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Cancer, Pathology Organizations Developing Clinical Guidelines for MMR, MSI Testing

NEW YORK – The College of American Pathologists (CAP), the American Society of Clinical Oncology (ASCO), the Association for Molecular Pathology (AMP), and Fight Colorectal Cancer (Fight CRC) are collaborating on the development of clinical guidelines for testing DNA mismatch repair (MMR) and microsatellite instability (MSI) status in patients with a range of cancer types.

On Wednesday, the groups opened a public comment period, asking relevant stakeholders — including pathologists who refer and perform molecular testing, oncologists, laboratory personnel, and healthcare professionals — for their views on draft guidelines entitled "MMR and MSI Testing in Patients Being Considered for Checkpoint Inhibitor Therapy," to make sure that the final recommendations are clinically practical.

The public has until March 13 to weigh in.

The panel developing these guidelines is specifically seeking to answer questions about which test modality best predicts DNA MMR, whether cancer type matters when choosing a testing modality, whether MMR by immunohistochemistry, MSI by PCR, or MSI by next-generation sequencing results predict improved clinical outcomes in patients treated with checkpoint inhibitors, and whether tumor mutation burden (TMB) can predict improved clinical outcomes in patients treated with checkpoint inhibitors.

Among the recommendations in the draft guidelines, the societies strongly recommended using MMR IHC and/or MSI by PCR for the detection of DNA mismatch repair defects in CRC patients being considered for checkpoint blockade therapy; strongly recommended using MMR IHC and/or MSI by PCR over MSI by NGS for the detection of DNA mismatch repair defects in gastroesophageal and small bowel cancer patients being considered for checkpoint blockade therapy; and strongly recommended MMR IHC over MSI by PCR or NGS for the detection of DNA mismatch repair defects in endometrial cancer patients being considered for checkpoint blockade therapy.

They also noted that pathologists should test for DNA mismatch repair in patients with other cancer types being considered for checkpoint blockade therapy, but added that the optimal approach for the detection of MMR defects has not been established.

Further, the societies said that pathologists should not use TMB as a surrogate for the detection of DNA mismatch repair defects. "If a tumor is identified as TMB-high, pathologists may perform IHC and/or MSI by PCR to determine if high TMB is secondary to mismatch repair deficiency," they wrote.

"This guideline is the first to address testing based more on the methodology status of a biomarker and less on the cancer type or tumor origin," guideline developer and pathologist Russell Broaddus said in a statement. "As we've learned more about patient response to checkpoint inhibitor therapy, we've seen that patients whose cancers had high levels of MSI or defective MMR would respond well, specifically to a checkpoint inhibitor drug such as pembrolizumab."

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