Project 4: Pharmacogenomics of Aromatase Inhibitors in Early Stage Postmenopausal Breast Cancer

项目4：芳香酶抑制剂在早期绝经后乳腺癌中的药物基因组学

• 批准号: 10017911
• 负责人: Liewei Wang
• 金额: $ 28.57万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-22 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017911
• 关键词: Address; Adherence; Adjuvant Therapy; Adverse event; Affect; Anabolism; Aromatase; Aromatase Inhibition; Aromatase Inhibitors; Biological Markers; Biology; Blood specimen; Breast; Chemoprevention; Clinic; Clinical; Clinical Management; Clinical Research; Clinical Trials; DNA; Data; Diagnosis; Disease; Drug Targeting; Estradiol; Estrogen Receptors; Estrogen receptor positive; Estrogens; Estrone; Event; Exemestane; Generations; Genes; Genetic; Genetic Markers; Genetic Variation; Genetic study; Genome; Genotype; Individual; Laboratory Study; Letrozole; Ligands; Matched Case-Control Study; Meta-Analysis; Multi-Institutional Clinical Trial; Outcome; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenomics; Phenotype; Play; Postmenopause; Prospective Studies; Publishing; Recurrence; Regulation; Resources; Role; Sampling; Series; Signal Transduction; Single Nucleotide Polymorphism; Tamoxifen; Testing; Treatment outcome; United States; Validation; Variant; Woman; adverse outcome; anastrozole; antitumor effect; arm; base; case control; experience; follow-up; functional genomics; genetic makeup; genetic variant; genome wide association study; genome-wide; hormone therapy; individual patient; interest; interpatient variability; malignant breast neoplasm; novel; personalized medicine; prospective; response; trial comparing; tumor

Project Summary Endocrine therapy plays a preeminent role in the management of the majority (about two thirds) of women with breast cancer whose tumors have the target, the estrogen receptor (ER). A recent meta-analysis showed that aromatase inhibitors (AIs) were superior to tamoxifen as adjuvant therapy in early-stage disease, but despite this superiority, about one-fifth of women had recurrence by 10 years. In addition to variability in outcomes, there is also a marked variability in tolerance, which can adversely impact adherence to treatment. The mechanism of action of AIs is inhibition of aromatase, thereby suppressing estrogen synthesis and reducing the ligand for the ER. The assumption is that all AIs produce sufficient estrogen suppression. However, our Preliminary Data showed marked variation in estradiol and estrone levels before and while on treatment with the AI anastrozole. However, it remains unknown whether the degree of estrogen suppression, or how to best quantify it, is related to degree of clinical benefit of these agents. We also have Preliminary Data from GWAS, using germline DNA from patients receiving AIs, showing that the variability in AI-related adverse events and outcomes is related to variation in host (germline) genetics. Furthermore, our preliminary findings with SNPs and genes identified to be associated with estrogen suppression by AIs and breast events (recurrences) provide a strong rational to test the hypothesis that genetic variation plays an important role in AI response, and this effect might be through the regulation of estrogen suppression, the mechanism of AI action. Of particular interest is that our functional studies of these genetic variants and genes also showed a SNP- and individual AI-dependent regulation of the expression of the aromatase gene. This novel finding has potentially important implications for precision AI treatment. Therefore, in this current proposal, we propose to take advantage of the extensive resources and Preliminary Data we have obtained. These include three major multi-center clinical trials involving all three third-generation AIs (anastrozole, exemestane, letrozole) for which we already have genome-wide genotyping available: 1) our own M3 study of anastrozole alone with estrogen levels pre and on anastrozole and anastrozole and anastrozole metabolite concentrations, 2) the MA.27 trial, comparing anastrozole and exemestane, from which we have published two GWAS relating to adverse events, and 3) the PreFace, a single-arm letrozole trial. MA.27 and PreFace have clinical follow-up data as well as biospecimens before and on AI treatment that would allow us to determine if the degree of estrogen suppression correlates with clinical AI treatment outcomes and, with genotyping data, the common or AI specific SNPs associated with these two phenotypes. We will then test the SNPs related to estrogen suppression in a prospective trial. Of crucial importance, we will also perform functional studies of those SNPs to elucidate mechanisms by which they might affect estrogen levels and AI response. These findings would have direct implications for the majority of women with breast cancer and would contribute to precision endocrine therapy with the AIs.

项目摘要 内分泌疗法在多数（约三分之二）的妇女的管理中起着重要作用 肿瘤具有靶标，雌激素受体（ER）的乳腺癌。最近的一项荟萃​​分析表明 芳香酶抑制剂（AIS）优于他莫昔芬作为早期疾病的辅助治疗 大约五分之一的妇女复发了10年。除了结果的可变性外， 容忍度上也有明显的差异，可能会对治疗的依从性产生不利影响。这 AIS的作用机理是抑制芳香酶，从而抑制雌激素合成并减少 ER的配体。假设所有AI都会产生足够的雌激素抑制。但是，我们的 初步数据显示，在治疗前后，雌二醇和雌二醇水平的变化明显变化 AI Anastrozole。但是，尚不清楚雌激素抑制程度还是如何最好 量化它与这些药物的临床益处有关。我们也有来自GWAS的初步数据， 使用接受AIS患者的生殖线DNA，表明与AI相关的不良事件的变异性和 结果与宿主（种系）遗传学的变化有关。此外，我们与SNP的初步发现 和基因与AIS和乳房事件（复发）确定与雌激素抑制有关 提供了强烈的理性来检验遗传变异在AI反应中起重要作用的假设， 这种影响可能是通过调节雌激素抑制的调节，即AI作用的机制。的 特别的兴趣是，我们对这些遗传变异和基因的功能研究也显示出SNP和SNP和 单个AI依赖性调节芳香酶基因的表达。这个小说的发现有可能 精度AI治疗的重要意义。因此，在当前的建议中，我们建议采取 我们获得的广泛资源和初步数据的优势。这些包括三个专业 多中心临床试验涉及所有三个第三代AIS（Anastrozole，Exemestane，letrozole）的临床试验 我们已经提供了全基因组的基因分型：1）单独使用雌激素的M3研究 水平前后的水平和阿拉斯特罗和阿纳斯特罗代谢产物浓度，2）MA.27试验， 比较Anastrozole和Exemestane，我们从中发表了两个与不良事件有关的GWA， 3）序言，一项单臂letrozole试验。 MA.27和序言具有临床随访数据以及 AI治疗前后的生物测量，这将使我们能够确定雌激素的程度是否 抑制与临床AI治疗结果以及基因分型数据相关，共同或AI 与这两种表型相关的特定SNP。然后，我们将测试与雌激素有关的SNP 在前瞻性试验中抑制。至关重要的是，我们还将对这些SNP进行功能研究 阐明它们可能影响雌激素水平和AI反应的机制。这些发现会 对大多数乳腺癌女性具有直接影响，并有助于精确 AIS内分泌疗法。