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

Abstract

<i>FGFR2</i> 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 <i>FGFR2</i> amplification and co-occurring resistance mechanisms in advanced gastric cancer. We assessed genomic characteristics of <i>FGFR2</i>-amplified advanced gastric cancer in a nationwide ctDNA screening study. We also analyzed <i>FGFR2</i> amplification status in paired tissue and plasma samples with advanced gastric cancer. In addition, we examined patients with <i>FGFR2</i>-amplified advanced gastric cancer identified by ctDNA sequencing who received FGFR inhibitors. <i>FGFR2</i> 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%). <i>FGFR2</i> amplification profiling of paired tissue and plasma revealed that <i>FGFR2</i> amplification was detectable only by ctDNA sequencing in 6 of 44 patients, which was associated with a worse prognosis. Two patients in whom <i>FGFR2</i> 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 <i>FGFR2</i> and <i>MET</i> co-amplification in ctDNA showed a limitation of benefit from FGFR inhibition, accompanied by a marked increase in the <i>MET</i> copy number. ctDNA sequencing identifies <i>FGFR2</i> 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 <i>FGFR2</i>-amplified advanced gastric cancer.