Definition of Outcome-Based Prostate-Specific Antigen (PSA) Thresholds for Advanced Prostate Cancer Risk Prediction

Abstract

We defined prostate-specific antigen (PSA) thresholds from a well calibrated risk prediction model for identifying and excluding advanced prostate cancer (PCa). We retrieved 902 biopsied patients with a pre-biopsy PSA determination (Roche assay). A logistic regression model predictive for PCa including the main effects [i.e., PSA, age, histological evidence of glandular inflammation (GI)] was built after testing the accuracy by calibration plots and Hosmer-Lemeshow test for goodness of fit. PSA thresholds were derived by assuming a diagnostic sensitivity of 95% (rule-out) and 80% (rule-in) for overall and advanced/poorly differentiated PCa. In patients without GI, serum PSA concentrations ≤ 4.1 (<65 years old) and ≤3.7 μg/L (≥65 years old) excluded an advanced PCa (defined as Gleason score ≥ 7 at biopsy), with a negative predictive value of 95.1% [95% confidence interval (CI): 83.0-98.7] and 88.8% (CI: 80.2-93.9), respectively, while PSA > 5.7 (<65) and >6.1 μg/L (≥65) should address biopsy referral. In presence of GI, PSA did not provide a valid estimate for risk of advanced cancer because of its higher variability and the low pre-test probability of PCa. The proposed PSA thresholds may support biopsy decision except for patients with asymptomatic prostatitis who cannot be pre-biopsy identified.

Keywords: calibration; immunoassay; inflammation; prostate cancer; risk prediction.

Figure 1

Distribution of age (left) and ln PSA concentrations (right) in patients with (black histograms) and without (grey histograms) prostatic cancer.

Figure 2

PSA—based diagnostic workup for patients < 65 years old, with no evidence of glandular inflammation on histology. This workflow includes recommendations on second level approaches inferred from the available literature (references reported in parentheses). The above values represent pre-biopsy serum PSA concentrations. In black, information derived by this study. Note: Recommended active surveillance implies PSA retesting after two years and it is stopped if the risk of advanced cancer increases according to an absolute PSA increase over 2 µg/L. It is reasonable to endorse the PSA retesting interval recommended by the American Urological Association [2]. PCa, prostatic cancer; NPV, negative predictive value; ISUP, International Society of Urological Pathology; PPV, positive predictive value; 4Kscore, 4-kallikrein panel score.

Figure 3

PSA—based diagnostic workup for patients ≥ 65 years old, asymptomatic for glandular inflammation, including recommendations on second level approaches inferred from the available literature (references reported in parentheses). The above values represent pre-biopsy serum PSA concentrations. In black, information derived by this study. Note: Recommended active surveillance implies PSA retesting after two years and it is stopped if the risk of advanced cancer increases according to an absolute PSA increase over 1 µg/L. It is reasonable to endorse the PSA retesting interval recommended by the American Urological Association [2]. PCa, prostatic cancer; NPV, negative predictive value; ISUP, International Society of Urological Pathology; PPV, positive predictive value; 4Kscore, 4-kallikrein panel score; MRI, multiparametric magnetic resonance imaging; PD-RAS, Prostate Imaging-Reporting and Data System.