Abstract
BackgroundSulfotransferase 1A1 (SULT1A1) participates in the elimination of 4-hydroxy-tamoxifen (4-OH-TAM), which is one of the major active metabolites of tamoxifen (TAM). Homozygous SULT1A1 variant allele genotype has been associated with lower catalytic activity and thermostability of the enzyme. Previous clinical studies suggest that the SULT1A1 rs9282861 polymorphism may influence the survival of breast cancer patients treated with TAM in the adjuvant setting. We investigated the effect of rs9282861 genotypes on the survival of Finnish breast cancer patients treated with adjuvant chemotherapy or TAM.MethodsThe rs9282861 genotypes of 412 Finnish breast cancer patients with early breast cancer were identified by using PCR-RFLP method. Seventy six patients were treated with adjuvant cyclophosphamide based chemotherapy only, 65 patients received adjuvant TAM, and four patients were treated with both adjuvant chemotherapy and TAM. Overall long-term survival (OS), breast cancer specific survival (BCSS), and relapse-free survival (RFS) by rs9282861 genotypes were evaluated by the Kaplan-Meier method and Cox regression analysis.ResultsThe multivariate analysis of 145 patients receiving either adjuvant TAM or chemotherapy showed a statistically significantly improved OS in patients with the rs9282861 homozygous variant AA genotype (hazard ratio [HR] = 0.50, 95% confidence interval [CI] = 0.29-0.88, P = 0.015). In the separate analyses of patients receiving only chemotherapy or adjuvant TAM, there were no statistically significant differences in survival.ConclusionsIn this prospective study, we observed a previously unreported association between the SULT1A1 rs9282861 genotype and OS of breast cancer patients treated with adjuvant chemotherapy or TAM. This novel finding suggests that the rs9282861 polymorphism modifies the long-term clinical outcome of patients receiving adjuvant TAM or chemotherapy.
Highlights
Sulfotransferase 1A1 (SULT1A1) participates in the elimination of 4-hydroxy-tamoxifen (4-OH-TAM), which is one of the major active metabolites of tamoxifen (TAM)
The impact of SULT1A1 rs9282861 genotype on the risk of breast cancer and response to TAM therapy has been reported in several studies; the variant AA genotype has been associated both with poorer overall survival (OS) [8] and with no effect on OS [9,10], whereas patients with the homozygous wild-type GG genotype have been reported to have a tendency towards improved distant recurrence-free survival (RFS) [11]
In summary, breast cancer patients with the SULT1A1 rs9282861 homozygous variant AA genotype and treated with either adjuvant TAM or chemotherapy had statistically significantly better OS compared with the carriers of other rs9282861 genotypes
Summary
Sulfotransferase 1A1 (SULT1A1) participates in the elimination of 4-hydroxy-tamoxifen (4-OH-TAM), which is one of the major active metabolites of tamoxifen (TAM). Homozygous SULT1A1 variant allele genotype has been associated with lower catalytic activity and thermostability of the enzyme. Previous clinical studies suggest that the SULT1A1 rs9282861 polymorphism may influence the survival of breast cancer patients treated with TAM in the adjuvant setting. We investigated the effect of rs9282861 genotypes on the survival of Finnish breast cancer patients treated with adjuvant chemotherapy or TAM. The impact of SULT1A1 rs9282861 genotype on the risk of breast cancer and response to TAM therapy has been reported in several studies; the variant AA genotype has been associated both with poorer overall survival (OS) [8] and with no effect on OS [9,10], whereas patients with the homozygous wild-type GG genotype have been reported to have a tendency towards improved distant recurrence-free survival (RFS) [11]
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