MET amplification in metastatic colorectal cancer: An acquired response to EGFR inhibition, not a de novo phenomenon

Background: MET amplification appears to be a predictive biomarker for MET inhibition. Prior studies reported a MET amplification rate of 9-18% in metastatic colorectal cancer ( mCRC) but do not differentiate increased gene copy numbers due to chromosomal level aberrations from focal gene amplifications. Validation of MET amplification rate in mCRC is critical to this field. Results: In tumor tissue-based analyses, overall MET amplification rate was 1.7% ( 10/590). MET amplification was seen in 0/103 ( 0%), 4/208 ( 1.9%) and 6/279 ( 2.2%) cases, in cohorts 1, 2 and 3, respectively. Rate of MET amplification in cfDNA of cohort 4 patients refractory to anti-EGFR therapy ( n = 53) was 22.6% ( 12/53) and was significantly higher compared to patients not exposed to anti-EGFR therapy ( p < 0.001). Materials and Methods: We analyzed MET amplification in mCRC ( n = 795) using different methods across multiple cohorts. Cohort 1 ( n = 103) and 2 ( n = 208) included resected liver metastases and tumor biopsies, respectively, tested for MET amplification using fluorescence in-situ hybridization [ amplification: MET/CEP7 ratio = 2.0]. Using another tissue-based approach, cohort 3 ( n = 279) included tumor biopsies sequenced with HiSeq ( Illumina) with full exome coverage for MET [ amplification: = 4 copies identified by an in-house algorithm]. Using a blood-based approach by contrast, cohort 4 ( n = 205) included patients in whom the full exome of MET in circulating-free DNA ( cfDNA) was sequenced with HiSeq. Conclusions: Contrary to prior reports, in this large cohort, MET amplification was a rare event in mCRC tissues. In plasma by stark contrast, MET amplification identified by cfDNA occurred in a sizable subset of patients that are refractory to anti-EGFR therapy.