Association of genetic variation in tamoxifen-metabolizing enzymes with overall survival and recurrence of disease in breast cancer patients
Association of genetic variation in tamoxifen-metabolizing enzymes with overall survival and recurrence of disease in breast cancer patients
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DOI：
10.1007/s10549-004-7751-x
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发表时间：
2005-06-01
影响因子：
3.8
通讯作者：
Ambrosone, CB
中科院分区：
文献类型：
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作者：
Nowell, SA;Ahn, JY;Ambrosone, CB
他莫昔芬多年来一直是乳腺癌辅助治疗的主要药物。我们试图确定他莫昔芬代谢途径的遗传变异是否影响接受他莫昔芬治疗的乳腺癌患者的总生存期。在一项乳腺癌患者的回顾性研究中，我们检测了CYP2D6（催化活性他莫昔芬代谢物形成的P450）和UGT2B15（促进活性代谢物消除的II期酶）的功能多态性。我们还研究了SULT1A1和UGT2B15变异等位基因的组合是否比单独检测基因时对他莫昔芬治疗患者的总生存有更大的影响。我们进行了一项回顾性研究，使用存档的石蜡块进行DNA提取，并从病理报告和医院肿瘤登记数据中获取临床特征、治疗和结果的信息（162名接受他莫昔芬治疗的患者和175名未接受他莫昔芬治疗的患者）。获得CYP2D6和UGT2B15基因型，并进行Cox比例风险建模。在调整了年龄、种族、诊断时的疾病阶段和激素受体状态后，我们发现CYP2D6基因型与两组乳腺癌患者的总生存率之间没有显著相关性。他莫昔芬治疗的UGT2B15高活性基因型患者复发风险增加，生存期较差。当UGT2B15和SULT1A1“高危”等位基因联合使用时，具有两种变异等位基因的女性的复发风险明显高于具有普通等位基因的女性，生存期较差。这些研究表明II期偶联酶的遗传变异会影响他莫昔芬治疗乳腺癌的疗效。
Tamoxifen has been a mainstay of adjuvant therapy for breast cancer for many years. We sought to determine if genetic variability in the tamoxifen metabolic pathway influenced overall survival in breast cancer patients treated with tamoxifen. We examined functional polymorphisms in CYP2D6, the P450 catalyzing the formation of active tamoxifen metabolites, and UGT2B15, a Phase II enzyme facilitating the elimination of active metabolite in a retrospective study of breast cancer patients. We also examined whether the combination of variant alleles in SULT1A1 and UGT2B15 had more of an impact on overall survival in tamoxifen-treated patients than when the genes were examined separately.We conducted a retrospective study using archived paraffin blocks for DNA extraction and data from pathology reports and hospital tumor registry data for information on clinical characteristics, treatment, and outcomes (162 patients receiving tamoxifen and 175 who did not). Genotypes for CYP2D6 and UGT2B15 were obtained and Cox proportional hazards modeling was performed.After adjusting for age, race, stage of disease at diagnosis, and hormone receptor status, we found no significant association between CYP2D6 genotype and overall survival in either group of breast cancer patients. Tamoxifen-treated patients with UGT2B15 high activity genotypes had increased risk of recurrence and poorer survival. When UGT2B15 and SULT1A1 'at-risk' alleles were combined, women with two variant alleles had significantly greater risk of recurrence and poorer survival than those with common alleles. These studies indicate that genetic variation in Phase II conjugating enzymes can influence the efficacy of tamoxifen therapy for breast cancer.