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

基本信息

批准号：
8642152
负责人：
Timothy L. Lash
金额：
$ 51.41万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8642152
关键词：
4-Hydroxy-Tamoxifen Adjuvant Adjuvant Therapy Affect Affinity Binding Biological Assay Biological Markers Cancer Patient Clinical Data Data Collection Diagnosis Drug Interactions Effectiveness Enzymes Estradiol Estrogen Receptor Status Estrogen Receptor alpha Estrogen Receptors Estrogens Estrone Evaluation Frequencies Gene Mutation Genes Genotype Guidelines Hydroxysteroid Dehydrogenases Influentials MCF7 cell Measures Medicine 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 prevent public health relevance success tumor tumor growth

项目摘要

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 (ER¿). 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 ER¿-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 ER¿+ 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. ER¿+ breast cancer patients whose tumor also expresses ER¿ may not need fully activated tamoxifen to prevent recurrence, whereas women with ER¿-negative tumors probably require full metabolic capacity. Aim #2: Assay ER¿ expression, estimate the association between metabolic inhibition and recurrence in ER¿ strata, and evaluate interaction between metabolic inhibition and ER¿ status in the combined population. Women whose tumors do not make a lot of estrogen to compete with tamoxifen (17¿-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 17¿HSD1 and 17¿HSD2 expression, estimate the association between 17¿HSD1/2 ratio >1-, versus d1-and recurrence, and evaluate the interaction between metabolic inhibition and this ratio.

描述（由申请人提供）：每年约有 200,000 名美国女性被诊断患有浸润性乳腺癌，其中约三分之一处于绝经前，三分之二患有表达雌激素受体 α (ER¿) 的肿瘤。这些女性通常接受他莫昔芬治疗。与雌激素竞争与雌激素受体的结合，但不会刺激肿瘤生长。五年的他莫昔芬治疗可将复发风险降低近一半。他莫昔芬耐药性——超越缺乏ER¿ - 收效甚微，因为他莫昔芬需要代谢激活才能优化其预防效果，迄今为止，研究仅关注他莫昔芬（及其代谢物）和雌激素（及其化合物）之间争夺雌激素受体的这一方面，但代谢抑制不太可能预测复发。所有急诊室的风险¿ + 患者。我们提出了一种创新的观点，将竞争双方以及雌激素受体本身纳入其中，在唯一的患者群体（绝经前女性）中，他莫昔芬仍然是一线内分泌治疗。目标#1：仅包括绝经前乳腺癌患者，收集数据，尽管指南仅建议绝经前女性使用他莫昔芬，并且有理由认为修改可能对她们最重要。研究人员对他莫昔芬代谢的药物抑制作用进行了研究，对影响最活跃他莫昔芬代谢物浓度的 13 种酶的 66 种遗传变异进行了基因分型，并评估了这些变异与 ER 复发之间的关联。 + 肿瘤也表达 ER 的乳腺癌患者¿可能不需要完全激活的他莫昔芬来预防复发，而患有 ER 的女性-阴性肿瘤可能需要完整的代谢能力。目标#2：检测 ER¿表达，估计代谢抑制与 ER 复发之间的关联地层，并评估代谢抑制和 ER¿ 之间的相互作用肿瘤不会产生大量雌激素来与他莫昔芬（17¿-羟基类固醇脱氢酶 1d2）竞争的女性可能不需要完全激活的他莫昔芬来预防复发，而肿瘤会产生大量雌激素来与他莫昔芬竞争。他莫昔芬可能需要充分的代谢能力。目标#3：检测 17¿ HSD1 和 17¿ HSD2 表达，估计 17¿ HSD1/2 比率 >1-，与 d1- 和复发相比，并评估代谢抑制与该比率之间的相互作用。