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New Guideline for Using Lab Tests to Improve Cancer Treatment

by | Oct 3, 2022 | Clinical Diagnostics Insider, Diagnostic Testing and Emerging Technologies, Special Focus-dtet

The new CAP guidance addresses use of immune checkpoint inhibitors for evaluating and treating patients with specific cancers.

A new evidence-based guideline from the College of American Pathologists (CAP) addresses the use of immune checkpoint inhibitors for evaluating and treating patients with certain forms of cancer. Specifically, the CAP guideline is designed to help pathologists and oncologists 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.

The Diagnostic Challenge

Pathologists use immunohistochemistry (IHC) tests that detect high levels of tumor microsatellite instability (MSI) or loss of DNA mismatch repair (dMMR) protein expression to screen for hereditary colorectal cancer or endometrial cancer secondary to Lynch syndrome. However, in recent years, IHC tests have been increasingly used for diagnosing and managing advanced solid tumor malignancies.

On May 23, 2017, the FDA cleared pembrolizumab immune checkpoint inhibitor therapy for patients with unresectable or high MSI or dMMR solid tumors when the disease has progressed after treatment and no satisfactory alternative treatments exist. While other similar cancer drugs have been cleared, this was the first tissue/site-agnostic oncology drug to receive FDA approval.

However, in issuing the approval, the agency left a crucial question unanswered: Which types of tests should pathologists use to evaluate DNA MMR proteins to determine patients’ eligibility for immune checkpoint inhibitor therapy? The possibilities include the following:

  • IHC tests
  • Polymerase chain reaction (PCR)-based MSI tests
  • Next-generation sequencing (NGS)-based MSI tests
  • NGS-based tests that assess tumor mutational burden (TMB)

The CAP Guideline

To shed light on this issue, CAP, the Association for Molecular Pathology (AMP), the American Society of Clinical Oncology (ASCO), and the patient advocacy group Fight Colorectal Cancer (Fight CRC) created an expert panel to make recommendations based on a systematic review of the literature. Unlike previous guidelines, the CAP guideline, published in the Archives of Pathology & Laboratory Medicine on Aug. 3, is based on both the methodology and status of the biomarker, i.e., MSI testing and dMMR assessment, rather than on the type of cancer or tumor origin.

“MMR/MSI is complex and likely a ‘one size fits all’ approach cannot be applied, at least not at this time,” wrote the authors of the guideline. “While this may be a frustrating message, the pathology and oncology communities should embrace this as an opportunity. We are well equipped to strategically bridge this data gap and provide the published evidence with well-designed studies of different cancer types.”

Even so, the guideline includes six recommendations and three good practice statements on the efficacy and utility of specific testing modalities across different cancer types. In general, the guideline emphasizes the use of IHC, particularly for tumor types other than colorectal and gastroesophageal/gastroesophageal junction/small bowel.

In particular, the guideline notes that large NGS panels that provide more genomic information often even identified patients with Lynch syndrome, but the main focus of the guideline was not the volume of data produced by said genomic approaches. The guideline concludes that MSI-NGS is an effective assay to evaluate patients with colorectal and gastroesophageal/gastroesophageal junction/small bowel cancers for immune checkpoint inhibitor therapy, but that there is not enough evidence to determine the efficacy of MSI-NGS in other types of cancer.

Moreover, the guideline suggests that “MMR-IHC is optimal only if the pathologist is competent in the interpretation of MMR-specific protein expression in different types of tumors. Training in the interpretation of MMR-IHC should be encouraged as a part of residency education and reviewed periodically in practice with experts, peers, or as a part of continuing education.”


Although there is still much work to be done, this CAP guideline is an important step toward the effective use of immune checkpoint inhibitors for advanced cancer treatment.

“We've seen that patients whose cancers had high levels of MSI or defective MMR can respond well to immune checkpoint inhibitor therapy,” said pathologist Russell Broaddus, MD, PhD, FCAP, who led the expert panel, in an Aug. 3 press release from CAP. “And now we have objective guidance to assess that status across a range of cancer types.” The expert panel notes that they will review the guideline every four years unless prompted to do so sooner by new research that could potentially change their original recommendations.

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