Tamoxifen has been the most important drug world-wide for the prevention and treatment of estrogen receptor (ER) positive breast cancer. Tamoxifen requires metabolic activation by cytochrome P450 (CYP) 2D6 to fully elicit its pharmacological activity.1-4 Our group was the first to translate these findings into clinical practice, and demonstrated a significantly higher risk of disease recurrence for women with decreased CYP2D6 metabolism.5,6 Based on these findings, an FDA advisory committee recently recommended a tamoxifen label change to warn caregivers regarding the importance of both genetic and drug-induced variation in the CYP2D6 enzyme.7 Our preliminary data provide an obvious step to the following critically important and unanswered research questions: 1) Can CYP2D6 genotype be used to select a specific hormonal therapy regimen for postmenopausal woman with early stage breast cancer? 2) Which of the most commonly used antidepressants with known weak inhibition of the CYP2D6 enzyme system are safe to administer for the treatment of tamoxifen-induced hot flashes?;and 3) How do gene copy number differences in SULT1A1, which encodes the primary enzyme responsible for conjugation of the active tamoxifen metabolites, affect the clinical outcomes of tamoxifen-treated patients. Through an established collaboration with the Austrian Breast and Colorectal Study Group (ABCSG), we have designed a matched case control study of the ABCSG trial 8 adjuvant tamoxifen and anastrozole trial, which demonstrated the superiority of sequencing of tamoxifen followed by anastrozole (compared to tamoxifen alone).8 We will genotype cases (those with disease recurrence) and controls to determine the effect of CYP2D6 genetic variation on breast cancer relapse in both treatment cohorts - those receiving tamoxifen alone and those receiving sequential tamoxifen then anastrozole. Additionally, we will prospectively study (in collaboration with the Consortium on Breast Cancer Pharmacogenomics) the extent to which the commonly administered antidepressants lower the plasma concentrations of endoxifen, a research question for which there are no data at this time. Finally, in the context of a completed cooperative group adjuvant tamoxifen trial (NCCTG 89-30-52), we will evaluate the role of genetic variation in SULT1A1, the enzyme responsible for conjugation of the active tamoxifen metabolites.

Public Health Relevance

Our proposal will determine whether inherited variability in the enzymes involved in tamoxifen biotransformation are associated with a preferential response to tamoxifen alone or a sequencing regimen of tamoxifen followed by an AI. This question is of utmost relevance, as there is no consensus as to which hormonal therapy regimen should be utilized for the treatment of postmenopausal breast cancer. Additionally, given that our data suggest that even a modest reduction in CYP2D6 enzyme activity leads to higher risk of breast cancer relapse, the determination of whether the most commonly administered antidepressants interfere with metabolic activation of tamoxifen has widespread clinical implications.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Biomarkers Study Section (CBSS)
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Song, Min-Kyung H
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Mayo Clinic, Rochester
United States
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Dudenkov, Tanda M; Ingle, James N; Buzdar, Aman U et al. (2017) SLCO1B1 polymorphisms and plasma estrone conjugates in postmenopausal women with ER+ breast cancer: genome-wide association studies of the estrone pathway. Breast Cancer Res Treat 164:189-199
Goetz, Matthew P; Suman, Vera J; Reid, Joel M et al. (2017) First-in-Human Phase I Study of the Tamoxifen Metabolite Z-Endoxifen in Women With Endocrine-Refractory Metastatic Breast Cancer. J Clin Oncol 35:3391-3400
Safgren, Stephanie L; Suman, Vera J; Kosel, Matthew L et al. (2015) Evaluation of CYP2D6 enzyme activity using a 13C-dextromethorphan breath test in women receiving adjuvant tamoxifen. Pharmacogenet Genomics 25:157-63
Haddad, Tufia C; Goetz, Matthew P (2015) Landscape of neoadjuvant therapy for breast cancer. Ann Surg Oncol 22:1408-15
Reid, Joel M; Goetz, Matthew P; Buhrow, Sarah A et al. (2014) Pharmacokinetics of endoxifen and tamoxifen in female mice: implications for comparative in vivo activity studies. Cancer Chemother Pharmacol 74:1271-8
Liu, Mohan; Goss, Paul E; Ingle, James N et al. (2014) Aromatase inhibitor-associated bone fractures: a case-cohort GWAS and functional genomics. Mol Endocrinol 28:1740-51
Goetz, Matthew P; Sun, James X; Suman, Vera J et al. (2014) Loss of heterozygosity at the CYP2D6 locus in breast cancer: implications for germline pharmacogenetic studies. J Natl Cancer Inst 107:
Goetz, M P; Ingle, J N (2014) CYP2D6 genotype and tamoxifen: considerations for proper nonprospective studies. Clin Pharmacol Ther 96:141-4
Province, M A; Goetz, M P; Brauch, H et al. (2014) CYP2D6 genotype and adjuvant tamoxifen: meta-analysis of heterogeneous study populations. Clin Pharmacol Ther 95:216-27
Brauch, Hiltrud; Schroth, Werner; Goetz, Matthew P et al. (2013) Tamoxifen use in postmenopausal breast cancer: CYP2D6 matters. J Clin Oncol 31:176-80

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