title: Association between sulfotransferase 1A1 genotype and survival of breast cancer patients receiving tamoxifen therapy.
abstract: 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.
authors.affiliation: S. Nowell, Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, USA. snowell@nctr.fda.gov
authors.forename: Susan
authors.initials: S
authors.lastname: Nowell
authors.forename: Carol
authors.initials: C
authors.lastname: Sweeney
authors.forename: Maria
authors.initials: M
authors.lastname: Winters
authors.forename: Angie
authors.initials: A
authors.lastname: Stone
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Lang
authors.forename: Laura F
authors.initials: LF
authors.lastname: Hutchins
authors.forename: Fred F
authors.initials: FF
authors.lastname: Kadlubar
authors.forename: Christine B
authors.initials: CB
authors.lastname: Ambrosone
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D015239:Arylsulfotransferase; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D015331:Cohort Studies; D005091:Exons; D005260:Female; D005838:Genotype; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009367:Neoplasm Staging; D011110:Polymorphism, Genetic; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D020845:Selective Estrogen Receptor Modulators / Q000627:therapeutic use*; D015238:Sulfotransferases / Q000235:genetics*; D016019:Survival Analysis; D013629:Tamoxifen / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D007527:Isoenzymes; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D015238:Sulfotransferases; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human