Microsatellite instability and mismatch repair deficency: equal predictive markers of immunotherapy?

Tumor-agnostic indication of immune checkpoint inhibitors in MMR deficient/microsatellite instabile (MSI) tumors generated a high demand for such molecular diagnostics. Guidelines mostly consider MMR deficiency testing by immunohistochemistry (IHC) and molecular testing of MSI equal, the only exeption is endometrial cancer. Furthermore, pathological guidelines consider MMR deficiency testing by IHC as primary choice. However, molecular epidemiology data demonstrate that the prevalences of MMR deficiency and MSI in various cancers are different. Furthermore, direct comparison of various test types to MMR IHC frequently reported significant differences. Last but not least, sporadic clinical analyses observed that selection of patients for immunotherapy by the MSI status of their tumors resulted in better efficacies as compared to selection based on MMR deficiency. These data question the current dogma that MMR deficiency testing by IHC and molecular testing of MSI status are equal predictive markers of immunotherapy of cancer.