A single prostate-specific antigen (PSA) test in midlife could help to identify men at low risk of prostate cancer for up to 20 years, supporting more personalised screening strategies and reducing overdiagnosis, according to a recent cohort study.

Published in JAMA Network Open, the study investigated whether clinical and blood-based biomarkers could help predict long-term prostate cancer risk and support risk-adapted screening approaches.

It analysed data from the Study of Health in Pomerania – a prospective population-based epidemiological  research initiative in northeastern Germany. Participants were randomly selected from the general population and underwent comprehensive examinations including clinical assessments, laboratory testing and, in some cases, whole-body magnetic resonance imaging (MRI).

Data were collected from October 1997 to September 2021, with final analyses completed in November 2025. This included 2,651 men aged 45 to 70 years who had no prostate cancer at baseline.

A subgroup of 1,119 participants underwent MRI, enabling estimation of prostate volume and calculation of PSA density. Median follow-up was 10.8 years for the overall cohort and 9.7 years in the imaging subgroup.

During follow-up, cumulative prostate cancer incidence in the cohort was 1.8% at five years, 4.6% at 10 years and 9.1% at 20 years. Mortality incidence was 0% at five years, 2.2% at 10 years and 10.2% at 20 years.

Age and PSA linked to higher prostate cancer risk

Multiple clinical and liquid biomarkers, including body mass index, waist-to-hip ratio, glycated haemoglobin, lipid levels and blood cell counts were assessed, alongside prostate cancer–specific biomarkers such as PSA and PSA density.

In both univariable and multivariable analyses, age, PSA and PSA density were consistently associated with an increased risk of prostate cancer. In multivariable models, age had a hazard ratio (HR) of 1.04 (95% CI 1.02–1.07), PSA had an HR of 1.06 (95% CI 1.04–1.07), and PSA density had an HR of 1.41 (95% CI 1.30–1.52).

Other clinical and biochemical markers did not demonstrate clear or consistent links with prostate cancer risk. In fact, white blood cell count showed an inverse relationship after adjustment (HR 0.87; 95% CI 0.79–0.96).

Baseline PSA strongly stratifies long-term risk

Baseline PSA levels were strongly associated with long-term prostate cancer incidence. Among the 1,482 men (55.9%) with PSA levels below 1.00 ng/mL, cumulative prostate cancer incidence was 0.1% at five years, 0.6% at 10 years and 3.3% at 20 years.

In contrast, risk increased substantially in men with higher PSA levels. Among those with PSA between 1.00 and 3.00 ng/mL (36.1% of the cohort), the cumulative incidence was 1.4% at five years, 5.0% at 10 years and 11.8% at 20 years.

For the 211 men with PSA levels above 3.00 ng/mL, the incidence increased to 14.5% at five years, 28.3% at 10 years and 34.8% at 20 years, with differences between groups statistically significant (P < 0.001).

In the imaging subgroup, PSA combined with age showed slightly better predictive performance than PSA density combined with age, with a 12-year area under the curve of 0.86 compared with 0.75.

Limitations and clinical implications

These findings suggested that a single PSA measurement in midlife may help to identify men at very low long-term risk of prostate cancer, but certain limitations need to be considered.

For example, no distinction could be made between clinically significant and insignificant prostate cancers because grading information was not available in the diagnostic coding used to identify cases, and prostate cancer-specific mortality was not assessed.

Whole-body MRI was used instead of dedicated prostate imaging protocols, which could have influenced estimates of prostate volume and PSA density. The statistical analysis depended on predefined Cox models, which might not detect non-linear associations or interactions between biomarkers, the authors said.

Despite these constraints, they concluded that risk-adapted screening strategies with extended intervals for men with low PSA levels could help to focus healthcare resources on individuals at higher risk while reducing unnecessary investigations and potential overdiagnosis.

Reference
Lindholz M et al. Clinical and Liquid Biomarkers of 20-Year Prostate Cancer Risk in Men Aged 40 to 70 Years. JAMA Netw Open 2026;9(2):e2556732.