Journal
JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS
Volume 220, Issue 4, Pages 581-593Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jamcollsurg.2014.12.057
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Funding
- National Comprehensive Cancer Network (NCCN) Oncology Research Program from GlaxoSmithKline, LLC (GSK)
- NCCN
- Vanderbilt-Ingram Cancer Center
- TJ Martell Foundation
- Robert J Kleberg Jr and Helen C Kleberg Foundation
- Cancer Center Support [5P30 CA068485]
- NATIONAL CANCER INSTITUTE [P30CA068485] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [S10OD016355] Funding Source: NIH RePORTER
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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. STUDY DESIGN: 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-cellerich 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-cellerich 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. (C) 2015 by the American College of Surgeons
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