The CYP2D6*4 polymorphism affects breast cancer survival in tamoxifen users.
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.
Bijl
Monique J
MJ
Department of Epidemiology, Erasmus MC, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands. m.bijl.1@erasmusmc.nl
van Schaik
Ron H N
RH
Lammers
Laureen A
LA
Hofman
Albert
A
Vulto
Arnold G
AG
van Gelder
Teun
T
Stricker
Bruno H Ch
BH
Visser
Loes E
LE
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
D018931:Antineoplastic Agents, Hormonal; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D011355:Prodrugs; D013629:Tamoxifen; C055492:4-hydroxy-N-desmethyltamoxifen; D019389:Cytochrome P-450 CYP2D6