title: The molecular profile of metastatic melanoma in Australia.
abstract: Targeted therapy directed at driver oncogenic mutations offers an effective treatment option for select patients with metastatic melanoma. The aim of this study was to assess the prevalence of clinically significant somatic mutations, specifically BRAF, NRAS and KIT, in a large cohort of Australian patients with metastatic melanoma. We performed a cross-sectional cohort study of consecutive patients with American Joint Committee on Cancer (AJCC) stage IIIc unresectable or stage IV melanoma managed at Melanoma Institute Australia, and affiliated sites, that underwent molecular testing between 22 June 2009 and 19 July 2013. Additionally, we examined the change in BRAF testing methodology and patient population over time, and how this influenced the prevalence of mutations. A total of 767 molecular tests were conducted for 733 patients. BRAF V600 mutation testing was performed for 713 patients (97.2%), with an overall mutation prevalence of 37.7% (269/713); 74.3% (200/269) were the V600E genotype and 22.3% (60/269) V600K. The BRAF mutation prevalence and proportion of BRAF V600E and V600K genotypes varied across the study period, as did testing methodology and the median age of the cohorts. Of 222 patients who underwent NRAS testing, 58 (26.1%) had a mutation identified. The overall prevalence of KIT mutations was 3.7% (11/296). In Australia the prevalence of BRAF mutations is lower than initially reported, although this remains the most common mutation identified in metastatic melanoma and an important therapeutic target. NRAS mutations are more prevalent than initially described; however, other mutations reported in melanoma, including KIT, are rare in an unselected population of patients.
authors.affiliation: Melanoma Institute Australia, Sydney, NSW, Australia; The University of Sydney, Sydney, NSW, Australia; Liz Plummer Cancer Centre, Cairns, Qld, Australia.
authors.forename: Megan
authors.initials: M
authors.lastname: Lyle
authors.affiliation: Melanoma Institute Australia, Sydney, NSW, Australia; The University of Sydney, Sydney, NSW, Australia.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Haydu
authors.affiliation: Melanoma Institute Australia, Sydney, NSW, Australia; The University of Sydney, Sydney, NSW, Australia; Royal North Shore Hospital, Sydney, NSW, Australia.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Menzies
authors.affiliation: Melanoma Institute Australia, Sydney, NSW, Australia; The University of Sydney, Sydney, NSW, Australia; Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
authors.forename: John F
authors.initials: JF
authors.lastname: Thompson
authors.affiliation: Melanoma Institute Australia, Sydney, NSW, Australia; The University of Sydney, Sydney, NSW, Australia; Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
authors.forename: Robyn P M
authors.initials: RP
authors.lastname: Saw
authors.affiliation: Melanoma Institute Australia, Sydney, NSW, Australia; The University of Sydney, Sydney, NSW, Australia; Royal North Shore Hospital, Sydney, NSW, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Spillane
authors.affiliation: Melanoma Institute Australia, Sydney, NSW, Australia; Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, NSW, Australia; Macquarie University, North Ryde, NSW, Australia.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kefford
authors.affiliation: Melanoma Institute Australia, Sydney, NSW, Australia; The University of Sydney, Sydney, NSW, Australia; Westmead Millennium Institute for Medical Research, Westmead, NSW, Australia.
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Mann
authors.affiliation: The University of Sydney, Sydney, NSW, Australia; Royal Prince Alfred Hospital, Camperdown, NSW, Australia; School of Medicine, University of Western Sydney, NSW, Australia.
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Cooper
authors.affiliation: The University of Sydney, Sydney, NSW, Australia; Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
authors.forename: Bing
authors.initials: B
authors.lastname: Yu
authors.affiliation: Melanoma Institute Australia, Sydney, NSW, Australia; The University of Sydney, Sydney, NSW, Australia; Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.affiliation: Melanoma Institute Australia, Sydney, NSW, Australia; The University of Sydney, Sydney, NSW, Australia; Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
authors.forename: Sandra A
authors.initials: SA
authors.lastname: O'Toole
authors.affiliation: Melanoma Institute Australia, Sydney, NSW, Australia; The University of Sydney, Sydney, NSW, Australia; Royal North Shore Hospital, Sydney, NSW, Australia. Electronic address: georgina.long@sydney.edu.au.
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001315:Australia / Q000453:epidemiology; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008545:Melanoma / Q000453:epidemiology / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D012878:Skin Neoplasms / Q000453:epidemiology / Q000235:genetics*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; D019009:Proto-Oncogene Proteins c-kit; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
keywords: BRAF; KIT; NRAS; OncoCarta; diagnosis; melanoma; molecular testing; pathology; somatic mutations; targeted therapy