CAP Guidelines for MMR and MSI Testing
Despite FDA approvals of immune checkpoint inhibitor (ICI) therapy, such as pembrolizumab, for patients that exhibit DNA mismatch repair deficiency (dMMR) or high levels of microsatellite instability (MSI-H), guidance is lacking on which clinical assays should be used to assess mismatch repair defects. The College of American Pathologists (CAP) convened an expert panel to develop such clinical assay recommendations. Methods that were considered included immunohistochemistry (IHC) for MMR proteins, polymerase chain reaction (PCR) for MSI analysis, next-generation sequencing (NGS) for MSI analysis, and NGS for tumor mutational burden (TMB) as a surrogate for MMR status.
Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy
Guideline from the College of American Pathologists in Collaboration with the Association for Molecular Pathology and Fight Colorectal Cancer. Bartley, Angela N., et al.
Recommendation 1:
Colorectal cancer (CRC)
For patients with CRC being considered for ICI, pathologists should use MMR-IHC and/or MSI-PCR for the detection of DNA mismatch repair defects. Although MMR-IHC or MSI-PCR are preferred, pathologists may use a validated MSI-NGS assay for detection of mismatch repair defects.
Recommendation 2:
Gastroesophageal (GEA) and small bowel cancer
For patients with GEA and small bowel cancer being considered for ICI therapy, pathologists should use MMR-IHC and/or MSI-PCR over MSI-NGS for the detection of mismatch repair defects.
Recommendation 3:
Endometrial cancer
For patients with endometrial cancer being considered for ICI therapy, pathologists should use MMR-IHC over MSI-PCR or MSI-NGS for the detection of mismatch repair defects.
Recommendation 4:
Other cancers
For patients with cancer types other than CRC, GEA, small bowel, and endometrial being considered for ICI therapy, pathologists should test for mismatch repair defects, although the optimal approach has not been established.
Recommendation 5: Using TMB as surrogate for mismatch repair defects
For all cancer patients being considered for ICI therapy based on mismatch repair defects, pathologists should not use TMB as a surrogate for detection of mismatch repair defects.
Recommendation 6: dMMR and Lynch syndrome
For cancer patients being considered for ICI therapy, if dMMR consistent with Lynch syndrome is identified, pathologists should communicate this finding to the treating physician.
Caris Comprehensive Profiling Enables Adherence to CAP Recommendations
Comprehensive molecular profiling from Caris Life Sciences® assesses DNA, RNA and proteins with multiple technologies (NGS DNA-WES & RNA-WTS, PyroSeq, IHC, ISH) to reveal a more complete molecular blueprint to help guide physicians with more individualized treatment decisions and provide the best care.
DNA
Whole Exome Sequencing
SNVs, Indels, CNAs & Karyotyping
RNA
Whole Transcriptome Sequencing
Gene Fusions, Variant Transcripts & Gene Expression
Protein
Immunohistochemistry
Tumor-Expressed Antigens
Caris Comprehensive Profiling Meets CAP Recommendations
By performing whole exome sequencing (WES), whole transcriptome sequencing (WTS) and IHC Analysis, Caris Life Sciences’ comprehensive profiling addresses the recommendations from the CAP guidelines.
| CAP Recommendations 1 | Related Caris Testing |
|---|---|
| 1. For CRC patients being considered for immune checkpoint inhibitor therapy, pathologists should use MMR-IHC and/or MSIPCR (or a validated MSI-NGS) to detect mismatch repair defects. | Caris offers analysis of MMR by IHC and by MSI-NGS, which has been validated against PCR for equivalency.2 |
| 2. For gastroesophageal or small bowel cancer patients being considered for immune checkpoint inhibitor therapy, pathologists should use MMR-IHC and/or MSI-PCR for detection of mismatch repair defects. | |
| 3. For endometrial cancer patients being considered for immune checkpoint inhibitor therapy, pathologists should use MMR-IHC over MSI-PCR or MSI-NGS. | |
| 4. For other cancer patients being considered for immune checkpoint inhibitor therapy, pathologists should test for mismatch repair defects but the optimal approach has not been established. | |
| 5. For all cancer patients being considered for immune checkpoint inhibitor therapy, pathologists should NOT use TMB as a surrogate for the detection of mismatch repair defects. | Caris reports TMB as an independent biomarker, not as a surrogate for MMR/MSI. Caris offers analysis of MMR by IHC and by MSI-NGS, which has been validated against PCR for equivalency.2 |
| 6. For cancer patients being considered for immune checkpoint inhibitor therapy, if a dMMR consistent with Lynch syndrome is identified, pathologists should communicate this to the physician. | Caris’ comprehensive approach analyzes both protein expression and gene mutations, and the Caris report calls out mutations potentially associated with Lynch syndrome. |
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Other Important Mismatch Repair Defect Assay Factors
The expert panel suggested an overall preference for mismatch repair defect detection using IHC, stating that IHC has the advantage of identifying the most probable gene defect as compared to MSI testing. The panel concluded that while MMRIHC, MSI-PCR and MSI-NGS have comparable performance metrics, any preference for MSI-PCR over MSI-NGS was due to reduced tissue requirements and turnaround times specifically for mismatch repair defect analysis. The panel also acknowledged the wider benefits of an NGS approach, which was beyond the scope of the current expert panel recommendations. Caris’ comprehensive molecular profiling provides potentially far more actionable results than just guidance on immune checkpoint inhibitor therapy, analyzing all DNA/RNA alterations and molecular signatures by NGS, plus 15+ proteins by IHC, providing a complete molecular picture to help guide physicians with treatment decisions and provide the best care.
Caris Molecular Profiling Menu
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