Tamoxifen, P450 and UGT Enzyme Genetic Variation, and Breast Cancer Recurrence/Mo

他莫昔芬、P450 和 UGT 酶遗传变异与乳腺癌复发/月

基本信息

批准号：
8734348
负责人：
KATHLEEN E MALONE
金额：
$ 8.54万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-16 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8734348
关键词：
21 year old 4-Hydroxy-Tamoxifen Address Adjuvant Therapy Affect Area CYP1B1 gene CYP2B6 gene CYP2C19 gene CYP2C9 gene CYP2D6 gene CYP3A4 gene CYP3A5 gene Case-Control Studies Cessation of life Classification Clinical Cytochrome P450 Diagnosis Disease Disputes Effectiveness Enzymes Estrogen receptor positive Evaluation Genes Genetic Variation Genotype Glucuronosyltransferase Goals Heterogeneity Inherited Joints Light Metabolic Pathway Metabolism Methods Patients Pharmaceutical Preparations Phase Phenotype Population Study Postmenopause Premenopause Prodrugs Recurrence Research Research Design Risk Sample Size Subgroup Tamoxifen Testing Therapeutic UGT1A8 UDP-glucuronosyltransferase Variant Woman adverse outcome bilirubin uridine-diphosphoglucuronosyl transferase 1A10 cancer recurrence cohort design experience follow-up genetic variant hormone therapy improved insight malignant breast neoplasm metropolitan mortality population based public health relevance research study response risk variant sound therapeutic effectiveness treatment response

项目摘要

DESCRIPTION (provided by applicant): Tamoxifen (TAM) is a standard endocrine therapy used in the treatment of estrogen receptor-positive (ER+) breast cancer. Despite its demonstrated efficacy, a substantial fraction of users will experience disease recurrence or mortality. The overall objective of this study is to address the impact of inherited genetic variation in drug metabolizing genes on the efficacy of TAM in treating breast cancer. TAM's therapeutic effectiveness has been attributed to the metabolites endoxifen and 4-hydroxytamoxifen; however, response to this therapy likely depends on the combined effects of multiple metabolites. The enzymes that most affect the conversion of TAM to its key metabolites are CYP2D6, CYP3A4, CYP3A5, but other important phase I and II enzymes include CYP2C9, CYP2C19, CYP2B6, CYP1B1, UGT2B7, UGT2B15, UGT1A4, UGT1A8, and UGT1A10. Variation within these genes could affect TAM's ability to be metabolized into its metabolites, thus impacting its efficacy. Among ER+ breast cancer cases treated with TAM, the primary aims of this study are to examine variation in the risk of breast cancer recurrence and death in relation to 1) genetic variation within the phase I enzymes CYP2D6, CYP3A4, CYP3A5, CYP2C9, CYP2C19, and CYP2B6, 2) genetic variation within the phase II enzymes CYP1B1, UGT2B7, UGT2B15, UGT1A4, UGT1A8, and UGT1A10, and 3) the combined variation within all genes in the TAM metabolic pathway. As secondary aims, we will examine the association between the risk of breast cancer recurrence and death and 1) the use of CYP2D6 inhibiting medications, 2) the joint effect of CYP2D6 genotype and use of CYP2D6 inhibiting medications, and 3) genetic variation within subgroups of pre- and post- menopausal women. These primary and secondary aims will be tested using cases accrued in three previous population-based case-control studies in the Seattle area. Our study population will consist of 983 women diagnosed with invasive ER+ breast cancer at ages 21-79 in the period 1990-1999, all of whom were treated with TAM. Unlike most previous research, this study will have excellent coverage of CYP2D6 allelic variants, allowing more accurate classification of metabolizer phenotypes, and will include other key genes in the TAM metabolic pathway. Further, it will be one of the first to consider the TAM metabolic pathway as a whole in relation to the risk of breast cancer recurrence and death. As previous findings have been inconsistent, possibly due to design constraints, the dispute as to whether CYP2D6 or other TAM metabolizing genes actually impact TAM efficacy remains unresolved. By improving on past limitations and incorporating other relevant genes, the results of the proposed study could shed new light on the hypothesized and biologically plausible association between variation in TAM metabolizing genes and the risk of breast cancer recurrence and death in TAM users. The absence of a means to identify in advance who will or will not benefit from TAM therapy is a significant clinica gap, and genetic variation within key metabolizing enzymes could potentially serve as an indicator of expected TAM response. 1

描述（由申请人提供）：他莫昔芬（TAM）是一种用于治疗雌激素受体阳性（ER+）乳腺癌的标准内分泌疗法。尽管具有疗效，但很大一部分用户会经历疾病复发或死亡率。这项研究的总体目的是解决遗传遗传变异对药物代谢基因对TAM治疗乳腺癌疗效的影响。 TAM的治疗有效性归因于代谢产物内昔芬和4-羟基氧莫昔芬。但是，对这种疗法的反应可能取决于多种代谢产物的综合作用。影响TAM转化为关键代谢产物的酶是CYP2D6，CYP3A4，CYP3A5，但其他重要的I和II期酶包括CYP2C9，CYP2C19，CYP2B6，CYP2B6，CYP2B6，CYP1B1，CYP1B1，UGT2B7，UGT2B15，UGT2B15，UGT21A4，UGT1A4，UGTT1A4，和UGTT1A8，和UGTT1A8，和UGTT1A8，和UGTT1A8，和UGTT1A8，和UGTTT1A8，和UGTTT1A8，和UGTTT1A8，和UGTTT1A8。这些基因内的变异可能会影响TAM代谢成其代谢产物的能力，从而影响其功效。在用TAM治疗的ER+乳腺癌病例中，这项研究的主要目的是检查乳腺癌复发和死亡的风险与1）相对于1）I阶段I酶CYP2D6，CYP3A4，CYP3A4，CYP3A5，CYP3A5，CYP2C9，CYP2C9，CYP2C19，CYP2C19，CYP2C19和CYP2B6，CYP2B6，2）II II的遗传2）的遗传变异。 UGT2B15，UGT1A4，UGT1A8和UGT1A10和3）在TAM代谢途径中所有基因内的合并变异。作为次要目的，我们将研究乳腺癌复发与死亡的风险和1）使用CYP2D6抑制药物的使用，2）CYP2D6基因型的联合作用与CYP2D6抑制药物的使用，以及3）3）遗传差异在前后妇女的遗传差异中。这些主要和次要目标将使用西雅图地区的三项基于人群的病例对照研究中所累积的病例进行测试。我们的研究人群将由1990 - 1999年期间21-79岁的983名妇女组成，这些妇女在21-79岁时被诊断出患有侵入性ER+乳腺癌，所有这些妇女都接受了TAM的治疗。与大多数先前的研究不同，这项研究将具有CYP2D6等位基因变体的出色覆盖，从而可以更准确地对代谢剂表型进行分类，并将在TAM代谢途径中包括其他关键基因。此外，它将是第一个考虑到与乳腺癌复发和死亡的风险有关的整体TAM代谢途径。由于以前的发现是不一致的，可能是由于设计限制，因此关于CYP2D6或其他TAM代谢基因的争议实际上会影响TAM疗效。通过改善过去的局限性并纳入了其他相关基因，拟议的研究的结果可以新阐明TAM代谢基因的变异与TAM使用者的乳腺癌复发和死亡的风险之间的假设和生物学上合理的关联。缺乏提前确定谁将从TAM治疗中受益的方法是一个显着的临床差异，而关键代谢酶内的遗传变异可能有可能作为预期TAM反应的指标。 1