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CYP2D6 polymorphisms influence the efficacy of adjuvant tamoxifen in Thai breast cancer patients
Sirachainan E,Jaruhathai S,Trachu N,Panvichian R
Pharmacogenomics and Personalized Medicine , 2012,
Abstract: Ekaphop Sirachainan,1 Sureerat Jaruhathai,1 Narumol Trachu,2 Ravat Panvichian,1 Thitiya Sirisinha,1 Touch Ativitavas,1 Vorachai Ratanatharathorn,1 Montri Chamnanphon,3 Chonlaphat Sukasem31Division of Medical Oncology, Department of Medicine, 2Research Center, Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, 3Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, ThailandAim: We evaluated single nucleotide polymorphisms (SNPs) of CYP2D6 to identify those that influence the efficiency of tamoxifen in adjuvant treatment of breast cancer through a matched case–control study.Methods: Peripheral blood DNA was collected from 20 patients with disease recurrence during adjuvant tamoxifen treatment and from 19 patients who had completed 5 years of tamoxifen therapy without recurrence of breast cancer. CYP2D6*4 (1846G > A; rs3892097), CYP2D6*10 (100C > T, rs1065852), and CYP2D6*5 (deletion) were genotyped. The correlation between disease-free survival (DFS) and genotype and clinical outcome were assessed using Kaplan–Meier analysis and a log-rank test.Results: We found the allelic frequency of CYP2D6*10 during this study. Patients with the CYP2D6*10 homozygous variant T/T genotype had a significantly shorter median of DFS than those with C/T (P = 0.036), but DFS was not significantly different from that of patients with the C/C genotype (P = 0.316). One patient who was a carrier both of CYP2D6 G/A (1846G > A) and T/T (100C > T) had DFS of 22.7 months.Conclusions: This study demonstrated that CYP2D6*10/*10 was significantly associated with shorter DFS in Thai breast cancer patients receiving tamoxifen. This was a pilot study investigating the correlation of CYP2D6 polymorphisms and their influence on clinical outcomes in Thai estrogen receptor-positive breast cancer patients.Keywords: breast cancer, CYP2D6 polymorphism, pharmacogenetics, single-nucleotide polymorphism (SNP), tamoxifen
CYP2D6 Genotype and Tamoxifen Response for Breast Cancer: A Systematic Review and Meta-Analysis  [PDF]
Danny W. K. Lum, Pablo Perel, Aroon D. Hingorani, Michael V. Holmes
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0076648
Abstract: Objective To evaluate evidence on the association between CYP2D6 genotype and tamoxifen response through. Design Systematic review and meta-analysis of prospective, cross-sectional and case-control studies published to 2012. For each study, relative risks and 95% confidence intervals were extracted and pooled with a fixed and random effects model. Heterogeneity, publication bias, subgroup, and meta-regression analyses were performed. Data Sources PubMed (inception-2012) and EMBASE (inception-2012). Eligibility Criteria for Selecting Studies Criteria for inclusion were studies reporting breast cancer outcomes in patients treated with tamoxifen and genotyped for polymorphisms in the CYP2D6 gene. Results Twenty-five studies of 13,629 individuals were identified, of which 22 investigated the association of CYP2D6 genotype with outcomes in breast cancer women all receiving tamoxifen treatment (“treatment-only” design). Three randomized trials evaluated the effect of CYP2D6 genotype on tamoxifen response (“effect modification” design). In analysis of treatment-only studies, the relative risk (RR) of all-cause mortality (>307 events in 4,936 patients) for carriers of a CYP2D6 reduced function allele was 1.11 (95% confidence interval (CI): 0.94 to 1.31) compared to individuals with normal/increased function CYP2D6 alleles. When we investigated a composite outcome including all-cause mortality and surrogate endpoints for overall survival (>307 events in 6,721 patients), carriers of a CYP2D6 reduced function allele had a RR of 1.27 (95% CI: 1.11 to 1.45). From two randomized trials that permitted effect-modification analysis, one had only 154 patients and showed evidence of effect modification of tamoxifen by CYP2D6 genotype for distant recurrence but was directionally opposite to that predicted, whereas a larger trial of 2,537 patients failed to show evidence of effect modification for breast cancer-free interval (P values for interaction 0.02 and 0.44, respectively). Conclusions Based on these findings, there is insufficient evidence to recommend CYP2D6 genotyping to guide tamoxifen treatment.
CYP2D6 polymorphisms influence the efficacy of adjuvant tamoxifen in Thai breast cancer patients
Sirachainan E, Jaruhathai S, Trachu N, Panvichian R, Sirisinha T, Ativitavas T, Ratanatharathorn V, Chamnanphon M, Sukasem C
Pharmacogenomics and Personalized Medicine , 2012, DOI: http://dx.doi.org/10.2147/PGPM.S32160
Abstract: lymorphisms influence the efficacy of adjuvant tamoxifen in Thai breast cancer patients Original Research (1158) Total Article Views Authors: Sirachainan E, Jaruhathai S, Trachu N, Panvichian R, Sirisinha T, Ativitavas T, Ratanatharathorn V, Chamnanphon M, Sukasem C Published Date October 2012 Volume 2012:5 Pages 149 - 153 DOI: http://dx.doi.org/10.2147/PGPM.S32160 Received: 24 March 2012 Accepted: 27 July 2012 Published: 17 October 2012 Ekaphop Sirachainan,1 Sureerat Jaruhathai,1 Narumol Trachu,2 Ravat Panvichian,1 Thitiya Sirisinha,1 Touch Ativitavas,1 Vorachai Ratanatharathorn,1 Montri Chamnanphon,3 Chonlaphat Sukasem3 1Division of Medical Oncology, Department of Medicine, 2Research Center, Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, 3Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand Aim: We evaluated single nucleotide polymorphisms (SNPs) of CYP2D6 to identify those that influence the efficiency of tamoxifen in adjuvant treatment of breast cancer through a matched case–control study. Methods: Peripheral blood DNA was collected from 20 patients with disease recurrence during adjuvant tamoxifen treatment and from 19 patients who had completed 5 years of tamoxifen therapy without recurrence of breast cancer. CYP2D6*4 (1846G > A; rs3892097), CYP2D6*10 (100C > T, rs1065852), and CYP2D6*5 (deletion) were genotyped. The correlation between disease-free survival (DFS) and genotype and clinical outcome were assessed using Kaplan–Meier analysis and a log-rank test. Results: We found the allelic frequency of CYP2D6*10 during this study. Patients with the CYP2D6*10 homozygous variant T/T genotype had a significantly shorter median of DFS than those with C/T (P = 0.036), but DFS was not significantly different from that of patients with the C/C genotype (P = 0.316). One patient who was a carrier both of CYP2D6 G/A (1846G > A) and T/T (100C > T) had DFS of 22.7 months. Conclusions: This study demonstrated that CYP2D6*10/*10 was significantly associated with shorter DFS in Thai breast cancer patients receiving tamoxifen. This was a pilot study investigating the correlation of CYP2D6 polymorphisms and their influence on clinical outcomes in Thai estrogen receptor-positive breast cancer patients.
Relationship between Genotypes Sult1a2 and Cyp2d6 and Tamoxifen Metabolism in Breast Cancer Patients  [PDF]
Ana Fernández-Santander, María Gaibar, Apolonia Novillo, Alicia Romero-Lorca, Margarita Rubio, Luis Miguel Chicharro, Armando Tejerina, Fernando Bandrés
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0070183
Abstract: Tamoxifen is a pro-drug widely used in breast cancer patients to prevent tumor recurrence. Prior work has revealed a role of cytochrome and sulfotransferase enzymes in tamoxifen metabolism. In this descriptive study, correlations were examined between concentrations of tamoxifen metabolites and genotypes for CYP2D6, CYP3A4, CYP3A5, SULT1A1, SULT1A2 and SULT1E1 in 135 patients with estrogen receptor-positive breast cancer. Patients were genotyped using the Roche-AmpliChip? CYP450 Test, and Real-Time and conventional PCR-RFLP. Plasma tamoxifen, 4-hydroxy-tamoxifen, N-desmethyl-tamoxifen, endoxifen and tamoxifen-N-oxide were isolated and quantified using a high-pressure liquid chromatography-tandem mass spectrometry system. Significantly higher endoxifen levels were detected in patients with the wt/wt CYP2D6 compared to the v/v CYP2D6 genotype (p<0.001). No differences were detected in the remaining tamoxifen metabolites among CYP2D6 genotypes. Patients featuring the SULT1A2*2 and SULT1A2*3 alleles showed significantly higher plasma levels of 4-hydroxy-tamoxifen and endoxifen (p = 0.025 and p = 0.006, respectively), as likely substrates of the SULT1A2 enzyme. Our observations indicate that besides the CYP2D6 genotype leading to tamoxifen conversion to potent hydroxylated metabolites in a manner consistent with a gene-dose effect, SULT1A2 also seems to play a role in maintaining optimal levels of both 4-hydroxy-tamoxifen and endoxifen.
Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer
Pia Wegman, Sauli Elingarami, John Carstensen, Olle St?l, Bo Nordenskj?ld, Sten Wingren
Breast Cancer Research , 2007, DOI: 10.1186/bcr1640
Abstract: In all, 677 tamoxifen-treated postmenopausal patients with breast cancer, of whom 238 were randomised to either 2 or 5 years of tamoxifen, were genotyped by using PCR with restriction fragment length polymorphism or PCR with denaturing high-performance liquid chromatography.The prognostic evaluation performed in the total population revealed a significantly better disease-free survival in patients homozygous for CYP2D6*4. For CYP3A5, SULT1A1 and UGT2B15 no prognostic significance was observed. In the randomised group we found that for CYP3A5, homozygous carriers of the *3 allele tended to have an increased risk of recurrence when treated for 2 years with tamoxifen, although this was not statistically significant (hazard ratio (HR) = 2.84, 95% confidence interval (CI) = 0.68 to 11.99, P = 0.15). In the group randomised to 5 years' tamoxifen the survival pattern shifted towards a significantly improved recurrence-free survival (RFS) among CYP3A5*3-homozygous patients (HR = 0.20, 95% CI = 0.07 to 0.55, P = 0.002). No reliable differences could be seen between treatment duration and the genotypes of CYP2D6, SULT1A1 or UGT2B15. The significantly improved RFS with prolonged tamoxifen treatment in CYP3A5*3 homozygotes was also seen in a multivariate Cox model (HR = 0.13, CI = 0.02 to 0.86, P = 0.03), whereas no differences could be seen for CYP2D6, SULT1A1 and UGT2B15.The metabolism of tamoxifen is complex and the mechanisms responsible for the resistance are unlikely to be explained by a single polymorphism; instead it is a combination of several mechanisms. However, the present data suggest that genetic variation in CYP3A5 may predict response to tamoxifen therapy.Tamoxifen is widely used as an endocrine treatment for patients with oestrogen-receptor (ER)-positive breast cancer. Five years of adjuvant tamoxifen therapy reduces the risk of recurrence and prolongs the survival of women with ER-positive tumours [1]. Nevertheless, in a proportion of patients, tumours are res
The Impact of CYP2D6 Genotyping on Tamoxifen Treatment  [PDF]
Roberta Ferraldeschi,William G. Newman
Pharmaceuticals , 2010, DOI: 10.3390/ph3041122
Abstract: Tamoxifen remains a cornerstone of treatment for patients with oestrogen-receptor-positive breast cancer. Tamoxifen efficacy depends on the biotransformation, predominantly via the cytochrome P450 2D6 (CYP2D6) isoform, to the active metabolite endoxifen. Both genetic and environmental (drug-induced) factors may alter CYP2D6 enzyme activity directly affecting the concentrations of active tamoxifen metabolites. Several studies suggest that germline genetic variants in CYP2D6 influence the clinical outcomes of patients treated with adjuvant tamoxifen. Here, we review the existing data relating CYP2D6 genotypes to tamoxifen efficacy.
Tailoring Adjuvant Endocrine Therapy for Postmenopausal Breast Cancer: A CYP2D6 Multiple-Genotype-Based Modeling Analysis and Validation  [PDF]
Ke-Da Yu,A-Ji Huang,Zhi-Ming Shao
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0015649
Abstract: Previous studies have suggested that postmenopausal women with breast cancer who present with wild-type CYP2D6 may actually have similar or superior recurrence-free survival outcomes when given tamoxifen in place of aromatase inhibitors (AIs). The present study established a CYP2D6 multiple-genotype-based model to determine the optimal endocrine therapy for patients harboring wild-type CYP2D6.
CYP2D6*4 polymorphisms and breast cancer risk  [PDF]
D Surekha
Biology and Medicine , 2010,
Abstract: CYP2D6 gene plays an important role in detoxification of many drugs and plays a crucial role in the metabolism oftamoxifen, used in endocrine therapy. In the present study, the heterozygous frequency IM (40.8%) was significantlyincreased in breast cancer patients when compared to controls. When the data on IM and PM were pooled,significant increase in the frequency of pooled genotype in disease group (42.4%) was observed as compared tocontrols (27.6%). The frequency of IM genotype was found to be increased in women with premenopausal breastcancer patients (43.5%) and patients with familial history of cancer (43.2%). Higher frequency of IM as well as pooledgenotypes PM+IM was found in cases with higher BMI and in patients occupied in agriculture (55.6%), patientspositive for estrogen receptor (47.8%), progesterone receptor (44.8%), HER2/neu (26.9%) and advanced stage. Ourresults suggested that the CYP2D6*4 polymorphism plays an important role in the breast cancer etiology and mighthelp in planning hormonal therapy where tamoxifen is used.
Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients
Pia Wegman, Linda Vainikka, Olle St?l, Bo Nordenskj?ld, Lambert Skoog, Lars-Erik Rutqvist, Sten Wingren
Breast Cancer Research , 2005, DOI: 10.1186/bcr993
Abstract: The patients were genotyped using PCR followed by cleavage with restriction enzymes.Carriers of the CYP2D6*4 allele demonstrated a decreased risk of recurrence when treated with tamoxifen (relative risk = 0.28, 95% confidence interval = 0.11–0.74, P = 0.0089). A similar pattern was seen among the SULT1A1*1 homozygotes (relative risk = 0.48, 95% confidence interval = 0.21–1.12, P = 0.074). The combination of CYP2D6*4 and/or SULT1A1*1/*1 genotypes comprised 60% of the patients and showed a 62% decreased risk of distant recurrence with tamoxifen (relative risk = 0.38, 95% confidence interval = 0.19–0.74, P = 0.0041).The present study suggests that genotype of metabolic enzymes might be useful as a guide for adjuvant endocrine treatment of postmenopausal breast cancer patients. However, results are in contradiction to prior hypotheses and the present sample size is relatively small. Findings therefore need to be confirmed in a larger cohort.The majority of breast tumours express oestrogen receptors (ERs). Several studies have shown that 5 years of tamoxifen therapy in breast cancer patients with receptor-positive tumours reduces the risk of recurrence and mortality [1]. However, about 30% of patients acquire tamoxifen resistance and relapse in the disease [1]. Several possible mechanisms for this have been suggested [2-4].Tamoxifen and its metabolites compete with endogenous oestrogen for the ligand-binding domain of the ER. The complex formation between tamoxifen, or its active metabolites, and the ER inhibits recruitment of co-activator complexes necessary for transcription of oestrogen-responsive genes [5]. The biotransformation of tamoxifen is mediated by cytochrome P450 enzymes mainly through demethylation and hydroxylation to form several primary metabolites, principally 4-OH-tamoxifen, α-OH-tamoxifen, N-desmethyl-tamoxifen, and 4-OH-N-desmethyl-tamoxifen. 4-OH-tamoxifen is considered to be a more potent anti-oestrogen than the mother substance and is capable of b
Endometrial cancer survival after breast cancer in relation to tamoxifen treatment: Pooled results from three countries
Michael E Jones, Flora E van Leeuwen, Wilhelmina E Hoogendoorn, Marian JE Mourits, Harry Hollema, Hester van Boven, Michael F Press, Leslie Bernstein, Anthony J Swerdlow
Breast Cancer Research , 2012, DOI: 10.1186/bcr3206
Abstract: We pooled case-patient data from the three largest case-control studies of tamoxifen in relation to endometrial cancer after breast cancer (1,875 patients: Netherlands, 765; United Kingdom, 786; United States, 324) and collected follow-up information on vital status. Breast cancers were diagnosed in 1972 to 2005 with endometrial cancers diagnosed in 1978 to 2006. We used Cox proportional hazards survival analysis to estimate hazard ratios (HRs) and 95% confidence intervals (CI).A total of 1,104 deaths occurred during, on average, 5.8 years following endometrial cancer (32% attributed to breast cancer, 25% to endometrial cancer). Mortality from endometrial cancer increased significantly with unfavorable non-endometrioid morphologies (P < 0.0001), International Federation of Gynaecology and Obstetrics staging system for gynecological malignancy (FIGO) stage (P < 0.0001) and age (P < 0.0001). No overall association was observed between tamoxifen treatment and endometrial cancer mortality (HR = 1.17 (95% CI: (0.89 to 1.55)). Tamoxifen use for at least five years was associated with increased endometrial cancer mortality (HR = 1.59 (1.13 to 2.25)). This association appeared to be due primarily to the excess of unfavorable histologies and advanced stage in women using tamoxifen for five or more years since the association with mortality was no longer significant after adjustment for morphological type and FIGO stage (HR = 1.37 (0.97 to 1.93)). Those patients with endometrioid tumors, who stopped tamoxifen use at least five years before their endometrial cancer diagnosis, had a greater mortality risk from endometrial cancer than endometrioid patients with no tamoxifen exposure (HR = 2.11 (1.13 to 3.94)). The explanation for this latter observation is not apparent.Patients with endometrial cancer after breast cancer who received tamoxifen treatment for five years for breast cancer have greater endometrial cancer mortality risk than those who did not receive tamoxifen. This
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