Tamoxifen biotransformation pathway pharmacogenomics

项目总结/摘要 他莫昔芬是目前世界上最重要的雌激素受体拮抗剂 (ER)乳腺癌阳性。他莫昔芬需要通过细胞色素P450（CYP）2D 6代谢活化， 引出其药理活性。1 -4我们的小组是第一个将这些发现转化为临床实践的小组，并且 表明CYP 2D 6降低的女性疾病复发的风险显著更高 基于这些发现，FDA咨询委员会最近推荐了他莫昔芬标签。 变更以警告护理人员CYP 2D 6中遗传和药物诱导变异的重要性 酶7 我们的初步数据提供了一个明显的步骤，以下列至关重要的和未回答的研究 问题：1）CYP 2D 6基因型是否可以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)最常用的抗- 已知对CYP 2D 6酶系统具有弱抑制作用的抑郁药， 治疗他莫昔芬引起的潮热？以及3）SULT 1A 1中的基因拷贝数差异如何， 其编码负责活性他莫昔芬代谢物结合的主要酶，影响 他莫昔芬治疗患者的临床结局。 通过与奥地利乳腺和结直肠研究组（ABCSG）的合作，我们 设计了一项ABCSG试验8辅助他莫昔芬和阿那曲唑试验的匹配病例对照研究， 证实了他莫昔芬测序后阿那曲唑测序的优越性（与他莫昔芬相比 我们将对病例（疾病复发者）和对照进行基因分型，以确定 两个治疗队列中CYP 2D 6遗传变异对乳腺癌复发的影响-仅接受他莫昔芬治疗的患者 以及那些接受他莫昔芬然后阿那曲唑的患者。此外，我们将前瞻性地研究（在 与乳腺癌药物基因组学联盟合作）， 给予抗抑郁药降低了内昔芬的血浆浓度，这是一个研究问题， 目前没有数据。最后，在已完成的合作组辅助他莫昔芬试验的背景下， （NCCTG 89-30-52），我们将评估SULT 1A 1中遗传变异的作用，SULT 1A 1是负责 活性他莫昔芬代谢物的缀合。项目叙述 我们的建议将确定是否遗传变异的酶参与他莫昔芬 生物转化与对单独的他莫昔芬的优先反应或对他莫昔芬的测序方案相关。 他莫昔芬和人工智能这一问题至关重要，因为在哪一个问题上没有共识。 激素治疗方案应用于治疗绝经后乳腺癌。此外，本发明还 考虑到我们的数据表明，即使是CYP 2D 6酶活性的适度降低也会导致更高的风险， 乳腺癌复发时，确定是否最常服用抗抑郁药 干扰他莫昔芬代谢活化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.