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
Authors: Lazzeri Massimo , Haese Alexander , Abrate Alberto , de la Taille Alexandre , Redorta Joan Palou , McNicholas Thomas , Lughezzani Giovanni , Lista Giuliana , Larcher Alessandro , Bini Vittorio , Cestari Andrea , Buffi Nicolòmaria , Graefen Markus , Bosset Olivier , Corvoisier Philippe Le , Breda Alberto , de la Torre Pablo , Fowler Linda , Roux Jacques , Guazzoni Giorgio 
Published: May 2013

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.