Effect of polygenic risk score for clinically significant prostate cancer in a screening program: The BARCODE 1 study results.

Abstract

10500 Background: Incidence of prostate cancer (PCa) is increasing, but there is no internationally agreed population screening program. Studies using an age-based PSA approach show a high rate of false-positive results as well as over-diagnosis of indolent PCa. Genome wide association studies identify common germline variants to calculate a polygenic risk score (PRS) associated with PCa risk. The BARCODE1 study used PRS to target PCa screening to those at higher risk based on genotype. Methods: European men aged 55-69yrs were recruited via Primary Care in the UK. PRS was constructed by summing weighted risk alleles for 130 PCa risk variants using germline DNA from saliva samples via mailed kits. Men with a PRS > 90th centile were invited for PCa screening using MRI and 12-core transperineal biopsy (including MRI fusion to target additional lesions where identified) irrespective of PSA result. Results: Invitation letters were sent to 40,292 men. 8,953 (22%) expressed an interest; 8,014 were eligible and sent a saliva kit. 6,644 consented; 6,393 were genotyped; 251 failed QC. A total of 6,142 participants had PRS calculated: 745 (12.1%) had a PRS > 90th centile and were invited to screening. 558/745 participants attended screening (121 declined, 66 excluded on health grounds). 551 underwent MRI and 468 had prostate biopsy resulting in 187 (40.0%) diagnoses of PCa, overall PCa detection rate 2.8%. Mean age at diagnosis 64.1yrs (range 57-73; median 64). Using NCCN criteria (2023) 103/187 (55.1%) of cancers were Intermediate or High Risk; 40/187 (21.4%) were Intermediate Unfavourable/High/Very High Risk. 119/187 (63.6%) men had a PSA <3.0ug/L; PPV of biopsy for PSA > 3.0ug/L was 49.6%. PPV of MRI (presence of PI-RADS 3-5 lesion) 60.4%. PPV of PRS alone 40%. 103/187 (55.1%) had Gleason >7; compared with 360/1014 (35.5%) p < 0.001 in the PSA directed ERSPC study. Conclusions: A population PCa screening program using PRS risk-stratification enriches for clinically significant PCa requiring treatment. It detects a high proportion of clinically significant disease compared with PSA or MRI based screening programs and MRI missed a significant proportion (17-67%) of cancers found on biopsy. This is the first study to assess if this approach will be useful in population screening programs. Clinical trial information: NCT03857477 . [Table: see text]