The CYP2D6*4 polymorphism affects breast cancer survival in tamoxifen users

Monique J Bijl; Ron H N van Schaik; Laureen A Lammers; Albert Hofman; Arnold G Vulto; Teun van Gelder; Bruno H Ch Stricker; Loes E Visser

doi:10.1007/s10549-008-0272-2

The CYP2D6*4 polymorphism affects breast cancer survival in tamoxifen users

Monique J Bijl, Ron H N van Schaik, Laureen A Lammers, Albert Hofman, Arnold G Vulto, Teun van Gelder, Bruno H Ch Stricker, Loes E Visser

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	125-30
Number of pages	6
Journal	Breast Cancer Research and Treatment
Volume	118
Issue number	1
DOIs	https://doi.org/10.1007/s10549-008-0272-2
Publication status	Published - Nov 2009
Externally published	Yes

Keywords

Aged
Aged, 80 and over
Alleles
Antineoplastic Agents, Hormonal/pharmacokinetics
Biotransformation/genetics
Breast Neoplasms/drug therapy
Cohort Studies
Cytochrome P-450 CYP2D6/deficiency
Cytochrome P-450 CYP2D6 Inhibitors
Female
Genotype
Humans
Middle Aged
Netherlands/epidemiology
Polymorphism, Single Nucleotide
Prodrugs/pharmacokinetics
Proportional Hazards Models
Survival Analysis
Tamoxifen/analogs & derivatives

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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.",

keywords = "Aged, Aged, 80 and over, Alleles, Antineoplastic Agents, Hormonal/pharmacokinetics, Biotransformation/genetics, Breast Neoplasms/drug therapy, Cohort Studies, Cytochrome P-450 CYP2D6/deficiency, Cytochrome P-450 CYP2D6 Inhibitors, Female, Genotype, Humans, Middle Aged, Netherlands/epidemiology, Polymorphism, Single Nucleotide, Prodrugs/pharmacokinetics, Proportional Hazards Models, Survival Analysis, Tamoxifen/analogs & derivatives",

author = "Bijl, {Monique J} and {van Schaik}, {Ron H N} and Lammers, {Laureen A} and Albert Hofman and Vulto, {Arnold G} and {van Gelder}, Teun and Stricker, {Bruno H Ch} and Visser, {Loes E}",

year = "2009",

month = nov,

doi = "10.1007/s10549-008-0272-2",

language = "English",

volume = "118",

pages = "125--30",

journal = "Breast Cancer Research and Treatment",

issn = "0167-6806",

publisher = "Springer New York",

number = "1",

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TY - JOUR

T1 - The CYP2D6*4 polymorphism affects breast cancer survival in tamoxifen users

AU - Bijl, Monique J

AU - van Schaik, Ron H N

AU - Lammers, Laureen A

AU - Hofman, Albert

AU - Vulto, Arnold G

AU - van Gelder, Teun

AU - Stricker, Bruno H Ch

AU - Visser, Loes E

PY - 2009/11

Y1 - 2009/11

N2 - 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.

AB - 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.

KW - Aged

KW - Aged, 80 and over

KW - Alleles

KW - Antineoplastic Agents, Hormonal/pharmacokinetics

KW - Biotransformation/genetics

KW - Breast Neoplasms/drug therapy

KW - Cohort Studies

KW - Cytochrome P-450 CYP2D6/deficiency

KW - Cytochrome P-450 CYP2D6 Inhibitors

KW - Female

KW - Genotype

KW - Humans

KW - Middle Aged

KW - Netherlands/epidemiology

KW - Polymorphism, Single Nucleotide

KW - Prodrugs/pharmacokinetics

KW - Proportional Hazards Models

KW - Survival Analysis

KW - Tamoxifen/analogs & derivatives

U2 - 10.1007/s10549-008-0272-2

DO - 10.1007/s10549-008-0272-2

M3 - Article

C2 - 19189212

SN - 0167-6806

VL - 118

SP - 125

EP - 130

JO - Breast Cancer Research and Treatment

JF - Breast Cancer Research and Treatment

IS - 1

ER -

The CYP2D6*4 polymorphism affects breast cancer survival in tamoxifen users

Abstract

Keywords

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