CYP2D6 Inhibition and Breast Cancer Recurrence in a Population-Based Study in Denmark

Timothy L Lash, Deirdre Cronin-Fenton, Thomas P Ahern, Carol L Rosenberg, Kathryn L Lunetta, Rebecca A Silliman, Jens Peter Garne, Henrik Toft Sørensen, Ylva Hellberg, Mariann Christensen, Lars Pedersen, Stephen Hamilton-Dutoit

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82 Citations (Scopus)

Abstract

Background Cytochrome P450 2D6 (CYP2D6) inhibition reduces the concentration of 4-hydroxylated tamoxifen metabolites, but the clinical relevance remains uncertain. Methods We conducted a large case-control study nested in the population of 11 251 women aged 35-69 years at diagnosis of stage I-III breast cancer between 1985 and 2001 on Denmark's Jutland Peninsula and registered with the Danish Breast Cancer Cooperative Group. We identified 541 recurrent or contralateral breast cancers among women with estrogen receptor-positive (ER+) disease treated with tamoxifen for at least 1 year and 300 cancers in women with ER-negative (ER-) disease never treated with tamoxifen. We matched one control subject per case patient on ER status, menopausal status, stage, calendar time, and county, genotyped the CYP2D6*4 allele to assess genetic inhibition, and ascertained prescription history to assess drug-drug inhibition. We estimated the odds ratio (OR), associating CYP2D6 inhibition with breast cancer recurrence and adjusted for potential confounding with logistic regression. To address bias from incomplete information on CYP2D6 function, we used Monte Carlo simulation to complete a record-level probabilistic bias analysis. All statistical tests were two-sided. Results The frequency of the CYP2D6*4 minor allele was 24% in case patients with ER+ tumors, 23% in case patients with ER- tumors, and 22% each in control subjects with ER+ and ER- tumors. In women with ER+ tumors, the associations of one functional allele with recurrence (OR = 0.99; 95% confidence interval = 0.76 to 1.3) and no functional allele with recurrence (OR = 1.4; 95% confidence interval = 0.84 to 2.3) were near null, as were those for women with ER- tumors. The near-null associations persisted when evaluated by intake of medications, by combining genotype with medication history, in the probabilistic bias analysis, or by restricting the analysis to women with ER expression confirmed by re-assay. Conclusion The association between CYP2D6 inhibition and recurrence in tamoxifen-treated patients is likely null or small.
Original languageEnglish
JournalJournal of the National Cancer Institute
Volume103
Pages (from-to)489-500
Number of pages12
ISSN0027-8874
DOIs
Publication statusPublished - 16 Mar 2011
Externally publishedYes

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