Modification of tamoxifen effectiveness by gene polymorphisms and other drugs

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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.