Association between sulfotransferase 1A1 genotype and survival of breast cancer patients receiving tamoxifen therapy

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 SULTIAI 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 bio-availability 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.