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

Tadayoshi Hashimoto; Yoshiaki Nakamura; Yoshito Komatsu; Satoshi Yuki; Naoki Takahashi; Naohiro Okano; Hidekazu Hirano; Koushiro Ohtsubo; Takashi Ohta; Eiji Oki; Tomohiro Nishina; Hisateru Yasui; Hisato Kawakami; Taito Esaki; Nozomu Machida; Ayako Doi; Shogen Boku; Toshihiro Kudo; Yoshiyuki Yamamoto; Akiyoshi Kanazawa; Tadamichi Denda; Masahiro Goto; Naoko Iida; Hiroshi Ozaki; Taro Shibuki; Mitsuho Imai; Takao Fujisawa; Hideaki Bando; Yoichi Naito; Takayuki Yoshino

doi:10.1038/s44276-024-00073-7

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

BJC Rep. 2024 Jul 25;2(1):54. doi: 10.1038/s44276-024-00073-7.

Authors

Tadayoshi Hashimoto^{1

2}, Yoshiaki Nakamura^{3

4}, Yoshito Komatsu⁵, Satoshi Yuki⁶, Naoki Takahashi⁷, Naohiro Okano⁸, Hidekazu Hirano⁹, Koushiro Ohtsubo¹⁰, Takashi Ohta¹¹, Eiji Oki¹², Tomohiro Nishina¹³, Hisateru Yasui¹⁴, Hisato Kawakami¹⁵, Taito Esaki¹⁶, Nozomu Machida¹⁷, Ayako Doi¹⁸, Shogen Boku¹⁹, Toshihiro Kudo²⁰, Yoshiyuki Yamamoto²¹, Akiyoshi Kanazawa²², Tadamichi Denda²³, Masahiro Goto²⁴, Naoko Iida¹, Hiroshi Ozaki¹, Taro Shibuki¹, Mitsuho Imai¹, Takao Fujisawa^{1

25}, Hideaki Bando^{1

2}, Yoichi Naito²⁶, Takayuki Yoshino^{1

2}

Affiliations

¹ Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan.
² Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
³ Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan. [email protected].
⁴ Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan. [email protected].
⁵ Department of Cancer Center, Hokkaido University Hospital, Sapporo, Japan.
⁶ Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan.
⁷ Department of Gastroenterology, Saitama Cancer Center, Saitama, Japan.
⁸ Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan.
⁹ Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tsukiji, Japan.
¹⁰ Department of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
¹¹ Department of Clinical Oncology, Kansai Rosai Hospital, Hyogo, Japan.
¹² Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
¹³ Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.
¹⁴ Department of Medical Oncology, Kobe City Medical Center General Hospital, Hyogo, Japan.
¹⁵ Department of Medical Oncology, Kindai University Hospital, Osaka, Japan.
¹⁶ Department of Gastrointestinal and Medical oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.
¹⁷ Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan.
¹⁸ Department of Clinical Oncology, St. Marianna University School of Medicine, Kanagawa, Japan.
¹⁹ Cancer Treatment Center, Kansai Medical University, Osaka, Japan.
²⁰ Department of Medical Oncology, Osaka International Cancer Institute Osaka Prefectural Hospital Organization, Osaka, Japan.
²¹ Department of Gastroenterology, University of Tsukuba Hospital, Ibaraki, Japan.
²² Department of Surgery Shimane Prefectural Central Hospital, Shimane, Japan.
²³ Division of Gastroenterology, Chiba Cancer Center, Chiba, Japan.
²⁴ Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University Hospital, Takatsuki, Japan.
²⁵ Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
²⁶ Department of Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

PMID: 39516322
DOI: 10.1038/s44276-024-00073-7

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 < 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.