title: BRAF mutations: signaling, epidemiology, and clinical experience in multiple malignancies.
abstract: BACKGROUND
  Mutations in BRAF were first reported in 2002. Since that time, the molecular basis for oncogenic signaling has been elucidated in multiple malignancies. The development of v-raf murine sarcoma viral oncogene homolog B (BRAF) inhibitors has helped improve clinical outcomes in malignant melanoma and is suggested by case reports in other malignancies.
  
  
  METHODS
  A review of pertinent articles examining the mechanisms of BRAF signaling in various cancer types and an update on clinical trials of BRAF inhibitions are presented.
  
  
  RESULTS
  Clinical response to BRAF inhibition varies by malignancy. In melanoma, single-agent vemurafenib or dabrafenib prolongs overall survival compared with chemotherapy, but both are limited by the development of acquired resistance in many patients. Results of early-phase clinical trials and case reports demonstrate responses in V600E-mutant non-small-cell lung cancer, thyroid cancer, and hairy cell leukemia. However, no significant difference in progression-free survival was seen in colorectal cancer with single-agent vemurafenib. Overcoming resistance to BRAF inhibition with combination therapy is an active area of research.
  
  
  CONCLUSIONS
  The detection of BRAF mutations represents an advance in delivering molecularly targeted therapies to patients with a variety of cancers. Acquired resistance limits the ability of BRAF inhibitors to produce long-term remissions; however, combining BRAF inhibitors with the mitogen-activated protein kinase pathway and/or other pathway inhibitors represents a promising method to improve long-term outcomes.
authors: Department of Internal Medicine, Division of Medical Oncology, University of Virginia Health System, Hematology/Oncology, Charlottesville, 22908, USA. rdh3q@virginia.edu.
authors: Richard D
authors: RD
authors: Hall
authors: Ragini R
authors: RR
authors: Kudchadkar
mesh_terms: D000818:Animals; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics / Q000628:therapy; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf