title: Preliminary results from a prospective trial of preoperative combined BRAF and MEK-targeted therapy in advanced BRAF mutation-positive melanoma.
abstract: BACKGROUND
  We conducted a prospective trial of BRAF and mitogen-activated protein kinase kinase (MEK) targeted therapy in advanced, operable BRAF mutation-positive melanoma to determine feasibility, tumor response rates, and biomarkers of response and resistance.
  
  
  METHODS
  Thirteen patients with locally or regionally advanced BRAF mutation-positive melanoma received dabrafenib 150 mg po bid for 14 days, followed by dabrafenib plus trametinib 2 mg po daily for 14 days before operation. Biopsies and tumor measurements were obtained at baseline and days 14 and 28. Formalin-fixed paraffin embedded specimens were analyzed with hematoxylin and eosin, Ki-67, cleaved caspase-3, CD8, phosphorylated extracellular signal-regulated kinase (ERK), and phosphorylated MEK immunostains.
  
  
  RESULTS
  Therapy was tolerated well, with toxicity ≥ grade 3 in 2 of 13 (15%) patients. All 12 patients receiving >14 days of therapy had substantial reduction in tumor volume (65% at day 14 and 78% at day 28) and underwent resection. After 14 days of dabrafenib therapy, there was a marked reduction in viable melanoma cells and a CD8 T-cell--rich infiltrate. Proliferation of the residual melanoma cells was reduced and apoptosis was increased. The cells continued to express phosphorylated ERK and phosphorylated MEK consistent with incomplete mitogen-activated protein kinase pathway inhibition.
  
  
  CONCLUSIONS
  Preoperative targeted therapy of advanced BRAF-mutant melanoma is feasible, well tolerated, induces brisk tumor responses, and facilitates correlative science. A CD8 T-cell-rich infiltrate indicates a potential immune-mediated mechanism of action. Both proliferation and apoptosis were inhibited, but the mitogen-activated protein kinase pathway remained activated, suggesting intrinsic resistance in a subset of tumor cells. Additional investigation of the anti-tumor immune response during targeted therapy and the mechanisms of intrinsic resistance can yield novel therapeutic strategies.
authors: Department of Pathology, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, TN.
authors: Adam S
authors: AS
authors: Johnson
authors: Department of Clinical Trials Shared Resource, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, TN.
authors: Holly
authors: H
authors: Crandall
authors: Department of Cancer Biology, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, TN.
authors: Kimberly
authors: K
authors: Dahlman
authors: Department of Surgery, Division of Surgical Oncology and Endocrine Surgery, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, TN. Electronic address: mark.kelley@vanderbilt.edu.
authors: Mark C
authors: MC
authors: Kelley
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001706:Biopsy; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005240:Feasibility Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*; D009154:Mutation; D010091:Oximes / Q000008:administration & dosage*; D011300:Preoperative Care / Q000379:methods; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*; D011728:Pyridones / Q000008:administration & dosage*; D011744:Pyrimidinones / Q000008:administration & dosage*; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D007093:Imidazoles; D010091:Oximes; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C561627:dabrafenib