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

描述(申请人提供)：他莫昔芬()是用于治疗雌激素受体阳性(ER+)乳腺癌的标准内分泌疗法。尽管其疗效已被证明，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探讨药物代谢基因的遗传变异对治疗乳腺癌疗效的影响。的疗效归因于代谢物艾多昔芬和4-羟基他莫昔芬；然而，这种疗法的疗效可能取决于多种代谢物的联合作用。对转化为关键代谢产物影响最大的酶是细胞色素P450酶D6、细胞色素P3A4、细胞色素P3A5，但其他重要的I、II相酶还有细胞色素P450 C9、细胞色素P4C19、细胞色素P450 B6、细胞色素P1B1、细胞色素2B7、细胞色素2B15、细胞色素1A4、细胞色素1A8和细胞色素T1A10。这些基因的变异可能会影响代谢成代谢物的能力，从而影响其疗效。在接受治疗的ER+乳腺癌患者中，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有关：1)细胞色素P450 D 6、细胞色素P3 A4、细胞色素P3A5、细胞色素P450 9、细胞色素P2 19和细胞色素P450 6的基因变异；2)细胞色素P1B1、UGT2B7、UGT2B15、UGT1A4、UGT1A8和UGT1A10基因的联合变异；3)代谢途径中所有基因的联合变异。作为次要目标，我们将研究乳腺癌复发和死亡的风险与1)使用CYP2D6抑制药物之间的关系，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基因变异。这些主要和次要目标将使用西雅图地区之前三项以人群为基础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年至1999年期间被诊断为浸润性ER+乳腺癌的女性，年龄21-79岁，所有人都接受了的治疗。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，从而能够更准确地对代谢物表型进行分类，并将包括代谢途径中的其他关键基因。此外，这将是第一批 从整体上考虑代谢途径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，可能是由于设计的限制，关于CYP2D6或其他代谢基因是否确实影响疗效的争议仍未解决。通过改进过去的局限性并纳入其他相关基因，拟议的研究结果可能会为假设和生物学上可信的代谢基因变异与使用者乳腺癌复发和死亡风险之间的关联提供新的线索。缺乏提前确定谁将或不会受益于治疗的手段是临床上的一个重大差距，关键代谢酶的基因变异可能会成为预期疗效的指标。1

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