Definition
MSI-H (Microsatellite Instability–High) refers to tumors that have a high frequency of mutations in microsatellite regions of DNA due to defective DNA mismatch repair (dMMR).
- Microsatellites: Short, repeated DNA sequences.
- MSI-H indicates genomic instability, which can drive cancer development.
Pathophysiology
- Normal mismatch repair (MMR): Corrects errors during DNA replication.
- Deficient MMR (dMMR): Leads to accumulation of errors → MSI-H phenotype.
- Common MMR gene defects: MLH1, MSH2, MSH6, PMS2.
- Can be sporadic (e.g., MLH1 promoter methylation) or hereditary (Lynch syndrome).
Associated Cancers
- Colorectal cancer (CRC) – ~15% of cases.
- Endometrial cancer – ~20–30% of cases.
- Gastric cancer – less common.
- Other solid tumors: Small bowel, pancreatic, prostate, bladder in some cases.
Clinical Significance
- Prognostic
- MSI-H colorectal cancers often have better prognosis in early stages.
- Predictive / Therapeutic Implications
- Checkpoint inhibitor therapy (immunotherapy) is effective:
- Pembrolizumab, Nivolumab, Dostarlimab.
- MSI-H tumors are less responsive to conventional fluoropyrimidine chemotherapy (e.g., 5-FU monotherapy in stage II CRC).
- Checkpoint inhibitor therapy (immunotherapy) is effective:
Testing
- Immunohistochemistry (IHC): Detects loss of MMR proteins.
- PCR or NGS: Confirms high microsatellite instability.
- Testing recommended for:
- All colorectal and endometrial cancers.
- Suspected Lynch syndrome.
Pharmacy / Clinical Considerations
- Immunotherapy dosing:
- Pembrolizumab: 200 mg IV q3w or 400 mg q6w (weight-based options may apply).
- Nivolumab: 240 mg IV q2w or 480 mg q4w.
- Monitoring: Immune-related adverse events (irAEs) such as colitis, hepatitis, pneumonitis, thyroiditis.
- Drug interactions: Generally minimal, but immunosuppressants may blunt efficacy.
- Patient selection: MSI-H/dMMR is a key biomarker guiding immunotherapy use.