Prostate cancer—early individualized screening is key
- Open Access
- 20.08.2025
- short review
Erschienen in:
Summary
Scientific evidence-based screening
Prostate cancer (PCa) ranks as the second most frequently diagnosed malignancy worldwide, with the highest incidence observed in Europe. It is also the third leading cause of cancer-related mortality in men [2]. Risk factors include family history, ethnicity, environmental exposures, and lifestyle choices. More than 100 common susceptibility loci have been linked to aggressive PCa, with BRCA 1 and BRCA 2 mutations being the most thoroughly investigated [3]. This review addresses various PCa screening methods and examines their relevance in contemporary urological practice.
Digital rectal examination—has it lost its gold standard?
Digital rectal examination (DRE) remains a robust indicator of advanced PCa, with around 18% of cases detected historically by abnormal DRE findings, even when prostate-specific antigen (PSA) levels fall within normal limits [4, 5].
Anzeige
Nonetheless, data presented by Shariat et al. indicate that using both DRE and PSA for PCa screening does not confer a clear advantage in terms of positive predictive value (PPV) and cancer detection rate (CDR) compared to PSA alone. While no significant difference in PPV was observed between DRE and PSA, PSA demonstrated a notably higher CDR. Although both methods exhibited similar PPV, significant differences emerged in CDR. Only about 20% of men with abnormal DRE or elevated PSA were ultimately diagnosed with PCa, and merely 1–2% of all screened individuals had PCa detected through either screening approach [6].
Considering the potential overdiagnosis of clinically insignificant PCa associated with PSA testing, these findings still suggest that PSA offers superior screening utility relative to DRE.
Further support for these conclusions comes from the PROBASE trial [7], a randomized controlled trial focusing on men aged 45. In this study, the true-positive detection rate of DRE compared to PSA was 0.22 (95% confidence interval [CI] 0.07–0.72), while the false-positive detection rate was 2.18 (95% CI 1.50–3.17), reinforcing the limited role of DRE in early detection. Additionally, PSA testing is considered a cost-effective method, whereas DRE may cause physical discomfort and psychological stress for patients [8, 9]. Consequently, many men avoid PCa screening and early detection efforts due to their aversion to DRE.
Therefore, the routine performance of the digital rectal examination should be critically reconsidered.
Anzeige
Is PSA testing still a reasonable method for detecting prostate cancer?
Over the years, PSA screening has been a topic of debate. In 2012, the U.S. Preventive Services Task Force (USPSTF) advised against PSA-based prostate cancer screening [10], primarily due to findings from the ERSPC and PLCO trials. The ERSPC trial revealed a 21% relative risk reduction in favor of screening after 11 years of follow-up, yet showed no overall survival benefit. Meanwhile, the PLCO trial reported no mortality benefit at 7 years and no improvement at 10 years, completed by 67% of participants [11, 12].
Another concern was the high number of men needing screening to identify a single cancer case. An extended follow-up of the ERSPC study by Schröder et al. showed that screening 1055 men uncovered 37 cancers, with no demonstrated effect on overall mortality [13]. Therefore, the USPSTF initially recommended against PSA screening, citing overdiagnosis, overtreatment, psychological and economic burdens, and minimal mortality benefit. Criticisms were directed at both trials, particularly the PLCO trial, where Shoag and Jim (2016) noted significant contamination in the control arm, with up to 90% of men undergoing PSA testing despite being in the nonscreened group [14].
In 2018, the USPSTF updated its stance, recommending that well-informed men aged over 55 should be offered periodic PSA-based early detection [15]. A systematic review and meta-analysis by Ilic et al., which encompassed five randomized screening trials and over 721,718 men, concluded that while PCa screening boosted the diagnosis of localized disease (risk ratio (RR): 1.39 [1.09–1.79]) and reduced advanced-stage PCa (T3–4, N1, M1; RR: 0.85 [0.72–0.99]), it did not confer a significant benefit for prostate cancer-specific mortality (incidence ratio (IR): 0.96 [0.85–1.08]) or overall survival (IR: 0.99 [0.98–1.01]). Nevertheless, a sensitivity analysis of studies with lower bias risk showed that PSA testing could avert one death per 1000 men screened over 10 years (incidence rate ratios (IRR) 0.79, 0.69–0.91; moderate certainty) [16].
Thus, while PSA screening can help detect more favorable disease stages and reduce PCa-specific mortality, these advantages are tempered by the risk of overdiagnosis and subsequent unnecessary treatments. To address this, identifying high-risk groups, customizing screening intervals, and integrating risk-based biopsy approaches, including multiparametric magnetic resonance imaging (mpMRI) and active surveillance (AS) for low-risk cases, are recommended strategies [1].
In practice, other parameters such as prostate-specific antigen density (PSA-D) can help refine the indication for biopsy. PSA‑D is calculated by dividing the serum PSA level by the prostate volume, and a value of < 0.1 or < 0.15 ng/mL may suggest a higher likelihood of significant PCa [17].
Research by Vickers et al. in 2013 demonstrated that baseline PSA in men aged 45–55 years could predict the likelihood of metastasis and, indirectly, PCa-related mortality. Specifically, a baseline PSA of 1.6 ng/mL at age 45–49 years or 2.4 ng/mL at age 51–55 might warrant more frequent follow-up, whereas a PSA below 0.44 ng/mL (age 45–49) or 0.53 ng/mL (age 51–55) might permit longer intervals between tests [18, 19]. Current European Association of Urology (EAU) guidelines advise follow-up intervals of 2 years for men with PSA levels under 1 ng/mL at age 40 and below 2 ng/mL at age 60. Additionally, based on data from the Prostate Cancer Intervention Versus Observation Trial (PIVOT) and European Randomized Study of Screening for Prostate Cancer (ERSPC), men with a life expectancy under 15 years may not benefit from PSA screening [1].
PSA screening remains controversial due to limited impact on overall mortality and concerns about overdiagnosis. Recent evidence supports a risk-adapted approach with selective screening and tools like PSA density and mpMRI to improve outcomes.
Risk calculators to avoid unnecessary biopsy
Throughout the diagnostic process, combining clinical parameters into risk calculators can optimize the detection of clinically significant PCa (csPCa). Tools incorporating variables such as age, DRE results, PSA levels, and prostate volume enable personalized estimates of PCa risk, thereby balancing detection rates against the need for biopsies [20].
Anzeige
One such calculator, created with data from 1486 men who underwent MRI and biopsy, was externally validated in a cohort of 946 men at two institutions. Using a risk threshold corresponding to 95% sensitivity in the original population could have lowered MRI usage by 22% in the validation cohort while missing only 5% of csPCa cases [21].
Numerous calculators have been developed from cohort studies. Chief among them is the European Randomized Study of Screening for Prostate Cancer (ERSPC)-derived risk calculator, which was updated to incorporate the 2014 ISUP Gleason grading and cribriform growth patterns [22], accessible at http://www.prostatecancer-riskcalculator.com/seven-prostate-cancer-risk-calculators.
Another widely used model is the Prostate Cancer Prevention Trial Risk Calculator 2.0 (PCPTRC 2.0), built from the PCPT cohort: https://riskcalc.org/PCPTRC/.
Nevertheless, these tools often require recalibration to local disease prevalence, which can shift over time and is challenging to measure accurately in routine clinical practice. Hence, employing risk calculators requires careful consideration of population-specific factors.
Anzeige
Should MRI of the prostate be used as a screening tool?
The growing availability of prostate MRI and the establishment of the Prostate Imaging-Reporting and Data System (PI-RADS) as a standard interpretive framework have made this modality indispensable for optimizing prostate cancer diagnosis. MRI effectively limits unnecessary biopsies in PI-RADS 1–2 lesions and boosts csPCa detection in PI-RADS 3–5 cases [23, 24].
With its high sensitivity, MRI has shown excellent negative predictive value (NPV) for excluding csPCa, not only on subsequent biopsy [25] but also over a 4-year follow-up [26]. However, the overall diagnostic accuracy, as well as the proportion of avoidable biopsies, depends on the PI-RADS threshold chosen to define a positive scan. In combined data sets of biopsy-naïve men and those with negative prior biopsies, a PI-RADS threshold of ≥ 3 could avoid 30% (95% CI 23–38) of biopsies while missing 11% (95% CI 6–18) of ISUP grade group ≥ 2 cancers; raising the threshold to ≥ 4 could avert 59% (95% CI 43–78) of biopsies while missing 28% (95% CI 14–48) of these cancers [27].
It is worth noting that PI-RADS ≤ 2 rates vary across trials. In the PRECISION, MRI-FIRST, and 4M studies, negative MRI results ranged from 21.1% to 49%, with ISUP grade group ≥ 2 prevalence rates of 27.7%, 37.5%, and 30%, respectively [23, 28, 29]. The MR PROPER trial, a prospective, multicenter, nonrandomized initiative for men with PSA > 3 ng/mL, found comparable detection rates for ISUP grade group ≥ 2 cancers using either MRI-based or risk calculator-based systematic biopsy. However, the MRI pathway avoided more unnecessary biopsies (55% vs. 42%; p < 0.01) [30].
Prostate MRI, guided by PI-RADS, improves detection of clinically significant prostate cancer while reducing unnecessary biopsies, especially in PI-RADS 1–2 cases. However, its diagnostic accuracy as a screening tool depends on the PI-RADS threshold, with higher cutoffs avoiding more biopsies but missing more cancers.
Anzeige
What is the role of biomarkers in prostate cancer identification?
Multiple urine, serum, and tissue-based biomarkers have been explored to refine PCa detection and risk stratification, potentially reducing unwarranted biopsies.
Stockholm3 test
The Stockholm3 test combines clinical data (e.g., age, first-degree family history, and previous biopsy history) with blood biomarkers (total PSA, free PSA, PSA ratio, human kallikrein 2, macrophage inhibitory cytokine‑1, and microseminoprotein) and a polygenic risk score. This multimodal approach helps identify ISUP grade group ≥ 2 PCa. In a PSA-screened population, using Stockholm3 alongside MRI has reduced clinically insignificant cancer diagnoses and may cut down the need for mpMRI scans [17, 31].
SelectMDX test
SelectMDX is a urine-based mRNA assay that measures HOXC6 and DLX1 expression to gauge PCa detection risk and the likelihood of high-risk disease [32]. In men with MRI PI-RADS scores < 4 or < 3, SelectMDX missed only 6.5% and 3.2% of csPCa cases, respectively, while avoiding 45.8% and 40% of biopsies [33]. Hendriks et al. found that MRI-based biopsy outperformed SelectMDX alone by reducing more biopsies and identifying more high-grade PCa. When used in tandem, more Gleason grade > 1 lesions were detected; however, the number of biopsies revealing low-grade or no cancer more than doubled [34]. Among men with PSA levels of 3–10 ng/mL, combining SelectMDX with MRI showed a 93% NPV [35]. Still, in the era of routine MRI and targeted biopsies, SelectMDX’s clinical utility remains uncertain [36]. However, broader clinical validation is necessary to confirm reliability of this first biomarker [37].
PRAISE-U project for early detection of prostate cancer in the EU
The PRAISE‑U project (https://uroweb.org/praise-u) endeavors to reduce PCa-related morbidity and mortality across EU Member States by leveraging advanced early detection methods. Working closely with its consortium partners, PRAISE‑U advocates for personalized, risk-based screening programs, aims to unify protocols and guidelines among Member States, and promotes the systematic collection and dissemination of relevant data to enhance PCa outcomes throughout Europe. Currently, individual fact sheets concerning the screening program for each country can be accessed within the framework of the PRAISE‑U concept. In the future, this project aims to significantly improve and harmonize prostate cancer screening across Europe.
Conclusion
A personalized approach to prostate cancer screening is paramount, taking into account an individual’s family history, baseline prostate-specific antigen (PSA) levels, and other risk factors to determine screening intervals and diagnostic methods.
Men without specific risk factors should be offered individualized PSA-based early detection starting at the age of 50 years. Men with a family history of prostate cancer or of African descent should begin screening at the age of 45 years, while men carrying breast cancer gene 2 (BRCA 2) mutations should start at 40 years. A baseline PSA measurement enables a risk-adapted follow-up strategy: men with an initial PSA level > 1 ng/mL at age 40 or > 2 ng/mL at age 60 should undergo screening every 2 years. In contrast, for men without elevated risk, screening intervals can safely be extended up to 8 years.
In the future, integrating PSA tests with MRI, risk calculators, and emerging biomarkers can improve detection rates of clinically significant disease while minimizing overdiagnosis and overtreatment even more. Ultimately, informed decision-making and shared discussions between physicians and patients are crucial to tailoring an optimal screening plan that aligns with each patient’s unique risk profile and preferences.
Conflict of interest
C. Leitsmann and F. Trummer declare that they have no competing interests.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.