title: Compound EGFR mutations and response to EGFR tyrosine kinase inhibitors.
abstract: BACKGROUND
  Non-small-cell lung cancers (NSCLCs) containing EGFR mutations are exquisitely sensitive to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). This is the case of the most common EGFR mutations affecting exon 18 (G719X), 19 (inframe deletions), and 21 (L858R and L861Q). However, the frequency of compound (i.e., double or complex) EGFR mutations-where an EGFR TKI sensitizing or other mutation is identified together with a mutation of unknown clinical significance-and their pattern of response/resistance to EGFR TKIs are less well described.
  
  
  METHODS
  We analyzed the EGFR mutation pattern of 79 cases of NSCLC harboring EGFR mutations and compiled the genotype-response data for patients with NSCLCs with compound EGFR mutations treated with EGFR TKIs.
  
  
  RESULTS
  Of the 79 EGFR-mutated tumors identified, 11 (14%) had compound mutations. Most involved the EGFR TKI-sensitizing G719X (n = 3, plus S768I or E709A), L858R (n = 4, plus L747V, R776H, T790M, or A871G), L861Q (n = 1, plus E709V), and delL747_T751 (n = 1, plus R776H). Eight patients received an EGFR TKI: three cases with G719X plus another mutation had partial responses (PRs) to erlotinib; of three cases with L858R plus another mutation, two displayed PRs and one (with EGFR-L858R+A871G) progressive disease (PD) to erlotinib; one NSCLC with EGFR-L861Q+E709A and one with delL747_T751+R776S had PRs to EGFR TKIs.
  
  
  CONCLUSIONS
  Compound EGFR mutations comprised 14% of all mutations identified during routine sequencing of exons 18-21 of EGFR in our cohort. Most patients with an EGFR TKI-sensitizing mutation (G719X, exon 19 deletion, L858R, and L861Q) in addition to an atypical mutation responded to EGFR TKIs. Reporting of the genotype-response pattern of NSCLCs with EGFR compound and other rare mutations, and the addition of this information to searchable databases, will be helpful to select the appropriate therapy for EGFR-mutated NSCLC.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Susumu
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Canepa
authors.forename: Alexandra S
authors.initials: AS
authors.lastname: Bailey
authors.forename: Sohei
authors.initials: S
authors.lastname: Nakayama
authors.forename: Norihiro
authors.initials: N
authors.lastname: Yamaguchi
authors.forename: Michael A
authors.initials: MA
authors.lastname: Goldstein
authors.forename: Mark S
authors.initials: MS
authors.lastname: Huberman
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Costa
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics*; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D005091:Exons; D005260:Female; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use; D017384:Sequence Deletion
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors