Pharmacogenomics in colorectal cancer: a genome-wide association study to predict toxicity after 5-fluorouracil or FOLFOX administration.

The development of genotyping technologies has allowed for wider screening for inherited causes of variable outcomes following drug administration. We have performed a genome-wide association study (GWAS) on 221 colorectal cancer (CRC) patients that had been treated with 5-fluorouracil (5-FU), either alone or in combination with oxaliplatin (FOLFOX). A validation set of 791 patients was also studied. Seven SNPs (rs16857540, rs2465403, rs10876844, rs10784749, rs17626122, rs7325568 and rs4243761) showed evidence of association (pooled P-values 0.020, 9.426E-03, 0.010, 0.017, 0.042, 2.302E-04, 2.803E-03) with adverse drug reactions (ADRs). This is the first study to explore the genetic basis of inter-individual variation in toxicity responses to the administration of 5-FU or FOLFOX in CRC patients on a genome-wide scale.

Impact of pharmacist interventions in older patients: a prospective study in a tertiary hospital in Germany.

BACKGROUND: Inappropriate pharmacotherapy among older adults remains a critical issue in our health care systems. Besides polypharmacy and multiple comorbidities, the age-related pharmacokinetic and pharmacodynamic changes may increase the risk of adverse drug reactions and medication errors. OBJECTIVE: The main target of this study was to describe the characteristics of pharmaceutical interventions in two geriatric wards (orthogeriatric ward and geriatric day unit) of a general teaching hospital and to evaluate the clinical significance of the detected medication errors. MATERIALS AND METHODS: The study was conducted between August 2014 and October 2015 and was based on a triple approach that included validation of medical orders, medication reconciliation at patients' admission, and a predischarge planning appointment with the patient. The validation of medical orders was based on analyzing the suitability of the drugs prescribed, the drug dose depending on the patient's characteristics, the presence of contraindications and interactions between drugs, and the proposal of alternative drugs included in the hospital formulary. RESULTS: A total of 2,307 interventions associated to a medication error in 15,282 medical orders for 1,859 older patients were recorded. The greater part of the interventions carried out on the orthogeriatric ward at admission and at discharge were due to omission of a drug in the medical order (20.0%) and clinically significant interactions requiring monitoring (30.4%), respectively. The main factor triggering pharmacist's recommendations on the geriatric day unit was clinically significant interactions (21.1%). With regard to the clinical severity of the detected errors, 68.1% were considered significant, 24.8% were of minor significance, and 7.2% were clinically serious. CONCLUSION: Our findings show the importance of clinical pharmacist involvement in the optimization of pharmacotherapy in older adults, ensuring that they receive effective, safe, and efficient drug therapy.

[Validation of genetic polymorphisms associated to the toxicity of chemotherapy in colorectal cancer patients]. / Validación de polimorfismos genéticos asociados a toxicidad al tratamiento quimioterápico en pacientes de cáncer colorrectal.

OBJECTIVE: To validate the associations previously found in three cohorts of patients from the General University Hospital Gregorio Marañón, between the polymorphisms rs1128503, rs2032582 and rs1045642 of the ABCB1 gene and the hand-foot syndrome and diarrhea in colorectal cancer patients treated with chemotherapy regimes containing Capecitabine and 5-Fluorouracil, respectively, and between the polymorphisms rs2297595 of the DPYD gene and nausea/vomiting, rs11615 of ERCC1 and neutropenia, and rs28399433 CYP2A6 and neutropenia, in colorectal cancer patients treated with FOLFOX or XELOX as adjuvant therapy. METHOD: Colorectal cancer patients treated with chemotherapy regimes, containing Capecitabine (n = 157), 5-Fluorouracil (n = 99) were included in the study, as well as patients treated with XELOX or FOLFOX (n = 83) as adjuvant therapy. The patients included were recruited from the Doce de Octubre University Hospital and from the Gregorio Marañón General University Hospital, and signed the informed consent form. DNA was obtained from blood samples. Genotyping was carried out with SNaPshot. Contingency tables were created for analyzing the associations between the genotypes and the adverse reactions. RESULTS: None of the associations previously identified was replicated in the validation cohort. CONCLUSIONS: Pharmacogenetic studies with a limited sample size must be validated with bigger cohorts, if possible by means of multicentre studies, reducing the variables to the maximum and should never be used in clinical practice without validation.

OBJETIVO: Validar las asociaciones, encontradas previamente en tres cohortes de pacientes del Hospital General Universitario Gregorio Marañón, entre los polimorfismos rs1128503, rs2032582 y rs1045642 del gen ABCB1 con síndrome manopie y diarrea en pacientes de cáncer colorrectal tratados con regímenes que contenían capecitabina y 5-Fluorouracilo, respectivamente, y entre los polimorfismos rs2297595 del gen DPYD con nauseas/vómitos, rs11615 ERCC1 y neutropenia, y rs28399433 CYP2A6 y neutropenia en pacientes de cáncer colorrectal tratados con FOLFOX o XELOX en adyuvancia. MÉTODO: Se incorporaron al estudio pacientes de cáncer colorrectal tratados con regímenes quimioterápicos que contenían capecitabina (n = 157), 5-fluorouracilo (n = 99) y pacientes tratados en adyuvancia con XELOX o FOLFOX (n = 83). Los pacientes participantes fueron reclutados en el Hospital Universitario Doce de Octubre y en el Hospital General Universitario Gregorio Marañón tras firmar consentimiento informado. Se extrajo ADN a partir de muestras de sangre. Los genotipados se realizaron mediante SNaPshot. Se realizaron tablas de contingencia para analizar las asociaciones entre genotipos y reacciones adversas. RESULTADOS: Ninguna de las asociaciones previamente identificadas fue replicada en la cohorte de validación. CONCLUSIONES: Los estudios farmacogenéticos con un tamaño muestral limitado deben ser validados en cohortes más numerosas, a ser posible en estudios multicéntricos, reduciendo al máximo las variables y nunca deben ser utilizados en clínica sin validar.