Treatment for gastrointestinal stromal tumor (GIST) focuses on tyrosine kinase inhibitors, the selection of which depends on specific mutations. We sought to determine the clinical use of liquid biopsy in advanced GIST. Liquid (n = 181) (FoundationOne Liquid CDx) and tissue (n = 2198) (FoundationOne and FoundationOne CDx) comprehensive genomic profiling of GIST were evaluated. The presence of circulating tumor DNA in liquid was determined via tumor fraction (TF), with an elevated TF defined as TF ≥ 1%. Liquid comprehensive genomic profiling revealed 30% (54/181) of samples had an elevated TF, among which the prevalence of KIT and PDGFRA alterations were 89% (48/54) and 2% (1/54), respectively. In patient-matched tissue/liquid samples (n = 49), the positive percent agreement of driver alterations in liquid with an elevated TF relative to tissue was 100%. Fifty-five percent (42/77) of liquid samples with a KIT driver mutation had a co-occurring imatinib-resistant alteration
a minority of cases harbored non-KIT mechanisms of resistance such as FGFR2 fusions and BRAF or EGFR alterations. The relative prevalence of imatinib resistance KIT exon 13 and 17 mutations was enriched in liquid compared with tissue. Finally, in the liquid cohort, 2.2%, 1.7%, and 1.1% of patients were predicted to harbor germline KIT, SDHx, or NF1 mutations, respectively. In conclusion, known driver and tyrosine kinase inhibitor--resistant mutations were identified in liquid biopsies of patients with GIST with high concordance to tissue in the presence of an elevated TF. Liquid biopsy may be valuable in the molecular classification and medical management of GIST.