Tumor Mutational Burden Assay Validation and Reporting

Publication Date: June 5, 2024
Last Updated: June 10, 2024

Testing

Laboratories should validate and report the enrichment method used in the tumor mutational burden (TMB) assay.
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Laboratories should validate and report the size and describe the genomic regions (i.e., exons, introns, intergenic regions) used for TMB calculation.
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Laboratories should validate TMB measurement against an orthogonal assay, and the method of TMB calculation used by the orthogonal comparison assay should be documented.
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Laboratories should include validation samples that reflect the intended use of the TMB assay with respect to both specimen type and representative tumor types.
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Laboratories may use reference materials to supplement but not supplant clinical samples for TMB assay validation.
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Laboratories may use in silico validation studies to supplement but not supplant a TMB assay “wet lab” validation.
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Laboratories should specify the sequencing mode (tumor-germline paired or somatic only) used by the TMB assay during TMB assay validation. If somatic-only sequencing is performed, filter settings used to remove common population variants should also be documented.
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Laboratories should establish the performance parameters of bioinformatic pipelines used for TMB calculation during validation.
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Reporting and Publication

Laboratories should report the name, version, properties and/or settings of bioinformatic pipeline software components used for TMB calculation.
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Laboratories should report the specific types and/or categories of variants included in and omitted from the TMB calculation.
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Laboratories should report the sequencing mode (tumor-germline paired or somatic only) used by the TMB assay. If somatic-only sequencing is performed, filter settings used to remove common population variants should be provided or made available upon request.

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Publications describing TMB assays intended for clinical applications, including description of clinical validation, should include performance characteristics that would facilitate methodological assessment.
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Publications describing TMB assays intended for clinical applications, including description of clinical validation, should include performance characteristics that would facilitate methodological assessment.
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Recommendation Grading

Disclaimer

The information in this patient summary should not be used as a substitute for professional medical care or advice. Contact a health care provider if you have questions about your health.

Overview

Title

Tumor Mutational Burden Assay Validation and Reporting

Authoring Organizations

Publication Month/Year

June 5, 2024

Last Updated Month/Year

June 17, 2024

Document Type

Guideline

Country of Publication

US

Document Objectives

Tumor mutational burden (TMB) has been recognized as a predictive biomarker for immunotherapy response in several tumor types. Several laboratories offer TMB testing, but there is significant variation in how TMB is calculated, reported, and interpreted among laboratories. TMB standardization efforts are underway, but no published guidance for TMB validation and reporting is currently available. Recognizing the current challenges of clinical TMB testing, the Association for Molecular Pathology convened a multidisciplinary collaborative working group with representation from the American Society of Clinical Oncology, College of American Pathologists, and Society for the Immunotherapy of Cancer to review the laboratory practices surrounding TMB and develop recommendations for the analytical validation and reporting of TMB testing based on survey data, literature review, and expert consensus. These recommendations encompass pre-analytical, analytical, and post-analytical factors of TMB analysis, and emphasize the relevance of comprehensive methodological descriptions to allow comparability between assays.

Inclusion Criteria

Male, Female, Adolescent, Adult, Child, Older adult

Health Care Settings

Ambulatory, Laboratory services, Outpatient

Intended Users

Laboratory technician, nurse, nurse practitioner, physician, physician assistant

Scope

Diagnosis, Assessment and screening, Management

Diseases/Conditions (MeSH)

D014408 - Biomarkers, Tumor

Keywords

Next-Generation Sequencing, tumor mutational burden, tumor assay

Source Citation

Larissa V. Furtado, Carlo Bifulco, Daniel Dolderer, Susan J. Hsiao, Benjamin R. Kipp, Neal I. Lindeman, Lauren L. Ritterhouse, Robyn L. Temple-Smolkin, Ahmet Zehir, Jonathan A. Nowak, 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, The Journal of Molecular Diagnostics, 2024, ISSN 1525-1578, https://doi.org/10.1016/j.jmoldx.2024.05.002

Methodology

Number of Source Documents
60
Literature Search Start Date
February 9, 2020
Literature Search End Date
August 17, 2023