Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, The Netherlands.
Leiden Network for Personalised Therapeutics, Leiden University Medical Center, Leiden, The Netherlands.
Breast Cancer Res Treat. 2018 Nov;172(2):401-411. doi: 10.1007/s10549-018-4923-7. Epub 2018 Aug 17.
Tamoxifen 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.
Samples 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.
In 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).
Our 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.
他莫昔芬的个体间变异性很大。最近，SULT1A1 基因 3'非翻译区（UTR）中的两个单核苷酸多态性（SNP），rs6839 和 rs1042157，与 SULT1A1 活性降低有关。本研究旨在探讨 rs6839 和 rs1042157 对接受他莫昔芬治疗的早期乳腺癌女性患者他莫昔芬代谢和无复发生存（RFS）的作用。
本研究使用 CYPTAM 研究（NTR1509）中收集的 667 例患者的样本进行基因分型（CYP2D6、SULT1A1 rs6839 和 rs1042157）和他莫昔芬及其代谢物的测量。根据 rs6839 和 rs1042157 导致的 SULT1A1 活性降低，患者被分为三组：低活性组（rs6839（GG）和 rs1042157（TT））；高活性组（rs6839（AA）和 rs1042157（CC））；和中活性组（rs6839 和 rs1042157 的所有其他组合）。探讨 SULT1A1 表型与临床结局（RFS）之间的关系。
低 SULT1A1 活性组的 Endoxifen 和 4-羟基他莫昔芬浓度明显高于中活性和高活性组（Endoxifen：31.23 vs. 30.51 vs. 27.00，p 值：0.016；4-羟基他莫昔芬：5.55 vs. 5.27 vs. 4.94，p 值：0.05）。在复发方面，低活性组与中活性和高 SULT1A1 活性组相比，结果有更好的趋势（调整后的危险比：0.297；95%CI 0.088-1.000；p 值：0.05）。
我们的结果表明，rs6839 和 rs1042157 单核苷酸多态性对接受辅助他莫昔芬治疗的女性患者的他莫昔芬及其代谢物的浓度和代谢比值以及无复发生存有轻微影响。
