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Despite evidence that pharmacogenetics can improve tamoxifen pharmacotherapy, there are few studies with American Indian and Alaska Native (AIAN) people. We examined variation in cytochrome P450 (CYP) genes ( CYP2D6 ,  CYP3A4 ,  CYP3A5 , and  CYP2C9 ) and tamoxifen biotransformation in AIAN patients with breast cancer ( n  = 42) from the Southcentral Foundation in Alaska and the Confederated Salish and Kootenai Tribes in Montana. We tested for associations between  CYP  diplotypes and plasma concentrations of tamoxifen and metabolites. Only the  CYP2D6  variation was significantly associated with concentrations of endoxifen ( P  = 0.0008) and 4‐hydroxytamoxifen ( P  = 0.0074), tamoxifen's principal active metabolites, as well as key metabolic ratios. The  CYP2D6  was also the most significant predictor of active metabolites and metabolic ratios in a multivariate regression model, including all four genes as predictors, with minor roles for other  CYP  genes. In AIAN populations,  CYP2D6  is the largest contributor to tamoxifen bioactivation, illustrating the importance of validating pharmacogenetic testing for therapy optimization in an understudied population.

Cytochrome P450 Genetic Variation Associated with Tamoxifen Biotransformation in American Indian and Alaska Native People