title: Correlation of BRAF Mutation Status in Circulating-Free DNA and Tumor and Association with Clinical Outcome across Four BRAFi and MEKi Clinical Trials.
abstract: OBJECTIVE
  Tumor-derived circulating cell-free DNA (cfDNA) is a potential alternative source from which to derive tumor mutation status. cfDNA data from four clinical studies of the BRAF inhibitor (BRAFi) dabrafenib or the MEK inhibitor (MEKi) trametinib were analyzed to determine the association between BRAF mutation status in cfDNA and tumor tissue, and the association of BRAF cfDNA mutation status with baseline factors and clinical outcome.
  
  
  METHODS
  Patients with BRAF V600 mutation-positive melanoma were enrolled in each study after central confirmation of BRAF status in tumor using a PCR-based assay. BRAF mutation status in cfDNA from patient plasma collected at baseline, 732 of 836 (88%) enrolled patients in total, was determined.
  
  
  RESULTS
  BRAF mutations were detectable in cfDNA in 76% and 81% of patients with BRAF V600E/V600K-positive tumors, respectively. Patients negative for BRAF mutations in cfDNA had longer progression-free survival (PFS) and overall survival in each of the four studies, compared with patients with detectable cfDNA BRAF mutations. The presence of BRAF-mutant cfDNA was an independent prognostic factor for PFS after multivariate adjustment for baseline factors in three of four studies. Patients negative for BRAF mutation-positive cfDNA in plasma had higher response rates to dabrafenib and trametinib.
  
  
  CONCLUSIONS
  BRAF mutations in cfDNA are detectable in >75% of late-stage melanoma patients with BRAF mutation-positive tumors. The lack of circulating, BRAF mutation-positive cfDNA is clinically significant for metastatic melanoma patients, and may be a prognostic marker for better disease outcome.
authors.affiliation: GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Ademi
authors.initials: A
authors.lastname: Santiago-Walker
authors.affiliation: GlaxoSmithKline, Collegeville, Pennsylvania. Robert.Gagnon@novartis.com.
authors.forename: Robert
authors.initials: R
authors.lastname: Gagnon
authors.affiliation: GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Jolly
authors.initials: J
authors.lastname: Mazumdar
authors.affiliation: GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Michelle
authors.initials: M
authors.lastname: Casey
authors.affiliation: Department of Medical Oncology, Melanoma Institute Australia and The University of Sydney, North Sydney, New South Wales, Australia.
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.affiliation: Department of Dermatology, University Hospital Essen, Essen, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
authors.forename: Keith
authors.initials: K
authors.lastname: Flaherty
authors.affiliation: Department of Medical Oncology, Melanoma Institute Australia and The University of Sydney, North Sydney, New South Wales, Australia. Westmead Hospital, Crown Princess Mary Cancer Centre, Sydney, New South Wales, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Kefford
authors.affiliation: Department of Dermatology, University Hospital Schleswig-Holstein, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Hauschild
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
authors.affiliation: GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Patricia
authors.initials: P
authors.lastname: Haney
authors.affiliation: GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Anne
authors.initials: A
authors.lastname: O'Hagan
authors.affiliation: GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Carver
authors.affiliation: GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Vicki
authors.initials: V
authors.lastname: Goodman
authors.affiliation: GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Legos
authors.affiliation: GlaxoSmithKline, Collegeville, Pennsylvania.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Martin
mesh_terms: D019943:Amino Acid Substitution; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D003062:Codon; D004273:DNA, Neoplasm / Q000097:blood; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D058990:Molecular Targeted Therapy; D009154:Mutation; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D003062:Codon; D004273:DNA, Neoplasm; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases