Tamoxifen biotransformation pathway pharmacogenomics

他莫昔芬生物转化途径药物基因组学

• 批准号: 8523013
• 负责人: MATTHEW Philip GOETZ
• 金额: $ 22.59万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-11 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8523013
• 关键词: Adjuvant; Adjuvant Study; Advisory Committees; Affect; Algorithms; Alleles; Antidepressive Agents; Aromatase Inhibitors; Breast; CYP2D6 gene; Cancer Relapse; Caregivers; Case-Control Studies; Citalopram; Clinical; Clinical Trials; Collaborations; Colorectal; Consensus; Cytochrome P-450 CYP2D6; DNA; Data; Disease; Disease-Free Survival; Enzymes; Escitalopram; Estrogen receptor positive; Formalin; Gene Dosage; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Guidelines; Hot flushes; Inherited; Label; Laboratories; Matched Case-Control Study; Metabolic Activation; Metabolic Biotransformation; Metabolism; North Central Cancer Treatment Group; Outcome; Paraffin Embedding; Paroxetine; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacogenomics; Plasma; Postmenopause; Prevention; Randomized; Recurrence; Regimen; Relapse; Research; Role; Sertraline; Staging; Stratification; System; Tamoxifen; Time; Tissues; Translating; Translations; Variant; Woman; anastrozole; base; case control; clinical practice; cohort; design; enzyme activity; gabapentin; high risk; hormone therapy; malignant breast neoplasm; prospective; response; tumor; venlafaxine

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.

项目摘要/摘要 他莫昔芬一直是全球预防和治疗雌激素受体的最重要药物 （ER）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 引起其药理活动。1-4我们的小组是第一个将这些发现转化为临床实践的人，并 证明CYP2D6降低的女性疾病复发的风险明显更高 FDA咨询委员会最近推荐了他莫昔芬标签，代谢。5,6。 更改以警告看护者，了解CYP2D6遗传和药物诱导的变异的重要性 酶7 我们的初步数据为以下至关重要且未解决的研究提供了明显的步骤 问题：1）CYP2D6基因型可以用于选择特定的激素治疗方案 绝经后妇女患有早期乳腺癌？ 2）哪个最常用的抗 CYP2D6酶系统已知弱抑制的抑制剂可以安全地管理 他莫昔芬引起的热闪光的处理？ 3）基因拷贝数如何在sult1a1中的差异， 它编码负责主动性他莫昔芬代谢产物偶联的主要酶会影响 他莫昔芬治疗的患者的临床结局。 通过与奥地利乳房和大肠研究小组（ABCSG）建立的合作，我们有 设计了ABCSG试验的匹配案例对照研究8辅助性他莫昔芬和Anastrozole试验，该试验是 证明了他莫昔芬测序的优越性，然后是阿拉斯特罗（与他莫昔芬相比 8）.8我们将基因型病例（患有疾病复发的病例）和对照来确定 两种治疗队列中乳腺癌复发的CYP2D6遗传变异 - 单独接受他莫昔芬的遗传变异 以及那些接受顺序他莫昔芬然后阿拉斯特罗的人。此外，我们将前瞻性研究（在 与乳腺癌药物基因组学联盟合作）通常 施用的抗抑制剂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，在完整的合作团体辅助他莫昔芬试验的背景下 （NCCTG 89-30-52），我们将评估遗传变异在Sult1a1中的作用，Sult1a1是负责的酶 活性他莫昔芬代谢物的结合。项目叙述 我们的建议将确定他莫昔芬涉及的酶的遗传变异性是否存在 生物转化与单独对他莫昔芬的优先响应或单独的优先反应有关 他莫昔芬紧随其后的是AI。这个问题是最重要的，因为尚无共识 应将激素治疗方案用于治疗绝经后乳腺癌。此外， 鉴于我们的数据表明，即使CYP2D6酶活性的适度降低也会导致更高的风险 乳腺癌复发，确定最常见的抗抑郁药是否 干扰他莫昔芬的代谢激活具有广泛的临床意义。

项目成果

CYP2D6 metabolism and patient outcome in the Austrian Breast and Colorectal Cancer Study Group trial (ABCSG) 8.

• DOI: 10.1158/1078-0432.ccr-12-2153
• 发表时间: 2013-01-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Goetz MP;Suman VJ;Hoskin TL;Gnant M;Filipits M;Safgren SL;Kuffel M;Jakesz R;Rudas M;Greil R;Dietze O;Lang A;Offner F;Reynolds CA;Weinshilboum RM;Ames MM;Ingle JN
• 通讯作者: Ingle JN

Reply to A.-S. Dieudonné et al and J.M. Rae et al.

回复 A.-S。

• DOI: 10.1200/jco.2013.49.6661
• 发表时间: 2013
• 期刊: Journal of clinical oncology : official journal of the American Society of Clinical Oncology
• 作者: Brauch,Hiltrud;Schroth,Werner;Goetz,MatthewP;Mürdter,ThomasE;Winter,Stefan;Ingle,JamesN;Schwab,Matthias;Eichelbaum,Michel
• 通讯作者: Eichelbaum,Michel