Last updated August 4, 2022

Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy

Summary of Recommendations

For patients with CRC being considered for immune checkpoint inhibitor therapy, pathologists should use MMR-IHC and/or MSI by PCR for the detection of DNA MMR defects. Although MMR-IHC or MSI by PCR are preferred, pathologists may use a validated MSI by NGS assay for the detection of DNA MMR defects. (S)
Note: MSI by NGS assay must be validated against MMR-IHC or MSI by PCR and must show equivalency.
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For patients with gastroesophageal and small bowel cancer being considered for immune checkpoint inhibitor therapy, pathologists should use MMR-IHC and/or MSI by PCR over MSI by NGS for the detection of DNA MMR defects. (S)
Note: This recommendation does not include esophageal squamous cell carcinoma.
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For patients with endometrial cancer being considered for immune checkpoint inhibitor therapy, pathologists should use MMR-IHC over MSI by PCR or NGS for the detection of DNA MMR defects. (S)
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For patients with cancer types other than CRC, GEA, small bowel, and endometrial being considered for immune checkpoint inhibitor therapy, pathologists should test for DNA MMR, although the optimal approach for the detection of MMR defects has not been established. (R)
Note: Assays must be adequately validated for the specific cancer type being tested with careful consideration of performance characteristics of MMR-IHC and MSI by NGS or PCR for the detection of DNA MMR defects.
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For all cancer patients being considered for immune checkpoint inhibitor therapy based upon defective MMR, pathologists should NOT use TMB as a surrogate for the detection of DNA MMR defects. If a tumor is identified as TMB-high, pathologists may perform IHC and/or MSI by PCR to determine if high TMB is secondary to MMR deficiency. (S)
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For cancer patients being considered for immune checkpoint inhibitor therapy, if an MMR deficiency consistent with Lynch Syndrome is identified in the tumor, pathologists should communicate this finding with the treating physician. (S)
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Recommendation Grading

Overview

Title

Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy

Authoring Organizations

Publication Month/Year

August 3, 2022

Document Type

Guideline

Country of Publication

US

Document Objectives

The US Food and Drug Administration (FDA) approved immune checkpoint inhibitor therapy for patients with advanced solid tumors that have DNA mismatch repair defects or high levels of microsatellite instability; however, the FDA provided no guidance on which specific clinical assays should be used to determine mismatch repair status. The objective is to develop an evidence-based guideline to identify the optimal clinical laboratory test to identify defects in DNA mismatch repair in patients with solid tumor malignancies who are being considered for immune checkpoint inhibitor therapy.

Inclusion Criteria

Male, Female, Adolescent, Adult, Child, Older adult

Health Care Settings

Laboratory services, Outpatient

Intended Users

Nurse, nurse practitioner, physician, physician assistant

Scope

Diagnosis, Assessment and screening

Diseases/Conditions (MeSH)

D053843 - DNA Mismatch Repair, D000082082 - Immune Checkpoint Inhibitors

Keywords

Immune Checkpoint Inhibitor, Mismatch repair, Microsatellite Instability Testing

Source Citation

Bartley AN, Mills AM, Konnick E, Overman M, Ventura CB, Souter L, Colasacco C, Stadler ZK, Kerr S, Howitt BE, Hampel H, Adams SF, Johnson W, Magi-Galluzzi C, Sepulveda AR, Broaddus RR. Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy. Arch Pathol Lab Med. 2022 Aug 3. doi: 10.5858/arpa.2021-0632-CP. Epub ahead of print. PMID: 35920830.