Prostate cancer screening: revisiting evidence after 23 years of ERSPC follow-up

According to recent estimates from the International Agency for Research on Cancer (IARC), prostate cancer represents the second most common male malignancy worldwide (14.2% of all cancers, second only to lung cancer) and the fifth leading cause of cancer mortality among men, responsible for nearly 400,000 deaths globally each year (1). Notably, recent U.S. statistics revealed that prostate cancer mortality has shown a significant upward trend over the past 24 years (2), a rise that appears especially pronounced in patients diagnosed with advanced-stage disease.

The measurement of prostate-specific antigen (PSA) remains the foundation of prostate cancer screening. Several PSA-derived parameters, including free PSA (fPSA) and the fPSA/total PSA ratio, PSA density (PSAD), PSA velocity, and composite indices such as the Prostate Health Index (PHI) and PHI density (PHID), have also been developed to improve specificity and reduce unnecessary biopsies (3). While PSA testing undoubtedly facilitates earlier cancer detection, its impact on disease-specific mortality remains a matter of controversy, so that the balance between early detection and risk of overdiagnosis and overtreatment continues to drive debate in the clinical and laboratory communities.

A large meta-analysis published in 2018, including five randomized controlled trials with 721,718 men, found no significant reduction in either all-cause mortality [incidence rate ratio (IRR) 0.99; 95% confidence interval (CI): 0.98–1.01] or prostate cancer-specific mortality (IRR 0.96; 95% CI: 0.85–1.08) attributable to PSA screening (4). In line with these findings, the U.S. Preventive Services Task Force (USPSTF) recommends against PSA screening in men aged 70 years and older and advises shared decision-making for younger individuals after discussing the potential benefits and harms (5). In contrast, the European Commission has proposed including prostate cancer screening within the framework of European Union (EU)-wide early detection initiatives (6). These opposing positions illustrate the persisting uncertainty surrounding the population-level benefits of PSA screening.

The most recent analysis from the European Randomized Study of Screening for Prostate Cancer (ERSPC) provides critical, long-term data informing this debate (7). Conducted across eight European countries, the ERSPC enrolled 162,236 men aged 55–69 years, who were randomized to receive repeated PSA screening or no screening invitation. After 23 years of follow-up, the study reported a 13% relative reduction in prostate cancer-specific mortality [rate ratio (RR) 0.87; 95% CI: 0.80–0.95], corresponding to an absolute risk reduction of 0.22% (95% CI: 0.10–0.34%). Approximately one prostate cancer death was prevented for every 456 men invited to screening. Although this benefit appears somewhat attenuated compared with earlier ERSPC reports (a 20% reduction at 16 years), it still supports the role of PSA-based screening in reducing prostate cancer mortality.

A notable methodological strength of the ERSPC is its standardized use of the Hybritech PSA assay across all participating centers. Analytical harmonization is a crucial aspect of large-scale screening trials, as assay variability has historically limited the comparability of PSA test results. Differences in calibration standards [e.g., World Health Organization (WHO) versus Hybritech] and inter-laboratory variation can influence PSA values, potentially altering biopsy thresholds and clinical interpretation (8,9). The adoption of a single, standardized assay platform in the ERSPC has minimized such variability, enhancing both internal validity and reproducibility. This represents a significant contribution to the field of laboratory and precision medicine, highlighting the importance of analytical consistency in multicenter studies.

The multicenter design and extended follow-up of the trial further strengthen its findings. Conducted in eight European countries, the study provides a representative population base and sufficient statistical power to detect long-term trends in mortality. Given the often slow and indolent natural history of prostate cancer, prolonged observation is essential to discern meaningful effects on mortality. The 23-year duration of follow-up provides an unusually robust evidence base.

Nonetheless, some limitations should be acknowledged. Variation in PSA cutoff thresholds (3.0 vs. 4.0 ng/mL), screening intervals (2–7 years), and biopsy protocols across ERSPC centers may have influenced detection rates and outcomes. These methodological inconsistencies could have attenuated or inflated the observed mortality benefit. Moreover, the magnitude of the 13% relative mortality reduction, while statistically significant, remains modest in absolute terms. The risks of false-positive results, unnecessary biopsies, and treatment-related complications (including urinary and sexual dysfunction) must be carefully considered when interpreting these data. Notably, the mortality benefit became evident primarily after 10 years of follow-up, reflecting the natural history of disease and the long latency required to observe the effects of early detection. The attenuation of benefit in older age groups (71–74 years) further supports the need for age- and risk-adapted screening approaches.

In conclusion, the 23-year ERSPC follow-up provides strong evidence that standardized PSA-based screening can modestly reduce prostate cancer mortality when implemented in a well-designed, harmonized multicenter setting. The study exemplifies the importance of assay standardization and methodological rigor in producing reliable data applicable to clinical and public health decision-making. However, the findings also reinforce the concept that PSA screening should not be applied indiscriminately (Figure 1). Notably, the benefits of PSA-based screening in reducing prostate cancer–specific mortality become evident in the ERSPC after approximately 9 to 11 years of follow-up, with reported RR of 0.83 (95% CI: 0.69–1.01) and 0.79 (95% CI: 0.67–0.93), respectively. These findings underscore the importance of targeting screening efforts toward populations with an anticipated life expectancy of at least 10 years. To this end, future strategies should move toward risk-adapted and precision-based models that integrate molecular biomarkers, imaging modalities, and individual risk profiling to optimize the balance between benefits and harms.

Figure 1 The still unresolved enigma of to screen or not to screen prostate cancer with prostate specific antigen.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Laboratory and Precision Medicine. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-2025-1-60/coif). G.L. serves as an Editor-in-Chief of Journal of Laboratory and Precision Medicine. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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