A New Era in Prostate Cancer Screening: Early Detection With Polygenic Risk Scores (PRS)

Prostate cancer, with 1.5 million new cases each year, is the most common cancer in men worldwide after skin cancer. In 2020, it caused approximately 375000 deaths worldwide. When diagnosed at an early stage, the 5-year survival rate reaches 100%; in those diagnosed at an advanced stage, it falls to 50%.

To date, the most widely used method of prostate cancer screening has been the PSA (prostate-specific antigen) test. However, PSA testing has been criticized for its high false-positive rate, overdiagnosis, and unnecessary biopsies . More effective, personalized screening strategies are therefore needed.

The results published on April 9, 2025, in NEJM come from the UK-based BARCODE1 study, which investigates whether a polygenic risk score (PRS) based on individuals' genetic profiles could enable more targeted prostate cancer screening.

A Polygenic Risk Score (PRS = polygenic risk score)is a measure used to assess an individual's genetic predisposition to various conditions by calculating the combined effect of many genetic variants (changes) . PRS is used to estimate an individual's genetic risk for a particular disease or trait. It combines the effects of multiple genetic variants identified through genome-wide association studies (GWAS).

BARCODE1: Initial Findings From Genetic Score-Based Screening

BARCODE1 enrolled individuals of European ancestry aged 55-69 who had not previously been diagnosed with prostate cancer. A total of 40292 individuals were invited. Among the respondents, 6393 individuals had their genetic risk calculated using PRS, and 745 individuals in the highest-risk 10% underwent further screening.

Regardless of their PSA levels, these high-risk individuals were evaluated using multiparametric MRI (mpMRI) and transperineal prostate biopsy .

Findings:

• Of the 745 individuals, 468 agreed to MRI and biopsy.
• Among them, 40% (187 individuals) were diagnosed with prostate cancer.
• Among those diagnosed, 55.1% had intermediate- or high-risk cancer (Gleason score ≥7).
• The current UK screening algorithm would have missed 71.8% of these cases.
• The positive predictive value in those with PSA >3 ng/mL was 61.1%, while in those with PI-RADS ≥3 on MRI it was 62.9% .

What Is a Polygenic Risk Score? What Is It Used For?

This genetic risk score, called PRS, is calculated from a weighted sum of 130 genetic variants (SNPs) in an individual's DNA that are known to increase prostate cancer risk. The score reflects the degree of inherited risk carried by the individual.

In BARCODE1:

• Individuals with a PRS at or above the 90th percentile generally had a 10-year prostate cancer risk above 3.8%, identifying the group most likely to benefit from early detection.

Noteworthy Data:

• Among individuals diagnosed with cancer, 63.1% had PSA levels ≤3 ng/mL .
• Among these individuals, 43.2% had clinically significant cancer (Gleason ≥7) .
• In other words, relying solely on PSA could miss a substantial proportion of early, treatable cases.

The Importance of MRI and Biopsy Findings

• Among individuals with negative MRI findings (PI-RADS ≤2) , 33.8% had cancer detected by biopsy.
• Even when MRI results were normal, evaluating genetically high-risk individuals with biopsy increased the detection of clinically significant cancers.
• This shows that genetic risk is an important marker independent of MRI results.

What Is the Risk of Overdiagnosis and Unnecessary Treatment?

As in any screening program, BARCODE1 also assessed the risk of overdiagnosis (detecting a cancer that would not cause symptoms during the person's lifetime). The results were as follows:

• Overdiagnosis rate among individuals with a high genetic score: 20.8%
• With screening based solely on PSA testing, the rate was 17.2%
• With screening based solely on MRI findings, it was 15.6% .

However, an important point is that: Patients with a Gleason score of 6 were all managed with active surveillance, avoiding unnecessary treatment.

What Does This Mean for Clinical Practice?

1. A polygenic risk scoredoes not replace existing tests such as PSA or MRI, but it could be a powerful complementary tool, particularly for younger individuals, in personalized screening programs .
2. The genetic risk score is calculated once and does not change over time. This makes it a cost-effective test.
3. The score is particularly important for ensuring that individuals with low PSA levels but high genetic risk are not missed.
4. When used alongside family history, age, and PSA levels, it may improve early detection rates.

Conclusion: Toward Personalized Prostate Cancer Screening

BARCODE1 offers compelling evidence of how genetic information can be used in population-based prostate cancer screening. Detecting serious cases through genetic screening that might otherwise be missed by conventional methods such as PSA and MRI is revolutionary in terms of early detection and gains in life expectancy

. However, for this approach to become widespread:

• Its validity in different ethnic groups must be tested,
• Cost-effectiveness analyses must be conducted,
• And national screening strategies must be updated using these data.