Tamoxifen biotransformation pathway pharmacogenomics

他莫昔芬生物转化途径药物基因组学

基本信息

批准号：
7656628
负责人：
MATTHEW Philip GOETZ
金额：
$ 50.89万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-11 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7656628
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 P450 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 Relapse Research Role Sertraline Staging Stratification System Tamoxifen Time Tissues Translating Translations Treatment Protocols Variant Woman anastrozole base case control clinical practice cohort design enzyme activity follow-up gabapentin high risk hormone therapy malignant breast neoplasm prospective public health relevance response tumor venlafaxine

项目摘要

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.

描述（由申请人提供）：他莫昔芬一直是全球预防和治疗雌激素受体（ER）阳性乳腺癌的最重要药物。他莫昔芬需要细胞色素p450（CYP）2d6的代谢激活，以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小组，疾病复发的风险明显更高，表明妇女对CYP2D6代谢的妇女均基于这些委员会的建议下降。5AS委员会的建议，FDA委员会的建议，FDA委员会的推荐，ap fda comment a fda aptory，fda complion the and fda complity aiffer complity a companding aif fif fif fda complity aif to aif fda complity aif inf fda，护理人员关于CYP2D6酶中遗传和药物诱导差异的重要性。7 我们的初步数据为以下至关重要且未解决的研究问题提供了一个明显的步骤：1）CYP2D6基因型是否可以用于选择针对早期乳腺癌的绝经后妇女的特定荷尔蒙治疗方案？ 2）哪种最常用的抗抑郁药对CYP2D6酶系统的已知弱抑制作用可以安全地治疗他莫昔芬诱导的热闪光？ 3）SULT1A1中的基因拷贝数差异如何编码负责主动他莫昔芬代谢物的主要酶，影响了他莫昔芬治疗的患者的临床结果。通过与奥地利乳房和结直肠研究小组（ABCSG）的既定合作，我们设计了一项匹配的案例对照研究，对ABCSG试验8 8辅助性他莫昔芬和Anastrozole试验，该试验的测序表现出了他莫昔芬的测序优势，证明了他莫昔芬的优越性，与抗tamoxifen相比（与tamoxifen相比）。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患者以及接受连续的他莫昔芬然后阿拉斯特罗的人。此外，我们还将前瞻性研究（与乳腺癌药物基因组学联盟合作），普遍施用的抗抑郁药降低了内昔芬的血浆浓度的程度，Entoxifen的血浆浓度是此时目前尚无数据的研究问题。最后，在完整的合作组辅助性他莫昔芬试验（NCCTG 89-30-52）的背景下，我们将评估遗传变异在Sult1a1中的作用，该酶是负责主动他莫昔芬代谢物的结合的酶。公共卫生相关性：我们的提案将确定他莫昔芬生物转化涉及的酶的遗传变异性是否与单独对他莫昔芬的优先反应或他莫昔芬的测序方案相关。这个问题至关重要，因为对于哪种激素治疗方案应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乳腺癌复发的风险更高，因此确定最常见的抗抑郁药是否干扰他莫昔芬的代谢激活是否广泛临床影响。