Prostate Health Index (Phi) and Prostate Cancer Antigen 3 (PCA3) Significantly Improve Prostate Cancer Detection at Initial Biopsy in a Total PSA Range of 2–10 ng/ml

Matteo Ferro,Daniela Terracciano,Sisto Perdonà,Claudia Mazzarella,Carlo Buonerba,Giuseppe Perruolo,Ottavio De Cobelli,Gennaro Musi,Felix K Chun,Dario Bruzzese,Ada Marino,Vincenzo Cosimato,Vittoria D’Esposito,Giuseppe Di Lorenzo,Zoran Culig

doi:10.1371/journal.pone.0067687

Abstract

Many efforts to reduce prostate specific antigen (PSA) overdiagnosis and overtreatment have been made. To this aim, Prostate Health Index (Phi) and Prostate Cancer Antigen 3 (PCA3) have been proposed as new more specific biomarkers. We evaluated the ability of phi and PCA3 to identify prostate cancer (PCa) at initial prostate biopsy in men with total PSA range of 2–10 ng/ml. The performance of phi and PCA3 were evaluated in 300 patients undergoing first prostate biopsy. ROC curve analyses tested the accuracy (AUC) of phi and PCA3 in predicting PCa. Decision curve analyses (DCA) were used to compare the clinical benefit of the two biomarkers. We found that the AUC value of phi (0.77) was comparable to those of %p2PSA (0.76) and PCA3 (0.73) with no significant differences in pairwise comparison (%p2PSA vs phi p = 0.673, %p2PSA vs. PCA3 p = 0.417 and phi vs. PCA3 p = 0.247). These three biomarkers significantly outperformed fPSA (AUC = 0.60), % fPSA (AUC = 0.62) and p2PSA (AUC = 0.63). At DCA, phi and PCA3 exhibited a very close net benefit profile until the threshold probability of 25%, then phi index showed higher net benefit than PCA3. Multivariable analysis showed that the addition of phi and PCA3 to the base multivariable model (age, PSA, %fPSA, DRE, prostate volume) increased predictive accuracy, whereas no model improved single biomarker performance. Finally we showed that subjects with active surveillance (AS) compatible cancer had significantly lower phi and PCA3 values (p<0.001 and p = 0.01, respectively). In conclusion, both phi and PCA3 comparably increase the accuracy in predicting the presence of PCa in total PSA range 2–10 ng/ml at initial biopsy, outperforming currently used %fPSA.

Highlights

The widespread use of prostate specific antigen (PSA) screening and extended prostate biopsy protocols strongly increased the incidence of prostate cancer (PCa) and the detection of low-risk tumors that may not clinically progress during lifetime
The largest AUC’s were obtained with phi (0.77; 95% C.I. 0.72 to 0.83), %p2PSA (0.76 with 95% C.I. 0.71 to 0.82) and Prostate Cancer Antigen 3 (PCA3) (0.73 with 95% C.I. 0.68 to 0.79) with no significant differences in pairwise comparison (p = 0.673 comparing %p2PSA vs phi, p = 0.417 comparing %p2PSA vs PCA3 and p = 0.247 comparing phi vs PCA3)
When considering the cutoff achieving the best combination of sensitivity and specificity, both %p2PSA and phi showed a significant improvement in sensitivity with respect to PCA3 (0.14, 95% C.I. [0.04 to 0.24], p = 0.01 and 0.19, 95% C.I. [0.08 to 0.30], p,0.01 respectively) without a significant difference in specificity

Summary

Introduction

The widespread use of PSA screening and extended prostate biopsy protocols strongly increased the incidence of PCa and the detection of low-risk tumors that may not clinically progress during lifetime. Preoperative tools (such as PSA and DRE) lack accuracy to avoid many negative biopsies and to predict confined PCa at radical prostatectomy (RP) [1]. Prostate cancer antigen 3 (PCA3) and phi (prostate health index) have been proposed as useful tools in prostate cancer patient care [2,3,4,5,6,7,8]. Stephan et al [9] compared urinary PCA3, transmembrane protease, serine 2 (TMPRSS2):v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) gene fusion (T2:ERG), and the serum phi for predicting biopsy outcome in a multicentre study including men with PSA values between 0–20 ng/ml undergoing first and repeat biopsy

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