, 2025-04-18 11:41:00
Incorporating a polygenic risk score into prostate cancer screening could enhance the detection of clinically significant prostate cancer that conventional screening may miss, according to results of the BARCODE 1 clinical trial conducted in the United Kingdom.
The study found that about 72% of participants with high polygenic risk scores were diagnosed with clinically significant prostate cancers, which would not have been detected with prostate-specific antigen (PSA) testing or MRI.
“With this test, it could be possible to turn the tide on prostate cancer,” study author Ros Eeles, PhD, professor of oncogenetics at The Institute of Cancer Research, London, England, said in a statement following the publication of the analysis in The New England Journal of Medicine.
Prostate cancer remains the second most commonly diagnosed cancer among men. As a screening tool, PSA testing has been criticized for leading to a high rate of false positive results and overdiagnosis — defined as a screen-detected cancer that would take longer to progress to clinical cancer than the patient’s lifetime. Both issues can result in overtreatment.
Given prostate cancer’s high heritability and the proliferation of genome-wide association studies identifying common genetic variants, there has been growing interest in using polygenic risk scores to improve risk stratification and guide screening.
“Building on decades of research into the genetic markers of prostate cancer, our study shows that the theory does work in practice — we can identify men at risk of aggressive cancers who need further tests and spare the men who are at lower risk from unnecessary treatments,” said Eeles.
An Adjunct to Screening?
The BARCODE 1 study, conducted in the United Kingdom, tested the clinical utility of a polygenic risk score as an adjunct to screening.
The researchers recruited men aged 55-69 years from primary care centers in the United Kingdom. Using germline DNA extracted from saliva, they derived polygenic risk scores from 130 genetic variants known to be associated with an increased risk for prostate cancer.
Among a total of 6393 men who had their scores calculated, 745 (12%) had a score in the top 10% of genetic risk (≥ 90th percentile) and were invited to undergo further screening.
Of these, 468 (63%) accepted the invite and underwent multiparametric MRI and transperineal prostate biopsy, irrespective of the PSA level. Overall, 187 (40%) were diagnosed with prostate cancer following biopsy. Of the 187 men with prostate cancer, 55% (n = 103) had disease classified as intermediate or high risk (Gleason score ≥ 7) per National Comprehensive Cancer Network criteria and therefore warranted further treatment.
Researchers then compared screening that incorporated polygenic risk scores with standard screening with PSA levels and MRI.
When participants’ risk was stratified by their polygenic risk score, 103 patients (55%) with prostate cancer could be classified as intermediate or higher risk, thus warranting treatment. Overall, 74 (71.8%) of those cancers would have been missed using the standard diagnostic pathway in the United Kingdom, which requires patients to have a high PSA level (> 3.0 μg/L) as well as a positive MRI result. These 74 patients either had PSA levels ≤ 3.0 μg/L or negative MRIs, which would mean these patients would typically fall below the action threshold for further testing.
Of the 103 participants warranting treatment, 40 of these men would have been classified as unfavorable intermediate, high, or very high risk, which would require radical treatment. Among this group, roughly 43% would have been missed using the UK diagnostic pathway.
However, the investigators estimated a rate of overdiagnosis with the use of polygenic risk scores of 16%-21%, similar to the overdiagnosis estimates in two prior PSA-based screening studies, signaling that the addition of polygenic risk scores does not necessarily reduce the risk for overdiagnosis.
Overall, “this study is the strongest evidence to date on the clinical utility of a polygenic score for prostate cancer screening,” commented Michael Inouye, professor of systems genomics & population health, University of Cambridge, Cambridge, England, in a statement from the UK nonprofit Science Media Centre (SMC).
“I suspect we will look back on this as a landmark study that really made the clinical case for polygenic scores as a new tool that moved health systems from disease management to early detection and prevention,” said Inouye, who was not involved in the study.
However, other experts were more cautious about the findings.
Dusko Ilic, MD, professor of stem cell sciences, King’s College London, London, England, said the results are “promising, especially in identifying significant cancers that would otherwise be missed,” but cautioned that “there is no direct evidence yet that using [polygenic risk scores] improves long-term outcomes such as mortality or quality-adjusted life years.”
“Modeling suggests benefit, but empirical confirmation is needed,” Ilic said in the SMC statement.
The hope is that the recently launched TRANSFORM trial will help answer some of these outstanding questions.
The current study suggests that polygenic risk scores for prostate cancer “would be a useful component of a multimodality screening program that assesses age, family history of prostate cancer, PSA, and MRI results as triage tools before biopsy is recommended,” David Hunter, MPH, ScD, with Harvard T. H. Chan School of Public Health, Boston, and University of Oxford, Oxford, England, wrote in an editorial accompanying the study.
“To make this integrated program a reality, however, changes to infrastructure would be needed to make running and analyzing a regulated genome array as easy as requesting a PSA level or ordering an MRI. Clearly, we are far from that future,” Hunter cautioned.
“A possible first step that would require less infrastructure could be to order a polygenic risk score only for men with a positive PSA result, then use the polygenic risk score to determine who should undergo an MRI, and then use all the information to determine whether biopsy is recommended,” Hunter said.
In his view, the current study is a “first step on a long road to evaluating new components of any disease screening pathway.”
The research received funding from the European Research Council, the Bob Willis Fund, Cancer Research UK, the Peacock Trust, and the National Institute for Health and Care Research Biomedical Research Centre at The Royal Marsden and The Institute of Cancer Research. Disclosures for authors and editorialists are available with the original article. Inouye and Ilic reported no relevant disclosures.