RESUMEN
The clinical importance of CYP2D6 genotype as predictor of tamoxifen efficacy is still unclear. Recent genotyping studies on CYP2D6 using DNA derived from tumor blocks have been criticized because loss of heterozygosity (LOH) in tumors may lead to false genotype assignment. Postmenopausal early breast cancer patients who were randomized to receive tamoxifen, followed by exemestane in a large randomized controlled trial were genotyped for five CYP2D6 alleles. CYP2D6 genotypes and phenotypes were related to disease-free survival during tamoxifen use (DFS-t) in 731 patients. By analyzing microsatellites flanking the CYP2D6 gene, patients whose genotyping results were potentially affected by LOH were excluded. In addition, exploratory analyses on 24 genetic variants of other metabolic enzymes and the estrogen receptor were performed. For the CYP2D6 analysis, only 2.3 % of the samples were excluded, because influence of LOH could not be ruled out. No association was found between the CYP2D6 genotype or predicted phenotype and DFS-t (poor vs. extensive metabolizers: unadjusted hazard ratio 1.33, 95 % CI 0.52-3.43; P = 0.55). DFS-t was associated with UGT2B15*2 (Vt/Vt + Wt/Vt vs. Wt/Wt: adjusted hazard ratio 0.47, 95 % CI 0.25-0.89; P = 0.019) and the estrogen receptor-1 polymorphism ESR1 PvuII (gene-dose effect: adjusted hazard ratio 1.63, 95 % CI 1.04-2.54; P = 0.033). In postmenopausal early breast cancer patients treated with adjuvant tamoxifen followed by exemestane neither CYP2D6 genotype nor phenotype did affect DFS-t. This is in accordance with two recent studies in the BIG1-98 and ATAC trials. Our study is the first CYP2D6 association study using DNA from paraffin-embedded tumor tissue in which potentially false interpretation of genotyping results because of LOH was excluded. Polymorphisms in the estrogen receptor-1 and UGT2B15 may be associated with tamoxifen efficacy, but these findings need replication.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Citocromo P-450 CYP2D6/genética , Tamoxifeno/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Aromatasa/administración & dosificación , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Receptor alfa de Estrógeno/genética , Femenino , Genotipo , Humanos , Pérdida de Heterocigocidad/genética , Persona de Mediana Edad , Polimorfismo Genético , Factores de RiesgoRESUMEN
Hypertension is an important side effect of sunitinib treatment. In a retrospective study in 255 patients, single-nucleotide polymorphisms (SNPs) in vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor receptor (VEGFR)-2, endothelin-1 (ET-1), and endothelium-derived nitric oxide synthase (eNOS) were multivariately tested against hypertension grades and changes in systolic blood pressure (SBP), diastolic BP (DBP), and mean arterial BP (MAP). Next, the association between hypertension and survival in patients with metastatic renal cell cancer (mRCC) was studied. Greater elevations in SBP and MAP were associated with the presence of a haplotype in VEGFA (P = 0.014 and P = 0.036, respectively). The tendency to develop grade 3 hypertension was associated with this haplotype and also with a SNP in eNOS (P = 0.031 and P = 0.045, respectively). In mRCC patients, sunitinib-induced hypertension was found to confer a survival benefit, with the mean overall survival being prolonged by 7.2 months (P = 0.035 and P = 0.026 for SBP and DBP elevations, respectively). Genetic polymorphisms in VEGFA and eNOS independently predict rise in BP and/or development of severe hypertension in sunitinib-treated patients. Grade 3 hypertension was found to be an independent factor for overall survival in patients with mRCC.
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Hipertensión/inducido químicamente , Hipertensión/genética , Indoles/efectos adversos , Óxido Nítrico Sintasa de Tipo III/genética , Polimorfismo de Nucleótido Simple/genética , Pirroles/efectos adversos , Factor A de Crecimiento Endotelial Vascular/genética , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/mortalidad , Femenino , Humanos , Hipertensión/mortalidad , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Neoplasias Renales/mortalidad , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Sunitinib , Tasa de Supervivencia/tendencias , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Adulto JovenRESUMEN
BACKGROUND: Previous studies have provided contradictory results regarding the interaction between the CYP2C9 and VKORC1 genotypes affecting various outcome measures. OBJECTIVES: We aimed to provide a definite answer regarding the question whether there exists a gene-gene interaction between the CYP2C9 and VKORC1 genotypes affecting the anticoagulant effect of phenprocoumon and acenocoumarol. PATIENTS/METHODS: The EU-PACT cohort dataset, which contains data on 624 phenprocoumon and 471 acenocoumarol patients, was used. Patient characteristics, pharmacogenetic data, International Normalized Ratios (INRs) and dosages were available. We investigated whether there was an interaction between the CYP2C9 and VKORC1 genotypes affecting the maintenance dose, time to severe over-anticoagulation and time to achieve stability during the first 180 days of phenprocoumon and acenocoumarol therapy, in addition to the effect of the separate genotypes. The interaction effect was investigated by adding the product term of the CYP2C9 and VKORC1 genotype classes for four different commonly used CYP2C9 classifications to the linear regression model - for the outcome measure maintenance dose - or to the Cox regression models - for the outcome measures time to severe over-anticoagulation and time to achieve stability. RESULTS: No significant interactions - all P-values above 0.23 for phenprocoumon and 0.30 for acenocoumarol - were observed for all outcome measures. CONCLUSIONS: There are no interactions between the CYP2C9 and VKORC1 genotypes affecting the maintenance dose, time to severe over-anticoagulation and time to achieve stability for phenprocoumon and acenocoumarol.
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Acenocumarol/uso terapéutico , Anticoagulantes/uso terapéutico , Hidrocarburo de Aril Hidroxilasas/genética , Coagulación Sanguínea/efectos de los fármacos , Coagulación Sanguínea/genética , Oxigenasas de Función Mixta/genética , Fenprocumón/uso terapéutico , Acenocumarol/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Anticoagulantes/efectos adversos , Citocromo P-450 CYP2C9 , Monitoreo de Drogas/métodos , Femenino , Genotipo , Humanos , Relación Normalizada Internacional , Modelos Lineales , Masculino , Persona de Mediana Edad , Países Bajos , Farmacogenética , Fenotipo , Fenprocumón/efectos adversos , Modelos de Riesgos Proporcionales , Vitamina K Epóxido ReductasasRESUMEN
BACKGROUND: The required acenocoumarol dose and the risk of underanticoagulation and overanticoagulation are associated with the CYP2C9 and VKORC1 genotypes. However, the duration of the effects of these genes on anticoagulation is not yet known. OBJECTIVES: In the present study, the effects of these polymorphisms on the risk of underanticoagulation and overanticoagulation over time after the start of acenocoumarol were investigated. PATIENTS/METHODS: In three cohorts, we analyzed the relationship between the CYP2C9 and VKORC1 genotypes and the incidence of subtherapeutic or supratherapeutic International Normalized Ratio (INR) values (< 2 and > 3.5) or severe overanticoagulation (INR > 6) for different time periods after treatment initiation. RESULTS: Patients with polymorphisms in CYP2C9 and VKORC1 had a higher risk of overanticoagulation (up to 74%) and a lower risk of underanticoagulation (down to 45%) in the first month of treatment with acenocoumarol, but this effect diminished after 1-6 months. CONCLUSIONS: Knowledge of the patient's genotype therefore might assist physicians to adjust doses in the first month(s) of therapy.
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Acenocumarol/farmacocinética , Anticoagulantes/farmacocinética , Hidrocarburo de Aril Hidroxilasas/genética , Coagulación Sanguínea/efectos de los fármacos , Oxigenasas de Función Mixta/genética , Acenocumarol/administración & dosificación , Acenocumarol/efectos adversos , Anciano , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversos , Hidrocarburo de Aril Hidroxilasas/metabolismo , Citocromo P-450 CYP2C9 , Esquema de Medicación , Cálculo de Dosificación de Drogas , Monitoreo de Drogas/métodos , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Relación Normalizada Internacional , Masculino , Errores de Medicación/prevención & control , Oxigenasas de Función Mixta/metabolismo , Países Bajos , Farmacogenética , Fenotipo , Polimorfismo Genético , Valor Predictivo de las Pruebas , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Vitamina K Epóxido ReductasasRESUMEN
PURPOSE: Our purpose was to investigate the feasibility of pharmacy-initiated pharmacogenetic (PGt) screening in primary care with respect to patient willingness to participate, quality of DNA collection with saliva kits, genotyping, and dispensing data retrieved from the pharmacy. METHODS: Polypharmacy patients aged >60 years who used at least one drug with Anatomical Therapeutic Chemical (ATC) code N06AA01-N06AX19 (antidepressants), A02BC01-A02BC05 (proton-pump inhibitors), N05AA01-N05AH04 (antipsychotics), or C07AB02 (metoprolol) in the preceding 2 years were randomly selected. DNA was collected with saliva kits and genotyped for CYP2D6 and CYP2C19 with the AmpliChip. Pharmacy dispensing records were retrieved and screened for drugs interacting with the patient's CYP2D6 and CYP2C19 genotype by using the evidence-based PGt guidelines from the Dutch Pharmacogenetics Working Group. RESULTS: Out of the 93 invited patients, 54 (58.1%) provided informed consent. Nine saliva samples (16.7%) contained too little DNA. Call rates for CYP2D6 and CYP2C19 were 93.3% and 100%, respectively. Frequencies of genotype-predicted phenotype were 2.4%, 38.1%, 54.8%, and 4.8% for CYP2D6 poor metabolizers (PM), intermediate metabolizers (IM), extensive metabolizers (EM), and ultrarapid metabolizers (UM) respectively. For CYP2C19 genotype-predicted phenotype, frequencies were 2.2%, 15.6%, and 82.2% for PM, IM, and EM, respectively. CONCLUSIONS: This study shows that pharmacy-initiated PGt screening is feasible for a primary care setting.
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Hidrocarburo de Aril Hidroxilasas/genética , Servicios Comunitarios de Farmacia , Citocromo P-450 CYP2D6/genética , Pruebas Genéticas , Anciano , Anciano de 80 o más Años , Citocromo P-450 CYP2C19 , ADN/análisis , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polifarmacia , Saliva/químicaRESUMEN
BACKGROUND: Pharmacogenetic markers related to drug metabolism and mechanisms of action could help to better select patients with metastatic colorectal cancer (mCRC) for treatment. Genetic interaction analysis is used as a rational tool to study the contribution of polygenic variation in relation to drug response. PATIENTS AND METHODS: A selection of 17 polymorphisms in genes encoding drug targets, pathway molecules and detoxification enzymes was analyzed in 279 previously untreated mCRC patients treated with capecitabine, oxaliplatin and bevacizumab (CAPOX-B). Multifactor dimensionality reduction analysis was used to identify a genetic interaction profile for progression-free survival (PFS). RESULTS: Median PFS was 10.9 [95% confidence interval (CI) 9.4-12.4] months. A genetic interaction profile consisting of the TYMS enhancer region and VEGF +405G>C polymorphisms was significantly associated with PFS. Median PFS was 13.3 (95% CI 11.4-15.3) and 9.7 (95% CI 7.6-11.8) months for the beneficial and unfavorable genetic profiles, respectively, corresponding to a hazards ratio for PFS of 1.58 (95% CI 1.14-2.19). None of the studied polymorphisms were individually associated with PFS. CONCLUSIONS: Our results support a genetic interaction between the TYMS enhancer region and VEGF +405G>C polymorphisms as a predictor of the efficacy of CAPOX-B in mCRC patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/genética , Polimorfismo Genético , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Bevacizumab , Capecitabina , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Elementos de Facilitación Genéticos , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Estudios de Asociación Genética , Genotipo , Humanos , Estimación de Kaplan-Meier , Reducción de Dimensionalidad Multifactorial , Metástasis de la Neoplasia , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Modelos de Riesgos Proporcionales , Timidilato Sintasa/genética , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/genéticaAsunto(s)
Antineoplásicos/efectos adversos , Indoles/efectos adversos , Leucopenia/inducido químicamente , Leucopenia/genética , Pirroles/efectos adversos , Trombocitopenia/inducido químicamente , Trombocitopenia/genética , Tirosina Quinasa 3 Similar a fms/genética , Humanos , Polimorfismo Genético , SunitinibRESUMEN
Over the last decades important progress is being made regarding disease modifying anti-rheumatic drugs (DMARDs) in the treatment of rheumatoid arthritis (RA). Nevertheless, a substantial part of the patients fail to achieve a good response and/or experience toxicity, which limits further treatment leading to progression of inflammation and destruction of joints. These high interindividual differences in drug response gave rise to the need for prognostic markers in order to individualize and optimize therapy with these antirheumatic agents. Besides demographic and clinical factors, studies in the research field of pharmacogenetics have reported potential markers associated with clinical response on treatment with methotrexate and TNF inhibitors. However, publicized conflicting results and underlying interpretation difficulties inhibit drawing definitive conclusions. Presently, clinical implementation of pharmacogenetics as an important step for individualizing drug therapy in RA is not feasible yet. Replication and prospective validation in large patient cohorts are required before pharmacogenetics can be used in clinical practice. This review provides the current state of art in genotyping RA patients as a potential guide for clinical decision making.
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Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Farmacogenética , Artritis Reumatoide/genética , Humanos , Polimorfismo de Nucleótido SimpleAsunto(s)
Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Haplotipos/genética , Metotrexato/uso terapéutico , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Modelos Genéticos , Humanos , Polimorfismo de Nucleótido Simple , Pronóstico , Resultado del TratamientoRESUMEN
OBJECTIVE: Methotrexate (MTX) is the most commonly used disease-modifying antirheumatic drug in juvenile idiopathic arthritis (JIA). Currently, individual response to MTX cannot be reliably predicted. Identification of clinical and genetic factors that influence the response to MTX could be helpful in realizing the optimal treatment for individual patients. METHODS: A cohort of 128 JIA patients treated with MTX were studied retrospectively. Eleven clinical parameters and genotypes of 6 single nucleotide polymorphisms in 5 genes related to the mechanism of action of MTX were compared between MTX responders and nonresponders using a multivariate regression analysis. RESULTS: The time from diagnosis to start of MTX treatment, physician's global assessment at baseline, and the starting dose were significantly associated with the response to MTX at 6 months after initiation. Patients with a shorter time from diagnosis to start of MTX and a higher disease activity according to the physician but with a lower MTX dose showed an increased response. The effect of the starting dose on MTX response seemed to be mainly due to the influence of the systemic JIA subtype. The time from diagnosis to start of MTX treatment and physician's global assessment at baseline were highly correlated. Therefore, the precise effect size of each independent variable could not be determined. CONCLUSION: In children with JIA, the time from diagnosis to start of MTX appears to be an important factor for MTX response. Our results suggest that an earlier start of MTX treatment will lead to an increased response.
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Antirreumáticos/uso terapéutico , Artritis Juvenil/tratamiento farmacológico , Metotrexato/uso terapéutico , Adolescente , Artritis Juvenil/genética , Niño , Preescolar , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Femenino , Frecuencia de los Genes , Humanos , Lactante , Masculino , Análisis Multivariante , Polimorfismo de Nucleótido Simple , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
This review presents recent data supporting the methotrexate (MTX) mechanisms of action, which are likely to account for its anti-proliferative and immunosuppressive effects in rheumatoid arthritis (RA). The effects of MTX in vivo may be mediated by reducing cell proliferation, increasing the rate of apoptosis of T cells, increasing endogenous adenosine release, altering the expression of cellular adhesion molecules, influencing production of cytokines, humoral responses and bone formation. Several reports indicate that the effects of MTX are influenced by genetic variants, specific dynamic processes and micro-environmental elements such as nucleotide deprivation or glutathione levels. The challenge for the future will be linking biological and genetic markers relevant to the response to MTX in RA.