Circulating Tumor DNA Mutations in Progressive Gastrointestinal Stromal Tumors Identify Biomarkers of Treatment Resistance and Uncover Potential Therapeutic Strategies.

Liquid biopsy circulating tumor DNA (ctDNA)-based approaches may represent a non-invasive means for molecular interrogation of gastrointestinal stromal tumors (GISTs). We deployed a customized 29-gene Archer LiquidPlex™ targeted panel on 64 plasma samples from 46 patients. The majority were known to harbor mutations ( = 41, 89.1%), while 3 were exon 18 D842V mutants and the rest ( = 2) were wild type for and . In terms of disease stage, 14 (30.4%) were localized GISTs that had undergone complete surgical resection while the rest ( = 32) were metastatic. Among ten patients, including 7 on tyrosine kinase inhibitors, with evidence of disease progression at study inclusion, mutations in ctDNA were detected in 7 cases (70%). Known somatic mutations in ( = 5) or ( = 1) in ctDNA were identified only among 6 of the 10 patients. These mutants included duplication, indels, and single-nucleotide variants. The median mutant AF in ctDNA was 11.0% (range, 0.38%-45.0%). In patients with metastatic progressive -mutant GIST, tumor burden was higher with detectable ctDNA mutation than in those without (median, 5.97 cm vs. 2.40 cm, = 0.0195). None of the known tumor mutations were detected in ctDNA for localized cases ( = 14) or metastatic cases without evidence of disease progression ( = 22). In patients with serial samples along progression of disease, secondary acquired mutations, including a potentially actionable exon 9 c.1633G>A mutation, were detected. ctDNA mutations were not detectable when patients responded to a switch in TKI therapy. In conclusion, detection of GIST-related mutations in ctDNA using a customized targeted NGS panel represents an attractive non-invasive means to obtain clinically tractable information at the time of disease progression.