title: Characterization of 298 Patients with Lung Cancer Harboring MET Exon 14 Skipping Alterations.
abstract: The hepatocyte growth factor receptor gene (MET) exon 14 skipping (METex14) has recently been described a potential driver alteration in lung cancer targetable by mesenchymal-to-epithelial transition factor (MET) tyrosine kinase inhibitors (TKIs).
  
  
  
  Well-validated hybrid capture-based comprehensive genomic profiling was performed at the request of individual treating physicians.
  
  
  
  Of 11,205 lung cancers profiled by comprehensive genomic profiling, 298 (2.7%) carcinomas harbored alterations predicted to cause METex14, including adenosquamous (8.2%), sarcomatoid (7.7%), histologic subtype not otherwise specified (3.0%), adenocarcinoma (2.9%), squamous cell (2.1%), large cell (0.8%), and SCLC (0.2%). Acinar features were present in 24% of the METex14 samples. Six cases (2%) harbored MET Y1003X mutations affecting binding of the MET-negative regulator, E3 ubiquitin protein ligase. The median age of all patients with METex14 was 73 years (range 43-95) and 60% were female. Concurrent, murine double minute gene (MDM2) amplification, cyclin-dependent kinase 4 gene (CDK4) amplification, and EGFR amplification were observed in 35%, 21%, and 6.4% of patients with METex14, respectively. KRAS mutation was observed in 3% of cases. Concurrent MET amplification (METamp) (median copy number 10) was identified in 15% of METex14 samples. Significant differences in tumor mutational burden and type of the METex14 alterations were observed between the METamp and non-METamp samples. Response to MET TKI was observed in both in patients with METamp and in patients without METamp METex14.
  
  
  
  Diverse targetable METex14 alterations were identified in patients with NSCLC across age groups, including elderly patients, and in all major NSCLC histologic subtypes with an overall frequency of 2.7%. These findings support the use of hybrid capture-based molecular profiling across NSCLC subtypes to identify patients who will potentially benefit from MET TKIs.
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: Alexa B
authors.initials: AB
authors.lastname: Schrock
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: Garrett M
authors.initials: GM
authors.lastname: Frampton
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: James
authors.initials: J
authors.lastname: Suh
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: Zachary R
authors.initials: ZR
authors.lastname: Chalmers
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: Mark
authors.initials: M
authors.lastname: Rosenzweig
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Erlich
authors.affiliation: Montefiore Medical Center, Bronx, New York.
authors.forename: Balazs
authors.initials: B
authors.lastname: Halmos
authors.affiliation: Hematology and Oncology, University of California Los Angeles Medical Center, Santa Monica, California.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Goldman
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Forde
authors.affiliation: Oncology Hematology Care, Inc., Cincinnati, Ohio.
authors.forename: Kurt
authors.initials: K
authors.lastname: Leuenberger
authors.affiliation: Thoracic Cancer Unit, Davidoff Cancer Center, Rabin Medical Center, Petach Tiqwa, Israel.
authors.forename: Nir
authors.initials: N
authors.lastname: Peled
authors.affiliation: University of Michigan Cancer Center, Ann Arbor, Michigan.
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Kalemkerian
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts; Department of Pathology, Albany Medical College, Albany, New York.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: Siraj M
authors.initials: SM
authors.lastname: Ali
authors.affiliation: Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California. Electronic address: Ignatius.ou@uci.edu.
authors.forename: Sai-Hong Ignatius
authors.initials: SH
authors.lastname: Ou
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D005091:Exons; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics*; D012907:Smoking / Q000009:adverse effects
chemical_list: C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
keywords: Genomic profiling; Lung cancer; MET Y1003 mutation; MET exon 14 alterations; MET exon 14 skipping; Splice site mutations