Cancer Screening for Persons at Risk for or Affected with Lynch Syndrome Evidence Summary

Guideline Objective

Cancer Care Ontario’s Prevention and Cancer Control portfolio with the Program in Evidence-Based Care developed this report to evaluate the existing evidence so as to inform the development of screening recommendations and risk reduction strategies for persons affected or at risk for Lynch syndrome in Ontario’s colorectal cancer (CRC) screening program (ColonCancerCheck). Lynch syndrome is an autosomal dominant genetic condition. These recommendations will inform program design and policy for screening in Ontario. 

The main objectives of this evidence review were to identify, among persons affected or at risk for Lynch syndrome:

i. The risk for Lynch syndrome cancers; 

ii. Screening protocols that are effective for each Lynch syndrome cancer;

iii. Risk reduction strategies that are effective for each Lynch syndrome cancer;

iv. The most effective surveillance protocol for persons with a CRC who do not have a total proctocolectomy.

A systematic review of the evidence was performed and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method was used to evaluate the quality of the evidence for each of the outcomes.

Patient Population

People affected or at risk for Lynch syndrome or Lynch-like syndrome. People affected with Lynch syndrome are defined as:

• People with a Lynch syndrome cancer and a known Lynch syndrome germline mutation; 
• People with a known Lynch syndrome germline mutation. 

People at risk for Lynch syndrome or Lynch-like syndrome, defined as:

• People with a Lynch syndrome cancer and a germline mutation of unknown significance (considered Lynch-like syndrome); 
• People with a Lynch syndrome cancer and evidence of MMR protein loss but who do not have a germline mutation and where sporadic microsatellite instability (MSI) has reasonably been ruled out (considered Lynch-like syndrome); 
• A relative of someone with confirmed Lynch syndrome; this relative has not undergone genetic testing. (Note: consider first-degree relative separately from second-degree relative if possible).

Relatives of those at risk for Lynch syndrome or of those with Lynch-like syndrome: 

• For example, (1) a relative of a person with a Lynch syndrome cancer and a germline mutation of unknown significance; this relative also has the germline mutation of unknown significance; or (2) a relative of a person with a Lynch syndrome cancer and evidence of MMR protein loss but who does not have a germline mutation and where sporadic MSI has reasonably been ruled out; this relative does not have a germline mutation.

Intended Guideline Users

The primary user is the Cancer Screening Program at Cancer Care Ontario. Other stakeholders include primary care physicians, colorectal surgeons, gastroenterologists, and pathologists. 

Research Questions

1. What is the risk for Lynch syndrome cancers for people affected or at risk for Lynch syndrome? Are there differences in risk for various germline mutations?
2. For each Lynch syndrome cancer, what cancer screening protocols are effective for people affected or at risk for Lynch syndrome?
   For those cancers, identify the following:
   • Which cancer screening modalities have been found to be effective by cancer type?
   • What is the evidence for ages of screening initiation and cessation?
   • What is the evidence for intervals between screening tests?
   • Are there differences in effectiveness for various germline mutations?
3. For each Lynch syndrome cancer, what risk reduction strategies are effective for people affected or at risk for Lynch syndrome?
   • What is the evidence for ages of initiation and cessation?
   • What is the evidence for timing of the strategy?
   • What is the evidence for each gene mutation?
4. What is the most effective colonoscopy surveillance protocol for persons with a colorectal cancer and a known or suspected Lynch syndrome germline mutation who did not have a total proctocolectomy?
   Specifically:
   • What is the evidence for frequency of colonoscopy surveillance?
   • What is the evidence for age of cessation of surveillance?
   • What is the evidence for each gene mutation?