From the Guidelines
Mismatch repair (MMR) deficiency and microsatellite instability (MSI) play crucial roles in colorectal cancer development and treatment decisions, with MMR-deficient/MSI-high tumors responding exceptionally well to immune checkpoint inhibitors such as pembrolizumab or nivolumab, as recommended by the most recent guidelines 1.
Importance of MMR and MSI in Colorectal Cancer
Mismatch repair (MMR) proteins (MLH1, MSH2, MSH6, and PMS2) normally correct DNA replication errors, but when these proteins are defective, it leads to MMR deficiency. This deficiency causes accumulation of mutations, particularly in microsatellite regions (repetitive DNA sequences), resulting in microsatellite instability (MSI). Approximately 15% of colorectal cancers exhibit MMR deficiency/MSI-high status, which can occur through inherited mutations (Lynch syndrome) or acquired changes like MLH1 promoter methylation.
Testing for MMR/MSI Status
Testing for MMR/MSI status is now standard practice for all colorectal cancer patients using immunohistochemistry for MMR proteins or PCR-based MSI testing, as emphasized by recent guidelines 1. This testing is crucial for identifying patients who may benefit from immune checkpoint inhibition.
Treatment Implications
MMR-deficient/MSI-high tumors typically have better prognosis than MMR-proficient tumors and respond poorly to standard chemotherapy like 5-fluorouracil. However, they respond exceptionally well to immune checkpoint inhibitors such as pembrolizumab or nivolumab, which are now approved for MMR-deficient metastatic colorectal cancer, as supported by recent studies 1. This differential response occurs because MMR-deficient tumors have high mutation loads, creating many neoantigens that can trigger immune responses when checkpoint inhibition removes the brakes on the immune system.
Key Points
- MMR deficiency and MSI are crucial in colorectal cancer development and treatment decisions
- Testing for MMR/MSI status is standard practice for all colorectal cancer patients
- MMR-deficient/MSI-high tumors respond exceptionally well to immune checkpoint inhibitors
- Recent guidelines recommend universal MMR or MSI testing for all patients with a personal history of colon or rectal cancer 1
From the Research
Role of Mismatch Repair (MMR) and Microsatellite Instability (MSI) in Colorectal Cancer
- MMR and MSI are critical in considering immunotherapy and chemotherapeutic drugs for patients with colorectal cancer (CRC) 2, 3, 4, 5, 6
- The status of MMR between primary CRC and metastatic tumor was found to be consistent, allowing for MMR testing to be performed at both sites 2
- MSI-H CRCs have distinct molecular, morphologic, and clinical features, and are more likely to respond to immunotherapy 3, 5, 6
- Deficit in one or more MMR proteins leads to frameshift mutations, resulting in microsatellite instability (MSI) 4
- MSI status is a biomarker with prognostic and predictive value of resistance to 5-fluorouracil and response to immune checkpoint inhibitor therapy 3, 4, 6
Detection and Clinical Significance of MSI
- MSI status can be identified by immunohistochemistry for MMR protein or PCR-based array for MMR gene 3, 4, 6
- MSI status is the only biomarker that can be used to select patients with high-risk stage II colon cancer for adjuvant chemotherapy 6
- Patients with MSI tumors exhibited significant response to anti-PD-1 inhibitors after the failure to conventional therapy 5, 6
- The National Comprehensive Cancer Network 2018 guidelines recommended MSI to be tested in all newly diagnosed CRCs 3
Immunotherapy in Colorectal Cancer
- Immunotherapy effectiveness was shown in a subgroup of patients with a BRAF mutation where the effectiveness of existing systemic treatment is low 5
- The proven predictive factor is dMMR/MSI-H, while PD-1 expression does not have this significance 5
- Results of clinical studies with nivolumab and pembrolizumab result in the inclusion of these drugs in mCRC treatment algorithms 3, 5