Genetic Predictors of Anti-Estrogen Clinical Activity in Breast Cancer Patients

说明(申请人提供)：雌激素在乳腺癌的发生和发展中起着重要的作用。包括选择性雌激素受体调节剂(SERM)的他莫昔芬在内的抗雌激素治疗，以及包括阿那曲唑、来曲唑和依西美坦在内的第三代芳香酶抑制剂(AI)，显然在降低乳腺癌死亡率方面发挥了重要作用，特别是在辅助环境中使用时。他莫昔芬也被证明可以预防乳腺癌。在所有新诊断的乳腺癌中，大约60%-70%是雌激素受体(ER)阳性的，但其中只有60%对内分泌治疗有反应。目前还不可能确定哪些ER阳性癌症患者将从内分泌治疗中受益，也不可能确定特定的治疗方法(他莫昔芬与AI)是否对个别患者最有效。我们假设，解释药物处置、药物靶点和药物作用的基因中的遗传性生殖线单核苷酸多态(SNPs)显著地导致患者之间从抗雌激素治疗中获益的差异。这项建议的目标是确定涉及药物和类固醇代谢酶以及雌激素信号通路的基因变异，并确定它们是否可以预测两种最广泛使用的抗雌激素药物他莫昔芬和阿那曲唑的益处和/或副作用。为了实现这一目标，我们将对参加了一项开创性的前瞻性随机临床试验的患者进行全面的基因分析，该试验确立了人工智能在乳腺癌治疗中的作用：Arimidex，Tamoxifen，单独或联合(ATAC)试验。ATAC试验比较了预先服用他莫昔芬和阿那曲唑5年的疗效和毒性。我们假设，遗传学方法可以确定哪种形式的内分泌治疗(他莫昔芬与阿那曲唑)比另一种更好。

DESCRIPTION (provided by applicant): Estrogenic hormones play a significant role in breast cancer development and progression. Anti-estrogenic therapies including the Selective Estrogen Receptor Modulator (SERM) tamoxifen, and the 3rd generation aromatase inhibitors (AI) including anastrozole, letrozole, and exemestane have clearly played a substantial role in decreasing breast cancer mortality rates, especially when used in the adjuvant setting. Tamoxifen has also been shown to prevent breast cancer. Approximately 60-70% of all newly diagnosed breast cancers are estrogen receptor (ER)-positive, but only 60% of these will respond to endocrine therapy. It is not currently possible to identify which patients with ER-positive cancers will benefit from endocrine therapy nor is it possible to determine whether a particular treatment approach (tamoxifen vs AI) will work best for an individual patient. We hypothesize inherited germline Single Nucleotide Polymorphisms (SNPs) in genes that account for drug disposition, drug targets, and drug's actions significantly contribute to the interpatient differences in benefit from anti-estrogen therapy. The goal of this proposal is to identify variants in genes involved in drug and steroid metabolizing enzymes, and the estrogen signaling pathway and determine whether they can predict benefit and/or side effects of two of the most widely used anti-estogens tamoxifen and anastrozole. To achieve this goal, we will conduct a comprehensive genotype analysis of patients who participated to one the seminal prospective randomized clinical trials that established the role AIs for the treatment of breast cancer: The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial. The ATAC trial compared the efficacy and toxicity of upfront tamoxifen versus anastrozole for 5 years. We hypothesize that a genetic approach can identify specific subsets of patients form whom one form of endocrine therapy (tamoxifen vs anastrozole) is better than the other.