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有乳腺癌病史的女性患对侧乳腺癌（CBC）的风险。众所周知，并不是所有人都以同样的效率代谢药物，也不是所有人都经历同样的与治疗有关的不良副作用的可能性。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。在药物代谢酶、功能靶点和药物转运体中常见的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，我们打算在女性环境、癌症和辐射流行病学（WECARE）研究中对代谢基因的一组关键功能多态性进行基因分型，WECARE是一项大型、基于人群的病例对照研究，研究对象是患有单侧和双侧乳腺癌的女性，该研究系统地收集了治疗和结果数据。在WECARE研究中，我们将研究参与他莫昔芬和其他化疗药物代谢的基因中选择的功能变异是否会改变这些治疗对CBC风险的保护作用。我们考虑了参与他莫昔芬代谢的以下关键基因（即CYP2D6， CYP3A5, SULT1A1, UGT2B15）和乳腺癌多化疗方案中常用药物的功能多态性，包括：环磷酰胺（即CYP3A5， GSTM1, GSTP1, GSTT1）；蒽环类药物（即CYP3A5， MDR1, GSTM1, GSTP1, GSTT1）和抗代谢物（即DHFR， TS， MTHFR）。我们建议对634名接受化疗或他莫昔芬治疗的双侧乳腺癌女性和1158名单侧乳腺癌对照患者进行基因分型。我们提出了一种研究设计，通过检查具有已知或可能功能影响的候选多态性，最大限度地利用这些关键途径中遗传变异性的可用信息。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基因型数据与Illumina 650K上的标签snp结合起来，以及从一项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。这将允许池分析追求子组分析和基于路径的统计建模方法。本研究采用了一种有效的方法来解决关于常用疗法的药物遗传学和55岁以下女性CBC风险的研究问题，这是以前没有解决的。这些结果将有助于我们的知识库，并有助于改进当前的临床策略，以确定适合个性化护理的药物，从而最大限度地减少不良事件并最大化长期结果。

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.