title: 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.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Department of Urology, Ospedale San Raffaele Turro, San Raffaele Scientific Institute, Milan, Italy. lazzeri.maximus@gmail.com
authors.forename: Massimo
authors.initials: M
authors.lastname: Lazzeri
authors.forename: Alexander
authors.initials: A
authors.lastname: Haese
authors.forename: Alberto
authors.initials: A
authors.lastname: Abrate
authors.forename: Alexandre
authors.initials: A
authors.lastname: de la Taille
authors.forename: Joan Palou
authors.initials: JP
authors.lastname: Redorta
authors.forename: Thomas
authors.initials: T
authors.lastname: McNicholas
authors.forename: Giovanni
authors.initials: G
authors.lastname: Lughezzani
authors.forename: Giuliana
authors.initials: G
authors.lastname: Lista
authors.forename: Alessandro
authors.initials: A
authors.lastname: Larcher
authors.forename: Vittorio
authors.initials: V
authors.lastname: Bini
authors.forename: Andrea
authors.initials: A
authors.lastname: Cestari
authors.forename: Nicolòmaria
authors.initials: N
authors.lastname: Buffi
authors.forename: Markus
authors.initials: M
authors.lastname: Graefen
authors.forename: Olivier
authors.initials: O
authors.lastname: Bosset
authors.forename: Philippe
authors.initials: P
authors.lastname: Le Corvoisier
authors.forename: Alberto
authors.initials: A
authors.lastname: Breda
authors.forename: Pablo
authors.initials: P
authors.lastname: de la Torre
authors.forename: Linda
authors.initials: L
authors.lastname: Fowler
authors.forename: Jacques
authors.initials: J
authors.lastname: Roux
authors.forename: Giorgio
authors.initials: G
authors.lastname: Guazzoni
mesh_terms: D016022:Case-Control Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D017430:Prostate-Specific Antigen / Q000097:blood*; D011471:Prostatic Neoplasms / Q000097:blood* / Q000175:diagnosis* / Q000235:genetics; D020033:Protein Isoforms / Q000097:blood
chemical_list: D020033:Protein Isoforms; D017430:Prostate-Specific Antigen
keywords: familial prostate cancer; p2PSA; positive biopsy; predictive models; prostate health index; prostate-specific antigen