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MMR/MSI Testing Guideline: Adding Clarity to Identify Patients for Immune Checkpoint Inhibitor Therapy

When the US Food and Drug Administration approved pembrolizumab immune checkpoint inhibitor therapy in 2017 for patients with MSI-High (MSI-H) and/or mismatch repair deficient (dMMR) cancers, it was significant, even exciting, because it represented the first FDA tissue/site agnostic approval of an oncology drug.

And yet, it was also a bit problematic for pathologists because absent in the approval was any guidance on what assays would be best to use to determine MSI-H or dMMR status.

To be sure, laboratories and pathologists have been challenged to quickly and efficiently develop molecular tests to manage patients with cancer. That many such tests are expensive, even to send out, has only added to that challenge.

Evidence-based clinical practice guidelines have helped pathologists meet these challenges. And now we go a step further with the new “Mismatch Repair (MMR) and Microsatellite Instability (MSI) Testing for Immune Checkpoint Inhibitor Therapy” guideline. It provides clarity for pathologists and oncologists to improve the evaluation of patients with colorectal, endometrial, gastroesophageal, small bowel, and certain other cancers who may be eligible for immune checkpoint inhibitor therapies.

The College of American Pathologists (CAP) collaborated with experts from the Association for Molecular Pathology (AMP), the American Society of Clinical Oncology (ASCO), and the patient advocacy group Fight Colorectal Cancer (Fight CRC) to develop this guideline. Each group appointed experts to serve on the guideline’s development panel, which included pathologists, oncologists, and patient representatives. (Seen left).

With six recommendations and three good practice statements, the guideline provides data and details regarding the efficacy and utility of specific testing modalities across applicable cancer types, including MMR by immunohistochemistry, MSI by polymerase chain reaction (PCR), and MSI by next generation sequencing (NGS), for patients being treated with immune checkpoint inhibitors.

As the pathologist who had the privilege to lead the expert panel in developing the guideline, I can attest to notable surprises throughout the process—a rigorous one that ensures transparency and limits bias by following the National Institute of Medicine’s established standards.

For example, it was surprising often the NGS literature over-stated findings and how often this literature was vague on its methodology. It was discouraging to often see key methodology details either buried in supplemental files or not present at all. What really surprised me was that manuscript reviewers and editors for very prominent journals with high impact factors seemed to overlook this. In my opinion, this may have set the field back and is not good for optimal patient care. It really demonstrates the relevance of the the old saying “the devil is in the details.” The good news here is that moving forward there are excellent opportunities for pathologists and oncologists to fill the knowledge gap to help make our testing benefit more patients.

Among our more noteworthy findings, it is clear that no one test captures all patients with mismatch repair deficiency. In other words, this will likely not be a one size fits all approach. For the most part, MMR IHC, PCR-based MSI, and MSI-NGS may be interchangeable for adenocarcinomas of the GI tract. However, outside of the GI tract, it is clear that MSI-PCR and MSI-NGS approaches fall short. There is evidence that MSI-PCR and MSI-NGS, if optimized for a cancer type, may be excellent methods for identifying patients with MMR defects. However, optimizing these complex technologies for different cancer types may prove to be too daunting for most clinical labs. As you can see in the Summary of Recommendations, we therefore broadly recommend MMR IHC as a default. This recommendation comes with the recognition that interpretation of these IHC tests can be difficult if the pathologist is not experienced with these. Moving forward, I believe we need to incorporate more interpretation of this type of IHC into residency and fellowship training.

As always, this CAP guideline includes following tools and resources to help you implement and apply the guidance.

Background, tools and resources
Published Guideline in
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After a 20 year faculty career at the University of Texas MD Anderson Cancer Center, Russell Broaddus, MD, PhD, moved to the University of North Carolina School of Medicine in Chapel Hill in September, 2019, to be the new Chairman of the Department of Pathology & Laboratory Medicine. He holds the Joe W. and Evelyn Grisham Distinguished Professorship. He is a surgical pathologist with sub-specialty expertise in gynecologic pathology and solid tumor molecular diagnostics. He was the Chair of the College of American Pathologists evidence-based guideline “MMR and MSI Testing in Patients Considered for Checkpoint Inhibitor Therapy.”

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