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 × 10−8). 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.

中文翻译：

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早期乳腺癌患者内多昔芬血清浓度和他莫昔芬辅助疗效的全基因组关联研究

他莫昔芬是乳腺癌辅助治疗内分泌治疗护理标准的一部分。然而，他莫昔芬的生存结果差异很大。恩多昔芬（endoxifen）的浓度是他莫昔芬的 30-100 倍，由 CYP2D6 酶生物激活，被描述为他莫昔芬代谢最相关的代谢物。进行了全基因组关联研究（GWAS），目的是确定与接受他莫昔芬的早期乳腺癌患者的内多昔芬血清浓度水平和临床结果相关的遗传多态性。对 CYPTAM 研究的 608 名女性进行了 GWAS（NTR1509/PMID：30120701）。种系 DNA 以及临床和生存特征都很容易获得。使用 Infinium Global Screening Array（686,082 个标记）进行基因分型，并使用 1000 个基因组进行单核苷酸多态性 (SNP) 插补。他莫昔芬（RFSt）期间的无复发生存被定义为主要临床结果。内多昔芬血清浓度作为连续变量进行分析。一些遗传变异达到了全基因组意义（磷值：≤5×10−8）。内多昔芬浓度分析确定了 430 个变体，位于TCF20和WBP2NL基因（22号染色体），与CYP2D6变体。在 RFSt 分析中，鉴定了几个 SNP（LPP基因：rs77693286，HR 18.3，95% CI：15.2–21.1； rs6790761，OR 18.2，95% CI：15.5–21.1）。内多昔芬浓度与含有 CYP2D6 基因的 22 号染色体有很强的相关性。