Circulating Tumor DNA Analysis Detects FGFR2 Amplification and Concurrent Genomic Alterations Associated with FGFR Inhibitor Efficacy in Advanced Gastric Cancer

Tomoko Jogo, Yoshiaki Nakamura, Kohei Shitara, Hideaki Bando, Hisateru Yasui, Taito Esaki, Tetsuji Terazawa, Taroh Satoh, Eiji Shinozaki, Tomohiro Nishina, Yu Sunakawa, Yoshito Komatsu, Hiroki Hara, Eiji Oki, Nobuhisa Matsuhashi, Takashi Ohta, Takeshi Kato, Koushiro Ohtsubo, Takeshi Kawakami, Naohiro OkanoYoshiyuki Yamamoto, Takanobu Yamada, Akihito Tsuji, Justin I. Odegaard, Hiroya Taniguchi, Toshihiko Doi, Satoshi Fujii, Takayuki Yoshino

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: FGFR2 amplification is associated with poor prognosis in advanced gastric cancer and its subclonal heterogeneity has been revealed. Here, we examined whether circulating tumor DNA (ctDNA) was useful for detecting FGFR2 amplification and co-occurring resistance mechanisms in advanced gastric cancer. Experimental Design: We assessed genomic characteristics of FGFR2-amplified advanced gastric cancer in a nationwide ctDNA screening study. We also analyzed FGFR2 amplification status in paired tissue and plasma samples with advanced gastric cancer. In addition, we examined patients with FGFR2-amplified advanced gastric cancer identified by ctDNA sequencing who received FGFR inhibitors. Results: FGFR2 amplification was more frequently detected by ctDNA sequencing in 28 (7.7%) of 365 patients with advanced gastric cancer than by tissue analysis alone (2.6%–4.4%). FGFR2 amplification profiling of paired tissue and plasma revealed that FGFR2 amplification was detectable only by ctDNA sequencing in 6 of 44 patients, which was associated with a worse prognosis. Two patients in whom FGFR2 amplification was detected by ctDNA sequencing after tumor progression following previous standard chemotherapies but not by pretreatment tissue analysis had tumor responses to FGFR inhibitors. A third patient with FGFR2 and MET co-amplification in ctDNA showed a limitation of benefit from FGFR inhibition, accompanied by a marked increase in the MET copy number. Conclusions: ctDNA sequencing identifies FGFR2 amplification missed by tissue testing in patients with advanced gastric cancer, and these patients may respond to FGFR inhibition. The utility of ctDNA sequencing warrants further evaluation to develop effective therapeutic strategies for patients with FGFR2-amplified advanced gastric cancer.

Original languageEnglish
Pages (from-to)5619-5627
Number of pages9
JournalClinical Cancer Research
Volume27
Issue number20
DOIs
Publication statusPublished - Oct 15 2021

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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