title: MET amplification in metastatic colorectal cancer: an acquired response to EGFR inhibition, not a de novo phenomenon.
abstract: 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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Kanwal
authors.initials: K
authors.lastname: Raghav
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Van
authors.initials: V
authors.lastname: Morris
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Chad
authors.initials: C
authors.lastname: Tang
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Pia
authors.initials: P
authors.lastname: Morelli
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Hesham M
authors.initials: HM
authors.lastname: Amin
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ganiraju C
authors.initials: GC
authors.lastname: Manyam
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Bradley
authors.initials: B
authors.lastname: Broom
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Overman
authors.affiliation: Sheikh Khalifa Bin Zayed Al Nahyan Institute of Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Kenna
authors.initials: K
authors.lastname: Shaw
authors.affiliation: Department of Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Funda
authors.initials: F
authors.lastname: Meric-Bernstam
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Dipen
authors.initials: D
authors.lastname: Maru
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: David
authors.initials: D
authors.lastname: Menter
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Lee M
authors.initials: LM
authors.lastname: Ellis
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Cathy
authors.initials: C
authors.lastname: Eng
authors.affiliation: Department of Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: David
authors.initials: D
authors.lastname: Hong
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Kopetz
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000073888:Cell-Free Nucleic Acids / Q000737:chemistry / Q000235:genetics; D000068818:Cetuximab / Q000627:therapeutic use; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005784:Gene Amplification; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008113:Liver Neoplasms / Q000556:secondary; D000077544:Panitumumab; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000073888:Cell-Free Nucleic Acids; D000077544:Panitumumab; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D000068818:Cetuximab
keywords: MET; amplification; circulating-free DNA; colorectal cancer; fluorescence in situ hybridization