Primary Resistance to Immune Checkpoint Inhibitors in Metastatic Colorectal Cancer and Misdiagnosis of MSI or dMMR Status


Key Points

  • Misdiagnosis of MSI or dMMR status was found in three of five cases of primary resistance to immune checkpoint inhibitor treatment.
  • In two cohorts, positive predictive value of local testing for MSI or dMMR status was 92.1% and 90.3%.

In a study reported in JAMA Oncology, Cohen et al found evidence that primary resistance to immune checkpoint inhibitor treatment in metastatic colorectal cancer (CRC) can be explained in some cases by misdiagnosis of microsatellite instability (MSI) or defective mismatch repair (dMMR) status.

Study Details

The study involved analysis of a single French center prospective cohort of 38 patients with disease diagnosed as MSI or dMMR by local laboratories who entered trials of immune checkpoint inhibitors between January 2015 and December 2016. The accuracy of MSI or dMMR status was also assessed in a retrospective cohort of 93 cases diagnosed as MSI or dMMR between January 1998 and December 2016 at 6 French sites. Primary resistance to immune checkpoint inhibitor treatment was defined as progressive disease on RECIST criteria at 6 to 8 weeks after the start of treatment without pseudoprogression.

All tumor samples were reevaluated for dMMR status with immunohistochemistry (IHC) with antibodies against MLH1, MSH2, MSH6, and PMS2, and for MSI status using polymerase chain reaction (PCR) with pentaplex markers and with the HSP110 T17 (HT17) repeat microsatellite marker assay.

MSI or dMMR Misdiagnosis

Among the 38 patients with MSI or dMMR receiving immune checkpoint inhibitor treatment, primary resistance to treatment was found in 5 (13%). Reassessment of MSI and dMMR status showed that three (60%) of the resistant tumors were microsatellite stable or exhibited proficient mismatch repair. These findings yielded a positive predictive value for MSI or dMMR status as assessed by local laboratories of 92.1% for the cohort. Of the three misdiagnosed cases, one was due to misinterpreted IHC results and two were due to misinterpreted pentaplex PCR results.

Among the 93 patients with MSI or dMMR in the retrospective who did not receive immune checkpoint inhibitor treatment, misdiagnosis of MSI or dMMR status by local laboratories occurred for 9 patients (10%), yielding a positive predictive value of 90.3%. All nine tumors in the misdiagnosed cases showed both proficient MMR and microsatellite stable status.

Four samples with discrepant findings exhibited microsatellite stable status on pentaplex PCR but dMMR status on IHC (1 in the immune checkpoint inhibitor–treated cohort and three in the retrospective cohort). The HT17 assay confirmed the MSI phenotype for two of the three cases in the retrospective cohort.

The investigators concluded, “Primary resistance of [metastatic] CRC displaying MSI or dMMR to immune checkpoint inhibitors is due mainly to misdiagnosis of their MSI or dMMR status. Larger studies are required to confirm these findings. Microsatellite instability or dMMR status should be tested routinely using both immunohistochemistry and polymerase chain reaction methods prior to treatment with immune checkpoint inhibitors.”

Alex Duval, MD, PhD, of the Institut National de la Santé et de la Recherche Médicale, Cancer United Research Associating Medicine University and Society, Centre de Recherche Saint-Antoine, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was supported by grants from the Institut National du Cancer and ARCAD Foundation. The study authors’ full disclosures may be found at

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