The BARCODE1 study was designed to test prospectively the performance of a polygenic risk score with regard to stratification for targeted screening as part of a prostate cancer screening programme in the general population. In a population-based prostate cancer screening programme 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) warranting treatment was higher than the percentage that would have been identified with the use of prostate-specific antigen (PSA) or magnetic resonance imaging (MRI).
To evaluate fully the implementation of polygenic risk score alongside established risk factors, 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 according to Dr. Rosalind A. Eeles of the Oncogenetics Team, Institute of Cancer Research in London, UK and colleagues, who reported the findings on 9 April 2025 in The New England Journal of Medicine.
The authors wrote in the background that screening with PSA assay has a high rate for false positive results. Research is focused on MRI-based screening, biomarkers, and modelling multiple risk factors.. Older age and family history of prostate cancer are established risk factors for prostate cancer. Prostate cancer is highly heritable. A small proportion of germline genetic risk is caused by rare pathogenic variants in DNA repair genes, and a greater proportion is due to the combined effect of multiple low-risk variants, called single-nucleotide polymorphisms (SNPs), from which a polygenic risk score can be calculated.
The study team recruited persons 55 to 69 years of age from primary care centres in the UK. Using germline DNA extracted from saliva, they derived polygenic risk scores from 130 variants known to be associated with an increased risk of prostate cancer. 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.
Among 40292 persons invited to participate, 8953 (22.2%) expressed interest in participating and 6393 had their polygenic risk score calculated; 745 (11.7%) had a polygenic risk score in the 90th percentile or higher and were invited to undergo screening. Of these 745 participants, 468 (62.8%) underwent MRI and prostate biopsy; prostate cancer was detected in 187 participants (40.0%). The median age at diagnosis was 64 years (range, 57 to 73).
Of the 187 participants with cancer, 103 (55.1%) had prostate cancer classified as intermediate or higher risk according to the 2024 National Comprehensive Cancer Network (NCCN) criteria, so treatment was indicated; cancer would not have been detected in 74 (71.8%) of these participants according to the prostate cancer diagnostic pathway currently used in the UK. In addition, 40 of the participants with cancer (21.4%) had disease classified as unfavourable intermediate risk or as high or very high risk according to NCCN criteria.
The authors commented that the current diagnostic pathway for suspected prostate cancer in the UK involves either a high PSA level or an abnormal digital rectal examination followed by a referral for MRI. If a lesion is present or there is other clinical concern, biopsy is indicated. If the participants of the BARCODE1 study had followed this pathway, prostate cancer would have been missed in 42.5% of those with clinically significant disease, and a prostate cancer diagnosis would have been avoided in 97.6% of those with clinically insignificant disease.
In an accompanied editorial article, Dr. David J. Hunter of the Nuffield Department of Population Health, University of Oxford in Oxford, UK and Department of Epidemiology, Harvard T.H. Chan School of Public Health in Boston, MA, US wrote that starting a prostate cancer screening programme with the assessment of a polygenic risk score would require large-scale investment in the management and analysis of genome arrays and would raise a host of questions about the storage of genetic data on populations and the use of the data in calculating and potentially counselling on the risk of many other diseases.
The BARCODE1 study suggests that, if available, a polygenic risk score for prostate cancer would be a useful component of a multimodality screening programme that assesses age, family history of prostate cancer, PSA, and MRI results as triage tools before biopsy is recommended. To make this integrated programme 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. However, we are far from that future.
The study was supported by a grant from the European Research Council Seventh Framework Program, a grant from Cancer Research UK, the Bob Willis Fund, the Peacock Trust, and the National Institute for Health and Care Research to the Biomedical Research Centre at the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust. The prostate risk clinic at the Royal Marsden NHS Foundation Trust where study participants were treated is funded in part by the Joseph Frazer Trust and the Royal Marsden Cancer Charity.
References
- McHugh JK, Bancroft EK, Saunders E, et al. for the BARCODE1 Steering Committee and Collaborators. Assessment of a Polygenic Risk Score in Screening for Prostate Cancer. N Engl J Med 2025;392:1406-1417.
- Hunter DJ. A Polygenic Risk Score in Practice. N Engl J Med 2025;392:1444-1446.