Background

Pathogenic variants in the mis-match repair genes (MMR) have been reported to increase the risk of early-onset aggressive prostate cancer (PrCa). The IMPACT study is prospectively evaluating Prostate Specific Antigen (PSA) screening in men with germline MMR pathogenic variants. Here we report the utility of PSA screening, PrCa incidence and tumour characteristics after the first screening round among men with and without these germline pathogenic variants.

Method

Healthy men aged 40–69 years with germline pathogenic variants in MLH1, MSH2, and MSH6 genes and male controls testing negative for a familial pathogenic variant in these genes, were recruited. Participants underwent PSA screening and if PSA >3.0ng/ml, were offered prostate biopsy. Screening outcome was assessed related to mutation status.

Results

204 MLH1 carriers, 199 MLH1 non-carriers, 305 MSH2 carriers, 210 MSH2 non-carriers, 135 MSH6 carriers, 177 MSH6 non-carriers were recruited. Within the first round of screening 56 men had PSA>3.0ng/ml, 35 biopsies were performed, and 18 PrCas diagnosed (13 MSH2 carriers, 1 MSH2 non-carrier; 4 MSH6 carriers).  Zero cancers were detected in MSH6 non-carriers, and MLH1 cohort. Cancer incidence was higher in MSH2 carriers than non-carriers (4.3% vs 0.5%; p=0.01) and MSH6 carriers than non-carriers respectively (3% vs 0%; p=0.04). MSH2 carriers were diagnosed younger (60 vs 66 years) and more likely to have clinically-significant disease than non-carriers (85% vs 0%).  MSH6 carriers were diagnosed at 64 years (median age) and 75% had clinically significant disease.

Conclusion

After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of PrCa, were diagnosed at a younger age and had more clinically significant disease compared with non-carriers. These findings support the use of targeted PSA screening in these men to identify clinically significant disease.  Future study screening rounds will help determine the utility of PSA screening in MLH1 carriers and provide further data on annual screening in MSH2 and MSH6 carriers.

Impact statement

After the first screening round of the IMPACT study, carriers with pathogenic variants in MSH2 and MSH6 genes had a higher incidence of PrCa, were diagnosed at a younger age and had more clinically significant disease compared with non-carriers.