© 2002 by Oxford University Press
Journal of the National Cancer Institute, Vol. 94, No. 21, 1635-1640,
November 6, 2002
© 2002 Oxford University Press
ARTICLE |
Association Between Sulfotransferase 1A1 Genotype and Survival of Breast Cancer Patients Receiving Tamoxifen Therapy
Affiliations of authors: S. Nowell, Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, and National Center for Toxicological Research, Division of Molecular Epidemiology, Jefferson, AR; C. Sweeney, Division of Epidemiology, University of Minnesota, Minneapolis; M. Winters, F. F. Kadlubar, National Center for Toxicological Research, Division of Molecular Epidemiology; A. Stone, Central Arkansas Veteran’s Health Care System, Little Rock; N. P. Lang, Central Arkansas Veteran’s Health Care System, and Department of Surgical Oncology, University of Arkansas for Medical Sciences; L. F. Hutchins, Arkansas Cancer Research Center, Little Rock; C. B. Ambrosone, D. H. Ruttenberg Cancer Center, Mt. Sinai School of Medicine, New York, NY.
Correspondence to: Susan Nowell, M.S., National Center for Toxicological Research, 3900 NCTR Dr., HFT 100, Jefferson, AR 72079 (e-mail: snowell{at}nctr.fda.gov).
Background: Human sulfotransferase 1A1 (SULT1A1) catalyzes the sulfation of a variety of phenolic and estrogenic compounds, including 4-hydroxytamoxifen (4-OH TAM), the active metabolite of tamoxifen. A functional polymorphism in exon 7 of the SULT1A1 gene (SULT1A1*2) has been described that generates an enzyme that has approximately twofold lower activity and is less thermostable than that of the common allele SULT1A1*1. We investigated the hypothesis that that high sulfation activity would increase the elimination of 4-OH TAM by examining whether the presence of this polymorphism affects the efficacy of tamoxifen therapy. Methods: We examined the relationship between the SULT1A1*2 allele and survival in a cohort of 337 women with breast cancer who received tamoxifen (n = 160) or who did not (n = 177). SULT1A1 genotype was determined by restriction fragment polymorphism analysis. Patient survival was evaluated according to SULT1A1 genotype using Kaplan–Meier survival functions. Hazard ratios (HRs) were calculated from adjusted Cox proportional hazards modeling. All statistical tests were two-sided. Results: Among tamoxifen-treated patients, those who were homozygous for the SULT1A1*2 low-activity allele had approximately three times the risk of death (HR = 2.9, 95% confidence interval [CI] = 1.1 to 7.6) as those who were homozygous for the common allele or those who were heterozygous (SULT1A1*1/*2). Among patients who did not receive tamoxifen, there was no association between survival and SULT1A1 genotype (HR = 0.7, 95% CI = 0.3 to 1.5). Conclusions: Sulfation of 4-OH TAM provides a previously unanticipated benefit, possibly due to alterations in the bioavailability of the active metabolite or to undefined estrogen receptor-mediated events. These data alternatively suggest that variability in the metabolism of tamoxifen may affect its efficacy.
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