Quantifying potential confounders of panel-based tumor mutational burden (TMB) measurement - PubMed (original) (raw)

Abstract

Objectives: Retrospective data including subgroup analyses in clinical studies have sparked strong interest in developing tumor mutational burden (TMB) as a predictive biomarker for immune checkpoint blockade. While individual factors influencing panel sequencing based measurement of TMB (psTMB) have been discussed in the recent literature, an integrative study quantifying, comparing and combining all potential confounders is still missing.

Material and methods: We separated different potential confounders of psTMB measurement including "panel size", "germline mutation filtering", "biological variance" and "technical variance" and developed a specific error model for each of these factors. Published experimental psTMB data were fitted to the error models to quantify the contribution of each of the confounders. The total psTMB variance was obtained as sum over the variance contributions of each of the confounders.

Results: Using a typical large panel (size 1-1.5 Mbp) total errors of 57 %, 42 %, 34 % and 28 % were observed for tumors with psTMB of 5, 10, 20 and 40 muts/Mbp. Even for large panels, the stochastic error connected to the panel size represented the largest of all contributions to the total psTMB variance, especially for tumors with TMB up to 20 muts/Mbp. Other sources of psTMB variability could be kept under control, but rigorous quality control, best practice laboratory workflows and optimized bioinformatics pipelines are essential.

Conclusion: A statistical framework for the analysis of complex, genomic biomarkers was developed and applied to the analysis of psTMB variability. The methods developed here can support the analysis of other quantitative biomarkers and their implementation in clinical practice.

Keywords: Confounders; Panel sequencing; Panel size; Stochastic error; TMB; Tumor mutational burden.

Copyright © 2020 Elsevier B.V. All rights reserved.

Conflict of interest statement

Declaration of Competing Interest Dr. Budczies has nothing to disclose. Dr. Kazdal reports personal fees from Pfizer Pharma GmbH, outside the submitted work. Dr. Allgäuer has nothing to disclose. Dr. Christopoulos reports personal fees from Roche, personal fees from Chugai, grants and personal fees from Novartis, grants from Takeda, outside the submitted work. Dr. Rempel has nothing to disclose. Mrs. Pfarr has nothing to disclose. Dr. Weichert reports personal fees from Roche, MSD, BMS, AstraZeneca, Pfizer, Merck, Lilly, Boehringer, Novartis, Takeda, Amgen, Astellas and grants from Roche, MSD, BMS, Bruker outside the submitted work. Dr. Fröhling reports personal fees from Amgen, grants from AstraZeneca, personal fees from Eli Lilly, grants from Pfizer, grants from PharmaMar, personal fees from Roche, personal fees from Bayer, outside the submitted work;. Dr. Thomas reports personal fees from AbbVie, grants, personal fees and non-financial support from BMS, personal fees and non-financial support from Boehringer, grants and personal fees from Celgene, personal fees from Lilly, personal fees and non-financial support from MSD, personal fees and non-financial support from Novartis, grants and personal fees from Roche, personal fees from Takeda, grants from AstraZeneca, outside the submitted work. Dr. Peters reports personal fees from Abbvie, personal fees from Amgen, personal fees from AstraZeneca, personal fees from Bayer, personal fees from Biocartis, personal fees from Boehringer-Ingelheim, personal fees from Bistrol-Myers Squibb, personal fees from Clovis, personal fees from Daiichi Sankyo, personal fees from Debiopharm, personal fees from Eli Lilly, personal fees from F. Hoffmann-La Roche, personal fees from Foundation Medicine, personal fees from Illumina, personal fees from Janssen, personal fees from Merck Sharp and Dohme, personal fees from Merck Serono, personal fees from Merrimack, personal fees from Novartis, personal fees from Pharma Mar, personal fees from Pfizer, personal fees from Regeneron, personal fees from Sanofi, personal fees from Seattle Genetics and Takeda, personal fees from AstraZeneca, personal fees from Boehringer-Ingelheim, personal fees from Bristol-Myers Squibb, personal fees from Eli Lilly, personal fees from F. Hoffmann-La Roche, personal fees from Merck Sharp and Dohme, personal fees from Novartis, personal fees from Pfizer, personal fees from Takeda, non-financial support from Sponsored by Amgen, non-financial support from AstraZeneca, non-financial support from Boehringer-Ingelheim, non-financial support from Bristol-Meyers Squibb, non-financial support from Clovis, non-financial support from F. Hoffmann-La Roche, non-financial support from Illumina, non-financial support from Merck Sharp and Dohme, non-financial support from Merck Serono, non-financial support from Novartis, non-financial support from Pfizer, personal fees from Sanofi, personal fees from Bioinvent, personal fees from Blueprint Medicine, outside the submitted work. Dr. Endris reports personal fees from Thermo Fisher, personal fees from Astra Zeneca, outside the submitted work. Dr. Schirmacher reports grants from QuIP, during the conduct of the study; grants and personal fees from BMS, grants and personal fees from MSD, grants and personal fees from Roche, grants and personal fees from AstraZeneca, grants and personal fees from Novartis, personal fees from Chugai, personal fees from AbbVie, grants from Sanofi-Aventis, personal fees from Ipsen, grants and personal fees from Pfizer, grants from Illumina, grants from Thermo Fisher, outside the submitted work. Dr. Stenzinger reports other from Ilumina, during the conduct of the study; personal fees from AstraZeneca, grants and personal fees from Bristol-Myers Squibb, personal fees from Novartis, personal fees from Thermo Fisher Scientific, personal fees from Illumina, personal fees from MSD, personal fees from Roche, grants from Chugai, outside the submitted work.

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