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

• 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
• 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

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。尽管其疗效已得到证实，但相当一部分使用者将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内昔芬和4-羟基他莫昔芬;然而，对这种疗法的反应可能取决于多种代谢物的联合作用。对TAM转化为其关键代谢物影响最大的酶是CYP 2D 6、CYP 3A 4、CYP 3A 5，但其他重要的I相和II相酶包括CYP 2C 9、CYP 2C 19、CYP 2B 6、CYP 1B 1、UGT 2B 7、UGT 2B 15、UGT 1A 4、UGT 1A 8和UGT 1A 10。这些基因内的变异可能会影响TAM被代谢成其代谢物的能力，从而影响其疗效。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1）I相酶CYP 2D 6、CYP 3A 4、CYP 3A 5、CYP 2C 9、CYP 2C 19和CYP 2B 6内的遗传变异，2）II相酶CYP 1B 1、UGT 2B 7、UGT 2B 15、UGT 1A 4、UGT 1A 8内的遗传变异，和UGT 1A 10，以及3）TAM代谢途径中所有基因内的组合变异。作为次要目的，我们将检查乳腺癌复发和死亡风险与1）使用CYP 2D 6抑制药物，2）CYP 2D 6基因型和使用CYP 2D 6抑制药物的联合作用，以及3）绝经前和绝经后妇女亚组内的遗传变异之间的关联。这些主要和次要目标将使用在西雅图地区的三个先前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1990-1999年期间被诊断为浸润性ER+乳腺癌的妇女，年龄在21-79岁，所有这些妇女都接受了TAM治疗。与大多数以前的研究不同，这项研究将非常好地覆盖CYP 2D 6等位基因变体，允许更准确地分类代谢表型，并将包括TAM代谢途径中的其他关键基因。此外，这将是第一个 将TAM代谢途径作为一个整体考虑与乳腺癌复发和死亡风险的关系。由于以前的研究结果不一致，可能是由于设计限制，关于CYP 2D 6或其他TAM代谢基因是否实际影响TAM疗效的争议仍未解决。通过改善过去的局限性并结合其他相关基因，拟议研究的结果可以揭示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合理关联。缺乏一种方法来提前确定谁将或不会受益于TAM治疗是一个显着的临床差距，关键代谢酶的遗传变异可能作为一个指标，预期TAM的反应。1