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

TLDR

The FDA approved immune‑checkpoint inhibitors for advanced solid tumors with mismatch‑repair defects or high microsatellite instability, yet it did not specify which clinical assays should be used to determine mismatch‑repair status. This guideline aims to identify the optimal laboratory test for detecting DNA mismatch‑repair defects in solid‑tumor patients being considered for immune‑checkpoint inhibitor therapy. An expert panel from the College of American Pathologists conducted a systematic review and applied the NASEM GRADE framework to develop recommendations, covering mismatch‑repair immunohistochemistry, microsatellite‑instability testing by PCR or next‑generation sequencing, and tumor‑mutation‑burden assessment by large‑panel NGS. Six recommendations and three good‑practice statements were issued, noting that evidence is strongest for gastrointestinal cancers, that the optimal assay varies by cancer type, that evidence is lacking for most non‑GI and endometrial cancers, and that immunohistochemistry is an acceptable alternative when evidence is absent.

Abstract

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.