title: Prospective blinded study of BRAFV600E mutation detection in cell-free DNA of patients with systemic histiocytic disorders.
abstract: Patients with Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) have a high frequency of BRAF(V600E) mutations and respond to RAF inhibitors. However, detection of mutations in tissue biopsies is particularly challenging in histiocytoses due to low tumor content and stromal contamination. We applied a droplet-digital PCR assay for quantitative detection of the BRAF(V600E) mutation in plasma and urine cell-free (cf) DNA and performed a prospective, blinded study in 30 patients with ECD/LCH. There was 100% concordance between tissue and urinary cfDNA genotype in treatment-naïve samples. cfDNA analysis facilitated identification of previously undescribed KRAS(G12S)-mutant ECD and dynamically tracked disease burden in patients treated with a variety of therapies. These results indicate that cfDNA BRAF(V600E) mutational analysis in plasma and urine provides a convenient and reliable method of detecting mutational status and can serve as a noninvasive biomarker to monitor response to therapy in LCH and ECD.
  
  
  CONCLUSIONS
  Patients with BRAF(V600E)-mutant histiocytic disorders have remarkable responses to RAF inhibition, but mutation detection in tissue in these disorders is challenging. Here, we identify that analysis of plasma and urinary cfDNA provides a reliable method to detect the BRAF(V600E) mutation and monitor response to therapy in these disorders.
authors.affiliation: Developmental Therapeutics Unit, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: David M
authors.initials: DM
authors.lastname: Hyman
authors.affiliation: Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Eli L
authors.initials: EL
authors.lastname: Diamond
authors.affiliation: Trovagene, Inc., San Diego, California.
authors.forename: Cecile Rose T
authors.initials: CR
authors.lastname: Vibat
authors.affiliation: Trovagene, Inc., San Diego, California.
authors.forename: Latifa
authors.initials: L
authors.lastname: Hassaine
authors.affiliation: Trovagene, Inc., San Diego, California.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Poole
authors.affiliation: Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Minal
authors.initials: M
authors.lastname: Patel
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Program), The MD Anderson Cancer Center, Houston, Texas.
authors.forename: Veronica R
authors.initials: VR
authors.lastname: Holley
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Program), The MD Anderson Cancer Center, Houston, Texas.
authors.forename: Goran
authors.initials: G
authors.lastname: Cabrilo
authors.affiliation: Trovagene, Inc., San Diego, California.
authors.forename: Timothy T
authors.initials: TT
authors.lastname: Lu
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Arcila
authors.affiliation: Human Oncology and Pathogenesis Program, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Young Rock
authors.initials: YR
authors.lastname: Chung
authors.affiliation: Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Raajit
authors.initials: R
authors.lastname: Rampal
authors.affiliation: Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Mario E
authors.initials: ME
authors.lastname: Lacouture
authors.affiliation: Program in Molecular Pharmacology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Program), The MD Anderson Cancer Center, Houston, Texas.
authors.forename: Funda
authors.initials: F
authors.lastname: Meric-Bernstam
authors.affiliation: Developmental Therapeutics Unit, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Human Oncology and Pathogenesis Program, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
authors.affiliation: Trovagene, Inc., San Diego, California.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Erlander
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Program), The MD Anderson Cancer Center, Houston, Texas.
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.affiliation: Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Human Oncology and Pathogenesis Program, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. abdelwao@mskcc.org.
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D001706:Biopsy; D002648:Child; D003062:Codon; D003430:Cross-Sectional Studies; D004252:DNA Mutational Analysis; D031249:Erdheim-Chester Disease / Q000175:diagnosis / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D011905:Genes, ras; D005838:Genotype; D015614:Histiocytosis / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D006646:Histiocytosis, Langerhans-Cell / Q000175:diagnosis / Q000235:genetics; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation; D049268:Positron-Emission Tomography; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D055815:Young Adult
chemical_list: D003062:Codon; D048493:Proto-Oncogene Proteins B-raf