Tamoxifen biotransformation pathway pharmacogenomics

项目摘要/摘要 他莫昔芬一直是世界上预防和治疗雌激素受体的最重要的药物 (呃)阳性乳腺癌。他莫昔芬需要细胞色素P450(CYP)2D6的代谢激活才能完全 1-4我们小组是第一个将这些发现转化为临床实践的小组，并且 显示CYP2D6降低的女性的疾病复发风险显著更高 基于这些发现，FDA的一个咨询委员会最近建议使用他莫昔芬标签 改变以警告照顾者关于遗传和药物诱导的CYP2D6变异的重要性 Enzyme.7 我们的初步数据为以下至关重要且尚未回答的研究提供了明显的一步 问题：1)CYP2D6基因是否可用于选择特定的激素治疗方案 患有早期乳腺癌的绝经后妇女？2)哪种最常用的抗乳腺癌药物 已知对CYP2D6酶系统有微弱抑制的抑制剂可以安全地用于 他莫昔芬引起潮热的治疗？以及3)SULT1A1基因拷贝数差异如何， 编码负责活性他莫昔芬代谢物结合的主酶，影响 三苯氧胺治疗患者的临床结果。 通过与奥地利乳房和结直肠研究小组(ABCSG)建立的合作，我们已经 设计了ABCSG试验8个佐剂他莫昔芬和阿那曲唑试验的配对病例对照研究 演示了他莫昔芬先测序后阿那曲唑的优势(与他莫昔芬相比 8我们将对病例(有疾病复发的病例)和对照进行分型，以确定 单用他莫昔芬的两个治疗队列中乳腺癌复发与CYP2D6基因变异的关系 接受序贯他莫昔芬和阿那曲唑的患者。此外，我们会前瞻性地研究(在 与乳腺癌药物基因组学联盟合作)在多大程度上通常 服用抗抑郁药可降低艾多昔芬的血浆浓度，这是一个研究问题 目前还没有数据。最后，在完成的合作团体佐剂他莫昔芬试验的背景下 (NCCTG 89-30-52)，我们将评估SULT1A1基因变异的作用，SULT1A1是负责 活性他莫昔芬代谢物的偶联。项目叙事 我们的建议将确定他莫昔芬所涉及的酶的遗传可变性 生物转化与单独对他莫昔芬或对 他莫昔芬之后是人工智能。这一问题具有极其重要的意义，因为对于哪一个问题没有达成共识 绝经后乳腺癌应采用激素治疗方案。另外， 鉴于我们的数据表明，即使是CYP2D6酶活性的适度降低也会导致更高的风险 乳腺癌复发时，是否最常用的抗抑郁药物的测定 干扰他莫昔芬的代谢激活具有广泛的临床意义。

PROJECT SUMMARY/ABSTRACT Tamoxifen has been the most important drug world-wide for the prevention and treatment of estrogen receptor (ER) positive breast cancer. Tamoxifen requires metabolic activation by cytochrome P450 (CYP) 2D6 to fully elicit its pharmacological activity.1-4 Our group was the first to translate these findings into clinical practice, and demonstrated a significantly higher risk of disease recurrence for women with decreased CYP2D6 metabolism.5,6 Based on these findings, an FDA advisory committee recently recommended a tamoxifen label change to warn caregivers regarding the importance of both genetic and drug-induced variation in the CYP2D6 enzyme.7 Our preliminary data provide an obvious step to the following critically important and unanswered research questions: 1) Can CYP2D6 genotype be used to select a specific hormonal therapy regimen for postmenopausal woman with early stage breast cancer? 2) Which of the most commonly used anti- depressants with known weak inhibition of the CYP2D6 enzyme system are safe to administer for the treatment of tamoxifen-induced hot flashes?; and 3) How do gene copy number differences in SULT1A1, which encodes the primary enzyme responsible for conjugation of the active tamoxifen metabolites, affect the clinical outcomes of tamoxifen-treated patients. Through an established collaboration with the Austrian Breast and Colorectal Study Group (ABCSG), we have designed a matched case control study of the ABCSG trial 8 adjuvant tamoxifen and anastrozole trial, which demonstrated the superiority of sequencing of tamoxifen followed by anastrozole (compared to tamoxifen alone).8 We will genotype cases (those with disease recurrence) and controls to determine the effect of CYP2D6 genetic variation on breast cancer relapse in both treatment cohorts - those receiving tamoxifen alone and those receiving sequential tamoxifen then anastrozole. Additionally, we will prospectively study (in collaboration with the Consortium on Breast Cancer Pharmacogenomics) the extent to which the commonly administered anti-depressants lower the plasma concentrations of endoxifen, a research question for which there are no data at this time. Finally, in the context of a completed cooperative group adjuvant tamoxifen trial (NCCTG 89-30-52), we will evaluate the role of genetic variation in SULT1A1, the enzyme responsible for conjugation of the active tamoxifen metabolites. PROJECT NARRATIVE Our proposal will determine whether inherited variability in the enzymes involved in tamoxifen biotransformation are associated with a preferential response to tamoxifen alone or a sequencing regimen of tamoxifen followed by an AI. This question is of utmost relevance, as there is no consensus as to which hormonal therapy regimen should be utilized for the treatment of postmenopausal breast cancer. Additionally, given that our data suggest that even a modest reduction in CYP2D6 enzyme activity leads to higher risk of breast cancer relapse, the determination of whether the most commonly administered anti-depressants interfere with metabolic activation of tamoxifen has widespread clinical implications.