title: Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor dabrafenib (GSK2118436).
abstract: OBJECTIVE
  Dabrafenib is a selective inhibitor of V600-mutant BRAF kinase, which recently showed improved progression-free survival (PFS) as compared with dacarbazine, in metastatic melanoma patients. This study examined potential genetic markers associated with response and PFS in the phase I study of dabrafenib.
  
  
  METHODS
  Baseline (pretreatment or archival) melanoma samples were evaluated in 41 patients using a custom genotyping melanoma-specific assay, sequencing of PTEN, and copy number analysis using multiplex ligation amplification and array-based comparative genomic hybridization. Nine patients had on-treatment and/or progression samples available.
  
  
  RESULTS
  All baseline patient samples had BRAF(V600E/K) confirmed. Baseline PTEN loss/mutation was not associated with best overall response to dabrafenib, but it showed a trend for shorter median PFS [18.3 (95% confidence interval, CI, 9.1-24.3) vs. 32.1 weeks (95% CI, 24.1-33), P=0.059]. Higher copy number of CCND1 (P=0.009) and lower copy number of CDKN2A (P=0.012) at baseline were significantly associated with decreased PFS. Although no melanomas had high-level amplification of BRAF, the two patients with progressive disease as their best response had BRAF copy gain in their tumors.
  
  
  CONCLUSIONS
  Copy number changes in CDKN2A, CCND1, and mutation/copy number changes in PTEN correlated with the duration of PFS in patients treated with dabrafenib. The results suggest that these markers should be considered in the design and interpretation of future trials with selective BRAF inhibitors in advanced melanoma patients.
authors.affiliation: Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. knathans@exchange.upenn.edu
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Martin
authors.forename: Bradley
authors.initials: B
authors.lastname: Wubbenhorst
authors.forename: Joel
authors.initials: J
authors.lastname: Greshock
authors.forename: Richard
authors.initials: R
authors.lastname: Letrero
authors.forename: Kurt
authors.initials: K
authors.lastname: D'Andrea
authors.forename: Steven
authors.initials: S
authors.lastname: O'Day
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Falchook
authors.forename: Hendrik-Tobias
authors.initials: HT
authors.lastname: Arkenau
authors.forename: Michael
authors.initials: M
authors.lastname: Millward
authors.forename: Michael P
authors.initials: MP
authors.lastname: Brown
authors.forename: Anna
authors.initials: A
authors.lastname: Pavlick
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
authors.forename: Bo
authors.initials: B
authors.lastname: Ma
authors.forename: Robert
authors.initials: R
authors.lastname: Gagnon
authors.forename: Martin
authors.initials: M
authors.lastname: Curtis
authors.forename: Peter F
authors.initials: PF
authors.lastname: Lebowitz
authors.forename: Richard
authors.initials: R
authors.lastname: Kefford
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
mesh_terms: D055028:Comparative Genomic Hybridization; D019938:Cyclin D1 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D018450:Disease Progression; D018572:Disease-Free Survival; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009367:Neoplasm Staging; D010091:Oximes / Q000008:administration & dosage*; D051059:PTEN Phosphohydrolase / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: C530104:CCND1 protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D007093:Imidazoles; D010091:Oximes; D019938:Cyclin D1; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051059:PTEN Phosphohydrolase; C561627:dabrafenib