title: BRAF mutation status is an independent prognostic factor for resected stage IIIB and IIIC melanoma: implications for melanoma staging and adjuvant therapy.
abstract: BACKGROUND
  5-year survival for melanoma metastasis to regional lymph nodes (American Joint Committee on Cancer stage III) is <50%. Knowledge of outcomes following therapeutic lymphadenectomy for stage III melanoma related to BRAF status may guide adjuvant use of BRAF/MEK inhibitors along with established and future therapies.
  
  
  OBJECTIVE
  To determine patterns of melanoma recurrence and survival following therapeutic lymph node dissection (TLND) associated with oncogenic mutations.
  
  
  METHODS
  DNA was obtained from patients who underwent TLND and had ⩾2 positive nodes, largest node >3cm or extracapsular invasion. Mutations were detected using an extended Sequenom MelaCARTA panel.
  
  
  RESULTS
  Mutations were most commonly detected in BRAF (57/124 [46%] patients) and NRAS (26/124 [21%] patients). Patients with BRAF mutations had higher 3-year recurrence rate (77%) versus 54% for BRAF wild-type patients (hazard ratio (HR) 1.8, p=0.008). The only prognostically significant mutations occurred in BRAF: median recurrence-free (RFS) and disease-specific survival (DSS) for BRAF mutation patients was 7 months and 16 months, versus 19 months and not reached for BRAF wild-type patients, respectively. Multivariate analysis identified BRAF mutant status and number of positive lymph nodes as the only independent prognostic factors for RFS and DSS.
  
  
  CONCLUSIONS
  Patients with BRAF mutations experienced rapid progression of metastatic disease with locoregional recurrence rarely seen in isolation, supporting incorporation of BRAF status into melanoma staging and use of BRAF/MEK inhibitors post-TLND.
authors: Surgical Oncology Group, School of Medicine, The University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia; Queensland Melanoma Project, Discipline of Surgery, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD, Australia. Electronic address: a.barbour@uq.edu.au.
authors: Andrew P
authors: AP
authors: Barbour
authors: Surgical Oncology Group, School of Medicine, The University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia.
authors: Yue Hang
authors: YH
authors: Tang
authors: Surgical Oncology Group, School of Medicine, The University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia.
authors: Nicola
authors: N
authors: Armour
authors: QIMR Berghofer Medical Research Institute, Oncogenomics Laboratory, Brisbane, QLD, Australia.
authors: Ken
authors: K
authors: Dutton-Regester
authors: QIMR Berghofer Medical Research Institute, Oncogenomics Laboratory, Brisbane, QLD, Australia.
authors: Lutz
authors: L
authors: Krause
authors: Surgical Oncology Group, School of Medicine, The University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia.
authors: Kelly A
authors: KA
authors: Loffler
authors: Department of Pathology, Princess Alexandra Hospital, Woolloongabba, QLD, Australia.
authors: Duncan
authors: D
authors: Lambie
authors: Queensland Melanoma Project, Discipline of Surgery, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD, Australia.
authors: Bryan
authors: B
authors: Burmeister
authors: Queensland Melanoma Project, Discipline of Surgery, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD, Australia.
authors: Janine
authors: J
authors: Thomas
authors: Queensland Melanoma Project, Discipline of Surgery, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD, Australia.
authors: B Mark
authors: BM
authors: Smithers
authors: QIMR Berghofer Medical Research Institute, Oncogenomics Laboratory, Brisbane, QLD, Australia.
authors: Nicholas K
authors: NK
authors: Hayward
mesh_terms: D004252:DNA Mutational Analysis; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007167:Immunotherapy; D053208:Kaplan-Meier Estimate; D008197:Lymph Node Excision; D008207:Lymphatic Metastasis; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000601:surgery / Q000628:therapy; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D017063:Outcome Assessment, Health Care / Q000706:statistics & numerical data; D011379:Prognosis; D016016:Proportional Hazards Models; D000090063:Proto-Oncogene Mas; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D018714:Radiotherapy, Adjuvant; D012878:Skin Neoplasms / Q000235:genetics* / Q000601:surgery / Q000628:therapy
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: Melanoma; Molecular diagnostic techniques; Oncogenes; Proto-oncogene proteins B-raf