Johnson Adam S, Crandall Holly, Dahlman Kimberly, Kelley Mark C
Department of Pathology, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, TN.
Department of Clinical Trials Shared Resource, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, TN.
J Am Coll Surg. 2015 Apr;220(4):581-93.e1. doi: 10.1016/j.jamcollsurg.2014.12.057. Epub 2015 Jan 30.
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.
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.
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.
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.
我们开展了一项针对晚期可手术切除的BRAF突变阳性黑色素瘤患者的BRAF和丝裂原活化蛋白激酶激酶（MEK）靶向治疗的前瞻性试验，以确定其可行性、肿瘤反应率以及反应和耐药的生物标志物。
13例局部或区域晚期BRAF突变阳性黑色素瘤患者接受150 mg达拉非尼口服，每日2次，共14天，然后在手术前14天接受达拉非尼加2 mg曲美替尼口服，每日1次。在基线、第14天和第28天进行活检和肿瘤测量。用苏木精和伊红、Ki-67、裂解的半胱天冬酶-3、CD8、磷酸化细胞外信号调节激酶（ERK）和磷酸化MEK免疫染色对福尔马林固定石蜡包埋标本进行分析。
治疗耐受性良好，13例患者中有2例（15%）出现≥3级毒性。所有接受治疗超过14天的12例患者肿瘤体积均大幅减小（第
