title: Correlation of BRAF and NRAS mutation status with outcome, site of distant metastasis and response to chemotherapy in metastatic melanoma.
abstract: BACKGROUND
  The prognostic significance of BRAF and NRAS mutations in metastatic melanoma patients remains uncertain, with several studies reporting conflicting results, often biased by the inclusion of patients treated with BRAF and MEK (MAPK) inhibitors. We therefore interrogated a historical cohort of patients free of the confounding influence of MAPK inhibitor therapy.
  
  
  METHODS
  Patients with available archival tissue first diagnosed with metastatic melanoma between 2002 and 2006 were analysed. Mutational analysis was performed using the OncoCarta Panel. Patient characteristics, treatment outcome and survival were correlated with BRAF/NRAS mutation status.
  
  
  RESULTS
  In 193 patients, 92 (48%) melanomas were BRAF-mutant, 39 (20%) were NRAS-mutant and 62 (32%) were wild-type for BRAF/NRAS mutations (wt). There was no difference in response to chemotherapy based on mutation status (35-37%). The distant disease-free interval (DDFI) was significantly shorter in patients with wt melanoma (27.9 months vs 35.1 for BRAF and 49.1 for NRAS) although this was not significant in multivariate analysis. Survival from stage IV melanoma diagnosis was not significantly different based on mutation status. The DDFI was significantly shorter in patients with BRAF(V600K/R) versus BRAF(V600E) melanoma in univariate and multivariate analyses.
  
  
  CONCLUSIONS
  BRAF and NRAS mutation status does not influence survival in metastatic melanoma.
authors.affiliation: 1] Melanoma Institute Australia, Sydney, New South Wales, Australia [2] Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead, New South Wales, Australia [3] Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, New South Wales, Australia [4] Discipline of Medicine, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: M S
authors.initials: MS
authors.lastname: Carlino
authors.affiliation: 1] Melanoma Institute Australia, Sydney, New South Wales, Australia [2] Discipline of Surgery, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: L E
authors.initials: LE
authors.lastname: Haydu
authors.affiliation: 1] Melanoma Institute Australia, Sydney, New South Wales, Australia [2] Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: H
authors.initials: H
authors.lastname: Kakavand
authors.affiliation: 1] Melanoma Institute Australia, Sydney, New South Wales, Australia [2] Discipline of Medicine, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: A M
authors.initials: AM
authors.lastname: Menzies
authors.affiliation: 1] Discipline of Medicine, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia [2] Department of Medical Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
authors.forename: A L
authors.initials: AL
authors.lastname: Hamilton
authors.affiliation: 1] Discipline of Medicine, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia [2] Department of Medical Genomics, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
authors.forename: B
authors.initials: B
authors.lastname: Yu
authors.affiliation: Department of Medical Genomics, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
authors.forename: C C
authors.initials: CC
authors.lastname: Ng
authors.affiliation: 1] Department of Medical Genomics, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia [2] Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia [3] School of Medicine, University of Western Sydney, Sydney, NSW, Australia.
authors.forename: W A
authors.initials: WA
authors.lastname: Cooper
authors.affiliation: 1] Melanoma Institute Australia, Sydney, New South Wales, Australia [2] Discipline of Surgery, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia [3] Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
authors.forename: J F
authors.initials: JF
authors.lastname: Thompson
authors.affiliation: 1] Melanoma Institute Australia, Sydney, New South Wales, Australia [2] Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead, New South Wales, Australia [3] Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, New South Wales, Australia [4] Discipline of Medicine, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: R F
authors.initials: RF
authors.lastname: Kefford
authors.affiliation: 1] Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia [2] Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia [3] The Kinghorn Cancer Centre and Cancer Program Garvan Institute of Medical Research, Victoria Street, Darlinghurst, New South Wales, Australia.
authors.forename: S A
authors.initials: SA
authors.lastname: O'Toole
authors.affiliation: 1] Melanoma Institute Australia, Sydney, New South Wales, Australia [2] Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia [3] Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
authors.forename: R A
authors.initials: RA
authors.lastname: Scolyer
authors.affiliation: 1] Melanoma Institute Australia, Sydney, New South Wales, Australia [2] Discipline of Medicine, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: G V
authors.initials: GV
authors.lastname: Long
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D018572:Disease-Free Survival; D005260:Female; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors / Q000235:genetics*; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human