title: The CYP2D6*4 polymorphism affects breast cancer survival in tamoxifen users.
abstract: Cytochrome P450 2D6 (CYP2D6) plays an important role in the formation of endoxifen, the active metabolite of tamoxifen. In this study the association between the most prevalent CYP2D6 null-allele in Caucasians (CYP2D6*4) and breast cancer mortality was examined among all incident users of tamoxifen in a population-based cohort study. Breast cancer mortality was significantly increased in patients with the * 4/*4 genotype (HR = 4.1, CI 95% 1.1-15.9, P = 0.041) compared to wild type patients. The breast cancer mortality increased with a hazard ratio of 2.0 (CI 95% 1.1-3.4, P = 0.015) with each additional variant allele. No increased risk of all-cause mortality or all-cancer mortality was found in tamoxifen users carrying a CYP2D6*4 allele. The risk of breast cancer mortality is increased in tamoxifen users with decreased CYP2D6 activity, consistent with the model in which endoxifen formation is dependent on CYP2D6 activity.
authors.affiliation: Department of Epidemiology, Erasmus MC, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands. m.bijl.1@erasmusmc.nl
authors.forename: Monique J
authors.initials: MJ
authors.lastname: Bijl
authors.forename: Ron H N
authors.initials: RH
authors.lastname: van Schaik
authors.forename: Laureen A
authors.initials: LA
authors.lastname: Lammers
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Arnold G
authors.initials: AG
authors.lastname: Vulto
authors.forename: Teun
authors.initials: T
authors.lastname: van Gelder
authors.forename: Bruno H Ch
authors.initials: BH
authors.lastname: Stricker
authors.forename: Loes E
authors.initials: LE
authors.lastname: Visser
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D018931:Antineoplastic Agents, Hormonal / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001711:Biotransformation / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D015331:Cohort Studies; D019389:Cytochrome P-450 CYP2D6 / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D005260:Female; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016016:Proportional Hazards Models; D016019:Survival Analysis; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D018931:Antineoplastic Agents, Hormonal; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D011355:Prodrugs; D013629:Tamoxifen; C055492:4-hydroxy-N-desmethyltamoxifen; D019389:Cytochrome P-450 CYP2D6