title: Distinguishing clinicopathologic features of patients with V600E and V600K BRAF-mutant metastatic melanoma.
abstract: OBJECTIVE
  Certain clinicopathologic features correlate with BRAF mutation status in melanoma including younger age and primary subtype. This study sought to determine the BRAF mutation status by age-decade and whether BRAF-mutant genotypes correlated with clinicopathologic features and outcome in patients with metastatic melanoma.
  
  
  METHODS
  A prospectively assembled cohort of Australian patients were followed from diagnosis of metastatic melanoma (N = 308). Clinicopathologic variables were correlated with BRAF mutational status, genotype, and survival.
  
  
  RESULTS
  Forty-six percent of patients had a BRAF mutation; 73% V600E, 19% V600K, and 8% other genotypes. An inverse relationship existed between BRAF mutation prevalence and age-decade (P < 0.001). All patients <30 years and only 25% ≥ 70 years had BRAF-mutant melanoma. Amongst BRAF-mutant melanoma, the frequency of non-V600E genotypes (including V600K) increased with increasing age. Non-V600E genotypes comprised <20% in patients <50 years and >40% in those ≥ 70 years. A higher degree of cumulative sun-induced damage correlated with V600K but not V600E melanoma (P = 0.002). The disease-free interval from diagnosis of primary melanoma to first distant metastasis was shorter for patients with V600K compared with V600E melanoma (17.4 vs. 39.2 months, P = 0.048), with no difference in survival thereafter. In patients BRAF tested at diagnosis of metastatic melanoma, one year survival from diagnosis of metastasis was significantly longer for patients with BRAF-mutant melanoma treated with an inhibitor (83%), than those not treated with an inhibitor (29%, P < 0.001), or patients with BRAF wild-type melanoma (37%, P < 0.001).
  
  
  CONCLUSIONS
  Different genotypes exist within BRAF-mutant metastatic melanoma, representing biologically and clinically discrete subtypes, suggesting distinct etiology and behavior.
authors.affiliation: Melanoma Institute Australia, Disciplines of Medicine, Surgery, Pathology, and Westmead Institute for Cancer Research, Westmead Millennium Institute, The University of Sydney, Sydney, New South Wales, Australia. alexander.menzies@sydney.edu.au
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Menzies
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Haydu
authors.forename: Lydia
authors.initials: L
authors.lastname: Visintin
authors.forename: Matteo S
authors.initials: MS
authors.lastname: Carlino
authors.forename: Julie R
authors.initials: JR
authors.lastname: Howle
authors.forename: John F
authors.initials: JF
authors.lastname: Thompson
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kefford
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D019943:Amino Acid Substitution; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008545:Melanoma / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D008875:Middle Aged; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000737:chemistry / Q000235:genetics*; D015996:Survival Rate; D016896:Treatment Outcome; D014466:Ultraviolet Rays / Q000009:adverse effects; D055815:Young Adult
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf