title: Genomic Correlate of Exceptional Erlotinib Response in Head and Neck Squamous Cell Carcinoma.
abstract: OBJECTIVE
  Randomized clinical trials demonstrate no benefit for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in unselected patients with head and neck squamous cell carcinoma (HNSCC). However, a patient with stage IVA HNSCC received 13 days of neoadjuvant erlotinib and experienced a near-complete histologic response.
  
  
  OBJECTIVE
  To determine a mechanism of exceptional response to erlotinib therapy in HNSCC.
  
  
  METHODS
  Single patient with locally advanced HNSCC who received erlotinib monotherapy in a window-of-opportunity clinical trial (patients scheduled to undergo primary cancer surgery are treated briefly with an investigational agent). Whole-exome sequencing of pretreatment tumor and germline patient samples was performed at a quaternary care academic medical center, and a candidate somatic variant was experimentally investigated for mediating erlotinib response.
  
  
  METHODS
  A brief course of erlotinib monotherapy followed by surgical resection.
  
  
  METHODS
  Identification of pretreatment tumor somatic alterations that may contribute to the exceptional response to erlotinib. Hypotheses were formulated regarding enhanced erlotinib response in preclinical models harboring the patient tumor somatic variant MAPK1 E322K following the identification of tumor somatic variants.
  
  
  RESULTS
  No EGFR alterations were observed in the pretreatment tumor DNA. Paradoxically, the tumor harbored an activating MAPK1 E322K mutation (allelic fraction 0.13), which predicts ERK activation and erlotinib resistance in EGFR-mutant lung cancer. The HNSCC cells with MAPK1 E322K exhibited enhanced EGFR phosphorylation and erlotinib sensitivity compared with wild-type MAPK1 cells.
  
  
  CONCLUSIONS
  Selective erlotinib use in HNSCC may be informed by precision oncology approaches.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts2Cancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge.
authors.forename: Eliezer M
authors.initials: EM
authors.lastname: Van Allen
authors.affiliation: Department of Pharmacology and Pharmacy, Li-Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong4Department of Biochemistry, Li-Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong5Department of Otolaryngology, University of Pittsb.
authors.forename: Vivian W Y
authors.initials: VW
authors.lastname: Lui
authors.affiliation: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania6Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Egloff
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Goetz
authors.affiliation: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Jonas T
authors.initials: JT
authors.lastname: Johnson
authors.affiliation: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Umamaheswar
authors.initials: U
authors.lastname: Duvvuri
authors.affiliation: Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Bauman
authors.affiliation: Blueprint Medicines, Cambridge, Massachusetts.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Stransky
authors.affiliation: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Breean R
authors.initials: BR
authors.lastname: Gilbert
authors.affiliation: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Kelsey P
authors.initials: KP
authors.lastname: Pendleton
authors.affiliation: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Simion
authors.initials: S
authors.lastname: Chiosea
authors.affiliation: Cancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge.
authors.forename: Carrie
authors.initials: C
authors.lastname: Sougnez
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts2Cancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Wagle
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Yu
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania.
authors.forename: David
authors.initials: D
authors.lastname: Close
authors.affiliation: Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Johnston
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle.
authors.forename: Aaron
authors.initials: A
authors.lastname: McKenna
authors.affiliation: Cancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Carter
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts2Cancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge.
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.affiliation: Cancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge13Department of Pathology, Massachusetts General Hospital, Boston.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts2Cancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge.
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.affiliation: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania14Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Grandis
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D001706:Biopsy; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D004252:DNA Mutational Analysis; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage*; D020022:Genetic Predisposition to Disease; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics* / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009154:Mutation; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D010641:Phenotype; D010766:Phosphorylation; D011237:Predictive Value of Tests; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D016032:Randomized Controlled Trials as Topic; D012074:Remission Induction; D000077195:Squamous Cell Carcinoma of Head and Neck; D013997:Time Factors; D014062:Tongue Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1