BJC reports · 2024
Different efficacy of tyrosine kinase inhibitors by KIT and PGFRA mutations identified in circulating tumor DNA for the treatment of refractory gastrointestinal stromal tumors.
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Hashimoto Tadayoshi, Nakamura Yoshiaki, Komatsu Yoshito, Yuki Satoshi, Takahashi Naoki, Okano Naohiro, Hirano Hidekazu, Ohtsubo Koushiro, Ohta Takashi, Oki Eiji, Nishina Tomohiro, Yasui Hisateru, Kawakami Hisato, Esaki Taito, Machida Nozomu, Doi Ayako, Boku Shogen, Kudo Toshihiro, Yamamoto Yoshiyuki, Kanazawa Akiyoshi, Denda Tadamichi, Goto Masahiro, Iida Naoko, Ozaki Hiroshi, Shibuki Taro, Imai Mitsuho, Fujisawa Takao, Bando Hideaki, Naito Yoichi, Yoshino Takayuki
Аннотация
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 < 0.001).
CONCLUSIONS: ctDNA-based analysis facilitates assessment of disease status and genomic profiles, thus potentially assisting in identifying optimal therapeutic strategies for advanced GIST patients.
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 < 0.001).
CONCLUSIONS: ctDNA-based analysis facilitates assessment of disease status and genomic profiles, thus potentially assisting in identifying optimal therapeutic strategies for advanced GIST patients.