title: Clinicopathologic features and outcomes of patients with lung adenocarcinomas harboring BRAF mutations in the Lung Cancer Mutation Consortium.
abstract: BACKGROUND
  The advent of effective targeted therapy for BRAF(V600E) -mutant lung adenocarcinomas necessitates further exploration of the unique clinical features and behavior of advanced-stage BRAF-mutant lung adenocarcinomas.
  
  
  METHODS
  Data were reviewed for patients with advanced lung adenocarcinomas enrolled in the Lung Cancer Mutation Consortium whose tumors underwent testing for mutations in epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), human epidermal growth factor receptor 2 (HER2), AKT1, BRAF, dual-specificity mitogen-activated protein kinase kinase 1 (MEK1), neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA); for anaplastic lymphoma kinase (ALK) translocations; and for MET amplification.
  
  
  RESULTS
  Twenty-one BRAF mutations were identified in 951 patients with adenocarcinomas (2.2%; 95% confidence interval [CI], 1.4%-3.4%): 17 (81%; 95% CI, 60%-92%) were BRAF(V600E) mutations, and 4 were non-BRAF(V600E) mutations. Among the 733 cases tested for all 10 genes, BRAF mutations were more likely to occur than most other genotypic abnormalities in current or former smokers (BRAF vs sensitizing EGFR, 82% vs 36%, mid-P < .001; BRAF vs ALK, 39%, mid-P = .003; BRAF vs other mutations, 49%, mid-P = .02; BRAF vs patients with more than 1 oncogenic driver [doubleton], 46%, mid-P = .04.) The double-mutation rate was 16% among patients with BRAF mutations but 5% among patients with other genomic abnormalities (mid-P = .045). Differences were not found in survival between patients with BRAF mutations and those with other genomic abnormalities (P > .20).
  
  
  CONCLUSIONS
  BRAF mutations occurred in 2.2% of advanced-stage lung adenocarcinomas, were most commonly V600E, and were associated with distinct clinicopathologic features in comparison with other genomic subtypes and with a high mutation rate in more than 1 gene. These findings underscore the importance of comprehensive genomic profiling in assessing patients with advanced lung adenocarcinomas.
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Liza C
authors.initials: LC
authors.lastname: Villaruz
authors.forename: Mark A
authors.initials: MA
authors.lastname: Socinski
authors.forename: Shira
authors.initials: S
authors.lastname: Abberbock
authors.forename: Lynne D
authors.initials: LD
authors.lastname: Berry
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Johnson
authors.forename: David J
authors.initials: DJ
authors.lastname: Kwiatkowski
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
authors.forename: Marileila
authors.initials: M
authors.lastname: Varella-Garcia
authors.forename: Wilbur A
authors.initials: WA
authors.lastname: Franklin
authors.forename: D Ross
authors.initials: DR
authors.lastname: Camidge
authors.forename: Lecia V
authors.initials: LV
authors.lastname: Sequist
authors.forename: Eric B
authors.initials: EB
authors.lastname: Haura
authors.forename: Mark
authors.initials: M
authors.lastname: Ladanyi
authors.forename: Brenda F
authors.initials: BF
authors.lastname: Kurland
authors.forename: Kelly
authors.initials: K
authors.lastname: Kugler
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.forename: Paul A
authors.initials: PA
authors.lastname: Bunn
authors.forename: Mark G
authors.initials: MG
authors.lastname: Kris
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058534:Class I Phosphatidylinositol 3-Kinases; D015331:Cohort Studies; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D048369:MAP Kinase Kinase 1 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D048369:MAP Kinase Kinase 1; D019869:Phosphatidylinositol 3-Kinases; D011518:Proto-Oncogene Proteins; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D019859:Proto-Oncogene Proteins c-met; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases; D018631:ras Proteins; C117307:KRAS protein, human; C484760:PIK3CA protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C491743:MET protein, human; C494918:AKT1 protein, human; C482119:BRAF protein, human; C482125:MAP2K1 protein, human
keywords: BRAF; Lung Cancer Mutation Consortium; clinicopathologic features; genomic profiling; lung adenocarcinomas