AUTHOR=Ko Tun Kiat , Lee Elizabeth , Ng Cedric Chuan-Young , Yang Valerie Shiwen , Farid Mohamad , Teh Bin Tean , Chan Jason Yongsheng , Somasundaram Nagavalli 

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

JOURNAL=Frontiers in Oncology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.840843

DOI=10.3389/fonc.2022.840843

ISSN=2234-943X

ABSTRACT=<p>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<sup>®</sup> LiquidPlex™ targeted panel on 64 plasma samples from 46 patients. The majority were known to harbor <italic>KIT</italic> mutations (<italic>n</italic> = 41, 89.1%), while 3 were <italic>PDGFRA</italic> exon 18 D842V mutants and the rest (<italic>n</italic> = 2) were wild type for <italic>KIT</italic> and <italic>PDGFRA</italic>. In terms of disease stage, 14 (30.4%) were localized GISTs that had undergone complete surgical resection while the rest (<italic>n</italic> = 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 <italic>KIT</italic> (<italic>n</italic> = 5) or <italic>PDGFRA</italic> (<italic>n</italic> = 1) in ctDNA were identified only among 6 of the 10 patients. These <italic>KIT</italic> 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 <italic>KIT</italic>-mutant GIST, tumor burden was higher with detectable <italic>KIT</italic> ctDNA mutation than in those without (median, 5.97 cm vs. 2.40 cm, <italic>p</italic> = 0.0195). None of the known tumor mutations were detected in ctDNA for localized cases (<italic>n</italic> = 14) or metastatic cases without evidence of disease progression (<italic>n</italic> = 22). In patients with serial samples along progression of disease, secondary acquired mutations, including a potentially actionable <italic>PIK3CA</italic> exon 9 c.1633G&gt;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.</p>