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NGS of Plasma ctDNA Valuable for Detecting KIT Mutations in Metastatic GIST
Next-generation sequencing (NGS) of plasma was found to be valuable for detecting KIT primary and secondary mutations in a study of patients with metastatic gastrointestinal stromal tumors (GIST; BMC Cancer. 2020 Feb 5. Epub ahead of print).
“[GIST] initiation and evolution is commonly framed by KIT/PDGFRA oncogenic activation, and in later stages by the polyclonal expansion of resistant subpopulations harboring KIT secondary mutations after the onset of imatinib resistance,” stated Cesar Serrano, MD, Vall d'Hebron University Hospital, Barcelona, Spain, and co-investigators, who proposed using circulating tumor (ct)DNA determination as a noninvasive dynamic biomarker in patients with GIST.
To assess this theory, Dr Serrano et al had 18 patients with GISTs undergo amplicon-based NGS across 60 clinically relevant genes in 37 plasma samples. The ctDNA alterations observed were compared with NGS of matched tumor tissue samples and cross-validated with droplet digital PCR.
Cell-free DNA mutations in plasma were detectable in 5 patients. NGS sensitivity for detecting cell-free DNA mutations overall was 28.6%, showing high concordance with droplet digital PCR confirmation.
As Dr Serrano and colleagues noted, ctDNA was detected only in patients with advanced GIST that did not respond to imatinib, forecasting tumor dynamics in serial monitoring. Furthermore, they observed relatively low ctDNA shedding in GIST.
Among 10 patients with imatinib resistance whose disease was progressing with sunitinib or regorafenib, KIT secondary mutations were the only mechanism of resistance found.
“ctDNA evaluation with amplicon-based NGS detects KIT primary and secondary mutations in metastatic GIST patients, particularly after imatinib progression,” Dr Serrano and co-investigators reported.
“GIST exhibits low ctDNA shedding, but ctDNA monitoring, when positive, reflects tumor dynamics,” they concluded.—Kaitlyn Manasterski
