Why do microsatellite instability (MSI) tumors have a better overall prognosis?

From the Guidelines

Microsatellite unstable tumors have a better overall prognosis due to their high immunogenicity, which triggers a stronger immune response against the cancer cells. This is primarily because these tumors develop due to defects in DNA mismatch repair genes, leading to the accumulation of numerous mutations and the production of abnormal proteins that the immune system recognizes as foreign 1. The heightened immunogenicity results in increased tumor-infiltrating lymphocytes that actively fight the cancer cells. Additionally, MSI tumors typically respond better to immunotherapy treatments like pembrolizumab and nivolumab, which enhance the body's natural immune response against the cancer 1. Some key points to consider include:

• The mutational burden in MSI tumors makes them genetically unstable, which can paradoxically limit their ability to develop aggressive metastatic capabilities.
• MSI status serves as a biomarker that helps clinicians select more effective personalized treatment approaches, including potentially avoiding certain chemotherapies that may be less effective in these tumors.
• The NCCN Guidelines recommend universal MMR or MSI testing for all patients with a personal history of colon or rectal cancer, highlighting the importance of MSI status in informing treatment decisions 1.
• Studies have shown that MSI-H tumors are more common in stage II disease than in stage III disease, and that patients with MSI-H tumors have a decreased likelihood to metastasize 1.
• A systematic review of 31 studies including 12,782 patients with CRC found that MSI was associated with longer survival and a longer progression-free survival duration 1. Overall, the combination of enhanced immune surveillance and better treatment response contributes to the improved survival rates observed in patients with MSI-positive cancers compared to those with microsatellite stable tumors.

From the Research

Microsatellite Instability and Prognosis

• Microsatellite instability (MSI) is a key biomarker in colorectal cancer (CRC), with crucial diagnostic, prognostic, and predictive implications 2.
• MSI-high (MSI-H) status is associated with a better prognosis in early-stage CRC and a lack of benefit from adjuvant treatment with 5-fluorouracil in stage II disease 2, 3.
• The identification of microsatellite stability status is clinically important as studies have revealed that MSI tumors have a better stage-adjusted survival compared with microsatellite stable tumors 3.

Immunotherapy and MSI

• Mismatch repair deficiency/microsatellite instability-high represents a good prognosis in early colorectal cancer settings without adjuvant treatment and a poor prognosis in patients with metastasis 4.
• Several clinical trials have demonstrated that mismatch repair deficiency or microsatellite instability-high is significantly associated with long-term immunotherapy-related responses and better prognosis in colorectal and noncolorectal malignancies treated with immune checkpoint inhibitors 4, 5.
• High microsatellite instability (MSI-H) and mutations in mismatch repair genes constitute a new molecular entity within CRC, which is characterized by a high mutational and neoantigen burden, frequent immune cell infiltration, and where immune checkpoint inhibitors have shown high response and survival rates compared to microsatellite stable (MSS) tumors 5.

Clinical Implications

• Testing for mismatch repair deficiency (MMR-D)/MSI is recommended during screening for Lynch syndrome, an autosomal-dominant hereditary disease that is characterized by germline mutations in the MMR genes and associated with an increased risk for several types of cancer 2.
• Characterization of the molecular basis of MSI in CRC is underway and initial results show that mutations in genes encoding kinases and candidate genes with microsatellite tracts are over-represented in MSI tumors 6.
• The approval of pembrolizumab in MSI-H tumors was the first agnostic FDA approval in solid tumors, highlighting the importance of MSI status in guiding immunotherapy treatment decisions 5.