|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
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
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{at}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.
The clinical benefit of the antiestrogen agent tamoxifen for the treatment of estrogen receptor (ER)–positive breast cancer has been evident for more than three decades by the eminent reduction of recurrence (47%) and mortality rates (26%).1 Yet, 30% to 50% of patients with adjuvant tamoxifen therapy relapse or die. Although this may be explained in part by tumor-dependent ER activation2 and downstream pathways classified by molecular profiles,3-5 it has become increasingly clear that treatment efficacy is considerably influenced by intrinsic host factors. Several lines of evidence suggest that the metabolites 4-hydroxytamoxifen (4-OH-TAM) and 4-hydroxy-N-desmethyltamoxifen (endoxifen) are the active therapeutic moieties. Compared with the parent drug, these two metabolites have at least 100-fold higher potency, in terms of binding to ER and of suppression of breast cancer cell proliferation.6-10 One of the principal mechanisms of tamoxifen-induced tumor cell growth inhibition is the activation of antiproliferative, transforming growth factor-beta (TGF-ß) signal transduction pathways. Accordingly, the degree of tumor cell growth inhibition has been shown to be exclusively mediated by 4-OH-TAM and endoxifen but not by other metabolites, and, moreover, was related to an upregulation of TGF-ß secretion and TGF-ß receptors.11 Thus, interindividual differences in the formation of these active metabolites could be an important source of variability in the response to tamoxifen. The cytochrome P450 enzyme CYP2D6 is one of the key enzymes for the formation of 4-OH-TAM and endoxifen,9,12,13 and loss of functional alleles of CYP2D6 leads to a poor-metabolizer (PM) phenotype. This phenotype has very low endoxifen plasma levels14 and a nonfavorable clinical outcome.15,16 Moreover, formation of the antiestrogenic metabolites is affected by drugs, such as selective serotonin reuptake inhibitors (SSRIs) used to treat hot flashes, that inhibit CYP2D6.8,14,16,17 Previous studies of the relationship between CYP2D6 genotypes and tamoxifen-related clinical outcomes have been restricted to the major PM allele *4, possibly leading to inaccurate genotype-phenotype assignments, because only 60% to 70% of the 7% to 10% PMs present in a European population may have been detected. The lack of a comprehensive assessment of the known CYP2D6 deficiency variants18-20 might explain the controversial data arising from these studies.15,16,21-23 Furthermore, in addition to PMs, the intermediate-metabolizer phenotype (IM), which occurs with a frequency of at least 10%, has an impaired CYP2D6 function that leads to decreased endoxifen plasma levels, similar to PMs.14 Hence, between 15% and 20% of European patient populations carry genetic CYP2D6 variants associated with a pronounced impairment in the formation of antiestrogenic tamoxifen metabolites. The current study investigated the role of CYP2D6 variants in the outcome of adjuvant tamoxifen therapy by a comprehensive PM- and IM-genotyping approach. In addition, we analyzed CYP3A5, CYP2B6, CYP2C9, and CYP2C19 variants because these enzymes contribute to the formation of antiestrogenic metabolites.
Patients Formalin-fixed, paraffin-embedded tumor specimens of 621 patients diagnosed with primary invasive breast cancer between 1986 and 2000 were obtained from the archival database at the Robert-Bosch Hospital Breast Center, Stuttgart, Germany. Inclusion criteria were based on the availability of clinical follow-up information and the availability of noncancerous breast tissue sufficient for DNA extraction. Relapse-free women with a follow-up of less than 8 months were excluded from the study. We identified three treatment groups based on patient records. The adjuvant monotherapy-tamoxifen treatment group (mTAM) included 206 ER-positive patient cases. There were 280 patients who did not received tamoxifen treatment, but who received either adjuvant chemotherapy or no drug therapy, and who served as a control group (noTAM). Patients receiving adjuvant tamoxifen and concomitant chemotherapy or patients with an unclear ER status (n = 135) were excluded from the analysis. Clinical characteristics of patients in the mTAM and noTAM groups are given in Table 1. The median age at the time of surgery was 60 years (range, 29 to 92 years), and the median postsurgery follow-up period was 71 months (range, 4 to 227 months). Because information on comedication of patients receiving SSRIs was incomplete, it was not included in the analyses. The use of archival patient materials was approved by the local ethics committee of the University Tuebingen.
Genotyping After histologic inspection, DNA was extracted from normal breast tissue using standard procedures. For genotyping, we used matrix-assisted, laser desorption/ionization, time-of-flight mass spectrometry (MALDI-TOF MS), as described in Jaremko et al.24 The CYP2D6 gene duplication and the *5 deletion alleles were determined using a TaqMan, real-time quantification assay, according to Schaeffeler et al.25 The following single nucleotide polymorphisms (SNPs) at CYP2D6 and CYP2C19 were analyzed: CYP2D6 *4, *5, *10, *41, and gene duplication; and CYP2C19 *2, *3, and *17 (–806C > T and –3402C > T). We also included other genes and polymorphisms of the primary tamoxifen biotransformation in our analyses. These were CYP3A5 *3, CYP2B6 (785A > G, –82T > C, 1459C > T, and 516G > T), and CYP2C9 *2 and *3 (Appendix Table A1, online only). Base numberings and allele definitions are in accord with the CYP Allele Nomenclature Committee (http://www.cypalleles.ki.se). All primer sequences are available on request. The CYP2D6-metabolizer status was defined as extensive (EM), based on the absence of *4 or *5 null alleles; heterozygote-extensive (hetEM), based on the presence of one null allele; or poor (PM or IM), based on either being homozygous for null alleles or having a combined null/IM status as defined by null/*10 or null/*41. For statistical reasons, individuals with duplicated genes were included in the EM group, provided that they were not carriers of null alleles. Because polymerase chain reaction–amplification rates were poor (50% to 60%) due to difficulties in designing specific primers that span short fragments (100 to 200 bp), the CYP2D6 PM-alleles *3, *6, *7, and *8 were not included in our analyses.
End Points and Statistical Analyses of Associations
Allele Frequencies Allele frequencies were calculated, and tests on deviation from the Hardy-Weinberg equilibrium were performed (Appendix Table A1, online only). Two polymorphisms, CYP2D6 *10 and CYP2C9 *2, were not in Hardy-Weinberg equilibrium. Observed allele frequencies matched those reported for populations of European descent.
Associations Between Genotypes and Clinical Outcome Two allele variants at CYP2D6 and two allele variants at CYP2C19 passed the multiple-comparison adjustment and showed significant associations with clinical outcome in the mTAM patient group but not in the noTAM control group. CYP2D6 null alleles *4 and *5 were associated with a higher frequency of relapse (OR, 2.13; 95% CI, 1.26 to 3.63; Pemp = .03). The unadjusted OR showed a two- to three-fold increased risk of relapse for CYP2D6 genotypes with at least one null allele (Table 2). Because IM genotypes had increased relapse rates similar to PMs, IM and PM genotypes subsequently were combined. The risk of relapse was close to two-fold for carriers of the PM (*4 or *5) and the PM/IM (null/*10 or null/*41) alleles (ORadj, 1.86; 95% CI, 1.13 to 3.08; P = .02; Table 2), assuming a proportional, stepwise increase of risk associated with zero, one, or two impaired alleles. For the adjuvant mTAM group, Kaplan-Meier estimates show a significant, nonfavorable RFT for carriers of one or two CYP2D6 PM/IM alleles when compared with the EM genotype (P = .04; Fig 1B). Patients carrying at least one impaired CYP2D6 allele with an inferred decreased enzyme activity phenotype showed shorter RFTs compared with the EM phenotype (P = .012; Fig 1C). These differences were not observed in the control group (Fig 1A). Adjusted analysis for two prognostic factors, tumor size and nodal status, showed nonfavorable RFTs (hazard ratio [HR], 2.24; 95% CI, 1.16 to 4.33; P = .02) and EFS rates (HR, 1.89; 95% CI, 1.10 to 3.25; P = .02) in patients with decreased CYP2D6 metabolic activity (Table 3). There was a nonsignificant trend that associated decreased-activity status with shorter OS (HR, 1.73; 95% CI, 0.88 to 3.41; P = .11).
The two CYP2C19-promoter polymorphisms that defined allele *17 (ie, –806C > T and –3402C > T) were significantly associated with a lower risk for relapse in the mTAM patient group (OR, 0.46; 95% CI, 0.25 to 0.86; Pemp = .03) than in the control group. With respect to genotype frequencies, the risk of relapse was reduced for genotypes with one or two *17 alleles, assuming a linear trend of allele dosage (ORadj, 0.43; 95% CI, 0.21 to 0.88; P = .02; Table 2). SNP –806C > T was in strong linkage disequilibrium with SNP –3402C > T. The association between the CYP2C19 genotype and the clinical outcome was demonstrated by Kaplan-Meier analysis. We observed a more favorable RFT for carriers of one or two CYP2C19 *17 alleles in the mTAM group when compared with the remainder of *1, *2, and *3 carriers (P = .05; Fig 2B). This effect was stronger when homozygous and heterozygous *17 carriers were combined (P = .03; Fig 2C). No such effect was observed in the control group (Fig 2A). Cox regression showed significantly more favorable RFTs (HR, 0.45; 95% CI, 0.21 to 0.92; P = .03) and improved EFS rates (HR, 0.58; 95% CI, 0.32 to 1.01; P = .05) for carriers of a *17 genotype (Table 3). Carriers of the *17 allele tended to have a longer OS rate, although it was not a statistically significant difference (HR, 0.61; 95% CI, 0.29 to 1.26; P = .18).
Kaplan-Meier analyses with combined CYP2D6 and CYP2C19 genotypes show that carriers of one CYP2D6 null allele (hetEM) with a moderate to nonfavorable tamoxifen-treatment outcome can be further stratified according to their CYP2C19 genotype status as a *17 carrier or not (Fig 3). This stratification allows more accurate discrimination of patients with poor and moderate outcomes within the hetEM group. Likewise, a proportion of 32% of patients with a favorable outcome could be identified based on a nonimpaired CYP2D6 status and increased CYP2C19 activity.
No associations between genotypes and treatment outcome or survival were observed for the remaining polymorphisms of CYP2C19 (*2 and *3), CYP3A5, CYP2B6, and CYP2C9.
We demonstrated a strong association between CYP2D6-PM and-IM genotypes and a nonfavorable treatment outcome in breast cancer patients receiving adjuvant tamoxifen therapy. Using the occurrence of a breast cancer event as the primary end point, our analyses support the feasibility of treatment-outcome prediction based on the patients' genetic constitution. In addition to verification in PMs, this pharmacogenetic relationship has been verified for the first time for patients with CYP2D6-IM status (ie, patients homozygous for either *41 or *10 or heterozygous in combination with null alleles), through comparison with patients not treated with tamoxifen. Moreover, we provide primary genetic evidence for a CYP2C19 polymorphism as a putative supplementary biomarker for the classification of patients with a favorable treatment outcome. In the absence of any other significant genotype-outcome relationship of the tested bioactivation enzymes, although the strongest end point (OS) did not reach statistical significance because of a limited sample size, our study emphasizes CYP2D6 and CYP2C19 as tamoxifen-predictive markers. The biologic plausibility of the CYP2D6 findings is easily explained by virtue of its function to primarily catalyze the formation of the pharmacologic active, antiestrogenic metabolite, endoxifen.9 Our finding with CYP2C19 is novel, and its specific role within tamoxifen metabolism is less distinct. CYP2D6 carriers of PM alleles *4 or *5 showed a greater risk for breast cancer relapse compared with patients who had normal CYP2D6 genotypes. This draws substance from our comprehensive genotyping approach that increased the detection rate of expected PMs among European patients by 10% to 15% compared with previous studies. Importantly, the non-genotyped null alleles *3, *6, *7, and *8 account for no more than 5% to 6% of overall detectable PMs,18,26 which corresponds to approximately one missed PM in the tamoxifen patient group. Moreover, as a unique feature, we performed combined analyses of carriers with either an IM or a homozygous-PM genotype. This allowed us to strengthen the findings of an association between RFTs or EFS rates and functionally impaired CYP2D6 variants, and it confirmed findings by Borges et al,14 who showed that IM-genotype carriers had low plasma levels of endoxifen, similar to homozygous-PM patients. We suggest that two functional CYP2D6 copies are required to receive a maximum benefit from tamoxifen treatment; this hypothesis is corroborated by our observed reduction in RFT rates in heterozygous-EM patients. The genetic paradigm of tamoxifen-treatment outcome has been accentuated recently by clinical observations of an impact of SSRI-comedication on the efficacy of tamoxifen treatment. Compelling pharmacologic evidence has been provided for the SSRI-associated, CYP2D6-inhibitory effects that transform the enzyme into a functionally impaired status, hence phenocopying a genetic impediment.14,16,17 The current study did not account for SSRI-comedication, because this information was not sufficiently available. However, some of our genotyped EM patients may have been subject to false phenotypic classification because of possible comedication with strong CYP2D6 inhibitors, such as paroxetine or fluoxetine, so our CYP2D6-PM assessment must be considered a minimum estimate. Although our study and studies by Goetz et al15,16 identified the genetic CYP2D6 status as an independent predictor for the outcome of tamoxifen treatment in women with early breast cancer, others did not observe this relationship.21,22,23 Discrepant results may be explained by differences in study designs, including size, different genetic models for the assessment of phenotypes, or stratification effects.27,28 Beyond that, it is important to note that the studies of others were limited to evaluation of the CYP2D6 *4 allele and the infrequent *6 allele.15 We extended the assessment of the patient subpopulation with decreased CYP2D6-metabolizer status and predicted low endoxifen levels from 6% to 15% by conducting additional testing for the gene-deletion allele *5, and by combined IM- and PM-genotype analysis, which considerably increased the power of our study. Our data point to an additional role of CYP2C19 *17 as a putative predictive marker, in that carriers of the CYP2C19 *17 genotype had a significant benefit trend toward reduced breast cancer recurrences and prolonged RFTs and EFS rates. The biologic plausibility for this relationship may be explained by increased gene expression of the CYP2C19 *17 allele, resulting in a putative ultra-rapid (UM) phenotype.29 CYP2C19 contributes to metabolism of tamoxifen to the antiestrogenic metabolite 4-OH-TAM, and it has in vitro activities similar to CYP2D6.9,12 It also contributes to the primary oxidation of tamoxifen to N-desmethyltamoxifen by an estimated in vivo rate of 7% (unpublished data). Although the overall contribution of CYP2C19 to the formation of antiestrogenic tamoxifen metabolites is probably moderate, carriers of CYP2C19 *17 may benefit from tamoxifen administration by an increased biotransformation of active metabolites. This CYP2C19 pathway may be relevant for patients with low levels of CYP3A4 or CYP2D6. The putative clinical significance of CYP2C19 *17 becomes evident from its 24% frequency in individuals of European descent. Therefore, we suggest that CYP2C19 *17 may serve as an auxiliary biomarker for the classification of breast cancer patients likely to benefit from tamoxifen. Our clinical association data are entirely consistent with recent findings of 4-OH-TAM and endoxifen as the antiestrogenic, active metabolites11 with similar effects on global gene expression.30 Decreased or increased plasma levels of these metabolites and therefore the response to tamoxifen may be predictable, as it has become evident from our combined RFT analysis of CYP2D6/CYP2C19 genotypes. Accordingly, a maximum treatment benefit may be expected for one third of all women receiving adjuvant tamoxifen. However, other, unexplored tamoxifen metabolites with agonistic effects on ER may counteract the known antiestrogenic effects, thus pointing to a possible role of defective CYP3A5 variants.23 Our findings are particularly important in light of the current debate on the effectiveness of tamoxifen for postmenopausal women with hormone receptor–positive breast cancer. Randomized trials demonstrated that the administration of an aromatase inhibitor after 5 years of tamoxifen31 or after 2 to 3 years tamoxifen32,33 significantly prolonged disease-free and overall survival. Because the definition of patient groups with nonfavorable and favorable tamoxifen treatment appears feasible through a priori genetic assessment of CYP2D6 and possibly of CYP2C19 metabolism, and given the long-term experience of tamoxifen as a safe and effective antihormonal treatment, we suggest using these assets to refine the choice of and/or sequencing of hormonal therapy in prospective clinical trials. In the future, the up-front, genotype-based prediction of outcome may add and refine the tailoring of antihormonal treatment strategies.
The author(s) indicated no potential conflicts of interest.
Conception and design: Werner Schroth, Peter Fritz, Matthias Schwab, Michel Eichelbaum, Hiltrud Brauch Financial support: Hiltrud Brauch Administrative support: Matthias Schwab, Michel Eichelbaum, Hiltrud Brauch Provision of study materials or patients: Peter Fritz, Wolfgang Simon Collection and assembly of data: Werner Schroth, Lydia Antoniadou, Peter Fritz, Thomas Muerdter Data analysis and interpretation: Werner Schroth, Lydia Antoniadou, Peter Fritz, Ulrich M. Zanger, Wolfgang Simon, Michel Eichelbaum, Hiltrud Brauch Manuscript writing: Werner Schroth, Lydia Antoniadou, Matthias Schwab, Ulrich M. Zanger, Michel Eichelbaum, Hiltrud Brauch Final approval of manuscript: Werner Schroth, Lydia Antoniadou, Peter Fritz, Matthias Schwab, Thomas Muerdter, Ulrich M. Zanger, Wolfgang Simon, Michel Eichelbaum, Hiltrud Brauch
We thank Susanne Gutzeit, Monika McClellan, and Ralf Kristen for technical support in tissue handling.
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.
1. Tamoxifen for early breast cancer: An overview of the randomised trials: Early Breast Cancer Trialists' Collaborative Group. Lancet 351:1451-1467, 1998[CrossRef][Medline] 2. Ring A, Dowsett M: Mechanisms of tamoxifen resistance. Endocr Relat Cancer 11:643-658, 2004 3. Paik S, Shak S, Tang G, et al: A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817-2826, 2004 4. Oh DS, Troester MA, Usary J, et al: Estrogen-regulated genes predict survival in hormone receptor-positive breast cancers. J Clin Oncol 24:1656-1664, 2006 5. Loi S, Haibe-Kains B, Desmedt C, et al: Definition of clinically distinct molecular subtypes in estrogen receptor-positive breast carcinomas through genomic grade. J Clin Oncol 25:1239-1246, 2007 6. Jordan VC: Metabolites of tamoxifen in animals and man: Identification, pharmacology, and significance. Breast Cancer Res Treatment 2:123-138, 1982[CrossRef][Medline] 7. Lien EA, Solheim E, Lea OA, et al: Distribution of 4-hydroxy-N-desmethyltamoxifen and other tamoxifen metabolites in human biological fluids during tamoxifen treatment. Cancer Res 49:2175-2183, 1989 8. 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 95:1758-1764, 2003 9. Desta Z, Ward BA, Soukhova NV, et al: Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: Prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther 310:1062-1075, 2004 10. Johnson MD, Zuo H, Lee KH, et al: Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res Treat 85:151-159, 2004[CrossRef][Medline] 11. Buck MB, Coller JK, Mürdter TE, et al: TGFbeta2 and TbetaRII are valid molecular biomarkers for the antiproliferative effects of tamoxifen and tamoxifen metabolites in breast cancer cells. Breast Cancer Res Treat [epub ahead of print on February 15, 2007] 12. Coller JK, Krebsfaenger N, Klein K, et al: The influence of CYP2B6, CYP2C9 and CYP2D6 genotypes on the formation of the potent antiestrogen Z-4-hydroxy-tamoxifen in human liver. Br J Clin Pharmacol 54:157-167, 2002[CrossRef][Medline] 13. Crewe HK, Notley LM, Wunsch RM, et al: Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: Formation of the 4-hydroxy, 4'-hydroxy and N-desmethyl metabolites and isomerization of trans-4-hydroxytamoxifen. Drug Metab Dispos 30:869-874, 2002 14. Borges S, Desta Z, Li L, et al: Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: Implication for optimization of breast cancer treatment. Clin Pharmacol Ther 80:61-74, 2006[CrossRef][Medline] 15. 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 23:9312-9318, 2005 16. Goetz MP, Knox SK, Suman VJ, et al: The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Res Treat 101:113-121, 2007[CrossRef][Medline] 17. Jin Y, Desta Z, Stearns V, et al: CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 97:30-39, 2005 18. Zanger UM, Raimundo S, Eichelbaum M: Cytochrome P450 2D6: Overview and update on pharmacology, genetics, biochemistry. Naunyn Schmiedebergs Arch Pharmacol 369:23-37, 2004[CrossRef][Medline] 19. 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. Clin Pharmacol Ther 76:128-138, 2004[CrossRef][Medline] 20. Toscano C, Klein K, Blievernicht J, et al: Impaired expression of CYP2D6 in intermediate metabolizers carrying the *41 allele caused by the intronic SNP 2988G>A: Evidence for modulation of splicing events. Pharmacogenet Genomics 16:755-766, 2006[Medline] 21. 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. Breast Cancer Res Treat 91:249-258, 2005[CrossRef][Medline] 22. Wegman P, Vainikka L, Stal O, et al: Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients. Breast Cancer Res 7:R284-R290, 2005[CrossRef][Medline] 23. Wegman P, Elingarami S, Carstensen J, et al: Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer. Breast Cancer Res 9:R7, 2007[CrossRef][Medline] 24. Jaremko M, Justenhoven C, Abraham BK, et al: MALDI-TOF MS and TaqMan assisted SNP genotyping of DNA isolated from formalin-fixed and paraffin-embedded tissues (FFPET). Hum Mutat 25:232-238, 2005[CrossRef][Medline] 25. Schaeffeler E, Schwab M, Eichelbaum M, et al: CYP2D6 genotyping strategy based on gene copy number determination by TaqMan real-time PCR. Hum Mutat 22:476-485, 2003[CrossRef][Medline] 26. 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. Pharmacogenetics 8:15-26, 1998[Medline] 27. Rae JM, Goetz MP, Hayes DF, et al: CYP2D6 genotype and tamoxifen response. Breast Cancer Res 7:E6, 2005[CrossRef][Medline] 28. Wegman PP, Wingren S: CYP2D6 variants and the prediction of tamoxifen response in randomized patients: Author response. Breast Cancer Res 7:E7, 2005[CrossRef][Medline] 29. Sim SC, Risinger C, Dahl ML, et al: A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther 79:103-113, 2006[CrossRef][Medline] 30. Lim YC, Li L, Desta Z, et al: Endoxifen, a secondary metabolite of tamoxifen, and 4-OH-tamoxifen induce similar changes in global gene expression patterns in MCF-7 breast cancer cells. J Pharmacol Exp Ther 318:503-512, 2006 31. Goss PE, Ingle JN, Martino S, et al: Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: Updated findings from NCIC CTG MA. 17. J Natl Cancer Inst 97:1262-1271, 2005 32. 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. N Engl J Med 350:1081-1092, 2004 33. Jakesz R, Jonat W, Gnant M, et al: Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: Combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 366:455-462, 2005[CrossRef][Medline] Submitted April 20, 2007; accepted July 17, 2007.
Related Editorial
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
, nonincreased and increased activity. EM, extensive metabolizer; hetEM, heterozygous extensive; PM, poor metabolizer; IM, intermediate metabolizer.
