生物谷报道：德国研究者说，编码P450的基因CYP2D6和CYP2C19变异可以预测使用他莫西芬治疗雌激素受体阳性乳腺癌的成功或者失败。美国斯图加特临床药理学院的Hiltrud Brauch博士对路透社记者说：“这种发现的临床重要性是通过基因型可以找到他莫西芬治疗可能有效的患者，还有那些需要替代治疗的患者，一个需要大型临床试验确定的结果。
11月20日出版的《临床肿瘤学杂志》上，Brauch博士及其同事检测了206名接受他莫西芬辅助治疗的患者和280名没有接受治疗的患者的基因型DNA。
研究者发现与功能性等位基因携带者相比，他莫西芬治疗组中有CYP2D6等位基因*4、*5、*10和 *41变异（抗雌激素代谢物形成降低有关基因）的患者，都与乳腺癌复发率明显升高有关，他们还发现这些患者的无复发持续时间缩短，以及无病生存率降低。
此外，与CYP2C19等位基因1、2、3携带者相比，携带高度酶活性促进子17等位基因变异的患者临床疗效较好。
Brauch博士说，这些发现有助于反驳一个药物治疗所有疾病的概念，根据基因型多型性选择内分泌治疗。由于内在特性，可以对不同疾病期的患者外周血和其它诊断材料进行基因型检测。这种检测可以在最早期将药物治疗个体化，给患者带来最大程度的好处。（生物谷援引中国公众科技网）
生物谷推荐原始出处：
Journal of Clinical Oncology, Vol 25, No 33 (November 20), 2007: pp. 5187-5193
© 2007 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2007.12.2705
Breast Cancer Treatment Outcome With Adjuvant Tamoxifen Relative to Patient CYP2D6 and CYP2C19 Genotypes
Werner Schroth, Lydia Antoniadou, Peter Fritz, Matthias Schwab, Thomas Muerdter, Ulrich M. Zanger, Wolfgang Simon, Michel Eichelbaum, Hiltrud Brauch
From the Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, the University Tuebingen, and the Robert Bosch Hospital, Stuttgart; and the Department of Clinical Pharmacology, University Hospital Tuebingen, Tuebingen, Germany
Address reprint requests to Hiltrud Brauch, PhD, Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 112, D-70376 Stuttgart, Germany; e-mail: hiltrud.brauch@ikp-stuttgart.de
Purpose: The clinical outcome of tamoxifen-treated breast cancer patients may be influenced by the activity of cytochrome P450 enzymes that catalyze the formation of antiestrogenic metabolites endoxifen and 4-hydroxytamoxifen. We investigated the predictive value of genetic variants of CYP2D6, CYP2C19, and three other cytochrome P450 enzymes for tamoxifen treatment outcome.
Patients and Methods: DNA from 206 patients receiving adjuvant tamoxifen monotherapy and from 280 patients not receiving tamoxifen therapy (71 months median follow-up) was isolated from archival material and was genotyped for 16 polymorphisms of CYP2D6, CYP2C19, CYP2B6, CYP2C9, and CYP3A5 by matrix-assisted, laser desorption/ionization, time-of-flight mass spectrometry, and by copy number quantification. Risk and survival estimates were calculated using logistic regression, Kaplan-Meier, and Cox regression analyses.
Results: Tamoxifen-treated patients carrying the CYP2D6 alleles *4, *5, *10, *41—all associated with impaired formation of antiestrogenic metabolites—had significantly more recurrences of breast cancer, shorter relapse-free periods (hazard ratio [HR], 2.24; 95% CI, 1.16 to 4.33; P = .02), and worse event-free survival rates (HR, 1.89; 95% CI, 1.10 to 3.25; P = .02) compared with carriers of functional alleles. Patients with the CYP2C19 high enzyme activity promoter variant *17 had a more favorable clinical outcome (HR, 0.45; 95% CI, 0.21 to 0.92; P = .03) than carriers of *1, *2, and *3 alleles.
Conclusion: Because genetically determined, impaired tamoxifen metabolism results in worse treatment outcomes, genotyping for CYP2D6 alleles *4, *5, *10, and *41 can identify patients who will have little benefit from adjuvant tamoxifen therapy. In addition to functional CYP2D6 alleles, the CYP2C19 *17 variant identifies patients likely to benefit from tamoxifen.
Supported by the Robert Bosch Foundation, Stuttgart, Germany.
Presented in part as a poster at the First AACR International Conference on Molecular Diagnostics in Cancer Therapeutic Development: Maximizing Opportunities for Individualized Treatment, Chicago, IL, September 12-15, 2006.
Ulrich M. Zanger is a named coinventor of pending patent applications directed to the detection of CYP2D6 *41 allele polymorphisms for diagnostic purposes and is entitled to share in any net income derived from licensing these patent rights under standard academic institutional policies.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article
