Different efficacy of tyrosine kinase inhibitors by KIT and PGFRA mutations identified in circulating tumor DNA for the treatment of refractory gastrointestinal stromal tumors

Abstract Background While advanced gastrointestinal stromal tumors (GISTs) are primarily treated with tyrosine kinase inhibitors (TKIs), acquired resistance from specific mutations in KIT or PDGFRA frequently occurs. We aimed to assess the utility of circulating tumor DNA (ctDNA) as a modality of therapeutic decision-making in advanced GIST. Methods We conducted a pooled analysis of SCRUM-Japan studies for advanced GIST patients. We compared patient characteristics analyzed with tissue and blood samples, assessed gene alteration profiles, and evaluated prognostic implications from ctDNA status. Results In 133 patients, tissue and blood samples were analyzed for 89 and 44 patients, respectively. ctDNA was detected in 72.7% of cases; no prior treatment or progressive disease was significantly associated with ctDNA-positivity. ctDNA-positive patients had significantly shorter progression-free survival compared with ctDNA-negative patients (hazard ratio = 3.92; P = 0.007). ctDNA genotyping revealed a complex landscape of gene alterations, characterized by multi-exonic mutations in KIT, compared with tissue-based analysis. Patients who received TKIs matched to the identified KIT mutation in ctDNA demonstrated significantly longer PFS than those with unmatched treatment (median, 8.23 vs. 2.43 months; P