New and integrated perspectives on modification of tamoxifen effectiveness

关于他莫昔芬有效性修改的新的综合视角

• 批准号: 8973797
• 负责人: Timothy L. Lash
• 金额: $ 9.89万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8973797
• 关键词: 4-Hydroxy-Tamoxifen; Adjuvant; Adjuvant Therapy; Adoption; Affect; Affinity; Binding; Biological Assay; Biological Markers; Breast Cancer Patient; Clinical; DNA Sequence Alteration; Data; Data Collection; Diagnosis; Drug Interactions; Effectiveness; Enzymes; Estradiol; Estrogen Receptor Status; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogens; Estrone; Evaluation; Frequencies; Genes; Genotype; Guidelines; Health; Hydroxysteroid Dehydrogenases; Influentials; MCF7 cell; Measures; Metabolic; Metabolic Activation; Metabolic Marker; Metabolism; Methods; Modeling; Modification; N-desmethyltamoxifen; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Population; Population Study; Premenopause; Preventive; Published Comment; Publishing; Recurrence; Research; Research Personnel; Resistance; Risk; Seminal; Side; Tamoxifen; Variant; Woman; cancer recurrence; epidemiology study; genetic variant; hormone therapy; innovation; malignant breast neoplasm; meetings; outcome forecast; personalized medicine; prevent; success; tumor; tumor growth

DESCRIPTION (provided by applicant): About 200,000 US women are diagnosed with invasive breast cancer each year. About one-third are pre-menopausal and two-thirds have tumors that express estrogen receptor alpha (ERα). These women usually receive tamoxifen therapy, which competes with estrogen for binding to the estrogen receptor, but does not stimulate tumor growth. Five-years of tamoxifen therapy reduces recurrence risk by almost half. Efforts to identify biomarkers of tamoxifen resistance-beyond the absence of ERα - have met little success. Because tamoxifen requires metabolic activation to optimize its preventive effect, markers of metabolic inhibition are ideal biomarker candidates. Studies to date have focused only on this aspect of the competition to occupy the estrogen receptor between tamoxifen (and its metabolites) and estrogen (and its compounds). However, metabolic inhibition is unlikely to strongly predict recurrence risk in all ERα+ patients. We propose an innovative perspective that incorporates both sides of the competition, as well as the estrogen receptor itself, in the only patient group (premenopausal women) for whom tamoxifen remains the first line endocrine therapy. No study has focused on pre-menopausal women, despite guidelines recommending only tamoxifen for pre- menopausal women, and despite reason to think the modification might be most important to them. Aim #1: Include only pre-menopausal breast cancer patients, collect data on their pharmaceutical inhibition of tamoxifen metabolism, genotype 66 genetic variants in 13 enzymes that affect the concentration of the most active tamoxifen metabolites, and evaluate the association between these variants and recurrence. ERα+ breast cancer patients whose tumor also expresses ERß may not need fully activated tamoxifen to prevent recurrence, whereas women with ERß-negative tumors probably require full metabolic capacity. Aim #2: Assay ERß expression, estimate the association between metabolic inhibition and recurrence in ERß strata, and evaluate interaction between metabolic inhibition and ERß status in the combined population. Women whose tumors do not make a lot of estrogen to compete with tamoxifen (17ß-hydroxysteroid dehydrogenase 1d2) may not need fully activated tamoxifen to prevent recurrence, whereas women whose tumors make a lot of estrogen to compete with tamoxifen probably require full metabolic capacity. Aim #3: Assay 17ßHSD1 and 17ßHSD2 expression, estimate the association between 17ßHSD1/2 ratio >1-, versus d1-and recurrence, and evaluate the interaction between metabolic inhibition and this ratio.

描述（由适用提供）：每年约有200,000名美国妇女被诊断出患有侵入性乳腺癌。大约三分之一是绝经前，三分之二的肿瘤表达雌激素受体α（ERα）。这些女性通常接受他莫昔芬治疗，该治疗与雌激素竞争与雌​​激素受体结合，但不会刺激肿瘤生长。他莫昔芬治疗的五年可将复发风险降低近一半。识别他莫昔芬抗性的生物标志物的努力 - 缺乏ERα-几乎没有成功。因为他莫昔芬需要代谢激活才能优化其预防作用，所以 代谢抑制的标记是理想的生物标志物候选者。迄今为止，研究仅集中在竞争的这一方面，以占据他莫昔芬（及其代谢物）和雌激素（及其化合物）之间的雌激素受体。但是，代谢抑制不可能强烈预测所有ERα+患者的复发风险。我们提出了一种创新的观点，其中包括竞争的两面以及雌激素受体本身，在唯一的患者组（绝经前妇女）中，他莫昔芬仍然是第一行内分泌疗法。没有研究专注于绝经前妇女，所需的准则仅建议他莫昔芬针对绝经前妇女，并且希望理由认为这种修改对她们可能是最重要的。 AIM＃1：仅包括绝经前乳腺癌患者，收集有关其药物抑制他莫昔芬代谢的数据，13个酶中的基因型66遗传变异，这些酶影响ERα+乳腺癌患者的肿瘤患者也可能不需要完全激活的tamoxifen来预防tamoxifen，而Ersifen的能力可能完全伴随着ER的能力。 AIM＃2：测定ERß表达，估计ERß地层中代谢抑制与复发之间的关联，并评估组合总体中代谢抑制与ERß状态之间的相互作用。肿瘤没有大量雌激素与他莫昔芬（17ß-羟基甾体脱氢酶1D2）竞争的妇女可能不需要完全激活的他莫昔芬来防止复发，而肿瘤的妇女则使大量雌激素与他莫昔芬竞争可能需要完全的代谢能力。 AIM＃3：测定17ßHSD1和17ßHSD2的表达，估计17ßHSD1/2比> 1-之间的关联，与D1及复发，并评估代谢抑制与该比率之间的相互作用。