The aim of this study was to determine whether the SULT1A1 rs9282861 genotype is associated with clinical outcome of patients diagnosed with early breast cancer and treated with either adjuvant TAM or chemotherapy. Our study had a median follow-up of nearly 12 years and it provides data on overall, breast cancer specific and relapse-free survival. The multivariate analysis of the combined patient population given either TAM or chemotherapy showed a statistically significant association between the studied rs9282861 SNP and OS, favouring patients with the homozygous variant AA genotype. However, in a separate analysis of patients receiving either adjuvant chemotherapy or TAM, the differences in survival were not statistically significant.
Our finding of improved survival of patients homozygous for the variant SULT1A1 rs9282861 A allele is in agreement with the hypothesis that the lower catalytic activity associated with the homozygyous AA variant genotype might lead to slower elimination of 4-OH-TAM, thus lengthening its duration of action. On the other hand, based on our results rs9282861 genotype is not a distinct predictive factor for the efficacy of adjuvant TAM or chemotherapy since BCSS did not differ significantly. As we analyzed all the 412 patients, including those who were given only adjuvant radiotherapy and those who did not receive any type of adjuvant treatment, there was no difference in OS or BCSS. Therefore, the rs9282861 genotype did not seem to be an independent prognostic factor in our unselected breast cancer patient population. Instead, the rs9282861 genotype emerged as a statistically significant prognostic factor as we analyzed OS specifically for the patients given medical adjuvant treatment.
However, our finding is not supported by previous clinical studies [8
]. To explain the improved OS of the carriers of the wild-type G allele, Nowell et al. [8
] suggested in their study of TAM treated breast cancer patients (n = 160) that the sulfated form of 4-OH-TAM is reabsorbed in the kidney and further desulfated in the breast tumours by steroid sulfatase, thus prolonging the duration of action of the active 4-OH-TAM. Another possible explanation was that the high-activity allele induces global expression of the SULT1A1 enzyme, followed by increased elimination of potentially harmful substrates.
In another study with a similar follow-up time as our study but with a slightly different approach, Wegman et al. [11
] investigated the influence of the SULT1A1
rs9282861 genotype on RFS of breast cancer patients treated with adjuvant TAM or no endocrine therapy. In the group of TAM-treated patients (n = 112) there was a trend of lower risk of distant recurrence among carriers of the wild-type GG genotype. It is noteworthy that in their study genotyping was made from tumour tissue, which may cause a risk of genotype misclassification. However, the most plausible reason for the discordant results between different studies is the lack of power due to small sample sizes.
The outcome of TAM therapy is probably not solely determined by a single SNP but a combination of several genetic factors. In addition to sulfation by SULTs, glucuronidation of TAM and its metabolites by uridine diphosphate glucuronosyltransferases (UGTs) offers a way of substrate elimination through the bile. Glucuronidation is probably the most effective way to excrete TAM and its derivatives [28
]. In fact, the UGT2B15
high activity genotype has been associated with an increased risk of recurrence and poorer survival in a group of TAM-treated patients [26
]. Furthermore, several other UGTs (UGT1A4, UGT2B7, UGT1A8 and UGT1A10) have been reported to be active against 4-OH-TAM [29
Polymorphisms associated with the CYP genes, especially CYP2D6
, may also have a substantial effect on the outcome of TAM therapy; CYP2D6 contributes to the formation of 4-OH-TAM in human liver [31
]. Moreover, TAM is metabolized to 4-desmethyl-TAM via CYP-dependent pathway by CYP3A4 and secondarily to endoxifen by CYP2D6, and decreased CYP2D6 enzyme activity has been associated with worse event-free survival and disease-free survival in patients treated with adjuvant TAM [32
], although contradictory results have also been reported [11
]. This complexity of TAM metabolism may explain the conflicting results in different studies.
There appears to be no studies on the role of SULT1A1
polymorphism in the pharmacokinetics of chemotherapeutic regimens, and the mechanism of this potential association is unclear. It is known that heterocyclic amines are activated by SULTs [33
]. The sulfonate group is often transferred to oxygen, which is frequently in the form of hydroxyl group [33
]. In theory, 4-OHCPA might serve as a substrate to SULT1A1 and possessing the high-activity SULT1A1
allele would increase the rate of elimination of CPA, thus decreasing the individual's exposure to its cytotoxic effects. However, none of the chemotherapeutic drugs given in the CMF regimen are known to act as substrates to SULT1A1. In addition, to date there are no pharmacokinetic or in vitro data available to support this hypothesis.
Our results clearly indicate that there may be an association between the SULT1A1
rs9292861 genotype and the survival of breast cancer patients, but further studies are warranted due to a relatively small sample size. Lack of specific data on the other medications used by the patients is also a limitation of our study. For example, concomitant use of CYP2D6 inhibitors, including selective serotonin reuptake inhibitor (SSRI) antidepressants, may reduce the efficacy of TAM [34
]. However, the influence of this potential confounding factor is anticipated to be minor since the use of SSRIs was uncommon in the 1990s.
Lastly, local radiotherapy was given to 77 patients (95.1%) receiving chemotherapy and to 47 patients (72.3%) treated with TAM. In the univariate analysis, the rs9282861 genotype was not associated with any differences in survival among patients who were given adjuvant radiotherapy but no adjuvant chemotherapy or hormonal therapy (n = 230). It is unlikely that radiotherapy interacts with SULT1A1 enzyme, which would result in various survival outcomes between SULT1A1 genotypes.