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Originally published as JCO Early Release 10.1200/JCO.2008.16.8377 on November 17 2008 © 2008 American Society of Clinical Oncology. Estrogen Receptor Genotypes Influence Hot Flash Prevalence and Composite Score Before and After Tamoxifen Therapy
From the Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN; Breast Oncology Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; and Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD Corresponding author: Vered Stearns, MD, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Bunting-Blaustein Cancer Research Bldg, 1650 Orleans St, Rm 145, Baltimore, MD 21231-1000; e-mail: vstearn1{at}jhmi.edu
Purpose Hot flashes are common and frequently lead to drug discontinuation among women prescribed tamoxifen. We determined whether genetic polymorphisms in estrogen receptors (ESRs) Patients and Methods We determined ESR1 PvuII and XbaI and ESR2-02 genotypes in 297 women who were initiating tamoxifen. One-week hot flash diaries were collected to calculate a hot flash score (frequency x severity) before and 1, 4, 8, and 12 months after starting tamoxifen. Results Approximately 80% of 297 participants reported hot flashes before or during the first year of tamoxifen. After 4 months of tamoxifen, premenopausal women who did not receive adjuvant chemotherapy had a four-fold increase in hot flash score (from 5.9 to 23.6; P = .003) compared with a 1.17-fold increase (from 19.6 to 23; P = .34) in those who received chemotherapy. In premenopausal women, increased number of ESR1 PvuII and XbaI CG alleles was associated with higher baseline hot flash scores compared with those who had other haplotypes (P = .0026). At 4 months, postmenopausal women with ESR1 PvuII CC and ESR2-02 GG genotypes had 4.6 times increases in hot flash scores than other postmenopausal women (56 v 12; P = .0007). Women who had the ESR2-02 AA genotype were significantly less likely to experience tamoxifen-induced hot flashes than women who carried at least one ESR-02 G allele (hazard ratio, 0.26; 95% CI, 0.10 to 0.63; P = .001). Conclusion Knowledge of menopausal status, prior chemotherapy, and ESR genotype may help predict which women are most likely to suffer hot flashes during tamoxifen treatment. published online ahead of print at www.jco.org on November 17, 2008 Supported in part by Pharmacogenetics Research Network Grants No. U-01 GM61373 (D.F.) and R-01 GM56898 (D.F.); Clinical Pharmacology Training Grant No. 5T32-GM-08425 (D.F.) from the National Institute of General Medical Sciences; Damon Runyon-Lilly Clinical Investigator award CI-3 from the Damon Runyon Cancer Research Foundation (V.S.); Fashion Footwear Foundation/QVC Presents Shoes on Sale (D.F.H.); and the General Clinical Research Centers at the University of Michigan (Grant No. M01-00042 from the National Institutes of Health), Georgetown University (Grant No. M01-RR13297 from the National Institutes of Health), and Indiana University (Grant No. M01-RR00750 from the National Institutes of Health). Presented in part at the 108th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, March 21-24, 2007, Anaheim, CA; and at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Clinical trial information can be found for the following: NCT00228930 [ClinicalTrials.gov]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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and β (ESR1 and ESR2, respectively) are associated with tamoxifen-induced hot flashes. 
