Study: Prostate cancer screening may benefit people with Lynch syndrome

IN-DEPTH REVIEW OF RESEARCH

Study background

Lynch syndrome is caused by an inherited mutation in one of the mismatch repair genes—MLH1, MSH2, MSH6, EPCAM or PMS2—which are associated with increased risk of colorectal, endometrial and ovarian and other cancers. Growing evidence suggests that men with Lynch syndrome have a slightly increased risk of prostate cancer, but no studies have yet examined whether this group might benefit from screening for the disease.

The Institute of Cancer Research in the UK started the IMPACT trial (Identification of Men with a genetic predisposition to ProstAte Cancer). This research asks whether screening men with a high genetic risk for prostate cancer is effective and leads to improved survival.

The IMPACT study includes a large group of men with Lynch syndrome who are screened and followed for prostate cancer. Two other studies in the US are also looking at PSA screening in people with Lynch syndrome, which will add important information to the IMPACT study.

This is the first study to examine the usefulness of screening for prostate cancer in people with Lynch syndrome. This report summarizes initial findings from participants at the time of entry to the study.

Researchers of this study wanted to know

Researchers of this study wanted to look at the usefulness of the PSA (prostate-specific antigen) test for detecting prostate cancer. They also wanted to determine how often people with Lynch syndrome are diagnosed with prostate cancer and how aggressive their cancer was at the time of diagnosis.

Populations looked at in this study

Men ages 40-69 who had genetic testing for a mutation in an MSH1, MSH2 or MSH6 gene were eligible for this study. Individuals with an inherited mutation in one of these genes and age-matched people without an inherited mutation were included.

• The average age of participants was 52.8 years old.
• The majority of participants reported European ancestry (94% European ancestry, 1% African or Caribbean ancestry, 4% Asian ancestry, 1% mixed ancestry and 1% unknown ancestry).
• Education level varied: 20% had a technical or vocational qualification and 41% were university graduates.
• 19% had a family history of prostate cancer.
• 22% had previous urinary symptoms.
• 38% had a previous PSA test.

Study design

From 2012 to 2020, 828 men were recruited for the study. Of those, 644 had a mutation in one of the mismatch repair genes (MLH1, MSH2 or MSH6) and 184 did not. To boost the sample size in the group without an inherited mutation, the researchers also included 134 people without mutations who participated in the BRCA IMPACT trial. For comparison, each person who tested positive for an inherited mutation was matched to a similarly aged person who did not have that mutation.

Researchers tested participants for PSA blood levels. or men whose PSA levels were above a threshold of 3.0 ng/mL, researchers recommended that they have a prostate biopsy.

Biopsy samples were then classified based on pathology( including Gleason score, T score, N/M staging and other visual appearance) as benign (no cancer cells) or high-, intermediate- or low-risk cancers. If the biopsy indicated prostate cancer was high risk (having features associated with a likelihood of spreading and being life-threatening), the participants were offered treatment according to current guidelines. If pathologists detected low-risk cancer, participants received an MRI and a second biopsy after three to six months.

Researchers compared how often prostate cancer was diagnosed among participants with a Lynch syndrome mutation to those without a mutation.

This study is ongoing. Researchers will continue to screen participants yearly for at least five years and follow up on prostate cancer diagnosis for at least 10 years.

Study findings

In this study, 56 men (6%) had prostate-specific antigen levels above 3.0 ng/L after initial screening, prompting a referral for a biopsy. Of these individuals, 35 consented to have a biopsy.

• Among the 18 men (51%) who underwent biopsies and received a cancer diagnosis:
  • 13 (4.3% of total cohort) had an inherited MSH2 mutation. This is a statistically significant difference.
    • The average age at diagnosis was 58 years.
  • 4 (3.0% of total cohort) had an inherited MSH6 mutation. This is a statistically significant difference.
    • The average age at diagnosis was 63 years.
  • 1 participant without an inherited mutation had prostate cancer. His age at diagnosis was 66 years.
• 11 of 13 (85%) individuals with an MSH2 mutation had tumors that were classified as high-risk cancers (n=8) or intermediate risk (n=3).
• 3 of 4 (75%) individuals with an MSH6 mutation had tumors that were classified as high-risk cancer (n=3).
• The cancer found in the individual who was in the control group was low risk and not clinically significant (treatment would not have an effect).
• Only 3 of 18 (17%) individuals diagnosed with prostate cancer reported urinary symptoms.

These findings support previous research indicating that people with Lynch syndrome, especially those with mutations in an MSH2 or MSH6 gene, are at increased risk for prostate cancer and are more likely to have aggressive forms of the disease. More than three-quarters of the tumors among MSH2 carriers and MSH6 carriers were clinically significant (treatment would have an effect), supporting the idea that the prostate-specific antigen test is useful for detecting high-risk prostate cancers and would not result in overdiagnosis for this group.

Strengths and limitations

Strengths

• This prospective trial is an international collaboration among 34 genetic and urology clinics in eight countries. It is the largest cohort of men with Lynch syndrome who have been screened for prostate cancer and were followed in a clinical trial.
• This is the first study to examine the usefulness of prostate cancer screening in people with Lynch syndrome.
• This study compared PSA levels and prostate cancer among age-matched people without mutations to those with Lynch syndrome mutations. This design allows the researchers to determine whether prostate cancer cases are found more frequently among those with Lynch syndrome and whether the stage of cancer is riskier.

Limitations

• Few cancers were diagnosed during this study. Future screening data from the ongoing IMPACT study and other similar studies are needed to confirm and strengthen these results.
• Follow-up data is not available yet for these participants, so the impact of screening on survival is not known.
• Most men (94%) were of European ancestry, so the results may not be generalizable to non-European populations.
• No people with EPCAM mutations were included. However, given the mechanism by which mutations in EPCAM affect the MSH2 gene function, researchers predict that men with an EPCAM mutation would have similar results as men with an MSH2 mutation.  
• Because no one with a PMS2 mutation was included, this study does not clarify the risks for cancer nor the benefit of PSA testing in men with this mutation.

Context

Lynch syndrome is associated with an increased risk of colorectal, endometrial, ovarian, stomach, small bowel, ureter and kidney cancers. Research over the last decade has also pointed to an increased risk for other cancers, including prostate cancer. Other studies have found contradictory results with no increased risk of prostate cancer for people with Lynch syndrome. However, few studies have examined risk based on mutations in specific genes.

The first screening round from the IMPACT trial confirms that Lynch syndrome is associated with an increased risk of prostate cancer and that some Lynch syndrome mutations carry more risk than others. This study supports previous studies showing that a mutation in the MSH2 gene conveys a greater risk of prostate cancer in people with Lynch syndrome.

PSA screening is the most effective prostate cancer biomarker. However, its limitations have been well documented. Some professional groups do not support routine PSA screening due to overdetection and treatment because it leads to too many "false positive" results, meaning suspicious PSA levels even though no cancer is found. However, this study suggests that PSA levels can help identify people with cancer among those with higher risk, including those with an inherited Lynch syndrome mutation.

Based on the results of the previous IMPACT study in people with BRCA mutations, the NCCN updated its guidelines to include annual prostate-specific antigen screening for men with a BRCA2 mutation beginning at age 40. If researchers find similar results in people with Lynch syndrome, the NCCN guidelines for this population may be updated as well.

Conclusions

Initial results for people with Lynch syndrome enrolled in the IMPACT trial confirm that individuals with an inherited mutation in MSH2 or MSH6 have an increased risk for prostate cancer. These findings also support the use of prostate-specific antigen testing in people with Lynch syndrome to detect early-stage, aggressive disease.

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posted 11/10/22