Genetic polymorphisms of 3\u2032-untranslated region of SULT1A1 and their impact on tamoxifen metabolism and efficacy

A B Sanchez-Spitman,J J Swen,Henk-Jan Guchelaar,D J A R Moes,V O Dezentjé,H Gelderblom

doi:10.1007/s10549-018-4923-7

A B Sanchez-Spitman, J J Swen + Show 4 more

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https://doi.org/10.1007/s10549-018-4923-7

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Abstract

PurposeTamoxifen has a wide inter-variability. Recently, two SNPs in the 3′-untranslated region (UTR) of the SULT1A1 gene, rs6839 and rs1042157, have been associated with decreased SULT1A1 activity. The aim of this study is to investigate the role of the rs6839 and rs1042157 on tamoxifen metabolism and relapse-free survival (RFS) in women diagnosed with early-breast cancer receiving tamoxifen.MethodsSamples from 667 patients collected in the CYPTAM study (NTR1509) were used for genotyping (CYP2D6, SULT1A1 rs6839 and rs1042157) and measurements of tamoxifen and metabolites. Patients were categorized in three groups depending on the decreased SULT1A1 activity due to rs6839 and rs1042157: low activity group (rs6839 (GG) and rs1042157 (TT)); high activity group (rs6839 (AA) and rs1042157 (CC)); and medium activity group (all the other combinations of rs6839 and rs1042157). Associations between SULT1A1 phenotypes and clinical outcome (RFS) were explored.ResultsIn the low SULT1A1 activity group, higher endoxifen and 4-hydroxy-tamoxifen concentrations were found, compared to the medium and high activity group (endoxifen: 31.23 vs. 30.51 vs. 27.00, p value: 0.016; 4-hydroxy-tamoxifen: 5.55 vs. 5.27 vs. 4.94, p value:0.05). In terms of relapse, the low activity group had a borderline better outcome compared to the medium and high SULT1A1 activity group (adjusted Hazard ratio: 0.297; 95% CI 0.088–1.000; p value: 0.05).ConclusionOur results suggested that rs6839 and rs1042157 SNPs have a minor effect on the concentrations and metabolic ratios of tamoxifen and its metabolites, and RFS in women receiving adjuvant tamoxifen.

Highlights

Tamoxifen is commonly used as adjuvant endocrine therapy to treat patients diagnosed with breast cancer [1, 2]
Of tamoxifen, endoxifen, 4-hydroxy-tamoxifen, and NDM-tamoxifen concentration levels by high, medium, and low SULT1A1 enzyme activity groups. b Association of tamoxifen, endoxifen, 4-hydroxytamoxifen, and NDM-tamoxifen metabolic ratios by high, medium, and low SULT1A1 enzyme activity groups. This is the first study in which the role of 3′-untranslated region (UTR) SULT1A1 rs6839 and rs1042157 Single-Nucleotide Polymorphisms (SNPs) on tamoxifen metabolism and clinical outcome in early-breast cancer patients was examined
This study shows that patients with low SULT1A1 activity [rs6839 (GG) and rs1042157 (TT)] reached higher endoxifen and 4-hydroxy-tamoxifen concentration levels, but this small effect did not translate in improved relapse-free survival (RFS)

Summary

Introduction

Tamoxifen is commonly used as adjuvant endocrine therapy to treat patients diagnosed with breast cancer [1, 2]. Thereafter, conversion into endoxifen takes place (Fig. 1), mainly controlled by CYP2D6, among other enzymes. Around 92% of tamoxifen metabolism accounts for the biotransformation of tamoxifen into NDM-tamoxifen, whereas the conversion of tamoxifen into 4-hydroxy-tamoxifen only represents 7% [3]. Both endoxifen and 4-hydroxy-tamoxifen have equal affinity for the estrogen receptor α [4], but endoxifen is considered the most clinically relevant tamoxifen metabolite, since it is found in 5–10 times higher concentrations than 4-hydroxy-tamoxifen [5]. While CYP2D6 is the rate-limiting enzyme in tamoxifen metabolism, it cannot fully explain the Breast Cancer Research and Treatment (2018) 172:401–411

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