Men who inherit an increased risk of cancer through Lynch syndrome could benefit from regular prostate-specific antigen (PSA) testing from age 40 to detect early signs of prostate cancer, according to research by scientists at The Institute of Cancer Research, London.

Lynch syndrome raises the risk of several cancer types, including bowel cancer, and affects 175,000 people in the United Kingdom—although only 5% of people with the condition know they have it.

Researchers found that annual PSA testing could pick up cases of prostate cancer up to eight times as often in men with genetic hallmarks of Lynch syndrome—faults in genes like MSH2 and MSH6—than in those without.

Ros Eeles, PhD, professor of oncogenetics at The Institute of Cancer Research, London, and Consultant in Clinical Oncology and Oncogenetics at The Royal Marsden NHS Foundation Trust, leads the IMPACT study. “Prostate cancer screening isn’t recommended for the general population, but we believe it could benefit some groups of men at high inherited risk,” she says. “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. We think that men with the gene faults causing Lynch syndrome are likely to benefit from regular PSA testing from the age of 40.”

Many of the cancer cases in men with Lynch syndrome were “clinically significant,” suggesting that targeted screening has the potential to save lives.

“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,” Eeles adds. “And because cancers in these men are more likely to be aggressive and potentially life-threatening, they would need to have radical treatment. 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.”

Researchers believe that targeted annual screening from age 40 could lead to earlier diagnosis and treatment of prostate cancer in this high-risk group of men.

“Picking up cancers early, when they are much more likely to be curable, is a vital part of our strategy to improve the lives of cancer patients,” says Kristian Helin, PhD, professor and chief executive of The Institute of Cancer Research, London. “Mass screening isn’t a good option in prostate cancer because of the risk of over-diagnosis, but in men who have an increased inherited risk of aggressive disease it makes more sense. This new study suggests that screening with an annual PSA test could lead to early detection of significant numbers of prostate cancer cases in men with inherited Lynch syndrome, leading to earlier treatment and increased survival. It’s an exciting example of the potential of genetics research and how it can impact our lives.”

Identifying that patients have Lynch syndrome could also guide their treatment since increasing evidence suggests that immunotherapies—which harness the immune system to attack cancer—may be particularly effective in men with these mutations if they have disease recurrence.

Study Details

The new research, part of the international IMPACT study, was published in The Lancet Oncology and was funded by Cancer Research UK, with additional support from the Ronald and Rita McAulay Foundation and the NIHR Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the ICR.

IMPACT involves 828 men from families with Lynch syndrome at 34 centers in eight different countries, and aims to assess whether regular PSA testing is an effective way to spot prostate cancer in men who carry certain genetic alterations that increase their risk.

Out of the 828 men participating in the study, more than 600 have faults in the so-called mismatch repair genes MLH1, MSH2, or MSH6, which are associated with Lynch syndrome—an inherited condition that increases the risk of various cancers, especially bowel cancer.

PSA screening is not recommended for men in the general population because it has not been shown to be beneficial, and there are concerns that it can lead to overdiagnosis and overtreatment of cases that would not have caused significant problems.

“Overall the PSA test is not reliable enough to be used as a national screening program for prostate cancer,” says Charles Swanton, MD, PhD, FRS FMedSci FRCP, professor and Cancer Research UK’s chief clinician. “But this research shows it could have promise as a test for people who are at higher risk of the disease. What’s needed now is research to find out how early the test can diagnose prostate cancer in this group and like any screening program, the potential harms and survival benefits would need to be investigated before it could be rolled out.

“We don’t currently recommend the PSA test for high-risk men who are asymptomatic,” he adds, “but if you’re concerned about your cancer risk it’s important you speak to your doctor.”

Of course, PSA screening could carry more promise for men who are at a high inherited risk. Men in the new study were offered an annual PSA test, and those with a PSA deemed high were offered a biopsy to determine whether they had prostate cancer.

Researchers found that annual PSA tests could effectively spot prostate cancer in men who inherited a mutation in the genes MSH2 or MSH6. Out of 305 men with faults in the MSH2 gene, 13 (4.3%) were diagnosed with prostate cancer—while only one noncarrier out of 210 (0.5%) was diagnosed with prostate cancer.

For MSH6 carriers, four out of 135 men (3%) were diagnosed with prostate cancer, while none of 177 noncarriers had a prostate cancer diagnosis (0%).

Men with the MSH2 gene fault were eight times more likely to be diagnosed with prostate cancer than noncarriers, and were diagnosed at a younger age—an average of 58 years compared with 66.

Crucially, men with the MSH2 gene fault more often had aggressive, potentially life-threatening tumors, with 85% showing “clinically significant” disease, compared with no noncarriers. This suggests overdiagnosis in MSH2 carriers is unlikely.

Meanwhile, MSH6 carriers were diagnosed at an average age of 62 years, and 75% had life-threatening, or “clinically significant,” tumors.

Next Steps in PSA Testing

Future screening rounds as part of the IMPACT study will help establish the benefits and any harms of annual screening in men carrying MLH1, MSH2, and MSH6 gene alterations, so that experts can conclude if the balance is favorable and if screening should be introduced for these groups.

The study detected no cancers in men with MLH1 mutations—another gene associated with Lynch syndrome—and longer follow-up will be needed before concluding whether these men are at an increased risk of prostate cancer and would benefit from targeted screening.

Researchers are planning another five-year follow-up to compare treatment outcomes in these men. Subsequent screening rounds and detection of cancers will also be important in determining whether the PSA threshold of 3.0ng/ml used in this study is appropriate.