A randomized phase II presurgical trial of transdermal 4-hydroxytamoxifen gel versus oral tamoxifen in women with ductal carcinoma in situ of the breast.
A randomized phase II presurgical trial of transdermal 4-hydroxytamoxifen gel versus oral tamoxifen in women with ductal carcinoma in situ of the breast.
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DOI：
10.1158/1078-0432.ccr-13-3045
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发表时间：
2014-07-15
期刊：
影响因子：
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通讯作者：
Khan SA
中科院分区：
文献类型：
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作者：
Lee O;Page K;Ivancic D;Helenowski I;Parini V;Sullivan ME;Margenthaler JA;Chatterton RT Jr;Jovanovic B;Dunn BK;Heckman-Stoddard BM;Foster K;Muzzio M;Shklovskaya J;Skripkauskas S;Kulesza P;Green D;Hansen NM;Bethke KP;Jeruss JS;Bergan R;Khan SA
局部经皮治疗乳房可以实现有效的靶器官药物输送，同时减少全身效应。我们进行了一项随机、双盲、安慰剂对照的II期试验，比较了4-羟基他莫昔芬凝胶（4-OHT）透皮给药与口服他莫昔芬（oral-T）治疗乳腺导管原位癌（DCIS）的疗效。27例绝经前和绝经后妇女随机分为4-OHT组（4 mg/d）和口服-T组（20 mg/d），疗程6-10周。血浆，乳头抽吸液，和乳房脂肪组织浓度的他莫昔芬及其主要代谢产物的液相色谱-串联质谱法测定。主要终点是通过免疫组织化学测量的DCIS病变中的Ki 67标记。在血浆中，胰岛素样生长因子-1（IGF-1），性激素结合球蛋白（SHBG）和凝血蛋白浓度进行了测定。治疗后Ki-67在4-OHT组中降低了3.4%，在口服T组中降低了5.1%（两组p < 0.03，组间p=0. 99）。4-OHT组和口服组的平均血浆4-OHT分别为0.2和1.1 ng/mL（p=0.0003），而4-OHT组和口服组的平均乳房脂肪组织4-OHT浓度分别为5.8 ng/g和5.4 ng/g（p=0.88）。口服T组血浆SHBG、因子VIII和von Willebrand因子显著升高，血浆IGF-1显著降低，但4-OHT组无此现象。两组的潮热发生率相似。应用于乳房皮肤的4-OHT凝胶的抗增殖作用与口服T相似，但对内分泌和凝血参数的影响降低。这些研究结果支持进一步评估局部透皮治疗DCIS和乳腺癌预防。
Local transdermal therapy to the breast may achieve effective target-organ drug delivery, while diminishing systemic effects. We conducted a randomized, double-blind, placebo-controlled phase II trial comparing transdermal 4-hydroxytamoxifen gel (4-OHT) to oral tamoxifen (oral-T) in women with ductal carcinoma in-situ (DCIS). 27pre and postmenopausal women were randomized to 4-OHT (4mg/day) or oral-T (20mg/day) for 6-10 weeks before surgery. Plasma, nipple aspirate fluid, and breast adipose tissue concentrations of tamoxifen and its major metabolites were determined by liquid chromatography-tandem mass spectrometry. The primary endpoint was Ki67 labeling in DCIS lesions, measured by immunohistochemistry. In plasma, insulin-like growth factor-1 (IGF-1), sex hormone-binding globulin (SHBG), and coagulation protein concentrations were determined. Post-therapy Ki-67 decreased by 3.4% in the 4-OHT and 5.1% in the oral-T group (p < 0.03 in both, between-group p=0. 99). Mean plasma 4-OHT was 0.2 and 1.1 ng/mL in 4-OHT and oral groups, respectively (p=0.0003), while mean breast adipose tissue concentrations of 4-OHT were 5.8 ng/g in the 4-OHT group and 5.4 ng/g in the oral group (p=0.88). There were significant increases in plasma SHBG, Factor VIII and von Willebrand factor and a significant decrease in plasma IGF-1 with oral-T, but not with 4-OHT. The incidence of hot flashes was similar in both groups. The anti-proliferative effect of 4-OHT gel applied to breast skin was similar to that of oral-T, but effects on endocrine and coagulation parameters were reduced. These findings support the further evaluation of local transdermal therapy for DCIS and breast cancer prevention.