Contribution of ABCB1 and CYP2D6 Genotypes to the Outcome of Tamoxifen Adjuvant Treatment in Premenopausal Women With Breast Cancer

被引:16
作者
Argalacsova, S. [1 ,2 ,3 ]
Slanar, O. [2 ,3 ,4 ]
Vitek, P. [5 ,6 ]
Tesarova, P. [1 ,2 ]
Bakhouche, H. [2 ,3 ]
Drazdakova, M. [2 ,4 ]
Bartosova, O. [2 ,3 ]
Zima, T. [2 ,4 ]
Pertuzelka, L. [1 ,2 ]
机构
[1] Charles Univ Prague, Dept Oncol, Fac Med 1, Prague, Czech Republic
[2] Gen Teaching Hosp, Prague, Czech Republic
[3] Charles Univ Prague, Fac Med 1, Inst Pharmacol, Prague, Czech Republic
[4] Charles Univ Prague, Fac Med 1, Inst Clin Biochem & Lab Diagnost, Prague, Czech Republic
[5] Charles Univ Prague, Fac Med 1, Inst Radiotherapy, Prague, Czech Republic
[6] Hosp Na Bulovce, Prague, Czech Republic
关键词
P-glycoprotein; SNP; Pharmacogenomics; Tamoxifen; CYP2D6; SINGLE NUCLEOTIDE POLYMORPHISMS; CYTOCHROME-P450; 2D6; CLINICAL-OUTCOMES; MDR1; GENE; PHARMACOGENETICS; ASSOCIATION; METABOLISM; FREQUENCY; SURVIVAL; ALLELE;
D O I
10.33549/physiolres.933234
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
Recent pre-clinical evidence suggests that the active metabolite of tamoxifen, endoxifen, is a substrate for efflux pump P-glycoprotein. The aim of our study was to evaluate, if the polymoprhisms within ABCB1 gene alter tamoxifen adjuvant treatment efficacy in premenopausal women. Totally 71 premenopausal women with estrogen receptor positive breast cancer indicated for tamoxifen adjuvant treatment were followed retrospectively for median period of 56 months. The gentic polymorphisms of CYP2D6 and ABCB1 were analyzed and potential covariates as tumor grading, staging, age at the diagnosis, comedication, quantitative positivity of ER or PR were also evaluated. Cox proportional-hazards regression model indicated that patients carrying at least one variant allele in ABCB1 rs1045642 had significantly longer time to event survival compared to wild type subjects. Non-significant trend was noted for better treatment outcome of patients carrying at least one variant allele in the SNP rs2032582, while for the CYP2D6 polymorphism poor metabolizer phenotype resulted in worse outcome in comparison to extensive metabolizers subjects with HR of 4.04 (95 % CI 0.31-52.19). Similarly, patients using CYP2D6 inhibitors had non-significantly shorter time-to-event as compared to never users resulting in hazard ratio of 2.06 (95 % CI 0.40-10.63). ABCB1 polymorphisms may affect outcome of tamoxifen adjuvant treatment in premenopausal breast cancer patiens. This factor should be taken into account in addition to the CYP2D6 polymorphism or phenotypic inhibition of CYP2D6 activity.
引用
收藏
页码:S539 / S547
页数:9
相关论文
共 34 条
[11]   Pharmacogenetics of Tamoxifeno. Who Should Undergo CYP2D6 Genetic Testing? [J].
Higgins, Michaela J. ;
Rae, James M. ;
Flockhart, David A. ;
Hayes, Daniel F. ;
Stearns, Vered .
JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK, 2009, 7 (02) :203-213
[12]   Functional polymorphisms of the human multidrug-resistance gene:: Multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo [J].
Hoffmeyer, S ;
Burk, O ;
von Richter, O ;
Arnold, HP ;
Brockmöller, J ;
Johne, A ;
Cascorbi, I ;
Gerloff, T ;
Roots, I ;
Eichelbaum, M ;
Brinkmann, U .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (07) :3473-3478
[13]   Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer [J].
Howell, A ;
Cuzick, J ;
Baum, M ;
Buzdar, A ;
Dowsett, M ;
Forbes, JF ;
Hoctin-Boes, G ;
Houghton, I ;
Locker, GY ;
Tobias, JS .
LANCET, 2005, 365 (9453) :60-62
[14]   P-Glycoprotein (ABCB1) Transports the Primary Active Tamoxifen Metabolites Endoxifen and 4-Hydroxytamoxifen and Restricts Their Brain Penetration [J].
Iusuf, Dilek ;
Teunissen, Sebastiaan F. ;
Wagenaar, Els ;
Rosing, Hilde ;
Beijnen, Jos H. ;
Schinkel, Alfred H. .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2011, 337 (03) :710-717
[15]   Association between CYP2D6 genotypes and the clinical outcomes of adjuvant tamoxifen for breast cancer: a meta-analysis [J].
Jung, Jin-A ;
Lim, Hyeong-Seok .
PHARMACOGENOMICS, 2014, 15 (01) :49-60
[16]   Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study [J].
Kelly, Catherine M. ;
Juurlink, David N. ;
Gomes, Tara ;
Duong-Hua, Minh ;
Pritchard, Kathleen I. ;
Austin, Peter C. ;
Paszat, Lawrence F. .
BMJ-BRITISH MEDICAL JOURNAL, 2010, 340 :355
[17]   CYP2D6 phenotype prediction from genotype: Which system is the best? [J].
Kirchheiner, J. .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 2008, 83 (02) :225-227
[18]   Impaired tamoxifen metabolism reduces survival in familial breast cancer patients [J].
Newman, William G. ;
Hadfield, Kristen D. ;
Latif, Ayshe ;
Roberts, Stephen A. ;
Shenton, Andrew ;
McHague, Christopher ;
Lalloo, Fiona ;
Howell, Sacha ;
Evans, D. Gareth .
CLINICAL CANCER RESEARCH, 2008, 14 (18) :5913-5918
[19]   Association of genetic variation in tamoxifen-metabolizing enzymes with overall survival and recurrence of disease in breast cancer patients [J].
Nowell, SA ;
Ahn, JY ;
Rae, JM ;
Scheys, JO ;
Trovato, A ;
Sweeney, C ;
MacLeod, SL ;
Kadlubar, FF ;
Ambrosone, CB .
BREAST CANCER RESEARCH AND TREATMENT, 2005, 91 (03) :249-258
[20]  
Pechandová K, 2006, FOLIA BIOL-PRAGUE, V52, P184