title: Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations.
abstract: OBJECTIVE
  To investigate the prevalence, distribution, and prognostic role of BRAF mutations in a large cohort of white patients with non-small-cell lung cancer (NSCLC).
  
  
  METHODS
  A retrospective series of 1,046 NSCLCs-comprising 739 adenocarcinomas (ADCs) and 307 squamous cell carcinomas (SCCs)-was investigated for BRAF mutations. High-resolution melting analysis followed by sequencing and strip hybridization assay were used. All patients were also analyzed for KRAS and EGFR mutations.
  
  
  RESULTS
  BRAF mutations were present in 36 ADCs (4.9%) and one SCC (0.3%; P = .001). Twenty-one of the mutations (56.8%) were V600E, and 16 (43.2%) were non-V600E. V600E mutations were significantly more prevalent in females (16 of 187 patients; 8.6%) than in males (five of 552 patients; 0.9%), as indicated by multivariate logistic regression analysis (hazard ratio [HR], 11.29; P < .001). V600E-mutated tumors showed an aggressive histotype characterized by micropapillary features in 80% of patients and were significantly associated with shorter disease-free and overall survival rates on both univariate (HR, 2.67; P < .001 and HR, 2.97; P < .001, respectively) and multivariate analyses (HR, 2.19; P = .011 and HR, 2.18; P = .014, respectively). All non-V600E mutations were found in smokers (P = .015) and were associated with neither clinicopathologic parameters nor prognosis. BRAF and EGFR were concomitantly mutated in two tumors.
  
  
  CONCLUSIONS
  We report for the first time to our knowledge that V600E and non-V600E BRAF mutations affect different patients with NSCLC. V600E mutations are significantly associated with female sex and represent a negative prognostic factor. In addition, we identified a number of other clinicopathologic parameters potentially useful for the selection of patients carrying BRAF mutations.
authors.affiliation: Center of Predictive Molecular Medicine, Center of Excellence on Aging (CeSI) University-Foundation, via Colle dell'Ara, 66100 Chieti, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Marchetti
authors.forename: Lara
authors.initials: L
authors.lastname: Felicioni
authors.forename: Sara
authors.initials: S
authors.lastname: Malatesta
authors.forename: Maria
authors.initials: M
authors.lastname: Grazia Sciarrotta
authors.forename: Luigi
authors.initials: L
authors.lastname: Guetti
authors.forename: Antonio
authors.initials: A
authors.lastname: Chella
authors.forename: Patrizia
authors.initials: P
authors.lastname: Viola
authors.forename: Carmela
authors.initials: C
authors.lastname: Pullara
authors.forename: Felice
authors.initials: F
authors.lastname: Mucilli
authors.forename: Fiamma
authors.initials: F
authors.lastname: Buttitta
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D004252:DNA Mutational Analysis; D005260:Female; D018773:Genes, erbB-1; D006801:Humans; D016015:Logistic Models; D008175:Lung Neoplasms / Q000473:pathology*; D008297:Male; D015999:Multivariate Analysis; D011379:Prognosis; D011518:Proto-Oncogene Proteins; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D012737:Sex Factors; D016019:Survival Analysis; D018631:ras Proteins
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins