Variants in tamoxifen metabolizing genes: a case-control study of contralateral breast cancer risk in the WECARE study.

Tamoxifen has been shown to greatly reduce risk of recurrence and contralateral breast cancer (CBC). Still, second primary contralateral breast cancer is the most common malignancy to follow a first primary breast cancer. Genetic variants in CYP2D6 and other drug-metabolizing enzymes that alter the metabolism of tamoxifen may be associated with CBC risk in women who receive the drug. This is the first study to investigate the impact of this variation on risk of CBC in women who receive tamoxifen. From the population-based Women's Environment Cancer and Radiation Epidemiology (WECARE) Study, we included 624 Caucasian women with CBC (cases) and 1,199 women with unilateral breast cancer (controls) with complete information on tumor characteristics and treatment. Conditional logistic regression was used to assess the risk of CBC associated with 112 single nucleotide polymorphisms (SNPs) in 8 genes involved in the metabolism of tamoxifen among tamoxifen users and non-users. After adjustment for multiple testing, no significant association was observed between any of the genotyped variants and CBC risk in either tamoxifen users or non-users. These results suggest that when using a tagSNP approach, common variants in selected genes involved in the metabolism of tamoxifen are not associated with risk of CBC among women treated with the drug.

[1]  C. Caldas,et al.  Re: CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the Breast International Group 1-98 trial and Re: CYP2D6 and UGT2B7 genotype and risk of recurrence in tamoxifen-treated breast cancer patients. , 2012, Journal of the National Cancer Institute.

[2]  V. Stanton.  Re: CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the Breast International Group 1-98 trial. , 2012, Journal of the National Cancer Institute.

[3]  J. Cuzick,et al.  CYP2D6 and UGT2B7 genotype and risk of recurrence in tamoxifen-treated breast cancer patients. , 2012, Journal of the National Cancer Institute.

[4]  P. Neven,et al.  CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the breast international group 1-98 trial. , 2012, Journal of the National Cancer Institute.

[5]  Jennifer D. Brooks,et al.  Variants in activators and downstream targets of ATM, radiation exposure, and contralateral breast cancer risk in the WECARE study , 2012, Human mutation.

[6]  R Peto,et al.  Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials , 2011, The Lancet.

[7]  K. Lunetta,et al.  Functional Polymorphisms in UDP-Glucuronosyl Transferases and Recurrence in Tamoxifen-Treated Breast Cancer Survivors , 2011, Cancer Epidemiology, Biomarkers & Prevention.

[8]  T. Lash,et al.  Clinical epidemiology and pharmacology of CYP2D6 inhibition related to breast cancer outcomes , 2011, Expert review of clinical pharmacology.

[9]  T. Fehm,et al.  Activity Levels of Tamoxifen Metabolites at the Estrogen Receptor and the Impact of Genetic Polymorphisms of Phase I and II Enzymes on Their Concentration Levels in Plasma , 2011, Clinical pharmacology and therapeutics.

[10]  P. Francis,et al.  Tamoxifen, cytochrome P450 genes and breast cancer clinical outcomes. , 2011, Breast.

[11]  K. Lunetta,et al.  CYP2D6 inhibition and breast cancer recurrence in a population-based study in Denmark. , 2011, Journal of the National Cancer Institute.

[12]  U. Langsenlehner,et al.  Impact of CYP2D6*4 genotype on progression free survival in tamoxifen breast cancer treatment , 2010, Current medical research and opinion.

[13]  C. Caldas,et al.  CYP2D6 gene variants: association with breast cancer specific survival in a cohort of breast cancer patients from the United Kingdom treated with adjuvant tamoxifen , 2010, Breast Cancer Research.

[14]  J. Cuzick,et al.  Effect of body mass index on recurrences in tamoxifen and anastrozole treated women: an exploratory analysis from the ATAC trial. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  H. Brauch,et al.  Pharmacogenomics of tamoxifen therapy. , 2009, Clinical chemistry.

[16]  A. Hofman,et al.  The CYP2D6*4 polymorphism affects breast cancer survival in tamoxifen users , 2009, Breast Cancer Research and Treatment.

[17]  C. Begg,et al.  Effect of systemic adjuvant treatment on risk for contralateral breast cancer in the Women's Environment, Cancer and Radiation Epidemiology Study. , 2008, Journal of the National Cancer Institute.

[18]  Wolfgang Simon,et al.  Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  V. Jordan.  New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer , 2007, Steroids.

[20]  Hyeong-Seok Lim,et al.  Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[22]  S. Wingren,et al.  Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer , 2007, Breast Cancer Research.

[23]  V. Jordan,et al.  The Science of Selective Estrogen Receptor Modulators: Concept to Clinical Practice , 2006, Clinical Cancer Research.

[24]  B. Bonanni,et al.  Polymorphism in the CYP2D6 tamoxifen-metabolizing gene influences clinical effect but not hot flashes: data from the Italian Tamoxifen Trial. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  D. Reich,et al.  Principal components analysis corrects for stratification in genome-wide association studies , 2006, Nature Genetics.

[26]  Fergus J Couch,et al.  Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  J. Scheys,et al.  Association of genetic variation in tamoxifen-metabolizing enzymes with overall survival and recurrence of disease in breast cancer patients , 2005, Breast Cancer Research and Treatment.

[28]  Y Wang,et al.  Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials , 2005, The Lancet.

[29]  T. Skaar,et al.  Endoxifen (4-hydroxy-N-desmethyl-tamoxifen) has anti-estrogenic effects in breast cancer cells with potency similar to 4-hydroxy-tamoxifen , 2005, Cancer Chemotherapy and Pharmacology.

[30]  J. Flaws,et al.  Polymorphisms in cytochrome P4503A5 (CYP3A5) may be associated with race and tumor characteristics, but not metabolism and side effects of tamoxifen in breast cancer patients. , 2005, Cancer letters.

[31]  Bryan Langholz,et al.  Study design: Evaluating gene–environment interactions in the etiology of breast cancer – the WECARE study , 2004, Breast Cancer Research.

[32]  L. Hutchins,et al.  Association between sulfotransferase 1A1 genotype and survival of breast cancer patients receiving tamoxifen therapy. , 2002, Journal of the National Cancer Institute.

[33]  J. Goldstein,et al.  Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data. , 2002, Pharmacogenetics.

[34]  N. Weiss,et al.  Tamoxifen therapy for primary breast cancer and risk of contralateral breast cancer. , 2001, Journal of the National Cancer Institute.

[35]  J. Abrams.  Tamoxifen: five versus ten years--is the end in sight? , 2001, Journal of the National Cancer Institute.

[36]  Ann Daly,et al.  Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression , 2001, Nature Genetics.

[37]  C. Ambrosone,et al.  Relationship of phenol sulfotransferase activity (SULT1A1) genotype to sulfotransferase phenotype in platelet cytosol. , 2000, Pharmacogenetics.

[38]  M. Hakama,et al.  Risk factors for contralateral breast cancer in Chennai (Madras), India. , 1998, International journal of epidemiology.

[39]  R. Weinshilboum,et al.  Phenol sulfotransferase pharmacogenetics in humans: association of common SULT1A1 alleles with TS PST phenotype. , 1997, Biochemical and biophysical research communications.

[40]  M. Green,et al.  Isolation and characterization of UGT2B15(Y85): a UDP-glucuronosyltransferase encoded by a polymorphic gene. , 1997, Pharmacogenetics.

[41]  N. Weiss,et al.  Population-based study of tamoxifen therapy and subsequent ovarian, endometrial, and breast cancers. , 1995, Journal of the National Cancer Institute.

[42]  H. Johansson,et al.  Adjuvant tamoxifen therapy for early stage breast cancer and second primary malignancies. Stockholm Breast Cancer Study Group. , 1995, Journal of the National Cancer Institute.

[43]  Yusuke Nakamura,et al.  Pharmacogenomics of tamoxifen: roles of drug metabolizing enzymes and transporters. , 2012, Drug metabolism and pharmacokinetics.

[44]  Jennifer D. Brooks,et al.  Body mass index and risk of second primary breast cancer: The WECARE Study , 2011, Breast Cancer Research and Treatment.

[45]  A. Howell,et al.  Comprehensive CYP2D6 genotype and adherence affect outcome in breast cancer patients treated with tamoxifen monotherapy , 2010, Breast Cancer Research and Treatment.

[46]  J. Dungan,et al.  Association Between CYP2D6 Polymorphisms and Outcomes Among Women With Early Stage Breast Cancer Treated With Tamoxifen , 2010 .

[47]  S. Lundgren,et al.  Effects of CYP2D6 and SULT1A1 genotypes including SULT1A1 gene copy number on tamoxifen metabolism. , 2008, Annals of oncology : official journal of the European Society for Medical Oncology.

[48]  David A. Flockhart,et al.  The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen , 2006, Breast Cancer Research and Treatment.

[49]  B. Pollock,et al.  Genotypic and allelic frequencies of SULT1A1 polymorphisms in women receiving adjuvant tamoxifen therapy , 2005, Breast Cancer Research and Treatment.

[50]  D. Flockhart,et al.  Clinical Significance of the Cytochrome P450 2C19 Genetic Polymorphism , 2002, Clinical pharmacokinetics.

[51]  B. Furr,et al.  The pharmacology and clinical uses of tamoxifen. , 1984, Pharmacology & therapeutics.

[52]  S. Lundgren,et al.  Associations between tamoxifen, estrogens, and FSH serum levels during steady state tamoxifen treatment of postmenopausal women with breast cancer , 2010, BMC Cancer.