Microsatellite instability and mismatch repair protein deficiency: equal predictive markers?

Area of Science:

• Oncology
• Molecular Pathology
• Cancer Immunology

Background:

• Clinical guidelines recommend mismatch repair (MMR) protein immunohistochemistry (IHC) or microsatellite instability (MSI) testing for predicting immunotherapy efficacy.
• MMR protein IHC is often considered the gold standard, with MSI testing reserved for specific situations or Lynch syndrome screening.

Purpose of the Study:

• To evaluate the equivalence of MMR protein IHC and MSI testing as predictive biomarkers for cancer immunotherapy.
• To investigate discrepancies between MMR deficiency and MSI status across different cancer types and phenotypes.

Main Methods:

• Review of molecular epidemiology studies comparing MMR IHC and MSI test results.
• Analysis of literature reporting discrepancies between MMR IHC and MSI testing, particularly in non-colorectal/endometrial cancers.
• Examination of clinical data correlating patient selection by dMMR versus MSI status with immunotherapy outcomes.

Main Results:

• Studies report varying rates of deficient MMR (dMMR) and MSI across cancer types.
• Significant discrepancies between MMR IHC and MSI tests are observed, especially in less common cancers and unusual dMMR phenotypes.
• Clinical data suggest differential efficacy of immune checkpoint inhibitors based on whether dMMR or MSI status guided patient selection.

Conclusions:

• The assumption that dMMR phenotype and MSI status are interchangeable predictive markers for immunotherapy requires re-evaluation.
• Current guidelines may need revision to account for observed discrepancies and their clinical implications.
• Further research is needed to clarify the distinct roles and predictive values of MMR IHC and MSI testing in immunotherapy selection.