Cohen R, et al. - In this post hoc analysis of a single-center, prospective cohort, researchers examined possible mechanisms underlying primary resistance to immune checkpoint inhibitors of metastatic colorectal cancer (mCRC) displaying microsatellite instability (MSI) or defective mismatch repair (dMMR). Findings revealed that the primary resistance of mCRC showing MSI or dMMR to immune checkpoint inhibitors is mainly due to misdiagnosis of their MSI or dMMR status. The authors suggested that microsatellite instability or dMMR status should be routinely tested using immunohistochemistry and polymerase chain reaction methods before treatment with immune checkpoint inhibitors.

Methods

• Study participants included 38 individuals who received their diagnosis of mCRC as MSI or dMMR by local laboratories and entered into trials of immune checkpoint inhibitors between January 1, 2015, and December 31, 2016.
• The accuracy of MSI or dMMR status was also evaluated in a retrospective cohort of 93 cases of mCRC diagnosed as MSI or dMMR in 6 French hospitals between January 1, 1998, and December 31, 2016.
• Researchers defined primary resistance of mCRC as progressive disease according to Response Evaluation Criteria in Solid Tumors criteria, 6-8 weeks after immune checkpoint inhibitors were initiated, without pseudo-progression.
• For this analysis, all tumor samples were reassessed for dMMR status using immunohistochemistry with antibodies directed against MLH1, MSH2, MSH6, and PMS2, and for MSI using polymerase chain reaction with pentaplex markers and with the HSP110 T17 (HT17) repeat.
• Positive predictive value was the primary outcome.

Results

• Of the 38 patients (15 women and 23 men; mean [SD] age, 55.6 [13.7] years) in the mCRC study showing MSI or dMMR, primary resistance to immune checkpoint inhibitors was observed in 5 patients (13%).
• Reassessment of the MSI or dMMR status showed that 3 (60%) of these 5 resistant tumors were microsatellite stable or had a proficient mismatch repair.
• Accordingly, the positive predictive value of MSI or dMMR status evaluated by local laboratories was 92.1%.
• In the retrospective cohort of 93 patients (44 women and 49 men; mean [SD] age, 56.8 [18.3] years) without immune checkpoint inhibitor treatment, the MSI or dMMR status was misdiagnosed by local evaluation at 10% (n=9), with a positive predictive value of 90.3%.
• MSI testing with the HT17 assay confirmed the MSI or dMMR status in 2 of 4 cases showing discrepant outcomes between immunohistochemistry and pentaplex polymerase chain reaction (ie, dMMR but microsatellite stable).