title: CYP2D6 inhibition and breast cancer recurrence in a population-based study in Denmark.
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.
  
  
  CONCLUSIONS
  The association between CYP2D6 inhibition and recurrence in tamoxifen-treated patients is likely null or small.
authors.affiliation: Department of Clinical Epidemiology, Aarhus University Hospital, Denmark. tl@dce.au.dk
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Lash
authors.forename: Deirdre
authors.initials: D
authors.lastname: Cronin-Fenton
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Ahern
authors.forename: Carol L
authors.initials: CL
authors.lastname: Rosenberg
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Lunetta
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Silliman
authors.forename: Jens Peter
authors.initials: JP
authors.lastname: Garne
authors.forename: Henrik Toft
authors.initials: HT
authors.lastname: Sørensen
authors.forename: Ylva
authors.initials: Y
authors.lastname: Hellberg
authors.forename: Mariann
authors.initials: M
authors.lastname: Christensen
authors.forename: Lars
authors.initials: L
authors.lastname: Pedersen
authors.forename: Stephen
authors.initials: S
authors.lastname: Hamilton-Dutoit
mesh_terms: D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000453:epidemiology* / Q000473:pathology; D016022:Case-Control Studies; D015986:Confounding Factors, Epidemiologic; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003718:Denmark / Q000453:epidemiology; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D055118:Medication Adherence; D008875:Middle Aged; D009010:Monte Carlo Method; D009364:Neoplasm Recurrence, Local / Q000453:epidemiology* / Q000517:prevention & control*; D009367:Neoplasm Staging; D016017:Odds Ratio; D011960:Receptors, Estrogen / Q000097:blood; D013629:Tamoxifen / Q000627:therapeutic use*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D011960:Receptors, Estrogen; D013629:Tamoxifen; D019389:Cytochrome P-450 CYP2D6