生物谷報道：德國研究者說,，編碼P450的基因CYP2D6和CYP2C19變異可以預(yù)測使用他莫西芬治療雌激素受體陽性乳腺癌的成功或者失敗。美國斯圖加特臨床藥理學(xué)院的Hiltrud Brauch博士對路透社記者說：“這種發(fā)現(xiàn)的臨床重要性是通過基因型可以找到他莫西芬治療可能有效的患者,，還有那些需要替代治療的患者,，一個需要大型臨床試驗確定的結(jié)果,。
11月20日出版的《臨床腫瘤學(xué)雜志》上，Brauch博士及其同事檢測了206名接受他莫西芬輔助治療的患者和280名沒有接受治療的患者的基因型DNA,。
研究者發(fā)現(xiàn)與功能性等位基因攜帶者相比,，他莫西芬治療組中有CYP2D6等位基因*4、*5,、*10和 *41變異（抗雌激素代謝物形成降低有關(guān)基因）的患者,，都與乳腺癌復(fù)發(fā)率明顯升高有關(guān)，他們還發(fā)現(xiàn)這些患者的無復(fù)發(fā)持續(xù)時間縮短,，以及無病生存率降低,。
此外，與CYP2C19等位基因1,、2,、3攜帶者相比，攜帶高度酶活性促進(jìn)子17等位基因變異的患者臨床療效較好,。
Brauch博士說,，這些發(fā)現(xiàn)有助于反駁一個藥物治療所有疾病的概念，根據(jù)基因型多型性選擇內(nèi)分泌治療,。由于內(nèi)在特性,，可以對不同疾病期的患者外周血和其它診斷材料進(jìn)行基因型檢測。這種檢測可以在最早期將藥物治療個體化,，給患者帶來最大程度的好處,。（生物谷援引中國公眾科技網(wǎng)）
生物谷推薦原始出處：
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: [email protected]
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
