Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands.
Clin Pharmacol Ther. 2024 Jul;116(1):155-164. doi: 10.1002/cpt.3255. Epub 2024 Mar 19.
Tamoxifen is part of the standard of care of endocrine therapy for adjuvant treatment of breast cancer. However, survival outcomes with tamoxifen are highly variable. The concentration of endoxifen, the 30-100 times more potent metabolite of tamoxifen and bioactivated by the CYP2D6 enzyme, has been described as the most relevant metabolite of tamoxifen metabolism. A genome-wide association study (GWAS) was performed with the objective to identify genetic polymorphisms associated with endoxifen serum concentration levels and clinical outcome in early-stage breast cancer patients receiving tamoxifen. A GWAS was conducted in 608 women of the CYPTAM study (NTR1509/PMID: 30120701). Germline DNA and clinical and survival characteristics were readily available. Genotyping was performed on Infinium Global Screening Array (686,082 markers) and single nucleotide polymorphism (SNP) imputation by using 1000 Genomes. Relapse-free survival during tamoxifen (RFSt) was defined the primary clinical outcome. Endoxifen serum concentration was analyzed as a continuous variable. Several genetic variants reached genome-wide significance (P value: ≤5 × 10). Endoxifen concentrations analysis identified 430 variants, located in TCF20 and WBP2NL genes (chromosome 22), which are in strong linkage disequilibrium with CYP2D6 variants. In the RFSt analysis, several SNP were identified (LPP gene: rs77693286, HR 18.3, 95% CI: 15.2-21.1; rs6790761, OR 18.2, 95% CI: 15.5-21.1). Endoxifen concentrations have a strong association with the chromosome 22, which contains the CYP2D6 gene.
他莫昔芬是乳腺癌辅助内分泌治疗标准治疗的一部分。然而，他莫昔芬的生存结果差异很大。endoxifen 是他莫昔芬的 30-100 倍强代谢物，由 CYP2D6 酶生物激活，已被描述为他莫昔芬代谢的最相关代谢物。进行了一项全基因组关联研究（GWAS），目的是确定与接受他莫昔芬治疗的早期乳腺癌患者的 endoxifen 血清浓度水平和临床结果相关的遗传多态性。在 CYPTAM 研究（NTR1509/PMID：30120701）中对 608 名女性进行了 GWAS。生殖系 DNA 和临床及生存特征易于获得。基因分型采用 Infinium Global Screening Array（686,082 个标记）进行，并使用 1000 Genomes 进行单核苷酸多态性（SNP）推断。无复发生存时间（RFSt）被定义为主要临床结局。endoxifen 血清浓度作为连续变量进行分析。几个遗传变异达到全基因组显著水平（P 值：≤5 × 10）。endoxifen 浓度分析确定了位于 TCF20 和 WBP2NL 基因（染色体 22）的 430 个变异，这些变异与 CYP2D6 变异强烈连锁不平衡。在 RFSt 分析中，确定了几个 SNP（LPP 基因：rs77693286，HR 18.3，95%CI：15.2-21.1；rs6790761，OR 18.2，95%CI：15.5-21.1）。endoxifen 浓度与包含 CYP2D6 基因的染色体 22 有很强的关联。
