title: Clinical and therapeutic implications of BRAF mutation heterogeneity in metastatic melanoma.
abstract: Heterogeneity of BRAF mutation in melanoma has been a controversial subject. Quantitative data on BRAF allele frequency (AF) are sparse, and the potential relationship with response to BRAF inhibitors (BRAFi) in patients with metastatic melanoma is unknown. We quantitatively measured BRAF AF in a cohort of treatment naïve metastatic melanoma samples by pyrosequencing and correlated with survival data in patients treated with BRAFi as part of their clinical care. Fifty-two samples from 50 patients were analysed. BRAF V600E mutations were detected in 71.1% of samples followed by V600K (25%) and V600R (3.9%). There was a wide range of AF from 3.9% to 80.3% (median 41.3%). In 33 patients treated with BRAFi, there was no difference in overall or progression-free survival when the patients were categorized into high or low AF groups. There was no correlation between AF and degree of response, and no difference in survival based on genotype.
authors.affiliation: Department of Anatomical Pathology, PathWest Laboratory Medicine, Queen Elizabeth II Medical Centre, Nedlands, WA, Australia.|School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, WA, Australia.
authors.forename: Nima
authors.initials: N
authors.lastname: Mesbah Ardakani
authors.affiliation: Department of Anatomical Pathology, PathWest Laboratory Medicine, Queen Elizabeth II Medical Centre, Nedlands, WA, Australia.|School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, WA, Australia.
authors.forename: Connull
authors.initials: C
authors.lastname: Leslie
authors.affiliation: Department of Anatomical Pathology, PathWest Laboratory Medicine, Queen Elizabeth II Medical Centre, Nedlands, WA, Australia.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Grieu-Iacopetta
authors.affiliation: Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
authors.forename: Wei-Sen
authors.initials: WS
authors.lastname: Lam
authors.affiliation: Centre for Applied Statistics, University of Western Australia, Crawley, WA, Australia.
authors.forename: Charley
authors.initials: C
authors.lastname: Budgeon
authors.affiliation: Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.|School of Medicine and Pharmacology, University of Western Australia, Crawley, WA, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Millward
authors.affiliation: Department of Anatomical Pathology, PathWest Laboratory Medicine, Queen Elizabeth II Medical Centre, Nedlands, WA, Australia.|School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, WA, Australia.
authors.forename: Benhur
authors.initials: B
authors.lastname: Amanuel
mesh_terms: D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology
chemical_list: D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF inhibitor; BRAF mutation; allele frequency; heterogeneity; malignant melanoma; pyrosequencing