Clinical and Liquid Biomarkers of 20-Year Prostate Cancer Risk in Men Aged 45 to 70 Years

Abstract

Importance 

Prostate cancer incidence is projected to double by 2040, yet optimal risk stratification approaches for screening remain unclear despite recent international endorsements of organized programs that call for risk-adapted algorithms using readily available biomarkers.

Objective 

To identify biomarkers for risk-adapted prostate cancer screening in men without prostate cancer.

Design, Setting, and Participants 

This cohort study used data from the Study of Health in Pomerania (SHIP), a prospective population-based research initiative in Germany that randomly invited participants aged 20 to 79 years who underwent comprehensive examinations with structured 20-year follow-up. Data were collected from October 17, 1997, through September 14, 2021, with final analysis completed November 16, 2025.

Exposures  Baseline clinical and liquid biomarkers, including body mass index, waist-to-hip ratio, and glycated hemoglobin, together with prostate cancer–specific biomarkers of serum prostate-specific antigen (PSA) and magnetic resonance imaging–derived prostate volume and PSA density.

Main Outcomes and Measures 

The primary outcome was long-term prostate cancer incidence. Cumulative incidence functions for prostate cancer and death were treated as competing risks. Cause-specific Cox models were used to estimate risk and assess the association between baseline biomarkers and long-term incidence.

Results 

Among 2651 men included in the study (median [IQR] age, 54.0 [48.0-62.0] years), 1482 (55.9%) had low baseline PSA levels (<1.00 ng/mL), with a cumulative prostate cancer incidence of 0.1% (95% CI, 0.0%-0.4%), 0.6% (95% CI, 0.3%-1.2%), and 3.3% (95% CI, 2.1%-4.8%) at 5, 10, and 20 years, respectively. In 958 men (36.1%) with intermediate PSA levels (1.00-3.00 ng/mL), prostate cancer incidence was 1.4% (95% CI, 0.7%-2.3%), 5.0% (95% CI, 3.6%-6.6%), and 11.8% (95% CI, 9.2%-14.8%) at 5, 10, and 20 years, respectively. In 211 men (8.0%) with high PSA levels (>3.00 ng/mL), prostate cancer incidence was 14.5% (95% CI, 10.1%-19.7%), 28.3% (95% CI, 22.2%-34.8%), and 34.8% (95% CI, 27.5%-42.2%) at 5, 10, and 20 years, respectively. Cumulative prostate cancer incidence differed significantly among the PSA groups (P < .001). In univariable and multivariable Cox regression, age (hazard ratio [HR], 1.04; 95% CI, 1.02-1.07), PSA (HR, 1.06; 95% CI, 1.04-1.07), and PSA density (HR, 1.41; 95% CI, 1.30-1.52) remained consistently associated with prostate cancer risk, whereas other variables showed either no association or inconsistent results across models.

Conclusions and Relevance 

This cohort study found that a low baseline PSA level was associated with low long-term prostate cancer risk among men aged 45 to 70 years, supporting risk-adapted screening with extended intervals for men with low PSA levels.

Lindholz M, Bülow R, Schoots IG, et al. Clinical and Liquid Biomarkers of 20-Year Prostate Cancer Risk in Men Aged 45 to 70 Years. JAMA Netw Open. 2026;9(2):e2556732. doi:10.1001/jamanetworkopen.2025.56732