Abstract 5741
Background
The advantages of plasma-based tumor mutational burden (TMB) include non-invasive, real-time assessment of mutational load, without the limitations of insufficient tissue. However, at low levels of tumor DNA shedding, TMB may be underestimated if a fraction of the genomic alterations is below assay limit of detection. Currently available blood TMB panels report a 1% tumor content limit of detection, which would result in about half of all clinical plasma samples (based on > 30,000 patients) with unevaluable TMB. Hence, clinically effective blood-based diagnostics must be highly sensitive and account for tumor shedding. Here, we present a comprehensive cfDNA-based TMB using a 500-gene (GuardantOMNI) and a 73-gene (Guardant360) panel.
Methods
We developed a statistical model to calculate TMB on plasma samples with low cell-free circulating tumor DNA (ctDNA) content. Theoretical panel performance was assessed in silico by subsetting mutations from whole exome sequencing (WES) to the Guardant panel space (2Mb for GuardantOMNI and 200Kb for Guardant360) from 9,104 TCGA samples and 30 lung cancer samples with published immunotherapy outcomes. Sensitivity was evaluated using 50 serially diluted cfDNA specimens. Analytical validation was performed against tissue-based WES TMB using matched plasma and tissue samples across multiple tumor types.
Results
High correlation was observed between TMB called on the Guardant panel and WES mutations from the TCGA dataset (r = 0.99 with GuardantOMNI; r = 0.92 with Guardant360). Subsetting WES from clinical outcome cohorts to each panel recapitulated the association with PFS on immunotherapy (HR = 0.41 with GuardantOMNI; HR = 0.27 with Guardant360). The sensitivity of detection was assessed down to 0.3% tumor content and 5ng cfDNA input. Lastly, we show high quantitative concordance between matched plasma and tissue WES samples for both GuardantOMNI and Guardant360.
Conclusions
We describe a plasma-based TMB score that correlates with tissue-derived TMB at tumor fractions down to 0.3%, enabling TMB calculation on > 70% of all clinical samples. Accurate reporting of TMB from a plasma sample has the potential to accelerate clinical trial enrollment and improve outcomes.
Clinical trial identification
Legal entity responsible for the study
Guardant Health, Inc.
Funding
Guardant Health, Inc.
Editorial Acknowledgement
Disclosure
K. Quinn, E. Helman, T. Nance, C. Artieri, J. Yen, J. Zhao, S. Fairclough, M. Sikora, D. Chudova, R.B. Lanman, A. Talasaz: Employee and ownership (stock): Guardant Health, Inc.