compared with those of free-to-total prostate specific antigen. RESULTS: In the 2 to 10 ng/ml prostate specific antigen range at 80% to 95% sensitivity the specificity and AUC (0.703) of the prostate health index exceeded those of prostate specific antigen and free-to-total prostate specific antigen. An increasing prostate health index was associated with a 4.7-fold increased risk of prostate cancer and a 1.61-fold increased risk of Gleason score greater than or equal to 4 + 3 = 7 disease on biopsy. The AUC of the index exceeded that of free-to-total prostate specific antigen (0.724 vs 0.670) to discriminate prostate cancer with Gleason 4 or greater + 3 from lower grade disease or negative biopsy. Prostate health index results were not associated with age and prostate volume. CONCLUSIONS: The prostate health index may be useful in prostate cancer screening to decrease unnecessary biopsy in men 50 years old or older with prostate specific antigen 2 to 10 ng/ml and negative digital rectal examination with minimal loss in sensitivity.

A prospective, multicenter, National Cancer Institute Early Detection Research Network study of [-2]proPSA: improving prostate cancer detection and correlating with cancer aggressiveness.

BACKGROUND: The free prostate-specific antigen (PSA) isoform, [-2]proPSA, has been shown to be associated with prostate cancer. The study objective was to characterize the clinical utility of serum [-2]proPSA for prostate cancer detection and assess its association with aggressive disease. METHODS: From among 669 subjects in a prospective prostate cancer detection study at four National Cancer Institute Early Detection Research Network clinical validation centers, 566 were eligible. Serum PSA, free PSA, and [-2]proPSA were measured (Beckman Coulter Access 2 Analyzer). RESULTS: Two hundred and forty-five (43%) of the 566 participants had prostate cancer on biopsy. At 70% specificity, the sensitivity of %[-2]proPSA ([-2]proPSA/fPSA) was 54% [95% confidence interval (CI), 48-61%; null hypothesis, 40%]. Including %[-2]proPSA in a multivariate prediction model incorporating PSA and %fPSA improved the performance (P<0.01). In the 2 to 4 ng/mL PSA range, %[-2]proPSA outperformed %fPSA (receiver operator characteristic-areas under the curve, 0.73 versus 0.61; P=0.01). At 80% sensitivity, %[-2]proPSA had significantly higher specificity (51.6%; 95% CI, 41.2-61.8%) than PSA (29.9%; 95% CI, 21.0-40.0%) and %fPSA (28.9%; 95% CI, 20.1-39.0%). In the 2 to 10 ng/mL PSA range, a multivariate model had significant improvement (area under the curve, 0.76) over individual PSA forms (P<0.01 to <0.0001). At 80% sensitivity, the specificity of %[-2]proPSA (44.9%; 95% CI, 38.4-51.5%) was significantly higher than PSA (30.8%; 95% CI, 24.9-37.1%) and relatively higher than %fPSA (34.6%; 95% CI, 28.5-41.4%). %[-2]proPSA increased with increasing Gleason score (P<0.001) and was higher in aggressive cancers (P=0.03). CONCLUSIONS: In this prospective study, %[-2]proPSA showed potential clinical utility for improving prostate cancer detection and was related to the risk of aggressive disease. IMPACT: The addition of %[-2]proPSA could affect the early detection of prostate cancer.