title: Copy Number Changes Are Associated with Response to Treatment with Carboplatin, Paclitaxel, and Sorafenib in Melanoma.
abstract: OBJECTIVE
  Copy number alterations have been shown to be involved in melanoma pathogenesis. The randomized phase III clinical trial E2603: carboplatin, paclitaxel, ± sorafenib (CP vs. CPS) offers a large collection of tumor samples to evaluate association of somatic mutations, genomic alterations, and clinical outcomes, prior to current FDA-approved therapies.
  
  
  METHODS
  Copy number and mutational analysis on 119 pretreatment samples was performed.
  
  
  RESULTS
  CPS therapy was associated with improved progression-free survival (PFS) compared with CP in patients with tumors with RAF1 (cRAF) gene copy gains (HR, 0.372; P = 0.025) or CCND1 gene copy gains (HR, 0.45; P = 0.035). CPS therapy was associated with improved overall survival (OS) compared with CP in patients with tumors with KRAS gene copy gains (HR, 0.25; P = 0.035). BRAF gene copy gain and MET amplification were more common in samples with V600K versus V600E mutations (P < 0.001), which was validated in The Cancer Genome Atlas (TCGA) dataset.
  
  
  CONCLUSIONS
  We observed improved treatment response with CPS in patients with melanoma whose tumors have RAF1 (cRAF), KRAS, or CCND1 amplification, all of which can be attributed to sorafenib targeting CRAF. These genomic alterations should be incorporated in future studies for evaluation as biomarkers.
authors: Hematology/Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Melissa A
authors: MA
authors: Wilson
authors: Dana Farber Cancer Institute, Boston, Massachusetts.
authors: Fengmin
authors: F
authors: Zhao
authors: Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Sanika
authors: S
authors: Khare
authors: Departments of Melanoma Medical Oncology and Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Jason
authors: J
authors: Roszik
authors: Departments of Melanoma Medical Oncology and Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Scott E
authors: SE
authors: Woodman
authors: Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Kurt
authors: K
authors: D'Andrea
authors: Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Bradley
authors: B
authors: Wubbenhorst
authors: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
authors: David L
authors: DL
authors: Rimm
authors: University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors: John M
authors: JM
authors: Kirkwood
authors: Section of Medical Oncology, Yale Cancer Center, New Haven, Connecticut.
authors: Harriet M
authors: HM
authors: Kluger
authors: Hematology/Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Lynn M
authors: LM
authors: Schuchter
authors: Dana Farber Cancer Institute, Boston, Massachusetts.
authors: Sandra J
authors: SJ
authors: Lee
authors: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts.
authors: Keith T
authors: KT
authors: Flaherty
authors: Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. knathans@exchange.upenn.edu.
authors: Katherine L
authors: KL
authors: Nathanson
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000627:therapeutic use*; D056915:DNA Copy Number Variations / Q000187:drug effects* / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods; D018572:Disease-Free Survival; D004311:Double-Blind Method; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics*; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D009367:Neoplasm Staging / Q000379:methods; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017239:Paclitaxel / Q000627:therapeutic use*; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D000077157:Sorafenib; D016896:Treatment Outcome
chemical_list: D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D016190:Carboplatin; D019859:Proto-Oncogene Proteins c-met; D048493:Proto-Oncogene Proteins B-raf; D017239:Paclitaxel