Measurement of ctDNA Tumor Fraction Identifies Informative Negative Liquid Biopsy Results and Informs Value of Tissue Confirmation.

PURPOSE:Liquid biopsy (LBx) for tumor profiling is increasingly used, but concerns remain regarding negative results. A lack of results may truly reflect tumor genomics, or it may be a false negative that would be clarified by tissue testing. A method of distinguishing between these scenarios could help clarify when follow-on tissue testing is valuable. EXPERIMENTAL DESIGN:Here we evaluate circulating tumor DNA (ctDNA) tumor fraction (TF), a quantification of ctDNA in LBx samples, for utility in identifying true negative results.We assessed concordance between LBx and tissue-based results, stratified by ctDNA TF, in a real-world genomic data set of paired samples across multiple disease types. We also evaluated the frequency of tissue results identifying driver alterations in lung cancer patients after negative LBx in a real-world clinicogenomic database. RESULTS:The positive percent agreement and negative predictive value between liquid and tissue samples for driver alterations increased from 63% and 66% for all samples to 98% and 97% in samples with ctDNA TF ≥1%. Among 505 lung cancer patients with no targetable driver alterations found by LBx who had subsequent tissue-based profiling, 37% had a driver, all of which had ctDNA TF <1%. CONCLUSIONS:Lung cancer patients with negative LBx and ctDNA TF ≥1% are unlikely to have a driver detected on confirmatory tissue testing; such informative negative results may benefit instead from prompt treatment initiation. Conversely, negative LBx with ctDNA TF <1% will commonly have a driver identified by follow-on tissue testing and should be prioritized for reflex testing.