Marcadores genéticos implicados en los resultados clínicos a los esquemas con trastuzumab en pacientes con cáncer de mama Her2-Positivo

En España en 2012, el cáncer de mama fue el cuarto con mayor incidencia, y el tercero en mortalidad, por detrás del cáncer de pulmón y del cáncer colorrectal. Aunque durante muchas décadas las diferentes características del paciente y del tumor como la edad, afectación axilar, tipo histológico, expresión de receptores (hormonales y HER2), han servido para la planificación del tratamiento, no justifican los comportamientos biológicos de la enfermedad. Una nueva clasificación surgió ante la necesidad de caracterizar a los tumores cuyos comportamientos eran similares y se definieron 4 subtipos con relevancia biológica y clínica realizando una análisis molecular: luminal A, luminal B, basal-like, HER2-enriched y normal-like. Las pacientes con cáncer de mama HER2-positivo tratados con esquemas de trastuzumab tienen buenos resultados clínicos iniciales. En el CM en fase inicial, la adición de trastuzumab a la quimioterapia neoadyuvante mejora sustancialmente la supervivencia global (SG) y reduce el riesgo de recurrencia en un 33%. Del mismo modo, trastuzumab en adyuvancia mejora sustancialmente la supervivencia libre de enfermedad en un 38% y la supervivencia global en un 34% y reduce sustancialmente el riesgo de recurrencia local y a distancia en un 42% y 40% respectivamente. A pesar de este efecto beneficioso, muchas pacientes experimentan resistencia a estos fármacos. Varios poliformismos genéticos de ABCB1, HER2 y CCND1 se han propuesto como predictores potenciales de los resultados clínicos a los esquemas de trastuzumab.Tesis Univ. Granada. Programa Oficial de Doctorado en: Farmaci

-Omic Approaches and Treatment Response in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an inflammatory disorder characterized by an aberrant activation of innate and adaptive immune cells. There are different drugs used for the management of RA, including disease-modifying antirheumatic drugs (DMARDs). However, a significant percentage of RA patients do not initially respond to DMARDs. This interindividual variation in drug response is caused by a combination of environmental, genetic and epigenetic factors. In this sense, recent -omic studies have evidenced different molecular signatures involved in this lack of response. The aim of this review is to provide an updated overview of the potential role of -omic approaches, specifically genomics, epigenomics, transcriptomics, and proteomics, to identify molecular biomarkers to predict the clinical efficacy of therapies currently used in this disorder. Despite the great effort carried out in recent years, to date, there are still no validated biomarkers of response to the drugs currently used in RA. -Omic studies have evidenced significant differences in the molecular profiles associated with treatment response for the different drugs used in RA as well as for different cell types. Therefore, global and cell type-specific -omic studies analyzing response to the complete therapeutical arsenal used in RA, including less studied therapies, such as sarilumab and JAK inhibitors, are greatly needed

ABCB1 gene polymorphisms and response to chemotherapy in breast cancer patients: a meta-analysis

The ABCB1 gene encodes the P-glycoprotein, an efflux pump for some antineoplastic agents which acts as a resistance mechanism to chemotherapy. Three SNPs (C3435T, C1236T and G2677T/A), are the most widely studied in ABCB1. The inconsistent conclusions about the association of these polymorphisms and the response to chemotherapy in breast cancer (BC) patients prompted us to conduct a meta-analysis. A total of nine (770 patients), five (566 patients) and three studies (367 patients) relating the ABCB1 C3435T, C1236T and G2677T/A polymorphisms respectively, were included. The main analysis revealed a lack of association between ABCB1 polymorphisms and response to chemotherapy in every genetic model: C3435T (dominant OR: 0.888; 95%CI: 0.558-1.413), C1236T (dominant OR: 1.968; 95%CI: 0.609-6.362) and G2677T/A (GG vs GT + GA + TT + TA + AA OR: 0.854; 95%CI: 0.418-1.744). Stratification by ethnicity, cancer type and response criteria did not change the pattern of results. The available evidence indicates that three polymorphisms within ABCB1; C3435T, C1236T and G2677T/A, cannot be considered a reliable predictor of response to chemotherapy in BC patients

Association of ABCB1 and VEGFA gene polymorphisms with breast cancer susceptibility and prognosis

Breast cancer (BC) is the most common cause of cancer-related death in women worldwide. Several ABCB1 and VEGFA gene polymorphisms, such as ABCB1-G1199 T/A (rs2229109), VEGFA -634 G > C (rs2010963), VEGFA 2578 C > A (rs699947) and VEGFA 7 C > T (rs25648) have been associated with risk of BC and clinical outcomes. The purpose of this study was to evaluate the association between these gene polymorphisms and BC risk and prognosis. A retrospective case-control study was conducted, including 84 BC cases and 119 controls of Spanish (European, Caucasian) origin. ABCB1-G1199 T/A (rs2229109), VEGFA -634 G > C (rs2010963), VEGFA 2578 C > A (rs699947) and VEGFA 7 C > T (rs25648) gene polymorphisms were analysed by TaqMan®. The genotypic logistic regression model adjusted by aged revealed no association with any of the polymorphisms and BC risk, although the C-allele of VEGFA 2578 C > A showed a trend to higher BC risk in the allelic and recessive models (p = 0.055 and 0.054, respectively). There was no influence of these gene polymorphisms on overall survival (OS). The univariate Cox model showed that carriers of the A-allele for VEGFA 2578 C > A tended to have longer OS compared to CC patients (CC vs A-allele Hazard ratio (HR): 2.08; CI95 % = 0.96-4.49; p = 0.0587). There was no association between the gene polymorphisms analysed and disease-free survival (DFS). The univariate Cox model showed a trend toward a longer DFS in patients carrying ABCB1-G1199 T/A GG genotype compared to those with A-allele (GG vs A-allele HR: 0.43; CI95 % = 0.18-1.03; p = 0.0612). No influence of ABCB1-G1199 T/A (rs2229109), VEGFA -634 G > C (rs2010963), VEGFA 2578 C > A (rs699947) and VEGFA 7 C > T (rs25648) gene polymorphisms on risk of developing BC was found in our study. There was no association between the polymorphisms studied and DFS and OS