By Lynda Williams, medwireNews Reporter
medwireNews: A polygenic risk score (PRS) could help direct prostate cancer screening towards those at highest risk for the disease, the BARCODE1 investigators report.
Study participants who scored in the 90th percentile or higher were referred for magnetic resonance imaging (MRI) and MRI-directed lesion biopsy where applicable, irrespective of their prostate specific antigen (PSA) level, whereas the standard UK diagnostic pathway only refers men for imaging and biopsy if they have an age-specified elevated PSA level or an abnormal digital rectal examination.
Based on having a high PRS, 40 men who then underwent MRI and biopsy were found to have clinically significant prostate cancer (Gleason score ≥7) warranting radical treatment. However, 42.5% of these men would not have been otherwise diagnosed based on a high PSA level and positive MRI, although a prostate cancer diagnosis would have been avoided in 97.6% of those with clinically insignificant disease, say Rosalind Eeles (Institute of Cancer Research, London, UK) and co-authors in The New England Journal of Medicine.
The researchers invited 40,292 persons assigned male at birth and aged 55–69 years who were attending primary care centres in the UK between March and July 2019 to undergo PRS assessment of germline DNA using a panel of 130 European-ancestry single nucleotide polymorphisms.
Of the 6393 men who participated, 11.7% scored in the 90th percentile or higher and were invited to undergo prostate cancer screening. MRI and MRI-directed biopsy of lesions scoring 3 or higher on the Prostate Image Reporting and Data System (PI-RADS) 5-point scale were completed for 62.8% of these 745 participants, 40.0% of whom were diagnosed with prostate cancer at a median 64 years of age.
Of these 187 diagnosed patients, 55.1% had favorable intermediate or more severe risk prostate cancer according to the National Comprehensive Cancer Network criteria, and 21.4% had unfavourable intermediate, high or very high-risk diagnoses requiring radical treatment, Eeles et al say.
Although 53.5% of these patients had elevated PSA or a PI-RADs lesion score of 3 or greater, just 16.0% met both criteria and would have progressed to biopsy by the conventional route. And of the 103 patients who required prostate cancer treatment, 71.8% would not have been diagnosed via the standard diagnostic pathway.
The BARCODE1 investigators emphasize that “almost all” of the patients with a 90th percentile or higher PRS had a 10-year absolute risk of prostate cancer above 3.8%, and therefore within a 3.5–4.0% range that has previously demonstrated to “yield the greatest number of quality-adjusted life-years gained.”
They note that participants who had a 10-year absolute risk above this cutoff but a PRS below the 90th percentile had a family history of prostate cancer, highlighting that the PRS “does not replace known risk factors but supplements them in risk stratification.”
The team estimates that 20.8% of participants aged 55–74 years with a PRS above the 90th percentile and screen-detected prostate cancer would have an overdiagnosis – defined as disease that would take longer than their remaining lifetime to progress to a clinical cancer. This compares with 17.2% of diagnosed participants with a PSA above 3.0 μg/L and 15.6% of diagnosed patients with a PI-RADS lesion score of 3 points or higher.
“All but one of the participants with prostate cancer with a Gleason score of 6 in our study (comprising 44.9% of the participants with detected prostate cancer) are under active surveillance”, they observe.
“Although some overdiagnosis occurred, overtreatment of indolent disease did not occur.”
The team notes that the study is limited by the “homogeneous” cohort of self-selected and highly educated European participants and say their “study provides a framework on which to build further research on the role of genetic risk in screening for cancer in persons of non-European ancestries”, including Black and Caribbean people who have a higher incidence of the disease.
And while the PRS is a one-off test, the team concludes that “further evaluation of the timing of polygenic risk score and subsequent screening algorithms will be needed to assess the trade-off of benefits, harms, and cost-effectiveness.”
News stories are provided by medwireNews, which is an independent medical news service provided by Springer Healthcare Ltd. © 2025 Springer Healthcare Ltd, part of the Springer Nature Group
N Engl J Med 2025; 392: 1406–1417