Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interindividual differences in drug disposition are important causes for adverse drug reactions and lack of drug response. The majority of phase I and phase II drug-metabolizing enzymes (DMEs) are polymorphic and constitute essential factors for the outcome of drug therapy. Recently, both genome-wide association (GWA) studies with a focus on drug response, as well as more targeted studies of genes encoding DMEs have revealed in-depth information and provided additional information for variation in drug metabolism and drug response, resulting in increased knowledge that aids drug development and clinical practice. In addition, an increasing number of meta-analyses have been published based on several original and often conflicting pharmacogenetic studies. Here, we review data regarding the pharmacogenomics of DMEs, with particular emphasis on novelties. We conclude that recent studies have emphasized the importance of CYP2C19 polymorphism for the effects of clopidogrel, whereas the CYP2C9 polymorphism appears to have a role in anticoagulant treatment, although inferior to VKORC1. Furthermore, the analgesic and side effects of codeine in relation to CYP2D6 polymorphism are supported and the influence of CYP2D6 genotype on breast cancer recurrence during tamoxifen treatment appears relevant as based on three large studies. The influence of CYP2D6 polymorphism on the effect of antidepressants in a clinical setting is yet without any firm evidence, and the relation between CYP2D6 ultrarapid metabolizers and suicide behavior warrants further studies. There is evidence for the influence of CYP3A5 polymorphism on tacrolimus dose, although the influence on response is less studied. Recent large GWA studies support a link between CYP1A2 polymorphism and blood pressure as well as coffee consumption, and between CYP2A6 polymorphism and cigarette consumption, which in turn appears to influence the lung cancer incidence. Regarding phase II enzyme polymorphism, the anticancer treatment with mercaptopurines and irinotecan is still considered important in relation to the polymorphism of TPMT and UGT1A1, respectively. There is a need for further clarification of the clinical importance and use of all these findings, but the recent research in the field that encompasses larger studies and a whole genome perspective, improves the possibilities be able to make firm and cost-effective recommendations for drug treatment in the future.
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PMID:Pharmacogenomics of drug-metabolizing enzymes: a recent update on clinical implications and endogenous effects. 2308 72

Nearly a decade ago, researchers identified a potential interaction between tamoxifen and strong CYP2D6 inhibitors, including several frequently used antidepressants. Based on evidence available at that time, a United States Food and Drug Administration advisory committee recommended tamoxifen's label be changed in October 2006, noting that postmenopausal women with estrogen receptor-positive breast cancer who are poor CYP2D6 metabolizers by genotype or drug interactions may be at increased risk of cancer recurrence. The impact of accumulating drug risk information on antidepressant use is unknown. We conducted a retrospective, longitudinal cohort study of 13,205 women aged 50-95 with breast cancer initiating tamoxifen between July 2004 and December 2009. We evaluated trends in strong, moderate, and weak CYP2D6-inhibitor antidepressants and tamoxifen co-prescribing and factors associated with ongoing strong inhibitor use. A propensity score matched control group (aromatase inhibitor initiators) was used to estimate changes in co-prescribing, accounting for secular trends. In each month, approximately 24 % of tamoxifen and aromatase inhibitor users were prescribed antidepressants. Among women using tamoxifen and antidepressants, 34 % used strong inhibitors between 2004 and 2006 versus 15 % in 2010. Strong inhibitor use decreased more among tamoxifen users than aromatase inhibitor users (difference-in-differences [DD] -0.09; 95 % confidence interval [CI] -0.15, -0.03). Weak inhibitor use increased among tamoxifen users from 32 % between 2004 and 2006 to 52 % in 2010, more rapidly than among aromatase inhibitor users (DD 0.15; CI 0.08, 0.23). The factor most strongly associated with strong inhibitor and tamoxifen co-prescribing after 2006 was prior strong inhibitor use (RR 4.73; CI 3.62-6.18). In conclusion, there were substantial declines in strong CYP2D6-inhibitor use among tamoxifen users following dissemination of information suggesting a potential for increased risk with co-prescribing. Whether patients and providers will continue to avoid strong inhibitor antidepressants is yet to be seen, but clinicians appear to be responsive to drug interaction risk information in this setting.
Breast Cancer Res Treat 2013 Jan
PMID:Trends in co-prescribing of antidepressants and tamoxifen among women with breast cancer, 2004-2010. 2314 65

This study was designed to investigate the frequency of CYP2D6 polymorphisms and evaluate the association between genetic polymorphisms of CYP2D6 and tamoxifen therapeutic outcome in Thai breast cancer patients. We recruited 48 breast cancer patients who received adjuvant tamoxifen for evaluating CYP2D6 genetic polymorphisms using microarray-based technology. Associations between genotypes-phenotypes and disease free survival were analyzed. Median follow up time was 5.6 years. The mean age of the subjects was 50 years. The 3 common allelic frequencies were 43.8% (*10), 36.5 (*1) and 10.4% (*2) which are related to extensive metabolizer (EM) and intermediate metabolizer (IM) with 70.8% and 29.2 %, respectively. No association between CYP2D6 genotypes and DFS was demonstrated. Nevertheless, exploratory analysis showed statistically significant shorter DFS in the IM group of post-menopause patients (HR, 6.85; 95% CI, 1.48 -31.69; P = 0.005). Furthermore, we observed statistically significant shorter DFS of homozygous CYP2D6*10 when compared with heterozygous CYP2D6*10 and other genotypes (P=0.005). CYP2D6*10 was the most common genotype in our subjects. Post-menopause patients with homozygous CYP2D6*10 and IM have shorter DFS. To confirm this relationship, larger samples and comprehensively designed trials in Thailand are required.
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PMID:Impact of CYP2D6 polymorphisms on tamoxifen responses of women with breast cancer: a microarray-based study in Thailand. 2316 78

Breast cancer is the top cancer among women, and its incidence is increasing worldwide. Although the mortality tends to decrease due to early detection and treatment, there is great variability in the rates of clinical response and survival, which makes breast cancer one of the most appealing targets for pharmacogenomic studies. The recognition that functional CYP2D6 polymorphisms affect tamoxifen pharmacokinetics has motivated the attempts of using CYP2D6 genotyping for predicting breast cancer outcomes. In addition to tamoxifen, the chemotherapy of breast cancer includes combinations of cytotoxic drugs, which are substrates for various xenobiotic metabolizing enzymes. Because of these drugs' narrow therapeutic window, it has been postulated that impaired biotransformation could lead to increased toxicity. In the present review, we performed a systematic search of all published data exploring associations between polymorphisms in xenobiotic metabolizing enzymes and clinical outcomes of breast cancer. We retrieved 43 original articles involving either tamoxifen or other chemotherapeutic protocols, and compiled all information regarding response or toxicity. The data indicate that, although CYP2D6 polymorphisms can indeed modify tamoxifen pharmacokinetics, CYP2D6 genotyping alone is not enough for predicting breast cancer outcomes. The studies involving other chemotherapeutic protocols explored a great diversity of pharmacogenetic targets, but the number of studies for each functional polymorphism is still very limited, with usually no confirmation of positive associations. In conclusion, the application of pharmacogenetics to predict breast cancer outcomes and to select one individual's chemotherapeutic protocol is still far from clinical routine. Although some very interesting results have been produced, no clear practical recommendations are recognized yet.
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PMID:Functional polymorphisms in xenobiotic metabolizing enzymes and their impact on the therapy of breast cancer. 2334 96

Cancer intervention strategies have been increasingly focused on developing therapies that are personalized and tailored to each individual's unique genetic profile. Evolving understanding of the metabolism and pharmacogenomics of tamoxifen, an early example of targeted therapy for women with hormone receptor-positive breast cancer, has created decision-making challenges for healthcare providers and their patients. This article reviews the pharmacology of tamoxifen, the genetics and physiology of the CYP2D6 enzyme system that has important effects on tamoxifen metabolism, and subset data analyses from large controlled, clinical trials that cast new light on previously held beliefs about the utility of CYP2D6 genotyping for predicting tamoxifen effectiveness and improved breast cancer outcomes in women with early-stage, hormone receptor-positive breast cancer.
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PMID:Tamoxifen benefits and CYP2D6 testing in women with hormone receptor-positive breast cancer. 2353 53

Tamoxifen has been shown to greatly reduce risk of recurrence and contralateral breast cancer (CBC). Still, second primary contralateral breast cancer is the most common malignancy to follow a first primary breast cancer. Genetic variants in CYP2D6 and other drug-metabolizing enzymes that alter the metabolism of tamoxifen may be associated with CBC risk in women who receive the drug. This is the first study to investigate the impact of this variation on risk of CBC in women who receive tamoxifen. From the population-based Women's Environment Cancer and Radiation Epidemiology (WECARE) Study, we included 624 Caucasian women with CBC (cases) and 1,199 women with unilateral breast cancer (controls) with complete information on tumor characteristics and treatment. Conditional logistic regression was used to assess the risk of CBC associated with 112 single nucleotide polymorphisms (SNPs) in 8 genes involved in the metabolism of tamoxifen among tamoxifen users and non-users. After adjustment for multiple testing, no significant association was observed between any of the genotyped variants and CBC risk in either tamoxifen users or non-users. These results suggest that when using a tagSNP approach, common variants in selected genes involved in the metabolism of tamoxifen are not associated with risk of CBC among women treated with the drug.
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PMID:Variants in tamoxifen metabolizing genes: a case-control study of contralateral breast cancer risk in the WECARE study. 2356 21

Tamoxifen is a widely utilized adjuvant anti-estrogen agent for hormone receptor-positive breast cancer, known to undergo CYP2D6-mediated bioactivation to endoxifen. However, little is known regarding additional genetic and non-genetic determinants of optimal endoxifen plasma concentration. Therefore, 196 breast cancer patients on tamoxifen were enrolled in this prospective study over a 24-month period. Blood samples were collected for pharmacogenetic and drug-level analysis of tamoxifen and metabolites. Regression analysis indicated that besides CYP2D6, the recently described CYP3A4*22 genotype, seasonal variation, and concomitant use of CYP2D6-inhibiting antidepressants were significant predictors of endoxifen concentration. Of note, genetic variation explained 33 % of the variability while non-genetic variables accounted for 13 %. Given the proposed notion of a sub-therapeutic endoxifen concentration for predicting breast cancer recurrence, we set the therapeutic threshold at 18 nM, the 20th percentile for endoxifen level among enrolled patients in this cohort. Nearly 70 % of CYP2D6 poor metabolizers as well as extensive metabolizers on potent CYP2D6-inhibiting antidepressants exhibited endoxifen levels below 18 nM, while carriers of CYP3A4*22 were twofold less likely to be in sub-therapeutic range. Unexpectedly, endoxifen levels were 20 % lower during winter months than mean levels across seasons, which was also associated with lower vitamin D levels. CYP3A4*22 genotype along with sunshine exposure and vitamin D status may be unappreciated contributors of tamoxifen efficacy. The identified covariates along with demographic variables were integrated to create an endoxifen concentration prediction algorithm to pre-emptively evaluate the likelihood of individual patients falling below the optimal endoxifen concentration.
Breast Cancer Res Treat 2013 May
PMID:CYP3A4 and seasonal variation in vitamin D status in addition to CYP2D6 contribute to therapeutic endoxifen level during tamoxifen therapy. 2358 71

Tamoxifen is a widely prescribed adjuvant anti-estrogen agent for estrogen receptor-positive breast cancer. Tamoxifen is known to undergo CYP2D6-mediated bioactivation to the active metabolite endoxifen. Endoxifen concentrations exhibit high interindividual variability, contributing to either sub-optimal tamoxifen efficacy or side effects in subsets of patients. However, the relationship between endoxifen exposure and tumor growth inhibition has not been well-characterized and little is known regarding the optimal in vivo endoxifen plasma level required for tumor inhibition. Pharmacokinetics-Pharmacodynamics (PK-PD) modeling was carried out to characterize the relationship between endoxifen concentration and tumor growth inhibition (TGI) in dose-ranging experiments in the human MCF7 xenograft bearing mouse model. Subsequently, simulations using human PK were used to determine the efficacious clinically relevant endoxifen concentration required to produce optimal tumor suppression. Based on the PK-PD model and simulations using clinical PK/concentration data of endoxifen, C stasis (100 % TGI) is observed at 53 nM, a concentration attained by many tamoxifen-treated patients. Importantly, PK-PD simulations indicate that mean steady-state levels observed in CYP2D6 extensive metabolizers are expected to result in optimal tumor suppression while mean concentrations observed in poor metabolizers are predicted to result in suboptimal TGI. Our study is the first to characterize the in vivo PK-PD relationship for endoxifen where clinically observed endoxifen concentrations are associated, in an exposure-dependent manner, with % TGI measured in a xenograft model. It is anticipated that endoxifen concentration achieved in individual patients is the limiting factor for achieving optimal tumor growth suppression.
Breast Cancer Res Treat 2013 May
PMID:Determination of clinically therapeutic endoxifen concentrations based on efficacy from human MCF7 breast cancer xenografts. 2360 84

Estrogen-receptor positive breast cancer accounts for 75% of diagnosed breast cancers worldwide. There are currently two major options for adjuvant treatment: tamoxifen and aromatase inhibitors. Variability in metabolizing enzymes determines their pharmacokinetic profile, possibly affecting treatment response. Therefore, prediction of therapy outcome based on genotypes would enable a more personalized medicine approach, providing optimal therapy for each patient. In this review, the authors will discuss the current evidence on the most important metabolizing enzymes in endocrine therapy, with a special focus on CYP2D6 and its role in tamoxifen metabolism.
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PMID:Impact of metabolizing enzymes on drug response of endocrine therapy in breast cancer. 2363 18

Tamoxifen contributes to decreased recurrence and mortality of patients with hormone receptor-positive breast cancer. As this drug is metabolized by phase I and phase II enzymes, the interindividual variations of their enzymatic activity are thought to be associated with individual responses to tamoxifen. Among these enzymes, CYP2D6 is considered to be a rate-limiting enzyme in the generation of endoxifen, a principal active metabolite of tamoxifen, and the genetic polymorphisms of CYP2D6 have been extensively investigated in association with the plasma endoxifen concentrations and clinical outcome of tamoxifen therapy. In addition to CYP2D6, other genetic factors including polymorphisms in various drug-metabolizing enzymes and drug transporters have been implicated to their relations to clinical outcome of tamoxifen therapy, but their effects would be small. Although the results of association studies are controversial, accumulation of the evidence has revealed us the important and critical issues in the tamoxifen pharmacogenomics study, namely the quality of genotyping, the coverage of genetic variations, the criteria for sample collection and the source of DNAs, which are considered to be common problematic issues in pharmacogenomics studies. This review points out common critical issues in pharmacogenomics studies through the lessons we have learned from tamoxifen pharmacogenomics, as well as summarizes the results of pharmacogenomics studies for tamoxifen treatment.
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PMID:Important and critical scientific aspects in pharmacogenomics analysis: lessons from controversial results of tamoxifen and CYP2D6 studies. 2365 26


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