The significance of the 4Kscore in predicting medium- to long-term prostate cancer risk: insights from the European prospective investigation into cancer and nutrition

The global burden of prostate cancer (PC) mortality is projected to double by 2040, largely due to increased life expectancy and population growth (1). Accordingly, early screening and detection of clinically significant PC will become increasingly crucial. Prostate-specific antigen (PSA) testing, introduced in the 1980s, has become an essential tool for diagnosis of PC and monitoring treatment, and is widely used in clinical practice. Notably, the “European Randomized Study of Screening for Prostate Cancer” recently conducted a follow-up study covering more than 20 years and found that PSA screening reduced PC mortality by 13% (2). However, despite these benefits, PSA-based screening has important limitations, including overdiagnosis leading to unnecessary interventions, which pose significant clinical challenges. To overcome the limited specificity of PSA alone, several PSA-derived parameters, including PSA velocity and density, have been introduced for improved risk stratification of PC. PSA velocity reflects changes in PSA levels over time, whereas PSA density indicates the ratio of PSA level to prostate volume and can be easily calculated. Although these parameters provide additional diagnostic information, their ability to distinguish clinically significant PC remains limited.

The latest version of the National Comprehensive Cancer Network (NCCN) guidelines for Prostate Cancer Early Detection, version 2.2026 (available at https://www.nccn.org/guidelines/guidelines-detail?id=1460), recommends multi-parametric magnetic resonance imaging (mpMRI) for patients who meet the PSA criteria for prostate biopsy. However, when mpMRI is unavailable or cannot be performed, use of additional biomarker tests before proceeding with a biopsy may be considered. One such biomarker assay included in the NCCN guidelines is the 4Kscore (OPKO Diagnostics, Woburn, MA, USA), a PC risk assessment test that combines four kallikrein biomarkers: total PSA, free PSA, intact PSA, and human kallikrein 2, along with clinical variables including age, history of negative biopsy, and digital rectal examination (DRE) findings. The NCCN guidelines recommend use of the 4Kscore both before the initial biopsy and after an initial negative biopsy. This recommendation is supported by results obtained in various studies, including a meta-analysis of USA and European cohorts (3), which demonstrated that the 4Kscore is a valid and clinically valuable biomarker for detection of high-grade PC. By addressing the limited specificity of PSA alone, the 4Kscore is considered to be a useful tool for reducing unnecessary biopsies, thus decreasing detection of PC cases with slow progression and also minimizing the risk of missing clinically significant disease.

Interestingly, each kallikrein biomarker, including PSA, has also been shown to predict the long-term risk of PC, including advanced disease (4,5). However, the clinical value of the 4Kscore for medium- to long-term prediction of PC has not been established, as most previous studies (6,7) have focused primarily on its short-term predictive performance. To address this, Smith-Byrne et al. (8) investigated the medium- to long-term risk predictive ability of the 4Kscore for PC using baseline blood samples obtained from 1,658 patients subsequently diagnosed with PC and 1,658 matched controls enrolled in the European Prospective Investigation into Nutrition for Cancer cohort. The study included patients with a relatively long median interval of 8.6 years between blood collection and cancer diagnosis, and aimed to determine whether the 4Kscore provided superior predictive performance as compared with a model based solely on total PSA for medium- to long-term PC risk assessment. The results obtained were the first to show that the 4Kscore did not improve prediction accuracy for PC as compared to prediction based on PSA alone. Similarly, the discriminative ability of the 4Kscore was inferior to that of PSA-based assessment for predicting high-grade disease as well as PC mortality risk. Although the 4Kscore has been validated as an accurate tool for short-term risk prediction, its performance may be attenuated over longer follow-up periods. Therefore, careful interpretation is necessary when applying the 4Kscore to medium- to long-term risk assessment in clinical practice.

A sub-analysis conducted by Smith-Byrne et al. (8) also evaluated the discriminative ability of the 4Kscore as compared with total PSA across a range of PSA levels and ages for prediction of progressive disease. They found that the 4Kscore had superior discriminative ability as compared with PSA-based assessment alone for prediction of overall PC risk, high-grade disease, and PC-specific mortality, though that was limited to men <60 years of age with PSA levels ≥2 ng/mL. These findings suggest that the 4Kscore may help to identify men in this age group who are likely to develop clinically significant PC in the future, well before diagnosis. The authors speculated that this improved predictive accuracy may reflect differences in the biological characteristics of PC in younger men. However, since their study did not provide sufficient evidence to support an age-related biological explanation, this speculation should be viewed with caution. To facilitate understanding of the study by Smith-Byrne et al. (8), a diagrammatic summary is shown in Figure 1.

Figure 1 Graphic summary of the study by Smith-Byrne et al. (8) conducted to evaluate the medium- to long-term predictive ability of the 4Kscore for PC. AUC, area under the curve; CI, confidence interval; EPIC, European Prospective Investigation into Cancer and Nutrition; PC, prostate cancer; PSA, prostate-specific antigen.

Another explanation to consider for interpreting these findings is the involvement of age-related differences of prostate volume in 4Kscore. Because PSA levels are positively correlated with prostate size, men affected by benign prostatic hyperplasia (BPH) may have higher 4Kscore values. The prevalence of BPH has been found to be approximately 50% in men up to 60 years of age (9), and increases thereafter in parallel with age and prostate volume (10). Accordingly, the influence of BPH on the 4Kscore may be less pronounced in men under age 60 years, thereby enabling an elevation in the score to more accurately reflect underlying malignancy. Although it is difficult to confirm this interpretation using the findings presented by Smith-Byrne et al. (8), because clinical data such as prostate weight were not incorporated, it is supported by results presented in the study by Guerard et al. (11) showing that “4K density”, obtained by dividing the 4Kscore by prostate volume, is useful for improving the detection rate of clinically significant PC. Nevertheless, this interpretation remains speculative and should be viewed with caution.

Although the findings of Smith-Byrne et al. (8) are informative and promising, it is important to recognize several limitations, as the authors themselves have noted. The study did not include key clinical variables in the 4Kscore, such as prior negative biopsy history or DRE findings. Accordingly, direct comparisons with previous studies that included such clinical details and evaluated the short-term predictive accuracy of the 4Kscore will be limited. Furthermore, because of the lack of clinical details, indications for performance of a biopsy during the observation period, such as elevated PSA, positive DRE findings, presence or absence of MRI findings, are also not available. In clinical practice, multiple factors, including biomarkers and clinical details, collectively serve to ultimately lead to a cancer diagnosis. Despite these limitations, their study was the first to demonstrate the medium- to long-term significance of the 4Kscore, with the findings suggesting that improved predictive accuracy may be limited to young men with elevated PSA levels. We believe that these findings are compelling and may lead to further research to clarify the role of the 4Kscore in long-term risk stratification.

In summary, using a large European cohort, the authors demonstrate that the 4Kscore has a limited benefit over PSA alone for prediction of medium- to long-term PC risk, and its usefulness may be limited to younger men with elevated PSA levels. These findings highlight the importance of age- and clinically targeted approaches for PC screening. Efforts to integrate multiple biomarkers and clinical parameters into routine clinical practice may contribute to improved early detection, personalized treatment, and disease monitoring in patients with PC. Prostate volume, which can be accurately assessed using MRI (12), is an established parameter for risk stratification, diagnosis, and longitudinal assessment of various prostate diseases. The prostate health index, another blood-based biomarker that combines PSA isoforms, has already been shown to be clinically useful (13). In addition, that study highlighted the roles of urine-based biomarkers and liquid biopsy approaches, including circulating tumor DNA analysis, for PC diagnosis and prognosis. Further studies that perform comparisons and combinations of these markers will help clarify the clinical significance of the 4Kscore as a cancer screening tool for selected patient populations.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research. The article has undergone external peer review.

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Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-0664/coif). The authors have no conflicts of interest to declare.

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