title: Comprehensive Genomic Profiling of Clinically Advanced Medullary Thyroid Carcinoma.
abstract: OBJECTIVE
  The aim of this study was to determine the genomic alterations of cancer-related genes in advanced medullary thyroid carcinoma during the course of clinical care.
  
  
  METHODS
  Hybrid-capture-based comprehensive genomic profiling was performed on 34 consecutive medullary thyroid carcinoma cases to identify all four classes of genomic alterations, and outcome for an index patient was collected.
  
  
  RESULTS
  RET was mutated in 88% (30/34) of cases, with RET M918T being responsible for 70% (21/30) of the RET alterations. The other RET alterations were RET E632_L633del, C634R, C620R, C618G/R/S, V804M, and RET amplification. Two of the four RET wild-type patients harbored mutations in KRAS or HRAS (1/34 each). The next most frequent genomic alterations were amplifications of CCND1, FGF3, and FGF19 and alterations in CDKN2A (3/34 each). One case with a RET M918T mutation developed acquired resistance to progressively dose-escalated vandetanib. When the mTOR inhibitor everolimus was added to continued vandetanib treatment, the patient achieved a second 25% reduction of tumor volume (RECIST 1.1) for 8 months.
  
  
  CONCLUSIONS
  Comprehensive genomic profiling identified the full breadth of RET alterations in metastatic medullary thyroid carcinoma and possible cooperating oncogenic driver alterations. This approach may refine the use of targeted therapy for these patients.
authors.affiliation: Foundation Medicine, Inc., Cambridge, Mass., USA.
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Heilmann
authors.forename: Vivek
authors.initials: V
authors.lastname: Subbiah
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: James X
authors.initials: JX
authors.lastname: Sun
authors.forename: Julia A
authors.initials: JA
authors.lastname: Elvin
authors.forename: Juliann
authors.initials: J
authors.lastname: Chmielecki
authors.forename: Steven I
authors.initials: SI
authors.lastname: Sherman
authors.forename: Ravi
authors.initials: R
authors.lastname: Murthy
authors.forename: Naifa L
authors.initials: NL
authors.lastname: Busaidy
authors.forename: Ishwaria
authors.initials: I
authors.lastname: Subbiah
authors.forename: Roman
authors.initials: R
authors.lastname: Yelensky
authors.forename: Chaitali
authors.initials: C
authors.lastname: Nangia
authors.forename: Jo-Anne
authors.initials: JA
authors.lastname: Vergilio
authors.forename: Saad A
authors.initials: SA
authors.lastname: Khan
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Erlich
authors.forename: Doron
authors.initials: D
authors.lastname: Lipson
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.forename: Manisha H
authors.initials: MH
authors.lastname: Shah
authors.forename: Siraj M
authors.initials: SM
authors.lastname: Ali
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
mesh_terms: D000368:Aged; D000813:Anilides / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D019938:Cyclin D1 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D000068338:Everolimus / Q000008:administration & dosage; D005260:Female; D051518:Fibroblast Growth Factor 3 / Q000235:genetics; D005346:Fibroblast Growth Factors / Q000235:genetics; D005784:Gene Amplification; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008715:Methionine; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods; D009154:Mutation / Q000187:drug effects; D010880:Piperidines / Q000008:administration & dosage; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011725:Pyridines / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D013912:Threonine; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*
chemical_list: D000813:Anilides; C530104:CCND1 protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; C117476:FGF19 protein, human; C496444:FGF3 protein, human; D051518:Fibroblast Growth Factor 3; C117307:KRAS protein, human; D010880:Piperidines; D011725:Pyridines; D011799:Quinazolines; D019938:Cyclin D1; C558660:cabozantinib; D013912:Threonine; D005346:Fibroblast Growth Factors; D000068338:Everolimus; D008715:Methionine; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); C452423:vandetanib