Abstract
Crizotinib has been used to counter MET gene amplification in a number of different human malignancies. Transient response to crizotinib in MET-amplified gastric cancer has been reported, but the mechanisms of resistance are not well studied. Here, we reported a stage IV gastric cancer patient with high levels of MET amplification. The implementation of crizotinib treatment led to significant symptomatic improvement in the first 2 months, but was followed by rapid disease progression. Periodic mutation profiling of patient's circulating tumor DNA (ctDNA) by next generation sequencing (NGS) revealed a number of genetic alterations including re-occurrence of MET amplification, multiple secondary MET mutations, a dramatic increase of FGFR2 gene relative copy number as well as mutations in other downstream and bypassing elements, which may collectively related to the patient's cancer progression. Our results illustrate the complex and heterogeneous molecular mechanisms for crizotinib resistance in this patient, and demonstrate the great potential of ctDNA profiling for treatment decision-making and prognosis in clinical practice.
Highlights
MET amplification is reported to occur in approximately 5% of gastric cancer patients, and targeted drug crizotinib is currently undergoing a clinical trial of advanced MET-positive gastric cancer (ClinicalTrials. gov identifier: NCT02435108) [1, 2]
We conducted targeted generation sequencing (NGS) on the circulating tumor DNA of a stage IV gastric cancer patient, and identified a reservoir of mutations that echoed the mutations found in a contemporaneous tissue biopsy including MET amplification
Mutation profiling of serial circulating tumor DNA (ctDNA) samples throughout the course of crizotinib treatment uncovered a dramatic change in the genomic landscape, which could be responsible for rapid development of drug resistance and disease progression
Summary
MET amplification is reported to occur in approximately 5% of gastric cancer patients, and targeted drug crizotinib is currently undergoing a clinical trial of advanced MET-positive gastric cancer (ClinicalTrials. gov identifier: NCT02435108) [1, 2]. MET amplification is reported to occur in approximately 5% of gastric cancer patients, and targeted drug crizotinib is currently undergoing a clinical trial of advanced MET-positive gastric cancer Administration of crizotinib to a small cohort of esophagogastric cancer patients with MET amplification resulted in initial tumor shrinkage; cancer progression occurred within months and the mechanisms for drug resistance were not elucidated [2]. We conducted targeted generation sequencing (NGS) on the circulating tumor DNA (ctDNA) of a stage IV gastric cancer patient, and identified a reservoir of mutations that echoed the mutations found in a contemporaneous tissue biopsy including MET amplification. Mutation profiling of serial ctDNA samples throughout the course of crizotinib treatment uncovered a dramatic change in the genomic landscape, which could be responsible for rapid development of drug resistance and disease progression
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