title: Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer.
abstract: OBJECTIVE
  BRAF mutations are found in a subset of non-small cell lung cancers (NSCLC). We examined the clinical characteristics and treatment outcomes of patients with NSCLC harboring BRAF mutations.
  
  
  METHODS
  Using DNA sequencing, we successfully screened 883 patients with NSCLC for BRAF mutations between July 1, 2009 and July 16, 2012. Baseline characteristics and treatment outcomes were compared between patients with and without BRAF mutations. Wild-type controls consisted of patients with NSCLC without a somatic alteration in BRAF, KRAS, EGFR, and ALK. In vitro studies assessed the biologic properties of selected non-V600E BRAF mutations identified from patients with NSCLC.
  
  
  RESULTS
  Of 883 tumors screened, 36 (4%) harbored BRAF mutations (V600E, 18; non-V600E, 18) and 257 were wild-type for BRAF, EGFR, KRAS, and ALK negative. Twenty-nine of 36 patients with BRAF mutations were smokers. There were no distinguishing clinical features between BRAF-mutant and wild-type patients. Patients with advanced NSCLC with BRAF mutations and wild-type tumors showed similar response rates and progression-free survival (PFS) to platinum-based combination chemotherapy and no difference in overall survival. Within the BRAF cohort, patients with V600E-mutated tumors had a shorter PFS to platinum-based chemotherapy compared with those with non-V600E mutations, although this did not reach statistical significance (4.1 vs. 8.9 months; P = 0.297). We identified five BRAF mutations not previously reported in NSCLC; two of five were associated with increased BRAF kinase activity.
  
  
  CONCLUSIONS
  BRAF mutations occur in 4% of NSCLCs and half are non-V600E. Prospective trials are ongoing to validate BRAF as a therapeutic target in NSCLC.
authors.affiliation: Department of Medical Oncology, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. scardarella@partners.org
authors.forename: Stephanie
authors.initials: S
authors.lastname: Cardarella
authors.forename: Atsuko
authors.initials: A
authors.lastname: Ogino
authors.forename: Mizuki
authors.initials: M
authors.lastname: Nishino
authors.forename: Mohit
authors.initials: M
authors.lastname: Butaney
authors.forename: Jeanne
authors.initials: J
authors.lastname: Shen
authors.forename: Christine
authors.initials: C
authors.lastname: Lydon
authors.forename: Beow Y
authors.initials: BY
authors.lastname: Yeap
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Sholl
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Johnson
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D003062:Codon; D005260:Female; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D003062:Codon; D048493:Proto-Oncogene Proteins B-raf