New and integrated perspectives on modification of tamoxifen effectiveness

描述（由申请人提供）：每年约有20万美国妇女被诊断患有浸润性乳腺癌。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（ER α）。这些妇女通常接受他莫昔芬治疗，它与雌激素竞争结合雌激素受体，但不刺激肿瘤生长。五年的他莫昔芬治疗可将复发风险降低近一半。除了缺乏ER α外，鉴定他莫昔芬耐药生物标志物的努力几乎没有成功。因为他莫昔芬需要代谢活化来优化其预防效果， 代谢抑制的标志物是理想的生物标志物候选物。迄今为止的研究仅集中在他莫昔芬（及其代谢物）和雌激素（及其化合物）之间竞争占据雌激素受体的这一方面。然而，代谢抑制不太可能强烈预测所有ER α +患者的复发风险。我们提出了一个创新的观点，包括双方的竞争，以及雌激素受体本身，在唯一的患者组（绝经前妇女），他莫昔芬仍然是一线内分泌治疗。 尽管指南建议绝经前妇女只使用他莫昔芬，尽管有理由认为这种改变对她们来说可能是最重要的，但没有研究关注绝经前妇女。 目标一：仅纳入绝经前乳腺癌患者，收集他们对他莫昔芬代谢的药物抑制数据，对影响最活跃的他莫昔芬代谢物浓度的13种酶中的66种遗传变异进行基因分型，并评估这些变异与复发之间的相关性。 ER α +乳腺癌患者的肿瘤也表达ER β，可能不需要完全活化的他莫昔芬来预防复发，而ER β阴性肿瘤的女性可能需要完全的代谢能力。 目标二：分析ER β表达，估计ER β分层中代谢抑制与复发之间的关联，并评估合并人群中代谢抑制与ER β状态之间的相互作用。 肿瘤不产生大量雌激素与他莫昔芬（17 β-羟基类固醇脱氢酶1d2）竞争的女性可能不需要完全激活他莫昔芬来防止复发，而肿瘤产生大量雌激素与他莫昔芬竞争的女性可能需要完全的代谢能力。 目标3：测定17 β HSD1和17 β HSD2表达，估计17 β HSD1/2比值> 1-与d1-和复发之间的关联，并评估代谢抑制与该比值之间的相互作用。

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.