Pharmacogenetics of Tamoxifen and Chemotherapies and Risk of Contralateral Breast

描述（由申请人提供）：辅助化疗和他莫昔芬已被证明可以降低既往有乳腺癌病史的女性患对侧乳腺癌（CBC）的风险。众所周知，并非所有个体都以相同的效率代谢药物或经历与治疗相关的不良副作用的可能性相同。预测代谢能力和结果的额外信息可以优化个体对药物治疗的反应并改善临床结果。药物代谢酶、功能靶点和药物转运蛋白的常见遗传多态性可能是这种区别的关键。在这项药物遗传学研究中，我们打算对妇女环境、癌症和放射流行病学（WECARE）研究中代谢基因的一组关键功能多态性进行基因分型，WECARE研究是一项针对单侧和双侧乳腺癌妇女的大型、基于人群的病例对照研究，系统收集了治疗和结局数据。我们将研究在WECARE研究中，他莫昔芬和其他化疗药物代谢相关基因的选定功能变体是否会改变这些治疗对CBC风险的保护作用。我们考虑了以下参与他莫昔芬代谢的关键基因的功能多态性（即，CYP 2D 6、CYP 3A 5、SULT 1A 1、UGT 2B 15）和乳腺癌综合化疗方案中常用的药物，包括：环磷酰胺（即，CYP 3A 5、GSTM 1、GSTP 1、GSTT 1）;蒽环类（即，CYP 3A 5、MDR 1、GSTM 1、GSTP 1、GSTT 1）和抗代谢物（即，我们建议对634名双侧乳腺癌妇女和1,158名单侧乳腺癌对照妇女进行基因分型，这些妇女接受化疗或他莫昔芬作为首次原发性乳腺癌的治疗。我们提出了一个研究设计，最大限度地利用现有的信息，通过检查候选多态性与已知的或可能的功能性影响，在这些关键途径的遗传变异。我们计划使用本研究的数据进行几个后续项目，包括将本研究中收集的功能多态性的基因型数据与Illumina 650 K上的tagSNP结合起来，以及从全基因组研究中收集的1，600名女性的额外数据，该研究预计将在WECARE研究中获得资助。这将允许汇总分析进行亚组分析和基于路径的统计建模方法。这项研究使用了一种有效的方法来解决有关常用疗法的药物遗传学和年龄小于55岁的女性CBC风险的研究问题，这是以前没有解决的问题。这些结果将有助于我们的知识基础，并有助于改善目前的临床策略，以确定合适的药物进行个性化护理，最大限度地减少不良事件和最大限度地提高长期结果。

DESCRIPTION (provided by applicant): Adjuvant chemotherapy and tamoxifen have been shown to reduce the risk of contralateral breast cancer (CBC) among women with a previous history of breast cancer. It is well recognized that not all individuals metabolize drugs with the same efficiency or experience the same likelihood of adverse side effects related to treatment. Additional information predicting metabolic capacity and outcomes may optimize an individual's response to drug therapy and improve clinical outcomes. Common genetic polymorphisms in drug metabolizing enzymes, functional targets and drug transporters may be key in this distinction. In this pharmacogenetic study, we intend to genotype a key set of functional polymorphisms in metabolic genes in the Women's Environment, Cancer and Radiation Epidemiology (WECARE) Study, a large, population-based, case-control study of women with unilateral and bilateral breast cancer that has systematically collected treatment and outcome data. We will investigate whether selected functional variants in genes involved in the metabolism of tamoxifen and other chemotherapeutic agents modify the protective effect of these treatments on the risk of CBC in the WECARE Study. We consider functional polymorphisms in the following key genes involved in the metabolism of tamoxifen (i.e., CYP2D6, CYP3A5, SULT1A1, UGT2B15) and drugs commonly used in polychemotherapy regimens for breast cancer including: cyclophosphamide (i.e., CYP3A5, GSTM1, GSTP1, GSTT1); anthracyclines (i.e., CYP3A5, MDR1, GSTM1, GSTP1, GSTT1) and antimetabolites (i.e., DHFR, TS, MTHFR) .We propose to genotype 634 women with bilateral breast cancer and 1,158 unilateral breast cancer controls who received the chemotherapy or tamoxifen as treatment for first primary breast cancer. We propose a study design that maximizes available information regarding genetic variability in these key pathways by examining candidate polymorphisms with known or likely functional effects. We plan several follow-up projects using data from this study including incorporating the genotype data collected on the functional polymorphisms in this study with tagSNPs on the Illumina 650K and additional data collection on 1,600 women from a genome-wide study that is expected to be funded in WECARE Study. This will allow for pooled analyses to pursue subgroup analyses and pathway-based statistical modeling approaches. This study uses an efficient approach to address research questions regarding the pharmacogenetics of commonly used therapies and risk of CBC among women younger than 55 years, which has not previously been addressed. These results will contribute to our knowledge base and help improve upon current clinical strategies to determine the right drug for individualized care that minimizes adverse events and maximizes long-term outcomes.