medwireNews: Men who carry germline mismatch repair pathogenic variants in the MSH2 and MSH6 genes, typically associated with Lynch syndrome, have a significantly higher incidence of prostate cancer than noncarriers, show early data from the IMPACT study.
Writing in The Lancet Oncology, Rosalind Eeles (The Institute of Cancer Research, Sutton, UK) and co-authors say that the findings “support the use of targeted prostate-specific antigen [PSA] screening in men with mismatch repair gene pathogenic variants to successfully detect clinically significant prostate cancers.”
The IMPACT study included 828 men from 34 genetic and urology clinics in eight countries who had no history of prostate cancer at baseline. Of these, 204 carried mismatch repair pathogenic variants in the MLH1 gene, 305 carried MSH2 variants, 135 carried MSH6 variants, and 184 were noncarrier controls (65 for MLH1, 76 for MSH2, and 43 for MSH6). An additional 134 noncarriers of all three variants were included to boost the size of the control groups.
During the first of five annual screening rounds, 6% of men had a PSA concentration above 3.0 ng/mL (median 5.1 ng/mL) and 4% underwent transrectal, ultrasound-guided, prostate biopsy.
Overall, 1.9% of participants were diagnosed with prostate cancer, but the incidence was significantly higher in MSH2 carriers than in MSH2 non-carrier controls (4.3 vs 0.5%) and in MSH6 carriers than MSH6 non-carrier controls (3.0 vs 0.0%). There were no cases in either MLH1-carriers or controls.
For clinically significant prostate cancer (intermediate risk or high risk based on NICE classification), the incidence remained significantly higher in MSH2 carriers versus controls (3.6 vs 0.0%) but the difference was not significant for MSH6 carriers versus controls (2.2 vs 0.0%).
Eeles and team point out that the majority of prostate cancer cases in both MSH2 (85%) and MSH6 (75%) carriers were clinically significant, which supports “retrospective reports of a more aggressive phenotype in these groups.”
They add that “prostate screening in this higher-risk context has potential to detect tumours that are highly likely to need treatment based on national and international guidelines without the limitations of over-detection seen in general population screening programmes.”
The positive predictive value (PPV) of biopsy for any cancer following a PSA result above 3.0 ng/mL was 51.4% overall, increasing to 72.2% in MSH2 carriers and 80.0% in MSH6 carriers. For MSH2 controls the PPV was 33.3%; it was not calculable in the other groups due to there being no positive cases.
The authors hypothesize that the “increasing evidence of germline pathogenic variants in mismatch repair genes predisposing to prostate cancer and aggressive disease” will lead to the expansion of prostate cancer screening and management guidelines “to include men with pathogenic variants in mismatch repair genes and other relevant germline variants over the coming years.”
However, in an accompanying comment, Francesco Montorsi and colleagues from IRCCS Ospedale San Raffaele in Milan, Italy, point out that “[t]he feasibility and cost-effectiveness of genomic testing to identify screening candidates in the overall population or in a subset of men at increased risk remains questionable.”
They also say that “the effectiveness of targeted, systematic PSA screening in men with germline mutations in mismatch repair genes such as MSH2 and MSH6 still needs to be proven.”
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