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Pharmacogenetics of Tamoxifen Biotransformation Is Associated With Clinical Outcomes of Efficacy and Hot Flashes

From the Departments of Oncology, Biostatistics, Pathology, and Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN; Department of Medicine, Division of Hematology/Oncology; University of Michigan School of Medicine, Ann Arbor, MI; Department of Medicine, Division of Clinical Pharmacology, Indiana University, Bloomington, IN; and Department of Medicine, Division of Hematology and Oncology; Mayo Clinic Jacksonville, Jacksonville, FL.

Address reprint requests to Matthew Goetz, MD, Department of Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: goetz.matthew{at}mayo.edu

PURPOSE: Polymorphisms in tamoxifen metabolizing genes affect the plasma concentration of tamoxifen metabolites, but their effect on clinical outcome is unknown.

METHODS: We determined cytochrome P450 (CYP)2D6 (*4 and *6) and CYP3A5 (*3) genotype from paraffin-embedded tumor samples and buccal cells (living patients) in tamoxifen-treated women enrolled onto a North Central Cancer Treatment Group adjuvant breast cancer trial. The relationship between genotype and disease outcome was determined using the log-rank test and Cox proportional hazards modeling.

RESULTS: Paraffin blocks were obtained from 223 of 256 eligible patients, and buccal cells were obtained from 17 living women. CYP2D6 (*4 and *6) and CYP3A5 (*3) genotypes were determined from 190, 194, and 205 patient samples and in 17 living women. The concordance rate between buccal and tumor genotype was 100%. Women with the CYP2D6 *4/*4 genotype had worse relapse-free time (RF-time; P = .023) and disease-free survival (DFS; P = .012), but not overall survival (P = .169) and did not experience moderate to severe hot flashes relative to women heterozygous or homozygous for the wild-type allele. In the multivariate analysis, women with the CYP2D6 *4/*4 genotype still tended to have worse RFS (hazard ratio [HR], 1.85; P = .176) and DFS (HR, 1.86; P = .089). The CYP3A5*3 variant was not associated with any of these clinical outcomes.

CONCLUSION: In tamoxifen-treated patients, women with the CYP2D6 *4/*4 genotype tend to have a higher risk of disease relapse and a lower incidence of hot flashes, which is consistent with our previous observation that CYP2D6 is responsible for the metabolic activation of tamoxifen to endoxifen.

Supported in part by Grant No. CA 90628-03, the Commonwealth Cancer Research Foundation, Breast Cancer Research Foundation, and Grant No. U-01 GM61373 from the National Institute of General Medical Sciences, Bethesda, MD.

M.P.G. and J.M.R. contributed equally to this work.

Presented in part at the San Antonio Breast Cancer Symposium 2004, San Antonio, TX, December 10, 2004.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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