title: Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma.
abstract: OBJECTIVE
  To assess the frequency and type of oncogenic BRAF mutations in metastatic melanoma and correlate BRAF status with clinicopathologic features and outcome.
  
  
  METHODS
  Consecutive BRAF-tested Australian patients with metastatic melanoma (n = 197) were observed prospectively. A comprehensive range of clinicopathologic variables were correlated with BRAF mutation status, and a survival analysis was conducted.
  
  
  RESULTS
  Forty-eight percent of patients had a BRAF mutation; 70 patients (74%) had V600E, 19 (20%) had V600K, and six (6%) had other genotypes. Other than age at diagnosis of distant metastasis (median age, 56 v 63 years for BRAF-mutant v BRAF wild-type patients, respectively; P < .001), there was no significant difference in clinical features of patients with metastatic melanoma by mutation status. Features of the antecedent primary melanoma significantly associated with a BRAF mutation (P < .05) were histopathologic subtype, presence of mitoses, single or occult primary melanoma, truncal location, and age at diagnosis of primary tumor ≤ 50 years. The interval from diagnosis of first-ever melanoma to distant metastasis was not significantly different between BRAF-mutant and BRAF wild-type patients; however, the median survival of patients with newly diagnosed metastatic melanoma was 5.7 months for BRAF-mutant patients not treated with a BRAF inhibitor, 8.5 months for BRAF wild-type patients, and not reached for BRAF-mutant patients treated with a BRAF inhibitor.
  
  
  CONCLUSIONS
  V600K mutations comprised 20% of BRAF mutations. Characteristics of the antecedent primary melanoma and age at diagnosis differed in BRAF-mutant and BRAF wild-type patients. The presence of mutant BRAF had no impact on the disease-free interval from diagnosis of first-ever melanoma to first distant metastasis; however, it may have impacted survival thereafter.
authors.affiliation: Melanoma Institute Australia, 40 Rocklands Rd, North Sydney, New South Wales, 2060, Australia. georgina.long@sydney.edu.au
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Menzies
authors.forename: Adnan M
authors.initials: AM
authors.lastname: Nagrial
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Haydu
authors.forename: Anne L
authors.initials: AL
authors.lastname: Hamilton
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Mann
authors.forename: T Michael
authors.initials: TM
authors.lastname: Hughes
authors.forename: John F
authors.initials: JF
authors.lastname: Thompson
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kefford
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D009517:New South Wales; D016017:Odds Ratio; D010641:Phenotype; D016016:Proportional Hazards Models; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D018570:Risk Assessment; D012307:Risk Factors; D012878:Skin Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf