Men who carry certain pathogenic variants in mismatch repair genes that characterize Lynch syndrome may have a higher risk of prostate cancer, shows a new study. However, for men who carry MSH2 and MSH6 variants, the risk of contracting cancer rises significantly.
Called IMPACT, the study, which was published online in The Lancet Oncology, is an international, prospective study of 828 men aged between 40 and 69 years who were prostate cancer free, but they carried germline pathogenic variants in one of the mismatch repair genes MLH1, MSH2, or MSH6.
The researchers, who were led by Rosalind A. Eeles, PhD, a specialist in oncogenetics with the Institute of Cancer Research, London, found that after one screening “a higher incidence of prostate cancer was detected in men with MSH2 and MHS6 pathogenic variants, compared with age-matched noncarrier controls.”
She and her team also found that MSH2 carriers “were diagnosed at a nonsignificantly younger age and had more clinically significant disease at diagnosis, compared with noncarriers. These data add evidence that prostate screening in this higher-risk context has potential to detect tumors that are highly likely to need treatment.”
The findings suggest that targeted prostate-specific antigen (PSA) screening in men with mismatch repair gene pathogenic variants is justifiable. “Testing for mismatch repair variants will likely become routine practice at diagnosis over the coming years,” the authors wrote.
Lynch syndrome can increase the risk of prostate cancer by 2-10 times, yet there is no international consensus for screening. The 2019 National Comprehensive Cancer Network guidelines recommend considering tumor testing for deficient mismatch repair in men with regional or metastatic prostate cancer. The NCCN also recommends germline testing for all newly diagnosed men with high-risk, very-high-risk, regional, or metastatic prostate cancer.
Currently, the PSA test is the most commonly used test, however, it is not recommended as a routine screening tool because of the negative consequences of overdetection. The American Cancer Society and European Association of Urology recommend PSA screening for men with a strong family history of prostate cancer. The EAU also supports annual PSA screening for men with BRCA2 variants.
“From a treatment perspective, knowledge of mismatch repair pathogenic variant status is increasingly important because of the evidence that mismatch repair-deficient prostate tumors can be sensitive to immune checkpoint inhibitors,” the investigators wrote.
NCCN guidelines support the use of the progressive death–1 inhibitor pembrolizumab (Keytruda, Merck) in these patients, among others.
Although immune checkpoint inhibitors are predominantly used to treat metastatic disease, “this field is rapidly evolving and we will likely see these treatments move earlier in the treatment pathway,” the authors predicted.
The findings in detail
The IMPACT study was established in 2005 to assess targeted PSA screening in men with BRCA1 or BRCA2 pathogenic variants. It was extended in 2012 to include men from families with MLH1, MSH2, and MSH6 pathogenic variants.
In this new report, within the first round of screening, 6% of the cohort had a PSA concentration higher than 3.0 ng/mL and the overall incidence of prostate cancer was 1.9%, the investigators noted.
MSH2 carriers were diagnosed at 58 years old on average, compared with 66 years old for the control group. MSH2-positive men had more clinically significant disease, compared with noncarriers. The incidence of prostate cancer was higher at 4.3% in MSH2 carriers than in controls at 0.5%. In MSH6 carriers, the incidence of prostate cancer was 3.0%, compared with 0% for controls.
Only 4% of men underwent a biopsy and only one cancer was found among the MSH2 noncarriers while no cancers were found in MLH1 carriers, MLH1 noncarriers, or MSH6 noncarriers.
The overall positive predictive value of using a PSA threshold of 3.0 ng/mL was 51.4%; separated by genetic status, the PPV in MSH2 carriers was higher at 72.2% and in MSH6 carriers, the PPV was 80%, the researchers noted.
Limitations of the study include the fact that the number of cancers detected in the study was relatively small, thus requiring further data from subsequent screening rounds.
One study coauthor disclosed a potential conflict of interest by holding a PSA test patent.