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