Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 312-321 |
| Number of pages | 10 |
| Journal | Clinical and Translational Science |
| Volume | 11 |
| Issue number | 3 |
| DOIs | |
| State | Published - May 2018 |
Funding
The authors thank Barbara Kavanaugh, Program Manager for the NWA-PGRN, for directing programmatic collaborations; Patricia L. Stapleton and Jesse M. Tsai in the Functional Genomics Laboratory at the University of Washington (P30ES007033) for performing the CYP2D6*5 assay. In Alaska, the authors sincerely thank customer-owners of the Southcentral Foundation for their input, guidance, and study participation; the ANMC Oncology and Hematology Clinic staff in assisting with patient recruitment; and the SCF Board of Directors and the SCF Research Oversight Committee. In Montana, the authors thank members of the CSKT Community Pharmacogenetics Advisory Council for their input and guidance on the research, and the CSKT Tribal Health Department and CSKT Tribal Council for their approval and support of this project. This work was supported by the Northwest-Alaska Pharmacogenomics Research Network (NWA-PGRN) (U01GM092676 and P01GM116691). B.A.K., A.E.F., K.E.T., and E.L.W. wrote the manuscript. K.E.T. and E.L.W. designed the research. B.A.K., R.R., A.E.F., L.I.M., B.D.S., J.A.B., M.J.O., L.T., H.F., C.L., P.B., B.P., D.N., K.H., D.A.D., T.A.T., K.E.T., and E.L.W. performed the research. B.A.K., A.E.F., T.A.T., and E.L.W. analyzed the data. B.P. and D.N. contributed new reagents/analytical tools. Source of Funding. This work was supported by the Northwest-Alaska Pharmacogenomics Research Network (NWA-PGRN) (U01GM092676 and P01GM116691).
| Funders | Funder number |
|---|---|
| Community Pharmacogenetics Advisory Council | |
| U01GM092676, P01GM116691 | |
| Southcentral Foundation | |
| P30ES007033 |
UN SDGs
This output contributes to the following UN Sustainable Development Goals (SDGs)
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SDG 3 Good Health and Well-being
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