Predictive Value of [−2]proPSA‐Related Indices for Prostate Cancer Detection Years Before Prostate‐Specific Antigen Elevation: Insights From a Five‐Year Longitudinal Screening Cohort

BACKGROUND: [-2]proPSA(p2PSA)-related indices have demonstrated diagnostic value for detecting prostate cancer (PC) in males with modest increases in prostate-specific antigen levels (PSA) of < 10 ng/mL. However, the "leak point" of p2PSA level in the blood circulation before developing screen-detectable PC remains uncertain. Therefore, this study evaluated the ability of p2PSA-related indices in the years before considering conventional biopsy indications. METHODS: This case-control study analyzed database and serum bank information from a population-based screening cohort in Gunma Prefecture. The case group included 58 males diagnosed with PC due to increased PSA (4-10 ng/mL) followed serially for 5 years. The control group comprised 58 males without PC based on biopsy who were matched to the case group by adjusted PSA levels (± 2 ng/mL) and age (± 5 years) at the time of biopsy. p2PSA, free PSA, and PSA were measured from frozen serum samples from 0 to 5 years before biopsy. RESULTS: p2PSA-to-free PSA ratio (%p2PSA) and prostate health index (phi) were significantly higher in the case group than in the control group from five, three, and 3 years before biopsy, respectively. The areas under the receiver operating characteristic curve for predicting PC were 0.437 for PSA, 0.637 for phi, 0.663 for %p2PSA, and 0.618 for free PSA-to PSA ratio (%fPSA) at 3 years before biopsy. CONCLUSIONS: p2PSA-related indices showed group-level differences between future PC cases and matched controls before PSA exceeded conventional cut-offs. These findings should be regarded as hypothesis-generating and require validation in prospective studies before clinical application to risk-stratified screening.