LOW DOSE TAMOXIFEN AND 4HPR IN EARLY BREAST CANCER

本项目的具体目标是寻求一种相互作用 低剂量他莫昔芬和合成类维生素A 4-HPR之间的关系， 绝经前妇女中的替代终点生物标志物（SEB） 或微创乳腺癌。这将通过一个 采用2x2析因设计的双盲安慰剂对照试验， 妇女将随机接受安慰剂或他莫昔芬，10 mg/天，或4- HPR，200 mg/天，或两种药物治疗两年。因为这两种药物都抑制 第二原发性乳腺癌发病率以及循环IGF-1水平 在绝经前妇女中，因为有大量证据表明， 这种生长因子在肿瘤的病理生理学中起着关键作用， 在乳腺癌中，主要的结果测量是血浆IGF-1的变化， 经过两年的干预。另一个重要的终点是 在通过定量评估的乳腺摄影密度百分比中， 测量.次要终点是上皮异型增生的变化 和Ki 67，通过超声引导细针抽吸获得。 对侧乳腺增加子宫内膜厚度的变化， 经阴道超声及导管法检测宫颈癌细胞增殖 吸引刮匙。最后，评估组合的毒性 治疗方案是试验的一个重要目的。共300名妇女 应在两年内累积，以检测10 ng/ml的相互作用， 血浆IGF-1和4%的乳腺摄影密度后，两年内 干预（功效= 90%，双侧5%显著性）。是合理 假设对血浆IGF-1和IGF-2的协同相互作用， 乳房X光摄影密度可能会导致实质性的预防效果， 乳腺癌SEB的有效性将通过以下方式进一步评估： 它们的基线相互关系以及 四个治疗组中这些SEB的变化。因此，这项研究可以 提供关于联合治疗活性的基本信息 乳腺癌发生和子宫内膜增生，这可能导致 实施安全和成功的第111阶段干预措施 目的是在更广泛的人群中降低乳腺癌的发病率， 风险女人

The specific aim of the present project is the search for an interaction between low-dose tamoxifen and the synthetic retinoid 4-HPR on a set of surrogate endpoint biomarkers (SEBs) in premenopausal women with in situ or minimally invasive breast cancer. This will be accomplished through a double-blind placebo controlled trial with a 2x2 factorial design, whereby women will be randomized to either placebo, or tamoxifen, 10 mg/day, or 4- HPR, 200 mg/day, or both agents for two years. Since both agents inhibit second primary breast cancer incidence as well as circulating IGF-l levels in premenopausal women and because there is substantial evidence for the critical role played by this growth factor in the pathophysiology of breast cancer, the main outcome measure is the change in plasma IGF-l after two years of intervention. Another important endpoint is he change in the percentage of mammographic density as assessed by quantitative measurement. Secondary endpoints are the change in epithelial dysplasia and Ki67 obtained by ultrasound-guided fine needle aspirate of the contralateral breast add the change in endometrial thickness and proliferation as valuated by transvaginal ultrasonography and pipelle aspiration curette. Finally, assessment of toxicity of the combination regimen is an important objective of the trial. A total of 300 women should be accrued in two years to detect an interaction of 10 ng/ml in plasma IGF-l and of 4% in mammographic density after two years of intervention (power = 90%, two-tailed 5% significance). It is reasonable to assume that a synergistic interaction upon plasma IGF-l and mammographic density could result in a substantial preventive effect on breast Carcinogenesis. The validity of SEBs will be further assessed by their baseline inter-relationships and also the correlations in the changes in these SEBs within the four treatment groups. The study may thus provide essential information on the activity of the combined treatment upon breast carcinogenesis and endometrial proliferation which may lead to the implementation of a safe and successful phase 111 intervention rial aimed at reducing breast cancer incidence in a broader population of at- risk women.