As reported in The Lancet Oncology by Bancroft et al, the first round of prostate cancer screening in the IMPACT study of men with pathogenic variants in mismatch repair genes showed an increased risk of prostate cancer in carriers of MSH2 and MSH6 variants compared with noncarrier controls.
As stated by the investigators, “Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2 that cause predisposition to various cancers, predominantly colorectal and endometrial cancer[s]. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer.”
Study Details
The prospective study included 828 men, including 644 carriers of mismatch repair pathogenic variants in MLH1, MSH2, or MSH6, enrolled from sites in eight countries between September 2012 and March 2020, and an additional 134 randomly selected noncarriers from a BRCA1 and BRCA2 cohort of IMPACT. Carriers were age-matched with noncarrier controls. Men with a baseline prostate-specific antigen (PSA) level of > 3.0 ng/mL were offered transrectal ultrasound-guided prostate biopsy, and histopathologic analysis was performed. Overall, 93% of men participating in the study were of European ancestry. All participants in the IMPACT study are undergoing a minimum of 5 years of annual screening.
Key Findings
In total, screening was performed in 204 MLH1 carriers vs 199 MLH1 noncarrier controls, 305 MSH2 carriers vs 210 MSH2 noncarrier controls, and 135 MSH6 carriers vs 177 MSH6 noncarrier controls.
During the first screening round, 56 men (6%) had a PSA of > 3.0 ng/mL, and 35 (4%) underwent biopsy. On the basis of PSA >3.0 ng/mL and biopsy, prostate cancer was detected in 18 (1.9%, 95% confidence interval [CI] = 1.1%–2.9%) of 962 men.
After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings.— Bancroft et al
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The incidence was 4.3% (13 of 305; 95% CI = 2.3%–7.2%) among MSH2 carriers vs 0.5% (1 of 210; 95% CI = 0.0%–2.6%) among MSH2 noncarrier controls (P = .001); 3.0% (4 of 135; 95% CI = 0.8%–7.4%) among MSH6 carriers vs 0% (0 of 177) among MLH1 noncarrier controls (P = .034); and 0% (0 of 204) among MLH1 carriers vs 0% (0 of 199) MLH1 noncarrier controls.
Positive predictive values were 51.4% (95% CI = 34.0%–68.6%) with biopsy using a PSA threshold of 3.0 ng/mL and 32.1% (95% CI = 20.3%–46.0%) using a PSA threshold of 3.0 ng/mL.
The incidence of clinically significant prostate cancer was 3.6% (95% CI = 1.8%–6.4%) among MSH2 carriers vs 0% among MSH2 noncarrier controls (P = .0037) and 2.2% (95% CI = 0.5%–6.4%) among MSH6 carriers vs 0% among MSH6 noncarrier controls (P = .080).
The investigators concluded, “After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched noncarrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings.”
Rosalind Eeles, PhD, of the Oncogenetics Team, The Institute of Cancer Research, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Cancer Research UK, Cancer Council of Tasmania, Cancer Australia, Asociación Española Contra el Cáncer, U.S. National Cancer Institute, Swedish Cancer Society, and others. For full disclosures of the study authors, visit thelancet.com.
