Skip to main content

Advertisement

SpringerLink
Log in

Association between CYP2D6 genotype and tamoxifen-induced hot flashes in a prospective cohort

  • Clinical Trial
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Women with reduced CYP2D6 activity have low endoxifen concentrations and likely worse long term benefits from tamoxifen. We investigated the association between CYP2D6 genotype and tamoxifen-induced hot flashes in a prospective cohort. We collected hot flash frequency and severity data over 12 months from 297 women initiating tamoxifen. We performed CYP2D6 genotyping using the AmpliChip CYP450 test and correlated inherited genetic polymorphisms in CYP2D6 and tamoxifen-induced hot flashes. Intermediate metabolizers had greater mean hot flash scores after 4 months of tamoxifen therapy (44.3) compared to poor metabolizers (20.6, P = 0.038) or extensive metabolizers (26.9, P = 0.011). At 4 months, we observed a trend toward fewer severe hot flashes in poor metabolizers compared to intermediate plus extensive metabolizers (P = 0.062). CYP2D6 activity may be a modest predictive factor for tamoxifen-induced hot flashes. The presence or absence of hot flashes should not be used to determine tamoxifen’s efficacy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Osborne CK (1998) Tamoxifen in the treatment of breast cancer. N Engl J Med 339:1609–1618. doi:10.1056/NEJM199811263392207

    Article  PubMed  CAS  Google Scholar 

  2. Jin Y, Desta Z, Stearns V et al (2005) CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 97:30–39

    Article  PubMed  CAS  Google Scholar 

  3. Stearns V, Johnson MD, Rae JM et al (2003) Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 95:1758–1764

    PubMed  CAS  Google Scholar 

  4. Goetz MP, Rae JM, Suman VJ et al (2005) Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 23:9312–9318. doi:10.1200/JCO.2005.03.3266

    Article  PubMed  CAS  Google Scholar 

  5. Schroth W, Antoniadou L, Fritz P et al (2007) Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol 25:5187–5193. doi:10.1200/JCO.2007.12.2705

    Article  PubMed  CAS  Google Scholar 

  6. Lim HS, Ju Lee H, Seok Lee K et al (2007) Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer. J Clin Oncol 25:3837–3845. doi:10.1200/JCO.2007.11.4850

    Article  PubMed  CAS  Google Scholar 

  7. Nowell S, Ahn J, Rae JM et al (2005) Association of genetic variation in tamoxifen-metabolizing enzymes with overall survival and recurrence of disease in breast cancer patients. Breast Cancer Res Treat 91:249–258. doi:10.1007/s10549-004-7751-x

    Article  PubMed  CAS  Google Scholar 

  8. Wegman P, Vainikka L, Stal O et al (2005) Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients. Breast Cancer Res 7:R284–R290. doi:10.1186/bcr993

    Article  PubMed  CAS  Google Scholar 

  9. Wegman P, Elingarami S, Carstensen J et al (2007) Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer. Breast Cancer Res 9:R7. doi:10.1186/bcr1640

    Article  PubMed  CAS  Google Scholar 

  10. Goetz MP, Suman V, Ames M et al (2009) Tamoxifen pharmacogenetics of CYP2D6, CYP2C19, and SULT1A1: long term follow-up of the North Central Cancer Treatment Group 89-30-52 adjuvant trial. Cancer Res 69(suppl):6037 abstract

    Google Scholar 

  11. Mortimer JE, Flatt SW, Parker BA et al (2008) Tamoxifen, hot flashes and recurrence in breast cancer. Breast Cancer Res Treat 108:421–426. doi:10.1007/s10549-007-9612-x

    Article  PubMed  CAS  Google Scholar 

  12. Cuzick J, Sestak I, Cella D et al (2008) Treatment-emergent endocrine symptoms and the risk of breast cancer recurrence: a retrospective analysis of the ATAC trial. Lancet Oncol 9:1143–1148. doi:10.1016/S1470-2045(08)70259-6

    Article  PubMed  CAS  Google Scholar 

  13. Jin Y, Hayes DF, Li L et al (2008) Estrogen receptor genotypes influence hot flash prevalence and composite score before and after tamoxifen therapy. J Clin Oncol 26:5849–5854. doi:10.1200/JCO.2008.16.8377

    Article  PubMed  Google Scholar 

  14. Borges S, Desta Z, Li L et al (2006) Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment. Clin Pharmacol Ther 80:61–74. doi:10.1016/j.clpt.2006.03.013

    Article  PubMed  CAS  Google Scholar 

  15. Finck G, Barton DL, Loprinzi CL et al (1998) Definitions of hot flashes in breast cancer survivors. J Pain Symptom Manage 16:327–333. doi:10.1016/S0885-3924(98)00090-6

    Article  PubMed  CAS  Google Scholar 

  16. Sloan JA, Loprinzi CL, Novotny PJ et al (2001) Methodologic lessons learned from hot flash studies. J Clin Oncol 19:4280–4290

    PubMed  CAS  Google Scholar 

  17. Blake MJ, Gaedigk A, Pearce RE et al (2007) Ontogeny of dextromethorphan O- and N-demethylation in the first year of life. Clin Pharmacol Ther 81:510–516. doi:10.1038/sj.clpt.6100101

    Article  PubMed  CAS  Google Scholar 

  18. Gaedigk A, Simon SD, Pearce RE et al (2008) The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clin Pharmacol Ther 83:234–242. doi:10.1038/sj.clpt.6100406

    Article  PubMed  CAS  Google Scholar 

  19. Madlensky L, Flatt SW, Natarajan L et al (2009) Hot flashes are associated with CYP2D6 genotype in breast cancer survivors taking tamoxifen. Cancer Res 69(suppl):6045 abstract

    Google Scholar 

  20. Snider NT, Sikora MJ, Sridar C et al (2008) The endocannabinoid anandamide is a substrate for the human polymorphic cytochrome P450 2D6. J Pharmacol Exp Ther 327:538–545. doi:10.1124/jpet.108.141796

    Article  PubMed  CAS  Google Scholar 

  21. Loprinzi CL, Zahasky KM, Sloan JA et al (2000) Tamoxifen-induced hot flashes. Clin Breast Cancer 1:52–56. doi:10.3816/CBC.2000.n.004

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported in part by the Pharmacogenetics Research Network grant number U-01 GM61373 (D.A.F.), which supports the Consortium on Breast Cancer Pharmacogenomics (COBRA); National Institutes of Health Clinical Pharmacology training grant number T32-GM08425 (D.A.F.); National Institute of General Medical Sciences, National Institutes of Health grant number K24RR020815 (D.A.F.); Damon Runyon-Lilly Clinical Investigator award CI-3 from the Damon Runyon Cancer Research Foundation (V.S.); and Fashion Footwear Charitable Foundation of New York/QVC Presents Shoes-on-Sale™ (D.F.H.) This publication was made possible by Grant Numbers M01-RR000042 (University of Michigan), M01-RR020359 (Georgetown University), and M01-RR00750 (Indiana University) from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NCRR or NIH.

Conflicts of interest statement

N.L.H. is on the Scientific Advisory Board of Otsuka Pharmaceuticals and has received research funding from AstraZeneca and Lilly Pharmaceuticals. J.M.R. has received research funding from Pfizer and speaking honoraria for Roche Diagnostics. T.S. has received speaking honoraria for Roche Diagnostics. AMS is a member of the speaker’s bureau and receives research funding from Glaxo-Smith Kline and is a consultant to Eli Lilly and Company. D.A.F. is on the Scientific Advisory Boards of Labcorp, Inc. and Otsuka Pharmaceuticals, is a consultant to Roche Molecular Diagnostics, and has received research funding from Pfizer and Novartis. D.F.H. has received research funding from AstraZeneca, Glaxo-Smith Kline, Pfizer, and Novartis. V.S. is on the Scientific Advisory Board of Otsuka Pharmaceuticals, has served as a consultant to Wyeth Pharmaceuticals, Concert Pharmaceuticals and JDS Pharmaceuticals, and has received research funding from Glaxo-Smith Kline, Pfizer, and Novartis.

Author information

Authors and Affiliations

  1. Breast Oncology Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA

    N. Lynn Henry & Daniel F. Hayes

  2. Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA

    N. Lynn Henry, James M. Rae & Daniel F. Hayes

  3. Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA

    James M. Rae & Matthew J. Sikora

  4. Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

    Lang Li, Faouzi Azzouz, Todd C. Skaar, Zereunesay Desta, Santosh Philips, Anne T. Nguyen & David A. Flockhart

  5. Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA

    Anna Maria Storniolo

  6. Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Bunting-Blaustein Cancer Research Building, 1650 Orleans Street, Room 145, Baltimore, MD, 21231-1000, USA

    Vered Stearns

Authors
  1. N. Lynn Henry
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. James M. Rae
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Faouzi Azzouz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Todd C. Skaar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zereunesay Desta
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Matthew J. Sikora
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Santosh Philips
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Anne T. Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Anna Maria Storniolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Daniel F. Hayes
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. David A. Flockhart
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Vered Stearns
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

Consortium on Breast Cancer Pharmacogenomics Investigators

Corresponding author

Correspondence to Vered Stearns.

Additional information

The description of the study design can be found on http://www.clinicaltrials.gov (NCT00228930).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lynn Henry, N., Rae, J.M., Li, L. et al. Association between CYP2D6 genotype and tamoxifen-induced hot flashes in a prospective cohort. Breast Cancer Res Treat 117, 571–575 (2009). https://doi.org/10.1007/s10549-009-0309-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-009-0309-1

Keywords

Search

Navigation