Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, The Netherlands.
Leiden Network for Personalised Therapeutics, Leiden University Medical Center, Leiden, The Netherlands.
Sci Rep. 2021 Jan 11;11(1):415. doi: 10.1038/s41598-020-79972-x.
CYP2C192 and CYP2C1917 might influence tamoxifen metabolism and clinical outcome. Our aim was to investigate the effect of CYP2C19 genotypes on tamoxifen concentrations and metabolic ratios (MRs) and breast cancer recurrence in a large cohort of Caucasian women. Genetic variants (CYP2D6 and CYP2C19 genotypes), tamoxifen and metabolites concentrations, baseline characteristics, and breast cancer recurrence from the CYPTAM study (NTR1509) were used. CYP2C192 and CYP2C1917 genotypes were evaluated as alleles and as groups based on CYP2D6 genotypes (high, intermediate and low activity). Log-rank test and Kaplan-Meier analysis were used to evaluate differences in recurrence defined as relapse-free survival (RFS). Classification tree analyses (CTAs) were conducted to assess the levels of interactions per polymorphism (CYP2D6 and CYP2C19 genotypes) on endoxifen concentrations. No differences in mean concentrations and MRs were observed when comparing CYP2C19 genotypes (CYP2C19*1/1; CYP2C191/2; CYP2C192/2; CYP2C191/17; CYP2C1917/17; CYP2C192/*17). Only significant differences (p value < 0.05) in mean concentrations and MRs were observed when comparing tamoxifen activity groups (high, intermediate and low activity). A log-rank test did not find an association across CYP2C19 genotypes (p value 0.898). CTAs showed a significant relationship between CYP2D6 and endoxifen (p value < 0.0001), but no association with CYP2C19 genotypes was found. CYP2C19 polymorphisms do not have a significant impact on tamoxifen metabolism or breast cancer relapse.
CYP2C192 和 CYP2C1917 可能影响他莫昔芬的代谢和临床结局。我们的目的是在一个大型高加索女性队列中研究 CYP2C19 基因型对他莫昔芬浓度和代谢比 (MRs) 以及乳腺癌复发的影响。使用了 CYPTAM 研究 (NTR1509) 的遗传变异 (CYP2D6 和 CYP2C19 基因型)、他莫昔芬和代谢物浓度、基线特征和乳腺癌复发数据。CYP2C192 和 CYP2C1917 基因型根据 CYP2D6 基因型 (高、中、低活性) 作为等位基因和组进行评估。对数秩检验和 Kaplan-Meier 分析用于评估复发定义为无复发生存 (RFS) 的差异。分类树分析 (CTA) 用于评估每个多态性 (CYP2D6 和 CYP2C19 基因型) 对内消旋他莫昔芬浓度的相互作用水平。比较 CYP2C19 基因型时，未见平均浓度和 MRs 存在差异 (CYP2C19*1/1；CYP2C191/2；CYP2C192/2；CYP2C191/17；CYP2C1917/17；CYP2C192/*17)。仅当比较他莫昔芬活性组 (高、中、低活性) 时，才观察到平均浓度和 MRs 的显著差异 (p 值 <0.05)。对数秩检验未发现 CYP2C19 基因型之间存在关联 (p 值 0.898)。CTA 显示 CYP2D6 和内消旋他莫昔芬之间存在显著关系 (p 值 <0.0001)，但未发现与 CYP2C19 基因型相关。CYP2C19 多态性对他莫昔芬代谢或乳腺癌复发没有显著影响。
