Genetic Test Errors May Help Explain Metastatic CRC Checkpoint Inhibitor Resistance

Patients with metastatic colorectal cancer should undergo dual assessment for genetic markers that predict response to immune checkpoint inhibitors

medwireNews: Misdiagnosis of microsatellite instability (MSI) or defective mismatch repair (dMMR) may explain why some patients with metastatic colorectal cancer (CRC) do not respond to immune checkpoint inhibitor (ICI) therapy, French researchers believe. 

Reporting in JAMA Oncology, Alex Duval, from the Sorbonne Université in Paris, and co-workers describe their post-hoc analysis of 38 patients with metastatic CRC who had been diagnosed with MSI or dMMR disease by local laboratories and entered into ICI trials. 

Five (13%) of these participants were diagnosed with primary resistance to ICI therapy. However, reassessment demonstrated that three of these patients had tumours that were microsatellite stable or had proficient mismatch repair. 

This translated to a positive predictive value of just 92.1% for MSI/dMMR status assessed by the local laboratories, the team writes. 

Finding that two of the three misdiagnosed patients had been screened with only one type of assay, the researchers “recommend dual testing with both IHC [immunohistochemistry] and pentaplex PCR [polymerase chain reaction] for all patients with [metastatic]CRC before treatment with immune checkpoint inhibitors”.

They also advise that “all samples showing discrepant results between PCR and IHC should be reassessed for MSI and dMMR status in specialized laboratories having this expertise.”

Alex Duval et al also examined the accuracy of MSI/dMMR testing in a group of 93 metastatic CRC patients attending six French hospitals who were diagnosed as positive for the genetic markers between 1998 and 2016. Misdiagnosis was uncovered in 10% of the patients, giving a positive predictive value for status of 90.3%. 

“This error rate, which biases the results of clinical trials, should be evaluated in larger studies”, the team emphasizes.

Finally, the researchers retested patients for dMMR using IHC with antibodies against MLH1, MSH2, MSH6 and PMS2, and for MSI using PCR with pentaplex markers and the HSP110 T17 repeat (HT17). 

Four patients had discrepant results between their IHC and pentaplex PCR findings but the HT17 assay was able to confirm status in two of these patients, prompting the investigators to suggest use of “HT17 as an additional marker because of its superior sensitivity.” 

 

Reference 

Cohen R, Hain E, Buhard O, et al. Association of primary resistance to immune checkpoint inhibitors in metastatic colorectal cancer with misdiagnos i s of microsatellite instability or mismatch repair deficiency status . JAMA Oncol; Advance online publication 15 November 2018.
doi:10.1001/jamaoncol.2018.4942

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