Modification of tamoxifen effectiveness by gene polymorphisms and other drugs

描述（由申请人提供）：在美国，每年有超过20万名妇女被诊断患有乳腺癌。大约三分之二的乳腺癌肿瘤是雌激素受体阳性的，因此它们的癌细胞与雌激素结合，雌激素激活受体并使肿瘤细胞生长。他莫昔芬是一种辅助激素药物疗法，它通过与雌激素受体结合来干扰这种生长刺激，从而阻止雌激素激活受体。五年的他莫昔芬治疗可将复发风险降低一半。他莫昔芬的代谢产物与雌激素受体的结合比他莫昔芬本身要容易100倍，因此它们是内部活性药物。其酶产生（GYP）或去除（SULT1A1和UGT2B15）活性代谢物的基因的多态性改变代谢物的血浆浓度。其他药物与他莫昔芬竞争这些酶，这也改变了代谢物的血浆浓度。我们将比较（1）具有降低CYP2D6、CYP3A5或CYP2C9酶功能的遗传多态性的女性的乳腺癌复发率与不具有这些多态性的女性的乳腺癌复发率，（2）具有降低SULT 1A1酶功能的遗传多态性的女性的乳腺癌复发率与不具有这些多态性的女性的乳腺癌复发率，和（3）处方SSRI抗抑郁药的女性乳腺癌复发率与未处方SSRI抗抑郁药的女性乳腺癌复发率之间的关系。来源人群将从丹麦乳腺癌合作组维护的世界上最好的乳腺癌患者临床数据库中确定。在10年的随访中，将在局部或远处复发病例及其匹配对照之间比较多态性和药物相互作用。比值比将根据与复发风险相关的患者、肿瘤和治疗特征进行调整。群体设置最大限度地减少了选择偏倚的可能性，数据库质量最大限度地减少了测量误差的可能性。相关性：乳腺癌仍然是美国女性中最常见的非皮肤癌。大多数患者都是激素治疗的候选人。了解基因多态性或药物相互作用对他莫昔芬疗效的影响将有助于患者和医生对激素治疗做出充分知情的决定。

DESCRIPTION (provided by applicant): More than 200,000 women are diagnosed with breast cancer in the United States each year. About two-thirds of breast cancer tumors are estrogen receptor positive, so their cancer cells bind estrogen, which activates the receptor and enables tumor cell growth. Tamoxifen, an adjuvant hormonal drug therapy, interferes with this growth stimulation by binding to the estrogen receptor, which keeps estrogen from activating the receptor. Five years of tamoxifen therapy reduces the risk of recurrence by half. Tamoxifen's metabolites bind the estrogen receptor 100-fold more readily than tamoxifen itself, so they are the internally active drug. Polymorphisms in the genes whose enzymes produce (GYP) or remove (SULT1A1 & UGT2B15) the active metabolites modify the metabolites' plasma concentrations. Other drugs compete with tamoxifen for these enzymes, which also modifies the metabolites' plasma concentrations. We will compare the rates of breast cancer recurrence in women (1) with genetic polymorphisms that reduce the enzyme function of CYP2D6, CYP3A5, or CYP2C9 to the rates of breast cancer recurrence in women who do not have these polymorphisms, (2) with genetic polymorphisms that reduce the enzyme function of SULT1A1 to the rate of breast cancer recurrence in women who do not have these polymorphisms, and (3) prescribed SSRI antidepressants to the rate of breast cancer recurrence in women not prescribed SSRI antidepressants. The source population will be identified from the world's finest clinical database of breast cancer patients, maintained by the Danish Breast Cancer Cooperative Group. Polymorphisms and drug interactions will be compared between cases of local or distant recurrence and their matched controls over ten years of follow-up. The odds ratio will be adjusted for patient, tumor, and therapy characteristics related to recurrence risk. The population setting minimizes the potential for selection bias and the database quality minimizes the potential for measurement error. Relevance: Breast cancer remains the most common non-skin cancer among US women. The majority of patients are candidates for hormonal therapy. Understanding the modification of tamoxifen effectiveness by genetic polymorphisms or drug interactions will help patients and physicians to make fully informed decisions about hormone therapy.