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

描述（由申请人提供）：雌激素激素在乳腺癌的发生和发展中起重要作用。包括选择性雌激素受体调节剂（SERM）他莫昔芬在内的抗雌激素疗法，以及包括阿那曲唑、来曲唑和依西美坦在内的第三代芳香化酶抑制剂（AI），在降低乳腺癌死亡率方面明显发挥了重要作用，尤其是在辅助治疗中使用时。它莫西芬也被证明可以预防乳腺癌。大约60-70%的新诊断乳腺癌是雌激素受体（ER）阳性，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vs人工智能）是否对个体患者最有效。我们假设遗传的种系单核苷酸多态性（snp）基因可以解释药物处置、药物靶点和药物作用，这在很大程度上导致了患者从抗雌激素治疗中获益的差异。本研究的目的是确定与药物和类固醇代谢酶相关的基因变异，以及雌激素信号通路，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，我们将对参加一项开创性前瞻性随机临床试验的患者进行全面的基因型分析，该试验确定了ai在乳腺癌治疗中的作用：Arimidex，他莫昔芬，单独或联合（ATAC）试验。ATAC试验比较了他莫昔芬和阿那曲唑5年的疗效和毒性。我们假设遗传方法可以识别特定的患者亚群，其中一种形式的内分泌治疗（他莫昔芬vs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.