Polygenic risk score may identify more clinically significant PCa than PSA, MRI

The use of a polygenic risk score to select patients to undergo prostate cancer (PCa) screening may identify more patients with clinically significant disease than the use of prostate-specific antigen (PSA) or MRI, according to data from the BARCODE1 trial (NCT03857477) published in the New England Journal of Medicine.¹

Professor Ros Eeles

“With this test, it could be possible to turn the tide on prostate cancer,” said professor Ros Eeles, of The Institute of Cancer Research, London, England, in a news release on the findings.² “We have shown that a relatively simple, inexpensive spit test to identify men of European heritage at higher risk due to their genetic makeup is an effective tool to catch prostate cancer early. 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.”

The polygenic risk score was developed using 130 variants known to be associated with an increased risk of prostate cancer. According to the authors, “Participants with a polygenic risk score in the 90th percentile or higher were invited to undergo prostate cancer screening with multiparametric [MRI] and transperineal biopsy, irrespective of PSA level.”

To be included in the study, patients had to be aged 55 to 69 years, of European ancestry, and have a World Health Organization performance status of 0 to 2. Additionally, participants could not have any psychological, familial, sociological, or geographical situation that would impede study participation.³

In total, 6393 patients had their polygenic risk score calculated. Of those, 745 (11.7%) had a risk score in the 90% percentile and were invited to undergo screening. MRI and prostate biopsy were completed in 468 (62.8%) of invited participants. The most common reason for patients choosing to withdraw from the study before and after MRI was reluctance to undergo prostate biopsy, reported by 40.7% of nonparticipants.

Of those who did participate, prostate cancer was detected in 187 patients (40%). The median age at diagnosis was 64 years (range, 57 to 73 years), and the median PSA level was 2.1 μg/L (range, 0.3 to 274).

The detected cancer was classified as intermediate- or high-risk disease (Gleason score of 7 or higher) per National Comprehensive Cancer Network (NCCN) criteria in 103 patients (55.1%). Additionally, the detected cancer was classified as unfavorable intermediate-, high-, or very high-risk per NCCN criteria in 40 patients (21.4%).

The current prostate cancer diagnostic pathway in the UK is based on high PSA levels and positive MRI results. If this pathway was used, prostate cancer would have been missed in 74 of the patients (71.8%) determined to have intermediate- or high-risk disease. Prostate cancer would have also been missed in 17 patients (42.5%) determined to have unfavorable intermediate-, high-, or very high-risk disease.

Of the 187 patients with cancer detected, 100 patients (53.5%) had either a high PSA level (defined as greater than 3.0 μg/L) or a lesion with a Prostate Imaging–Reporting and Data System (PI-RADS) score of 3 or higher.

The authors also noted, “Only 30 (16.0%) had both a high PSA level and a lesion with a PI-RADS score of 3 or higher and therefore met the standard criterion for progression to prostate biopsy in accordance with the traditional management pathway in the United Kingdom.”

The investigators also estimate that disease was overdiagnosed in 39 participants with a risk score in at least the 90% percentile. They defined overdiagnosis as patients’ screen-detected prostate cancer taking longer than their remaining lifetime to progress to clinical disease.

Based on these findings, the authors concluded, “In a population-based prostate cancer screening program involving participants in the top decile of risk as determined by a polygenic risk score, the percentage found to have clinically significant prostate cancer (Gleason score 7 or higher) warranting treatment in accordance with national guidelines was higher than the percentage that would have been identified with the use of PSA or MRI.”

However, they acknowledge that future research is still warranted.

“To evaluate fully the implementation of polygenic risk score alongside established risk factors in a national screening program, further research is required, including research into the recommended age at which to obtain a polygenic risk score, tests of replication in persons of non-European ancestry, and an evaluation of economic effects.”

The BARCODE1 study remains ongoing, with final completion planned for December 2028.³

“We’re now excited to be rolling out our updated test, PRODICT, to diverse populations—as Black men are twice as likely to develop prostate cancer—and younger groups, as those with a genetic predisposition are more likely to be diagnosed at younger ages,” Eeles added in the news release.² “We are also currently comparing the saliva test to other potential screening options, as part of the TRANSFORM trial, to assess the most cost-effective and accurate way to screen men for prostate cancer.”

REFERENCES

1. McHugh JK, Bancroft EK, Saunders E, et al. Assessment of a polygenic risk score in screening for prostate cancer. N Engl J Med. 2025;392(14):1406-1417. doi:10.1056/NEJMoa2407934

2. Simple spit test could finally turn the tide on prostate cancer. News release. The Institute of Cancer Research. April 9, 2025. Accessed April 10, 2025. https://www.icr.ac.uk/about-us/icr-news/detail/simple-spit-test-could-finally-turn-the-tide-on-prostate-cancer

3. The BARCODE 1 study (full study): the use of genetic profiling to guide prostate cancer targeted screening. (BARCODE1). ClinicalTrials.gov. Last updated August 13, 2024. Accessed April 10, 2025. https://clinicaltrials.gov/study/NCT03857477