Top

Published in:

01-10-2009 | Clinical Trial

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

Authors: N. Lynn Henry, James M. Rae, Lang Li, Faouzi Azzouz, Todd C. Skaar, Zereunesay Desta, Matthew J. Sikora, Santosh Philips, Anne T. Nguyen, Anna Maria Storniolo, Daniel F. Hayes, David A. Flockhart, Vered Stearns, Consortium on Breast Cancer Pharmacogenomics Investigators

Published in: Breast Cancer Research and Treatment | Issue 3/2009

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.

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

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 97:30–39PubMedCrossRef

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 95:1758–1764PubMed

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 PubMedCrossRef

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 PubMedCrossRef

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 PubMedCrossRef

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 PubMedCrossRef

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 PubMedCrossRef

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 PubMedCrossRef

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

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 PubMedCrossRef

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 PubMedCrossRef

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 PubMedCrossRef

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 PubMedCrossRef

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 PubMedCrossRef

16.

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

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 PubMedCrossRef

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 PubMedCrossRef

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

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 PubMedCrossRef

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 PubMedCrossRef

Title: Association between CYP2D6 genotype and tamoxifen-induced hot flashes in a prospective cohort
Authors: N. Lynn Henry
James M. Rae
Lang Li
Faouzi Azzouz
Todd C. Skaar
Zereunesay Desta
Matthew J. Sikora
Santosh Philips
Anne T. Nguyen
Anna Maria Storniolo
Daniel F. Hayes
David A. Flockhart
Vered Stearns
Consortium on Breast Cancer Pharmacogenomics Investigators
Publication date: 01-10-2009
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 3/2009
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-009-0309-1

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2009

Complementary and alternative therapy use before and after breast cancer diagnosis: the Pathways Study

Detection of occult HER2 mRNA-positive tumor cells in the peripheral blood of patients with operable breast cancer: evaluation of their prognostic relevance

Tolerability of and adherence to combination oral therapy with gefitinib and capecitabine in metastatic breast cancer

Axillary web syndrome after axillary dissection in breast cancer: a prospective study

Founder mutations account for the majority of BRCA1-attributable hereditary breast/ovarian cancer cases in a population from Tuscany, Central Italy

Never use anthracyclines with trastuzumab: it is time to reconsider the taboo

Keynote webinar | Spotlight on antibody–drug conjugates in cancer