BJU Int. 2013 Aug;112(3):313-21. doi: 10.1111/bju.12217.

Clinical performance of serum prostate-specific antigen isoform [-2]proPSA (p2PSA) and its derivatives, %p2PSA and the prostate health index (PHI), in men with a family history of prostate cancer: results from a multicentre European study, the PROMEtheuS project.

Lazzeri M, Haese A, Abrate A, de la Taille A, Redorta JP, McNicholas T, Lughezzani G, Lista G, Larcher A, Bini V, Cestari A, Buffi N, Graefen M, Bosset O, Le Corvoisier P, Breda A, de la Torre P, Fowler L, Roux J, Guazzoni G.

Department of Urology, Ospedale San Raffaele Turro, San Raffaele Scientific Institute, Milan, Italy.



OBJECTIVES: To test the sensitivity, specificity and accuracy of serum prostate-specific antigen isoform [-2]proPSA (p2PSA), %p2PSA and the prostate health index (PHI), in men with a family history of prostate cancer (PCa) undergoing prostate biopsy for suspected PCa. To evaluate the potential reduction in unnecessary biopsies and the characteristics of potentially missed cases of PCa that would result from using serum p2PSA, %p2PSA and PHI.

PATIENTS AND METHODS: The analysis consisted of a nested case-control study from the PRO-PSA Multicentric European Study, the PROMEtheuS project. All patients had a first-degree relative (father, brother, son) with PCa. Multivariable logistic regression models were complemented by predictive accuracy analysis and decision-curve analysis.

RESULTS: Of the 1026 patients included in the PROMEtheuS cohort, 158 (15.4%) had a first-degree relative with PCa. p2PSA, %p2PSA and PHI values were significantly higher (P < 0.001), and free/total PSA (%fPSA) values significantly lower (P < 0.001) in the 71 patients with PCa (44.9%) than in patients without PCa. Univariable accuracy analysis showed %p2PSA (area under the receiver-operating characteristic curve [AUC]: 0.733) and PHI (AUC: 0.733) to be the most accurate predictors of PCa at biopsy, significantly outperforming total PSA ([tPSA] AUC: 0.549), free PSA ([fPSA] AUC: 0.489) and %fPSA (AUC: 0.600) (P ≤ 0.001). For %p2PSA a threshold of 1.66 was found to have the best balance between sensitivity and specificity (70.4 and 70.1%; 95% confidence interval [CI]: 58.4-80.7 and 59.4-79.5 respectively). A PHI threshold of 40 was found to have the best balance between sensitivity and specificity (64.8 and 71.3%, respectively; 95% CI 52.5-75.8 and 60.6-80.5). At 90% sensitivity, the thresholds for %p2PSA and PHI were 1.20 and 25.5, with a specificity of 37.9 and 25.5%, respectively. At a %p2PSA threshold of 1.20, a total of 39 (24.8%) biopsies could have been avoided, but two cancers with a Gleason score (GS) of 7 would have been missed. At a PHI threshold of 25.5 a total of 27 (17.2%) biopsies could have been avoided and two (3.8%) cancers with a GS of 7 would have been missed. 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 by 8.7 and 10%, respectively (P ≤ 0.001). p2PSA, %p2PSA and PHI were directly correlated with Gleason score (ρ: 0.247, P = 0.038; ρ: 0.366, P = 0.002; ρ: 0.464, P < 0.001, respectively).

CONCLUSIONS: %p2PSA and PHI are more accurate than tPSA, fPSA and %fPSA in predicting PCa in men with a family history of PCa. Consideration of %p2PSA and PHI results in the avoidance of several unnecessary biopsies. p2PSA, %p2PSA and PHI correlate with cancer aggressiveness.

© 2013 BJU International.

KEYWORDS: familial prostate cancer, p2PSA, positive biopsy, predictive models, prostate health index, prostate-specific antigen

PMID: 23826841



Notwithstanding the fact PSA has a low specificity and sensitivity, especially in the grey zone of tPSA between 2 and 10 ng/ml, the debate about the PSA testing and screening remains matter of discussion and uncertainness. Since 2009, with two outstanding publications in NEJM, several high quality papers addressed such this issue. No conclusion could be drawn, and currently statements on prostate-specific antigen (PSA)–based prostate cancer (PCa) testing and screening are widely disparate. In the United States, the use of the test is discouraged in all men regardless of age, family history, and race. In Europe, many urologists have remained circumspect about the balance of benefits and harms. However no definitive conclusions has been obtained as data and evidence are incomplete. Doubts remains about overall mortality, cancer-specific mortality, statistical power of screening studies and failure to address the time-to-event. In other words, the unsolved problem is the overdiagnosis and overtreatment resulting from tPSA testing.

In oncology an ideal biomarkers should be scientifically plausible, non invasive, clinically useful and result in high accuracy and favourable cost/benefit ratio. Although it remains true, for prostate cancer we need something more. We have to look into a more complex perspective. An ideal prostate cancer biomarker should discriminate not only men with or without PCa, but men with indolent from clinically significant PCa, guide the decision making process and be useful in the follow-up. For many years PSA has been considered an ideal biomarker for PCa. However, the key question is not whether PSA testing is effective but whether it does more good than harm.

As tPSA testing is under siege, more sensitive and specific isoform of tPSA have been investigated. Within the different isoform of tPSA the [-2] truncated form of proPSA in serum has been the focus of many clinical studies in the last years. After preliminary report, the development and validation of [-2]proPSA and its derivates underwent the necessary step in developing new markers. Several researchers investigated and reported the [-2]proPSA analytic validity, which stands for analytic accuracy, reliability, and reproducibility related to the marker assay, and the [-2]proPSA clinical validity, which showed as the test has a suitably strong association with a clinical outcome of interest. However from a clinical point of view, in order to introduce the test into the clinical practice, you have to show the clinical utility: a direct patient care impact with a favourable balance of benefits to harm. The main step ahead was represented by the PRO-PSA Multicentric European Study (PROMEtheuS) project. The Prometheus project is an observational, prospective cohort study, carried out between April 2011 and July 2012, at five high-volume European departments of urology: Ospedale San Raffaele Turro, Milan, Italy; Martini-Clinic Prostate Cancer Center University Hamburg- Eppendorf, Hamburg, Germany; Hoˆpital Henri Mondor Service d’Urologie, Paris, France; Fundacio´ Puigvert Department of Urology, Barcelona, Spain; and Lister Hospital Department of Urology, Stevenage, United Kingdom. The study was developed to test the sensitivity, specificity, and accuracy of p2PSA and its derivatives, %p2PSA ([(p2PSA pg/ml) / (fPSA ng/ml x 1000)] x 100) and the PHI [(p2PSA/fPSA) squad tPSA)] in a sample representative of European male population. Authors stratified results according different settings under clinical perspective. Accordingly, in men with tPSA levels of 2–10 ng/ml, who had undergone prostate biopsy in the grey zone, [-2] proPSA and PHI improved the predictive accuracy for the detection of overall PCa (and also GS ≥7 disease) compared to PSA and derivatives. Furthermore at 90% sensitivity, the PHI cut-off of 27.6 could avoid 100 (15.5%) biopsies, missing 26 (9.8%) cancers. The inclusion of PHI in a multivariable logistic regression model, based on patient age, prostate volume, digital rectal examination and biopsy history, significantly increased predictive accuracy by 7% from. Decision curve analysis showed that using the PHI based nomogram resulted in the highest net benefit. The PROMEtheruS project revealed also that PHI represented the best tool to predict positive biopsy outcome in young men (< 60 years old) and patients with family history of PCa. As regard patients with family history, similarly to previous studies in the general population, PHI outperformed tPSA and %fPSA for PCa detection on biopsy (AUC 0.73, 0.55 and 0.60, respectively). In addition, both [-2]proPSA and PHI were directly associated with GS in men with a positive family history. Overall, the authors reported that using a PHI cut-off value of 25.5 would have avoided 17.2% of biopsies while missing only very few GS 7 cancers. Finally in obese patients, %p2PSA and PHI values are significantly and even more accurate than the currently used tests in determining the presence of PCa and could avoid unnecessary biopsies without missing significant PCa.

In conclusion the PROMEtheuS project revealed that [-2]proPSA and PHI are more accurate than the currently used tests (PSA and derivatives) in predicting the presence of PCa at biopsy. Their implementation in clinical practice has the potential to significantly increase physicians’ ability to detect PCa and avoid unnecessary biopsies in different clinical setting.

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