Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy


Angela N. Bartley, From the Department of Pathology, St. Joseph Mercy Hospital, Ann Arbor, Michigan (Bartley).
Anne M. Mills, The Department of Pathology, University of Virginia, Charlottesville (Mills).
Eric Konnick, The Department of Laboratory Medicine and Pathology, University of Washington, Seattle (Konnick).
Michael Overman, The Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston (Overman).
Christina B. Ventura, Surveys (Ventura, Colasacco), College of American Pathologists, Northfield, Illinois.
Lesley Souter, Methodology Consultant, Smithville, Ontario, Canada (Souter).
Carol Colasacco, Surveys (Ventura, Colasacco), College of American Pathologists, Northfield, Illinois.
Zsofia K. Stadler, The Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York (Stadler).
Sarah Kerr, Hospital Pathology Associates, PA, Minneapolis, Minnesota (Kerr).
Brooke E. Howitt, The Department of Pathology, Stanford University, Stanford, California (Howitt).
Heather Hampel, The Department of Internal Medicine, The Ohio State University, Columbus (Hampel).
Sarah F. Adams, The Department of Obstetrics & Gynecology, University of New Mexico, Albuquerque (Adams).
Wenora Johnson, Fight Colorectal Cancer, Springfield, Missouri (Johnson).
Cristina Magi-Galluzzi, The Department of Pathology, University of Alabama at Birmingham, Birmingham (Magi-Galluzzi).
Antonia R. Sepulveda, Department of Pathology, George Washington University, Washington, District of Columbia (Sepulveda).
Russell R. Broaddus, The Department of Pathology & Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill (Broaddus).

Document Type

Journal Article

Publication Date



Archives of pathology & laboratory medicine




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.