Tamoxifen biotransformation pathway pharmacogenomics

描述(申请人提供)：他莫昔芬一直是全球最重要的预防和治疗雌激素受体(ER)阳性乳腺癌的药物。他莫昔芬需要细胞色素P450(CYP)2D6的代谢激活才能充分激发其药理活性。1-4我们的小组第一个将这些发现转化为临床实践，并证明了CYP2D6代谢降低的女性的疾病复发风险显著更高。5，6基于这些发现，FDA的一个咨询委员会最近建议更改他莫昔芬的标签，以警告照顾者注意遗传和药物诱导的CYP2D6酶变异的重要性。7 我们的初步数据为以下关键的和尚未回答的研究问题提供了明显的步骤：1)是否可以使用CYP2D6基因来为患有早期乳腺癌的绝经后妇女选择一种特定的激素治疗方案？2)对于他莫昔芬引起的潮热的治疗，哪些最常用的抗抑郁药是安全的？(3)SULT1A1中的基因拷贝数差异如何影响他莫昔芬治疗患者的临床结果。 通过与奥地利乳腺和结直肠研究小组(ABCSG)的既定合作，我们设计了一项ABCSG试验8佐剂他莫昔芬和阿那曲唑试验的配对病例对照研究，该研究证明了先测序后服用他莫昔芬和阿那曲唑的优越性(与单独使用他莫昔芬相比)。8我们将对病例(有疾病复发的病例)和对照进行基因分型，以确定在两个治疗队列中--单用他莫昔芬的患者和序贯接受他莫昔芬再接受阿那曲唑的治疗队列中，CYP2D6基因变异对乳腺癌复发的影响。此外，我们将(与乳腺癌药物基因组学联盟合作)前瞻性地研究常用抗抑郁药降低艾多昔芬血浆浓度的程度，这是一个目前没有数据的研究问题。最后，在完成的合作团体佐剂他莫昔芬试验(NCCTG 89-30-52)的背景下，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结合的酶。 公共卫生相关性：我们的提案将确定他莫昔芬生物转化所涉及的酶的遗传可变性是否与对他莫昔芬单独的优先反应或他莫昔芬的测序方案随后的人工智能有关。这个问题非常重要，因为对于应该使用哪种激素治疗方案来治疗绝经后乳腺癌，还没有达成共识。此外，鉴于我们的数据表明，即使是轻微的CYP2D6酶活性降低也会导致乳腺癌复发的风险增加，因此确定最常用的抗抑郁药是否干扰他莫昔芬的代谢激活具有广泛的临床意义。

DESCRIPTION (provided by applicant): 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 antidepressants 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 antidepressants 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. PUBLIC HEALTH RELEVANCE: 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 antidepressants interfere with metabolic activation of tamoxifen has widespread clinical implications.