Preliminary results from a prospective trial of preoperative combined BRAF and MEK-targeted therapy in advanced BRAF mutation-positive melanoma.

Authors:
Adam S Johnson
Adam S Johnson
Vanderbilt-Ingram Cancer Center
United States
Holly Crandall
Holly Crandall
Vanderbilt-Ingram Cancer Center
United States
Kimberly Dahlman
Kimberly Dahlman
Vanderbilt-Ingram Cancer Center
Mark C Kelley
Mark C Kelley
Vanderbilt University Medical Center
United States

J Am Coll Surg 2015 Apr 30;220(4):581-93.e1. Epub 2015 Jan 30.

Department of Surgery, Division of Surgical Oncology and Endocrine Surgery, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, TN. Electronic address:

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-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.

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Source
https://linkinghub.elsevier.com/retrieve/pii/S10727515150007
Publisher Site
http://dx.doi.org/10.1016/j.jamcollsurg.2014.12.057DOI Listing

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April 2015
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