Combination Chemoprevention: Prevention of Both ER-Positive & ER-Negative BC

使用药物治疗（化学预防）预防乳腺癌现在是可能的。临床试验 证明了用抗雌激素药物治疗乳腺癌高危的正常妇女， （选择性雌激素受体调节剂，或SERM）可以大大降低他们的风险，发展乳腺癌 癌然而，SERM通常不被高危女性使用，因为它们不是100%有效的。 并且因为抗雌激素的长期治疗具有显著的副作用。此外，虽然长期 抗雌激素降低ER阳性乳腺癌的风险，但不能降低ER阴性乳腺癌的风险。 因此，需要更有效和毒性更小的策略来预防所有类型的乳腺癌。我们有 先前显示RXR选择性类维生素A（“rexinoids”）防止ER阴性乳腺癌的发展， 在小鼠临床前模型中的癌症，并且SERM和rexinoids的组合特别是 有效我们还进行了临床试验，使用SERM或rexinoids（作为单一药物）治疗高风险 并证明这些药物是可以容忍的。在这里，我们将测试假设， ER阳性和ER阴性乳腺癌可以通过联合不同机制的药物来预防 通过联合这些药物，我们将诱导癌前乳腺组织的细胞凋亡， 短期使用联合预防药物将导致有效的预防和减少副作用。（一） 我们将调查是否与SERM他莫昔芬和rexinoid贝沙罗汀慢性治疗完全 在p53-null小鼠模型中预防乳腺癌（其中ER阳性和ER阴性乳腺癌均 癌症发展），并确定这种联合治疗是否诱导癌前乳腺癌细胞凋亡 细胞(2)我们将研究短期使用他莫昔芬和贝沙罗汀治疗是否有效 预防乳腺癌的发展，我们将研究这种短期的机制， 治疗可以提供持久的保护。(3)我们将在绝经前进行II期临床试验， 使用他莫昔芬加贝沙罗汀联合治疗乳腺癌风险增加的女性， 在高危妇女中短期治疗是否会诱导细胞凋亡或抑制乳腺癌细胞的增殖， 上皮细胞这些研究将为测试这种抗雌激素和抗雌激素的组合奠定基础。 rexinoid在未来的III期乳腺癌预防试验中用于有乳腺癌风险的女性。

Prevention of breast cancer using medical therapy (chemoprevention) is now possible. Clinical trials have demonstrated that treatment of normal women at high risk of breast cancer with anti-estrogen drugs (selective estrogen receptor modulators, or SERMs) can substantially reduce their risk of developing breast cancer. However, SERMs are frequently not used by high risk women because they are not 100% effective and because chronic therapy with anti-estrogens has significant side effects. In addition, while long-term anti-estrogens reduce the risk of ER-positive breast cancer, they do not reduce ER-negative breast cancer. Thus, more effective and less toxic strategies to prevent all types of breast cancer are needed. We have previously shown that RXR-selective retinoids ("rexinoids") prevent the development of ER-negative breast cancer in preclinical models in mice, and that the combination of SERMs and rexinoids is particularly effective. We have also conducted clinical trials using SERMs or rexinoids (as single agents) in high risk women and have demonstrated that these agents are tolerable. Here we will test the hypotheses that both ER-positive and ER-negative breast cancer can be prevented by combining drugs with different mechanisms of action, that by combining these drugs we will induce apoptosis in premalignant mammary tissue, and that short-term use of combined preventive agents will result in effective prevention with reduced side effects. (1) We will investigate whether chronic therapy with the SERM tamoxifen and the rexinoid bexarotene will totally prevent breast cancer in the p53-null mouse model (in which both ER-positive and ER-negative breast cancers develop) and determine whether this combination therapy induces apoptosis in precancerous breast cells. (2) We will investigate whether short-term treatment with tamoxifen and bexarotene will effectively prevent the development of breast cancer, and we will investigate the mechanism by which this short-term treatment can provide long-lasting protection. (3) We will conduct a Phase II clinical trial in premenopausal women at increased risk of breast cancer using the combination of tamoxifen plus bexarotene to determine whether short-term treatment in high risk women will induce apoptosis or suppress proliferation of mammary epithelial cells. These studies will lay the foundation for testing this combination of an anti-estrogen and a rexinoid in women at risk of breast cancer in future Phase III breast cancer prevention trials.