Primary Resistance to Immune Checkpoint Inhibitors in Metastatic Colorectal Cancer—Beyond the Misdiagnosis—In Reply

In Reply We thank Xu and colleagues for their interest in our article.¹ We agree that there may be other specific mechanisms besides the misdiagnosis of microsatellite instability/defective mismatch repair status, including those described by Xu et al, underlying the primary resistance of true MSI tumors to immunotherapy. Although not a resistance mechanism per se, most of apparent primary resistance to immunotherapy observed in clinical trials so far is likely owing to misdiagnosis of the MSI/dMMR status. From a clinical viewpoint, medical oncologists, pathologists, and molecular biologists need be aware of this so that patients who experience continued disease progression following the start of immune checkpoint inhibitor (ICI) treatment can be immediately reassessed for MSI/dMMR status. This is important because otherwise ICI treatment could potentially be continued until the next radiological evaluation (with the hypothesis of a pseudoprogression).