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Brief Report
November 15, 2018

Association of Primary Resistance to Immune Checkpoint Inhibitors in Metastatic Colorectal Cancer With Misdiagnosis of Microsatellite Instability or Mismatch Repair Deficiency Status

Author Affiliations
  • 1Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche Scientifique 938 and Site de Recherche Intégré contre le Cancer, Cancer United Research Associating Medicine University and Society, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, Sorbonne Université, Paris, France
  • 2Department of Medical Oncology, Assistance Publique des Hôpitaux de Paris, Hôpital Saint-Antoine, Sorbonne Université, Paris, France
  • 3Department of Pathology, Assistance Publique des Hôpitaux de Paris, Hôpital Pitié-Salpétrière, Sorbonne Université, Paris, France
  • 4Department of Pathology, Assistance Publique des Hôpitaux de Paris, Hôpital Lariboisière, Paris, France
  • 5Department of Pathology, Assistance Publique des Hôpitaux de Paris, Hôpital Saint-Louis, Sorbonne Université, Paris, France
  • 6Université Lille, Unité Mixte de Recherche Scientifique 1172 e Jean-Pierre Aubert Research Centre e Jean-Pierre Aubert Research Center, Lille, France
  • 7Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche Scientifique 1172, Team “Mucins, Epithelial Differentiation and Carcinogenesis,” Lille, France
  • 8Centre Hospitalier Universitaire Lille, Institut de Pathologie, Lille, France
  • 9Department of Pathology, Institut du Cancer de Montpellier, Montpellier, France
  • 10Department of Pathology, Sorbonne Université, Assistance Publique des Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France
JAMA Oncol. Published online November 15, 2018. doi:10.1001/jamaoncol.2018.4942
Key Points

Question  What are the determinants of primary resistance to immune checkpoint inhibitors in metastatic colorectal cancers with microsatellite instability or mismatch repair deficiency?

Findings  In this cohort study of 38 patients with metastatic colorectal cancer, misdiagnosis of microsatellite instability or mismatch repair deficiency status was responsible for 3 of 5 cases of primary resistance to immune checkpoint inhibitors. These patients had been included in trials of immune checkpoint inhibitors based on positive microsatellite instability or mismatch repair deficiency tumor status, as determined by the institutes who referred them for enrollment in the trials.

Meaning  Microsatellite instability or mismatch repair deficiency status with both immunohistochemistry and polymerase chain reaction should be obtained for patients with metastatic colorectal cancer prior to treatment with immune checkpoint inhibitors.

Abstract

Importance  Primary resistance to immune checkpoint inhibitors is observed in 10% to 40% of patients with metastatic colorectal cancer (mCRC) displaying microsatellite instability (MSI) or defective mismatch repair (dMMR).

Objective  To investigate possible mechanisms underlying primary resistance to immune checkpoint inhibitors of mCRC displaying MSI or dMMR.

Design, Setting, and Participants  This post hoc analysis of a single-center, prospective cohort included 38 patients with mCRC diagnosed 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 assessed in a retrospective cohort comprising 93 cases of mCRC that were diagnosed as MSI or dMMR between January 1, 1998, and December 31, 2016, in 6 French hospitals. Primary resistance of mCRC was defined as progressive disease according to Response Evaluation Criteria in Solid Tumors criteria, 6 to 8 weeks after initiation of immune checkpoint inhibitors, without pseudo-progression. 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.

Main Outcomes and Measures  The primary outcome was positive predictive value.

Results  Among the 38 patients (15 women and 23 men; mean [SD] age, 55.6 [13.7] years) in the study with mCRC displaying MSI or dMMR, primary resistance to immune checkpoint inhibitors was observed in 5 individuals (13%). Reassessment of the status of MSI or dMMR revealed that 3 (60%) of these 5 resistant tumors were microsatellite stable or displayed proficient mismatch repair. The positive predictive value of MSI or dMMR status assessed by local laboratories was therefore 92.1% (95% CI, 78.5%-98.0%). 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, misdiagnosis of the MSI or dMMR status by local assessment was 10% (n = 9), with a positive predictive value of 90.3% (95% CI, 82.4%-95.0%). Testing for MSI with the HT17 assay confirmed the MSI or dMMR status in 2 of 4 cases showing discrepant results between immunohistochemistry and pentaplex polymerase chain reaction (ie, dMMR but microsatellite stable).

Conclusions and Relevance  Primary resistance of mCRC 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.

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