Oncotarget

Research Papers:

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

Kanwal Raghav, Van Morris, Chad Tang, Pia Morelli, Hesham M. Amin, Ken Chen, Ganiraju C. Manyam, Bradley Broom, Michael J. Overman, Kenna Shaw, Funda Meric-Bernstam, Dipen Maru, David Menter, Lee M. Ellis, Cathy Eng, David Hong, Scott Kopetz _

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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: skopetz@mdanderson.org

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.

Author Information

Kanwal Raghav

Van Morris

Chad Tang

Pia Morelli

Hesham M. Amin

Ken Chen

Ganiraju C. Manyam

Bradley Broom

Michael J. Overman

Kenna Shaw

Funda Meric-Bernstam

Dipen Maru

David Menter

Lee M. Ellis

Cathy Eng

David Hong

Scott Kopetz
Primary Contact  _


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