Should all patients with colon cancer be tested for Microsatellite Instability (MSI)?

MSI Testing in Colon Cancer: Clinical Recommendations

Yes, all patients with colon cancer should be tested for Microsatellite Instability (MSI) regardless of age or family history. 1

Rationale for Universal MSI Testing

• Universal MSI/MMR (mismatch repair) testing in colorectal cancer is now recommended by multiple guidelines due to its important implications for prognosis, treatment decisions, and identification of Lynch syndrome 1
• The National Comprehensive Cancer Network (NCCN) endorses MSI testing for all colorectal cancer patients, as it provides critical information that impacts treatment decisions and survival outcomes 1
• The international expert consensus (JSCO-ESMO-ASCO-JSMO-TOS) strongly recommends MSI/MMR testing for all patients with advanced solid tumors that have a high incidence of MSI/dMMR, which includes colorectal cancer 1

Clinical Implications of MSI Status

Prognostic Value

• MSI-H (high microsatellite instability) status is associated with improved survival in colorectal cancer patients, particularly in early-stage disease 1, 2
• Patients with MSI-H tumors have better disease-free survival rates compared to those with microsatellite stable (MSS) tumors 3
• MSI-H tumors are associated with distinct clinicopathological features including younger age at diagnosis, right-sided tumor location, and mucinous histology 4, 2

Treatment Decisions

• MSI status influences treatment decisions, particularly regarding adjuvant chemotherapy in stage II colon cancer 1
• Patients with MSI-H tumors may have decreased benefit or potentially detrimental effects from fluoropyrimidine-based adjuvant therapy alone 1
• MSI-H status is a predictor of sensitivity to immunotherapy-based treatments, opening new therapeutic options for patients with metastatic disease 1, 5

Lynch Syndrome Identification

• MSI testing is crucial for identifying patients who may have Lynch syndrome, an autosomal dominant hereditary condition that increases risk for several cancer types 1
• Approximately 10-15% of colorectal cancers exhibit MSI, with a portion of these being related to Lynch syndrome 1, 5

Testing Methods

• Immunohistochemistry (IHC) is highly recommended as the primary testing method (sensitivity and specificity approximately 85%) 1

  • IHC evaluates protein expression of the four mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) 1
  • Loss of protein expression indicates potential mismatch repair deficiency 1

• PCR-based MSI testing is recommended either upfront or when IHC results are equivocal or unavailable 1

  • MSI-H is defined as instability in two or more of the five microsatellite markers in the NCI-recommended panel 1

• Next-generation sequencing (NGS) is also recommended as an alternative when validated 1

Timing of Testing

• MSI/MMR testing should be performed at the time of diagnosis of colorectal cancer 1
• Early testing allows for timely treatment planning and consideration of genetic counseling if Lynch syndrome is suspected 1

Potential Limitations and Considerations

• There is a 5-10% false-negative rate with both IHC and MSI testing 1
• While the revised Bethesda guidelines have been used historically to select patients for testing, up to 30% of patients with Lynch syndrome may not meet these criteria 1, 6
• Testing only right-sided colon cancers in patients under 60 years would miss a significant portion of MSI-H cases 6

Conclusion

Universal MSI testing for all colon cancer patients is strongly recommended based on current guidelines. The information provided by MSI testing has significant implications for prognosis, treatment selection, and identification of hereditary cancer syndromes, ultimately improving patient outcomes and quality of life.