CYP2D6*10基因多态性与雌激素受体阳性乳腺癌患者TAM疗效的相关性研究
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摘要
背景：CYP2D6多态性可能影响高加索人群中的女性乳腺癌患者服用TAM后的疗效,而在中国人群中最常见的突变型为CYP2D6*10。
目的：通过分析服用TAM的雌激素受体阳性乳腺癌患者CYP2D6*10基因多态性,探讨CYP2D6*10基因型与TAM疗效的相关性。
方法：对123例激素受体阳性正在服用TAM的乳腺癌患者,采用聚合酶链反应一限制性片断长度多态性(PCR-RFLP)方法进行CYP2D6*10多态性检测,将突变型与野生型及杂合子两组间患者的DFS及DSS进行单因素及多因素分析。
结果：123名患者中位随访34个月,17例出现局部复发或远处转移,7例与乳腺癌相关性的死亡事件。绘制]Kaplan-Meier生存曲线,Log-rank检验,未发现突变型与野生型及杂合子组间病人的DFS及DSS有差别(P值分别为0.425、0.470)。经Cox回归模型进行多因素分析发现CYP2D6*10基因型与患者DFS短有相关性(0R=3.429：95%CI1.143～10.285：P=0.028),与DSS无相关性(P=0.636)
结论：CYP2D6*10基因多态性与服用TAM的雌激素受体阳性的乳腺癌患者DFS相关,且是一项独立的疗效预测因子。根据CYP2D6*10基因型指导临床TAM个体化用药是可行的。
Background:Human cytochrome P450 2D6 (CYP2D6) genotype may affect the efficacy of tamoxifen treatment in Caucasian women with breast cancer. The most common polymorphism of CYP2D6 in Chinese women is variant 10(188 C to T).
Purpose:Investigated the association between CYP2D6*10 genotype and efficacy in Estrogen-Receptor positive breast cancer patients receiving tamoxifen treatment We evaluat the predictive value of genetic variants of cytochrome P450 enzymes CYP2D6 for tamoxifen treatment outcome.
Method:DNA from 123 patients who taking TAM and was genotyped for CYP2D6*10 by using polymerase chain reactionrestriction fragment length polymorphism (PCR-RFLP) method, Risk and survival estimates were calculated using Kaplan-Meier, and Cox regression analyses.statistical analysis using SPSS 16.0 software, testing level ofα= 0.05.
Result:123 patients,17 patients had local recurrence or distant metastasis,7 cases of breast cancer deaths.Drawn by the Kaplan-Meier method of survival curve,Log-rank test, the CYP2D6*10 genotype was not significantly associated with DFS and DSS in the C/T and C/C genotype, the T/T genotype three subgroups (P values were 0.425,0.470 respectively).But in multivariate analysis, as compared with the C/T and C/C genotype, the T/T genotype remained an independent prognostic marker of DFS(HR=3.429;95% CI 1.143～10.285 P=0.028),but no correlation with DSS (P=0.636).
Conclusion:
CYP2D6*10 genotype and taking TAM estrogen receptor-positive breast cancer patients with DFS-related, and is an independent prognostic factor.According to the CYP2D6*10 genotype on the clinical use of drugs.TAM individualized guidance is feasible in breast cancer patients.
目的：通过分析服用TAM的雌激素受体阳性乳腺癌患者CYP2D6*10基因多态性,探讨CYP2D6*10基因型与TAM疗效的相关性。
方法：对123例激素受体阳性正在服用TAM的乳腺癌患者,采用聚合酶链反应一限制性片断长度多态性(PCR-RFLP)方法进行CYP2D6*10多态性检测,将突变型与野生型及杂合子两组间患者的DFS及DSS进行单因素及多因素分析。
结果：123名患者中位随访34个月,17例出现局部复发或远处转移,7例与乳腺癌相关性的死亡事件。绘制]Kaplan-Meier生存曲线,Log-rank检验,未发现突变型与野生型及杂合子组间病人的DFS及DSS有差别(P值分别为0.425、0.470)。经Cox回归模型进行多因素分析发现CYP2D6*10基因型与患者DFS短有相关性(0R=3.429：95%CI1.143～10.285：P=0.028),与DSS无相关性(P=0.636)
结论：CYP2D6*10基因多态性与服用TAM的雌激素受体阳性的乳腺癌患者DFS相关,且是一项独立的疗效预测因子。根据CYP2D6*10基因型指导临床TAM个体化用药是可行的。
Background:Human cytochrome P450 2D6 (CYP2D6) genotype may affect the efficacy of tamoxifen treatment in Caucasian women with breast cancer. The most common polymorphism of CYP2D6 in Chinese women is variant 10(188 C to T).
Purpose:Investigated the association between CYP2D6*10 genotype and efficacy in Estrogen-Receptor positive breast cancer patients receiving tamoxifen treatment We evaluat the predictive value of genetic variants of cytochrome P450 enzymes CYP2D6 for tamoxifen treatment outcome.
Method:DNA from 123 patients who taking TAM and was genotyped for CYP2D6*10 by using polymerase chain reactionrestriction fragment length polymorphism (PCR-RFLP) method, Risk and survival estimates were calculated using Kaplan-Meier, and Cox regression analyses.statistical analysis using SPSS 16.0 software, testing level ofα= 0.05.
Result:123 patients,17 patients had local recurrence or distant metastasis,7 cases of breast cancer deaths.Drawn by the Kaplan-Meier method of survival curve,Log-rank test, the CYP2D6*10 genotype was not significantly associated with DFS and DSS in the C/T and C/C genotype, the T/T genotype three subgroups (P values were 0.425,0.470 respectively).But in multivariate analysis, as compared with the C/T and C/C genotype, the T/T genotype remained an independent prognostic marker of DFS(HR=3.429;95% CI 1.143～10.285 P=0.028),but no correlation with DSS (P=0.636).
Conclusion:
CYP2D6*10 genotype and taking TAM estrogen receptor-positive breast cancer patients with DFS-related, and is an independent prognostic factor.According to the CYP2D6*10 genotype on the clinical use of drugs.TAM individualized guidance is feasible in breast cancer patients.
引文
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[1]EBCTCG. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival:an overview of the randomised trials[J]. Lancet,2005;365(9472):1687-717.
[2]EBCTCG. Tamoxifen for early breast cancer:an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group[J].Lancet, 1998;351(9114):1451-67.
[3]李鹤成,温险峰,沈坤炜等.绝经前雌激素受体阳性乳腺癌患者三苯氧胺辅助治疗的临床价值[J].中华普通外科杂志,2002；17(10)：629-630
[4]Wang jY,Seah ES,Lee Ej.Pharmacogeneticacthe molecular genetica ob CYP2D6 dependent drug metaboliam[J].Oncologist,2005,10(2):104-111.
[5]Jordan VC, Collins MM, Rowsby L,et al.Monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity[J].Endocrinol,1977; 75:305-16.
[6]Punglia RS,Burstein HJ, Winer EP, Weeks JC.Pharmacogenomic variation of CYP2D6 and the choice of optimal adjuvant endocrine therapy for postmenopausal breast cancer:a modeling analysis[J].Natl Cancer Inst, 2008;100(9):642-8.
[7]Love RR,Duc NB, Havighurst TC,et al.HER-2/neu overexpression and response to oophorectomy plus tamoxifen adjuvant therapy in estrogen receptor positive premenopausalwomen with operable breast cancer [J].Clin Oncol,2003, 21:453-457.
[8].Ingle JN, Suman VJ, Mailliard JA et al.Randomized trial of tamoxifen alone or combined with fluoxymesterone as adjuvant therapy in postmenopausal women with resected estrogen receptor positive breast cancer.North Central Cancer Treatment Group Trial 89-30-52.Breast Cancer Res Treat[J]. 2006,98(2):217-222
[9]Osborne CK,Bardou V,Hopp TA,et al.Role of the estrogen receptor coactivator AIB1(SRC-3)and HER-2/neu in tamoxifen resistance in breast cancer [J].J Natl Cancer Inst,2003,95:353-361.
[10]Hayes DF, Thor AD. c-erbB-2 in breast cancer:development of a clinically useful marker[J].Semin Oncol,2002;29:231-45.
[11]Pritchard KI. Use of ErbB-1 and ErbB-2 to select endocrine therapy for breast cancer:will it play in Peoria? [J].Clin Oncol,2001;19:3795-7.
[12],Deeken JF, Figg WD, Bates SE, et al.Toward individualized treatment: prediction of anticancer drug disposition and toxicity with pharmacogenetics [J]. Anticancer Drugs,2007;18(2):111-126.
[13]Lee W, Lockhart AC, Kim RB,et al.Cancer pharmacoge-nomics:powerful tools in cancer chemotherapy and drug development[J].Oncologist,2005; 10(2):104-111.
[14].Griese EU, Zanger UM, Brudermanns U, et al. Assessment of the predictive power of genotypes for the in-vivo catalytic function of CYP2D6 in a German population[J].Pharmacogenetics,1998;8(1):15-26.
[15].Raimundo S, Toscano C, Klein K, et al.A novel intronic mutation,2988G>A, with high predictivity for impaired function of cytochrome P450 2D6 in white subjects[J].Clin Pharmacol Ther,2004;76(2):128-38.
[16].Sachse C, Brockmoller J, Bauer S,et al.Cytochrome P450 2D6 variants in a Caucasian population:allele frequencies and phenotypic consequences[J].Am J Hum Genet 1997;60(2):284-95.
[17]Sistonen J, Sajantila A, Lao O, et al.CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure [J]. Pharmacogenet Genomics,2007;17(2):93-101.
[18]Cui YM, Teng CH, Pan AX, et al.Atomoxetine pharmacokinetics in healthy Chinese subjects and effect of the CYP2D6*3 10 allele[J].BrJ Clin Pharm acol, 2007;64:445-449.
[19]Jordan VC, Brodie AM. Development and evolution of therapies targeted to the estrogen receptor for the treatmentand prevention of breast cancer[J].Steroids, 2007;72(1):7-25.
[20]Howell A, Cuzick J, Baum M, et al. Results of the ATAC(Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer[J].Lancet,2005;365(9453):60-2.
[21]Goss PE, Ingle JN, Martino S,et al.A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer[J].N Engl Med,2003;349(19):1793-802.
[22]Coombes RC,Hall E,Gibson LJ,et al.A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer[J]. N Engl Med,2004;350(11):1081-92.
[23]Goetz MP, Rae JM, Suman VJ, et al.Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes[J].Clin Oncol,2005;23(36):9312-8.
[24]Goetz MP, Knox SK, Suman VJ, et al.The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen[J].Breast Cancer Res Treat, 2007;101(1):113-21.
[25]Schroth W, Antoniadou L, Fritz P, et al. Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes[J].Clin Oncol,2007;25(33):5187-93.
[26]Lim HS, Ju LH, Seok LK,et al.Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer[J].J Clin Oncol,2007;25(25):3837-45.
[27]Xu Y, Sun Y, Yao L, et al. Association between CYP2D6*10 genotype and survival of breast cancer patients receiving tamoxifen treatment[J]. Ann Oncol, 2008;19(8):1423-9.
[28]Kiyotani K, Mushiroda T, Sasa M, et al. Impact of CYP2D6*10 on recurrence-free survival in breast cancer patients receiving adjuvant tamoxifen therapy[J].Cancer Sci,2008;99(5):995-9.
[29]Nowell SA, Ahn J, Rae JM, et al.Association of genetic variation in tamoxifen-metabolizing enzymes with overall survival and recurrence of disease in breast cancer patients[J].Breast Cancer Res Treat,2005;91(3):249-58.
[30]Wegman P, Vainikka L, Stal O, et al. Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients[J].Breast Cancer Res,2005;7(3):R284-90.
[31]Wegman P, Elingarami S, Carstensen J, et al.Genetic variants of CYP3A5, CYP2D6, SULT1A1,UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer[J].Breast Cancer Res,2007;9(1):R7.
[32]Barron TI, Connolly R, Bennett K, et al.Early discontinuation of tamoxifen:a lesson for oncologists[J].Cancer,2007;109(5):832-9.
[33]Fallowfield L. Acceptance of adjuvant therapy and quality of life issues[J].Breast, 2005;14(6):612-6.
[34]Owusu C, Buist DS, Field TS, et al. Predictors of tamoxifen discontinuation among older women with estrogen receptorpositive breast cancer[J].Clin Oncol, 2008;26(4):549-55.
[35]Mortimer JE, Flatt SW, Parker BA, et al.Tamoxifen, hot flashes and recurrence in breast cancer[J]. Breast Cancer Res Treat,2008;108(3):421-6.
[36].Loprinzi CL, Kugler JW, Sloan JA, et al.Venlafaxine in management of hot flashes in survivors of breast cancer:a randomised controlled trial[J].Lancet, 2000;356(9247):2059-63.
[37]Loprinzi CL, Sloan JA, Perez EA, et al. Phase III evaluation of fluoxetine for treatment of hot flashes [J].Clin Oncol,2002;20(6):1578-83.
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[39].Stearns V,Johnson MD, Rae JM, et al. Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine[J].Natl Cancer Inst[J]2003;95(23):1758-64.
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