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。尽管它已被证明有效，但很大一部分使用者会经历疾病复发或死亡。本研究的总体目标是解决药物代谢基因的遗传变异对 TAM 治疗乳腺癌疗效的影响。 TAM 的治疗效果归因于代谢物艾多昔芬和 4-羟基他莫昔芬；然而，对该疗法的反应可能取决于多种代谢物的综合作用。对 TAM 转化为其关键代谢物影响最大的酶是 CYP2D6、CYP3A4、CYP3A5，但其他重要的 I 期和 II 期酶包括 CYP2C9、CYP2C19、CYP2B6、CYP1B1、UGT2B7、UGT2B15、UGT1A4、UGT1A8 和 UGT1A10。这些基因内的变异可能会影响 TAM 代谢成代谢物的能力，从而影响其功效。在接受 TAM 治疗的 ER+ 乳腺癌病例中，本研究的主要目的是检查乳腺癌复发和死亡风险的变化与以下因素相关：1) I 期酶 CYP2D6、CYP3A4、CYP3A5、CYP2C9、CYP2C19 内的遗传变异，和 CYP2B6，2) II 期酶 CYP1B1、UGT2B7 内的遗传变异， UGT2B15、UGT1A4、UGT1A8 和 UGT1A10，以及 3) TAM 代谢途径中所有基因内的组合变异。作为次要目标，我们将检查乳腺癌复发和死亡风险与 1) CYP2D6 抑制药物的使用，2) CYP2D6 基因型和 CYP2D6 抑制药物的使用的联合效应，以及 3) 亚组内的遗传变异之间的关联绝经前和绝经后妇女。这些主要和次要目标将使用西雅图地区之前三项基于人群的病例对照研究中积累的病例进行测试。我们的研究人群将包括 983 名在 1990 年至 1999 年期间被诊断患有侵袭性 ER+ 乳腺癌、年龄在 21 岁至 79 岁之间的女性，所有这些女性都接受了 TAM 治疗。与大多数以前的研究不同，这项研究将很好地覆盖 CYP2D6 等位基因变异，从而可以更准确地对代谢表型进行分类，并将包括 TAM 代谢途径中的其他关键基因。此外，这将是首批将 TAM 代谢途径作为一个整体来考虑与乳腺癌复发和死亡风险的关系。由于之前的研究结果不一致（可能是由于设计限制），关于 CYP2D6 或其他 TAM 代谢基因是否实际上影响 TAM 功效的争议仍未解决。通过改进过去的局限性并纳入其他相关基因，拟议研究的结果可以为 TAM 代谢基因变异与 TAM 使用者乳腺癌复发和死亡风险之间的假设和生物学上合理的关联提供新的线索。缺乏提前确定谁会或不会从 TAM 治疗中受益的方法是一个重大的临床差距，关键代谢酶内的遗传变异可能会作为预期 TAM 反应的指标。 1