New and integrated perspectives on modification of tamoxifen effectiveness

描述(申请人提供)：每年约有20万名美国女性被诊断为浸润性乳腺癌。大约三分之一的人是绝经前的，三分之二的人有表达雌激素受体α(ERα)的肿瘤。这些女性通常接受他莫昔芬治疗，这种疗法与雌激素竞争结合雌激素受体，但不会刺激肿瘤生长。他莫昔芬治疗五年可将复发风险降低近一半。除了缺乏ERα外，识别他莫昔芬耐药性生物标记物的努力收效甚微。因为他莫昔芬需要代谢激活来优化其预防效果， 代谢抑制标志物是理想的候选生物标志物。到目前为止，研究只集中在他莫昔芬(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。然而，代谢抑制不太可能强烈预测所有ERα+患者的复发风险。我们提出了一个创新的观点，包括竞争双方以及雌激素受体本身，在唯一的患者组(绝经前妇女)中，他莫昔芬仍然是内分泌治疗的一线药物。没有研究关注绝经前的女性，尽管指南只建议绝经前的女性使用他莫昔芬，尽管有理由认为这种修改可能对她们最重要。目的#1：仅包括绝经前乳腺癌患者，收集他们药物抑制他莫昔芬代谢的数据，13种酶的66个基因变异影响最活跃的他莫昔芬代谢产物的浓度，并评估这些变异与复发的关系。ERα+乳腺癌患者的肿瘤也表达ER？可能不需要完全激活的他莫昔芬来预防复发，而ER？阴性肿瘤的女性可能需要完全的代谢能力。目的#2：检测ER？的表达，评估代谢抑制与ER？层复发之间的关系，以及在联合人群中代谢抑制与ER？状态之间的交互作用。那些肿瘤不产生大量雌激素来与他莫昔芬竞争的女性可能不需要完全激活的他莫昔芬来防止复发，而那些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。目的#3：检测17？HSD1和17？HSD2的表达，评估17？HSD1/2比值和d1-与复发的关系，并评价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.