Editor’s Note: Prostate cancer is one of the most common malignancies in men, and the widespread use of prostate-specific antigen (PSA) testing has significantly improved early diagnosis rates. However, a series of prostate cancer screening trials in Europe have found that PSA-based screening benefits only a subset of patients. How can more prostate cancer patients benefit from screening? Are there other biomarkers that can be used for screening? A recent article published in European Urology discusses these questions. We have summarized the key points for our readers.

PSA-based screening can reduce prostate cancer mortality, but it can also lead to overtreatment by detecting indolent tumors. The recent analysis of the CAP trial on PSA screening for prostate cancer highlighted this dilemma: Men aged 50-69 in the trial group were invited to undergo a one-time PSA screening, while the control group received no such invitation. Traditionally, a PSA level above 3.0 ng/ml would prompt a prostate biopsy. After a median follow-up of 15 years, the absolute reduction in prostate cancer mortality in the screened group was only 0.09%, while the diagnosis rate of low-risk prostate cancer increased.

The challenge of early detection lies in specificity. Ideally, early screening should identify aggressive and potentially lethal tumors while avoiding the detection of low-risk and very low-risk cases. Based on extensive evidence, clinical guidelines support the use of secondary non-invasive tests to improve the specificity of PSA screening. Magnetic resonance imaging (MRI) can help clinicians detect clinically significant tumors. However, limitations in insurance coverage, MRI availability, and inter-reader consistency may restrict its use in real-world settings.

Recently, scholars reported on the Göteborg-2 Biomarker (G2B) study, which analyzed the impact of 4Kscore testing following PSA screening (without MRI) on improving prostate cancer screening procedures. This study involved 38,000 patients, of whom those with PSA >3.0 ng/ml were invited for MRI scans. MRI was recommended for patients with suspicious lesions (PI-RADS scores of 3-5), and targeted biopsies were suggested. Among them, 571 patients underwent 4Kscore testing. Using the 4Kscore algorithm, with a preset threshold of 7.5%, 338 patients (59%) would have proceeded to MRI. At this threshold, the positive predictive value and negative predictive value for detecting Grade 2 or higher tumors were 15% and 99%, respectively. Researchers noted that performing the 4Kscore test before MRI could increase specificity and potentially avoid 41% of MRI scans and 28% of biopsies. Furthermore, this approach could reduce the diagnosis of low-risk tumors by 23%, with only 4% of intermediate-risk patients missed.

The screening algorithm and results were similar to those of the recently published ProScreen trial. Patients also underwent PSA testing, 4Kscore, MRI, and targeted biopsies. However, in the ProScreen trial, patients with elevated PSA density (>0.15 ng/ml²) but negative MRI results received 12-core systematic biopsies. By integrating modern diagnostic tools, the detection rate of high-risk prostate cancer (1.65%) remained similar to previous rates, while the diagnosis rate of low-risk prostate cancer (0.41%) decreased.

These studies highlight advancements in modern prostate cancer screening methods and current debates. Prostate cancer screening has historically been considered a one-step process, relying on a single or few PSA values. Biomarkers like the 4Kscore offer a simplified yet efficient multi-step approach. Commercially available biomarkers (based on blood or urine samples) are easy to implement, less resource-intensive, and allow for more selective use of MRI and/or biopsies. Thus, adding biomarkers could enhance the value of screening and benefit more patients. In prostate cancer, “more is better.”

Of course, there are limitations to these biomarker tests. First, given that most patients ultimately did not undergo biopsy due to low 4Kscore results or negative MRI findings, the reported negative predictive value of 4Kscore (99% at the 7.5% threshold) may be inflated. Additionally, both the G2B and ProScreen studies did not use a second PSA test before biomarker testing. Moreover, patients with PI-RADS scores of 3-5 underwent only targeted biopsies, and the absence of systematic biopsies limits further understanding.

Clinicians must weigh the use of biomarkers and MRI results as prerequisites for biopsies. Inevitably, more efficient diagnostic algorithms may delay (or even miss) a small number of high-risk patients. There is subjectivity in balancing biomarker/MRI-driven algorithms against MRI-based methods. As clinical guideline committees consider these screening algorithms, they must carefully weigh these trade-offs and listen to patient preferences when assuming the new risk/benefit profile of novel prostate cancer early detection methods.