A randomized trial of low-dose tamoxifen on breast cancer proliferation and blood estrogenic biomarkers
A randomized trial of low-dose tamoxifen on breast cancer proliferation and blood estrogenic biomarkers
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DOI：
10.1093/jnci/95.11.779
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发表时间：
2003-06-04
期刊：
影响因子：
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通讯作者：
Veronesi, U
中科院分区：
文献类型：
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作者：
Decensi, A;Robertson, C;Veronesi, U
背景：他莫昔芬可降低乳腺癌高风险妇女的乳腺癌风险，但可增加子宫内膜肿瘤和静脉血栓栓塞的风险，可能呈剂量依赖性。我们使用替代终点标志物（Ki-67表达）和与乳腺癌、心血管疾病和骨折风险相关的血液生物标志物，比较了他莫昔芬1mg /天、5mg /天与标准剂量20mg /天对乳腺癌增殖的影响。方法：我们随机分配120名雌激素受体（ER）阳性乳腺癌患者服用他莫昔芬，剂量分别为1、5或20 mg/天，持续4周。在治疗前（基线）和治疗后检测肿瘤增殖标志物Ki-67和乳腺癌生物标志物（胰岛素样生长因子- 1、性激素结合球蛋白）、心血管疾病（胆固醇、甘油三酯、超敏c反应蛋白、纤维蛋白原、抗凝血酶- iii）和骨折（I型胶原c端肽）风险的表达。将所有水平与两个非随机对照组（34名雌激素受体阴性乳腺癌妇女和29名雌激素受体阳性乳腺癌妇女）的水平进行比较。数据采用协方差分析。所有统计检验均为双侧检验。结果：Ki-67的表达在3个他莫昔芬组均有所降低，但各组间降低幅度差异无统计学意义（P = 0.81）。相对于基线，Ki-67表达在他莫昔芬组中位数下降了15.0%(95%可信区间= 0.0% ~ 24.1%)，而在非随机对照组中位数上升了12.8%（95%可信区间= 0.0% ~ 19.6%）。一些血液生物标志物显示了与他莫昔芬的剂量-反应关系，包括胰岛素样生长因子- 1的降低，性激素结合球蛋白的增加，低密度脂蛋白-胆固醇、超敏c反应蛋白、纤维蛋白原和抗凝血酶- iii水平的降低。结论：低剂量他莫昔芬对Ki-67表达的影响与标准剂量相当，尽管对血液生物标志物的影响是可变的。低剂量他莫昔芬的效果应在随机试验中进一步评估。
Background: Tamoxifen reduces the risk of breast cancer in women at high risk for the disease but increases the risk for endometrial tumors and venous thromboembolisms, possibly in a dose-dependent fashion. We compared the effects of tamoxifen at 1 mg/day and 5 mg/day with those of the standard dose of 20 mg/day on breast cancer proliferation using a surrogate endpoint marker (Ki-67 expression) and blood biomarkers associated with breast cancer, cardiovascular disease, and bone fracture risk. Methods: We randomly assigned 120 women with estrogen receptor (ER)-positive breast cancer to tamoxifen at 1, 5, or 20 mg/day for 4 weeks. Expression of the tumor proliferation marker Ki-67 and of biomarkers of breast cancer (insulin-like growth factor-I, sex hormone-binding globulin), cardiovascular disease (cholesterol, triglycerides, ultrasensitive C-reactive protein, fibrinogen, antithrombin-III), and bone fracture (type I collagen C-telopeptide) risk were determined before (baseline) and after treatment. All levels were compared with those in two nonrandomized control groups (34 women with ER-negative breast cancer and 29 additional women with ER-positive breast cancer). Data were analyzed by analysis of covariance. All statistical tests were two-sided. Results: Expression of Ki-67 decreased in all three tamoxifen groups, with no difference in the magnitude of reduction among groups (P = .81). Relative to baseline, Ki-67 expression decreased by a median of 15.0% (95% confidence interval = 0.0% to 24.1%) among the tamoxifen groups but increased by 12.8% (95% confidence interval = 0.0% to 19.6%) among the nonrandomized control groups. Several blood biomarkers showed dose-response relationships with tamoxifen, including decreased insulin-like growth factor-I, increased sex hormone-binding globulin, and decreased low-density lipoprotein-cholesterol, ultrasensitive C-reactive protein, fibrinogen, and antithrombin-III levels. Conclusions: The effects on Ki-67 expression of lower doses of tamoxifen were comparable to those achieved with the standard dose, although the effects on blood biomarkers were variable. The effects of lower doses of tamoxifen should be assessed further in randomized trials.