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

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。尽管证明了其疗效，但很大一部分使用者将经历疾病复发或死亡。本研究的总体目的是探讨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产物endoxifen和4-hydroxytamoxifen；然而，对这种疗法的反应可能取决于多种代谢物的综合作用。最能影响TAM转化为其关键代谢产物的酶是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。这些基因的变异会影响TAM代谢为其代谢物的能力，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研究乳腺癌复发和死亡风险的变异与1)I期酶CYP2D6、CYP3A4、CYP3A5、CYP2C9、CYP2C19和CYP2B6的遗传变异，2)II期酶CYP1B1、UGT2B7、UGT2B15、UGT1A4、UGT1A8和UGT1A10的遗传变异，以及3)TAM代谢途径中所有基因的联合变异。作为次要目的，我们将研究乳腺癌复发和死亡风险之间的关系，1)使用CYP2D6抑制药物，2)CYP2D6基因型和使用CYP2D6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。这些主要和次要目标将通过在西雅图地区进行的三个先前基于人群的病例对照研究中积累的病例进行检验。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+乳腺癌的年龄在21-79岁的女性，她们都接受了TAM治疗。与以往的大多数研究不同，本研究将对CYP2D6等位基因变异进行极好的覆盖，使代谢表型的分类更加准确，并将包括TAM代谢途径中的其他关键基因。此外，它将是第一个

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