Relationship Between MSH2, MSH6 and Prostate Cancer Incidence Highlights Value of PSA Screenings

The increased risk of prostate cancer associated with MSH2 and MSH6 pathogenic variants point to a need for annual PSA screening in men over the age of 40.

The initial findings from the IMPACT study (NCT00261456) revealed that men who carry the MSH2 and MSH6 pathogenic variants are at an increased risk for prostate cancer compared with age-matched non-carrier individuals.1 The risk identified in these pathogenic variants, which are associated with Lynch Syndrome, highlight the potential value of regular prostate-specific antigen (PSA) screening starting at age 40.

“Prostate cancer screening isn’t recommended for the general population, but we believe it could benefit some groups of men at high inherited risk. Our new findings show that PSA testing in men with Lynch syndrome is much more likely to pick up life-threatening prostate cancer than in the general population,” Rosalind (Ros) Eeles, FMedSci, PhD, FRCP, FRCR, IMPACT study lead, professor of oncogenetics at The Institute of Cancer Research and a consultant in clinical oncology and oncogenetics at The Royal Marsden NHS Foundation Trust, said in a news release.2

Lynch syndrome is characterized by pathogenic variants in MLH1, MSH2, MSH6, or PMS2, which are mismatch repair genes. The familial cancer syndrome is associated with a predisposition to several cancers, including colorectal and endometrial. Data suggest that these genetic alterations confer an increased risk of early-onset, aggressive prostate cancer as well.1

As such, the goals of the IMPACT study were to assess the utility of PSA screening in men with and without germline pathogenic variants in the genes in question, understand the incidence of prostate cancer among these men, and characterize tumors after the first round of screening.

The primary end point of the study was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of these pathogenic variants compared with non-carriers.

Overall, the international prospective study enrolled 828 men with mismatch repair gene pathogenic variants without a previous diagnosis of prostate cancer. Of these, 4 did not undergo PSA screening. Of the men who did undergo PSA screening, 203 were MLH1 carriers, 199 were MLH1 non-carrier controls, 303 were MSH2 carriers, 210 were MSH2 non-carrier controls, 134 were MSH6 carriers, and 177 were MSH6 non-carrier controls. An additional 134 BRCA1/BRCA2 non-carriers were randomly selected to increase the sample size for the non-carrier control groups.

Additionally, of the 828 men with confirmed pathogenic variants, 186 (19%) had a family history of prostate cancer.

Patients had to be between 40 and 69 years of age. They were required to have undergone genetic testing and tested positive or negative for known familial pathogenic variants. Men who had a 50% risk of inheriting a pathogenic variant but had not undergone genetic testing yet were eligible for enrollment.

Overall, patients were a median age of 53 years (range, 46-59). Most were of European ancestry (94%) and 41% were university graduates. Most patients did not have previous urinary symptoms (78%) or a previous PSA test (62%).

Men whose PSA level was higher than 3.0 ng/mL were offered a transrectal, ultrasound-guided prostate biopsy and histopathological analysis. Additionally, all participants are receiving at least 5 years of annual screening.

Within the first round of screening, 6% (n = 56) of men had a PSA concentration above 3.0 ng/mL and 4% (n = 35) underwent a prostate biopsy.

The results showed a prostate cancer incidence of 1.9% (n = 18; 95% CI, 1.1%-2.9%). The incidence of prostate cancer was 4.3% in MSH2 carriers (n = 13; 95% CI, 2.3%-7.2%), 0.5% in MSH2 non-carriers (n = 1; 0.0%-2.6%), and 3% in MSH6 carriers (n = 4; 95% CI 0.8%-7.4%). No cases of prostate cancer were identified in MLH1 carriers or non-carriers, or MSH6 non-carriers.

Using a PSA threshold of more than 3.0 ng/mL, prostate cancer was detected more frequently among MSH2 carriers vs non-carriers (4.3% vs 0.5%; P = .011) and MSH6 carriers vs non-carriers (3% vs 0%; P = 0.034).

Ultimately, the positive predictive value of a prostate biopsy with a PSA threshold of 3.0 ng/mL was 51.4% (95% CI, 34%-68.6%). The positive predictive value of a PSA threshold of 3.0 ng/mL was 32.1% (95% CI, 20.3%-46%).

“Targeted screening has the potential to pick out aggressive prostate cancers at an early stage in men at high inherited risk, increasing their chances of survival. Because cancers in these men are more likely to be aggressive and potentially life-threatening, they would need to have radical treatment,” Eeles concluded. “I anticipate that these results, and evidence from our ongoing follow-up work, will influence future national and international screening guidelines for this group of men, with the aim of picking out prostate cancer earlier and potentially saving lives.”2

References

  1. Bancroft EK, Page EC, Brook MN, et al. A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study. Lancet Oncol. Published online October 19, 2021. Accessed October 29, 2021. doi:10.1016/S1470-2045(21)00522-2
  2. Targeted prostate cancer screening could benefit men with inherited cancer syndrome. News release. The Institute of Cancer Research. October 19, 2021. Accessed October 29, 2021. https://bit.ly/2ZBqlwZ

This article was originally published on OncLive as “PSA Screening for Aggressive Prostate Cancer Supported in Men With Lynch Syndrome–Associated Pathogenic Variants”