New and integrated perspectives on modification of tamoxifen effectiveness

描述（由申请人提供）：每年约有20万美国女性被诊断为浸润性乳腺癌。大约三分之一的人处于绝经前，三分之二的人患有表达雌激素受体α （ER¿）的肿瘤。这些妇女通常接受他莫昔芬治疗，它与雌激素结合雌激素受体竞争，但不刺激肿瘤生长。5年的他莫昔芬治疗使复发风险降低了近一半。识别他莫昔芬耐药生物标志物的努力——除了缺乏ER¿之外——几乎没有取得成功。因为他莫昔芬需要代谢激活来优化其预防效果，

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.