title: Clinical utility of a blood-based BRAF(V600E) mutation assay in melanoma.
abstract: BRAF inhibitors (BRAFi) have led to clinical benefit in patients with melanoma. The development of a blood-based assay to detect and quantify BRAF levels in these patients has diagnostic, prognostic, and predictive capabilities that could guide treatment decisions. Blood BRAF(V600E) detection and quantification were performed on samples from 128 patients with stage II (19), III (67), and IV (42) melanoma. Tissue BRAF analysis was performed in all patients with stage IV disease and in selected patients with stage II and III disease. Clinical outcomes were correlated to initial BRAF levels as well as BRAF level dynamics. Serial analysis was performed on 17 stage IV melanoma patients treated with BRAFi and compared with tumor measurements by RECIST. The assay was highly sensitive (96%) and specific (95%) in the stage IV setting, using a blood level of 4.8 pg as "positive." BRAF levels typically decreased following BRAFi. A subset of these patients (5) had an increase in BRAF(V600E) values 42 to 112 days before clinical or radiographic disease progression (PD). From 86 patients with resected, stage II or III melanoma, 39 had evidence of disease relapse (45.3%). Furthermore, BRAF mutation in the blood after surgical resection in these patients was not associated with a difference in relapse risk, although tissue BRAF status was only available for a subset of patients. In summary, we have developed a highly sensitive and specific, blood-based assay to detect BRAF(V600) mutation in patients with melanoma.
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts. dpanka@bidmc.harvard.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Panka
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Buchbinder
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Anita
authors.initials: A
authors.lastname: Giobbie-Hurder
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Aislyn P
authors.initials: AP
authors.lastname: Schalck
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: Laleh
authors.initials: L
authors.lastname: Montaser-Kouhsari
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: Alireza
authors.initials: A
authors.lastname: Sepehr
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Donald P
authors.initials: DP
authors.lastname: Lawrence
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: David F
authors.initials: DF
authors.lastname: McDermott
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: Rachel
authors.initials: R
authors.lastname: Cohen
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: Alexander
authors.initials: A
authors.lastname: Carlson
authors.affiliation: MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wargo
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Ryan
authors.initials: R
authors.lastname: Merritt
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: Virginia J
authors.initials: VJ
authors.lastname: Seery
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: Anasuya
authors.initials: A
authors.lastname: Gunturi
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Dennie
authors.initials: D
authors.lastname: Fredrick
authors.affiliation: Georgetown-Lombardi Comprehensive Cancer Center, Washington, District of Columbia.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Atkins
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: James W
authors.initials: JW
authors.lastname: Mier
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Sullivan
mesh_terms: D019943:Amino Acid Substitution; D045744:Cell Line, Tumor; D003062:Codon; D004252:DNA Mutational Analysis / Q000379:methods* / Q000592:standards; D005838:Genotype; D006801:Humans; D007963:Leukocytes, Mononuclear; D008545:Melanoma / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics*; D058990:Molecular Targeted Therapy; D009154:Mutation; D009367:Neoplasm Staging; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
chemical_list: D003062:Codon; D048493:Proto-Oncogene Proteins B-raf