Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy: Guideline From the
Angela N Bartley1, Anne M Mills2, Eric Konnick3
1From the Department of Pathology, St. Joseph Mercy Hospital, Ann Arbor, Michigan (Bartley).
Context.—:
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.
Objective.—:
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.
Design.—:
The College of American Pathologists convened an expert panel to perform a systematic review of the literature and develop recommendations. Using the National Academy of Medicine-endorsed Grading of Recommendations Assessment, Development and Evaluation approach, the recommendations were derived from available evidence, strength of that evidence, open comment feedback, and expert panel consensus. Mismatch repair immunohistochemistry, microsatellite instability derived from both polymerase chain reaction and next-generation sequencing, and tumor mutation burden derived from large panel next-generation sequencing were within scope.
Results.—:
Six recommendations and 3 good practice statements were developed. More evidence and evidence of higher quality were identified for colorectal cancer and other cancers of the gastrointestinal (GI) tract than for cancers arising outside the GI tract.
Conclusions.—:
An optimal assay depends on cancer type. For most cancer types outside of the GI tract and the endometrium, there was insufficient published evidence to recommend a specific clinical assay. Absent published evidence, immunohistochemistry is an acceptable approach readily available in most clinical laboratories.
Insights
Determining DNA mismatch repair status for immune checkpoint inhibitors requires specific clinical assays. An optimal assay depends on cancer type, with immunohistochemistry being a widely available option when evidence is limited.
Area of Science:
- Oncology
- Molecular Diagnostics
- Pathology
Background:
- The US FDA approved immune checkpoint inhibitor therapy for advanced solid tumors with DNA mismatch repair defects or high microsatellite instability.
- No specific clinical assays were recommended by the FDA for determining mismatch repair status.
Purpose of the Study:
- To develop an evidence-based guideline for selecting the optimal clinical laboratory test to identify DNA mismatch repair defects.
- To guide the selection of tests for patients with solid tumor malignancies considered for immune checkpoint inhibitor therapy.
Main Methods:
- A systematic literature review and expert panel consensus were employed.
- The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was utilized.
- Included assays: mismatch repair immunohistochemistry, microsatellite instability (polymerase chain reaction and next-generation sequencing), and tumor mutation burden (next-generation sequencing).
Main Results:
- Six recommendations and three good practice statements were developed.
- More evidence was available for colorectal and other gastrointestinal (GI) cancers than for non-GI cancers.
- Evidence quality varied, with more robust data for GI tract malignancies.
Conclusions:
- The optimal clinical assay for determining mismatch repair status is cancer-type dependent.
- For most cancers outside the GI tract and endometrium, insufficient evidence exists to recommend a specific assay.
- Immunohistochemistry is an acceptable and readily available approach in the absence of specific published evidence.
