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Association for Molecular Pathology Releases New Tumor Mutational Burden Testing Recommendations

NEW YORK – The Association for Molecular Pathology on Thursday published a new set of evidence-based recommendations for the analytical validation and reporting of tumor mutational burden (TMB) testing.

TMB is a predictive biomarker for immune checkpoint inhibitor (ICI) therapies, which takes the form of a score derived as a measure of the number of mutations per sequenced megabase of DNA. ICI therapies have transformed patient care for a subset of individuals with multiple cancer types, and there continues to be significant interest in predictive biomarkers.

But stakeholders have raised issues with the fact that methods to calculate TMB can vary across different laboratories. In addition, factors like tumor type and even ethnic background have been shown to affect the utility of certain TMB methods or cutoff points. AMP's TMB working group, which included representation from the American Society of Clinical Oncology (ASCO), College of American Pathologists (CAP), and Society for Immunotherapy of Cancer (SITC), was established to take stock of existing practices and develop evidence-based standards for the analytical validation and reporting of clinical TMB tests.

"While TMB has emerged as a potential predictive biomarker for ICI therapy, the variety of approaches for calculating and reporting TMB and [the] few comprehensive methodological descriptions regarding clinical assay validation pose significant challenges to adoption," Larissa Furtado, chair of the AMP TMB working group and a molecular pathologist at St. Jude Children's Research Hospital, said in a statement.

Susan Hsiao, chair of the 2024 AMP clinical practice committee and associate professor of pathology at Columbia University, added that, as with all of the associations evidence-based guidelines, the CPC plans to continually "reassess and modify the TMB recommendations as new technological and scientific advances become available."

AMP said the new recommendations cover pre-analytical, analytical, and post-analytical factors of TMB analysis. They also emphasize the importance of clearly describing methodology in publications to allow clear comparisons between different commercial or research assays. The full publication, "Recommendations for Tumor Mutational Burden Assay Validation and Reporting: A Joint Consensus Recommendation of the Association for Molecular Pathology, College of American Pathologists, and Society for Immunotherapy of Cancer,” is available online ahead of publication in the Journal of Molecular Diagnostics.

In introducing their takeaways, the authors of the recommendations said one major finding from their analysis was that drawing conclusions about the details of TMB calculation and reporting is notably difficult because methodological descriptions are often incomplete or completely absent in published studies. As such, the team stressed the need for greater transparency moving forward.

Despite these limitations, the authors also provided 13 direct recommendations, including that labs validate and report their enrichment methods and the size of their sequencing panels. In addition, they should validate their own TMB measurement against an orthogonal assay, with the method of TMB calculation used by the orthogonal comparator also documented.

Validation samples should reflect the intended use of the TMB assay "with respect to both specimen type and representative tumor types," the group recommended. Clinical samples should be used, with reference materials and in silico approaches providing "support" only.

In reporting results, the consensus authors wrote that labs should make sure to include their assay's name, version, sequencing platform, and "sequencing mode" (tumor-germline or somatic only). The same should be true for any standalone bioinformatic tools to filter and organize variants. They should specifically report any types or categories of variants included or omitted from their TMB calculation.

AMP is not alone in seeking to address TMB assay standardization. Previously, the nonprofit Friends of Cancer Research convened a harmonization project, which led to the development and release of calibration support tools to help compare and align TMB calls from different test platforms, and a subsequent publication in Annals of Oncology.