Clinical studies have established TMB, a measurement of mutations in the tumor genome, as a predictive biomarker for clinical efficacy of immune checkpoint inhibitors (ICIs). There is a lack of standardization for TMB estimation and reporting, which is critical for ensuring consistency for clinical implementation. An international collaboration organized by Friends of Cancer Research (Friends) and Qualitätssicherungs-Initiative Pathologie GmbH (QuIP) is establishing recommendations for achieving consistency in TMB estimation and reporting.
Friends and QuIP are using complementary TMB harmonization approaches. Friends will conduct in silico analyses where TCGA data will be compared between TMB estimates derived from whole exome sequencing (WES) and commercial targeted gene panels, followed by the use of patient-derived tumor cell lines to establish a universal reference standard for the alignment of panel-derived estimates. QuIP will compare TMB estimates from selected tissue (NSCLC and other solid tumors) using a WES-derived reference standard with commercial next-generation sequencing panels and lab-developed tests at several German academic institutions. These data will inform consistency of TMB estimation, assay comparability, and TMB cutoff values for potential clinical use.
Preliminary data indicate several components influence TMB estimation: preanalytical factors (eg, input material quality/quantity), sequencing parameters (eg, enrichment technologies), library preparation, bioinformatics (eg, filtering of germline variants), FFPE-induced deamination artifacts, mutation types, and clonal vs subclonal events. Analyses of panel size and composition suggest that larger panels may yield more reliable TMB estimation and that the panel should include actionable targets, genes associated with mutagenesis (eg, microsatellite instability), and potential negative predictors of response (eg, mutated β2M, JAK1/2, PTEN).
The Friends and QuIP collaboration will establish recommendations for reliable and reproducible TMB measurement to ensure consistent identification of patients who are likely to respond to ICIs.
Clinical trial identification
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Medical writing assistance was provided by Amrita Dervan, MSc, of Spark Medica Inc. (US), funded by Bristol-Myers Squibb.
A. Stenzinger: Advisory board and honoraria for talks: AstraZeneca, Novartis, BMS, Roche, Illumina, Thermo Fisher. All other authors have declared no conflicts of interest.