Research Papers:
MET amplification in metastatic colorectal cancer: an acquired response to EGFR inhibition, not a de novo phenomenon
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Abstract
Kanwal Raghav1, Van Morris1, Chad Tang2, Pia Morelli1, Hesham M. Amin3, Ken Chen4, Ganiraju C. Manyam4, Bradley Broom4, Michael J. Overman1, Kenna Shaw5, Funda Meric-Bernstam6, Dipen Maru3, David Menter1, Lee M. Ellis7, Cathy Eng1, David Hong6, Scott Kopetz1
1Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
3Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
4Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
5Sheikh Khalifa Bin Zayed Al Nahyan Institute of Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
6Department of Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
7Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Correspondence to:
Scott Kopetz, email: [email protected]
Keywords: amplification, MET, circulating-free DNA, fluorescence in situ hybridization, colorectal cancer
Received: March 14, 2016 Accepted: May 05, 2016 Published: July 13, 2016
ABSTRACT
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.
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