RESUMEN
The Hippo pathway regulates tissue growth and cell fate. In colon cancer, Hippo pathway deregulation promotes cellular quiescence and resistance to 5-Fluorouracil (5-Fu). In this study, 14 polymorphisms in 8 genes involved in the Hippo pathway (MST1, MST2, LATS1, LATS2, YAP, TAZ, FAT4 and RASSF1A) were evaluated as recurrence predictors in 194 patients with stages II/III colon cancer treated with 5-Fu-based adjuvant chemotherapy. Patients with a RASSF1A rs2236947 AA genotype had higher 3-year recurrence rate than patients with CA/CC genotypes (56 vs 33%, hazard ratio (HR): 1.87; P=0.017). Patients with TAZ rs3811715 CT or TT genotypes had lower 3-year recurrence rate than patients with a CC genotype (28 vs 40%; HR: 0.66; P=0.07). In left-sided tumors, this association was stronger (HR: 0.29; P=0.011) and a similar trend was found in an independent Japanese cohort. These promising results reveal polymorphisms in the Hippo pathway as biomarkers for stages II and III colon cancer.The Pharmacogenomics Journal advance online publication, 15 September 2015; doi:10.1038/tpj.2015.64.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias del Colon/genética , Recurrencia Local de Neoplasia , Polimorfismo de Nucleótido Simple , Transducción de Señal/genética , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética , Aciltransferasas , Anciano , Antimetabolitos Antineoplásicos/uso terapéutico , California , Quimioterapia Adyuvante , Colectomía , Neoplasias del Colon/patología , Neoplasias del Colon/terapia , Femenino , Fluorouracilo/uso terapéutico , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Heterocigoto , Homocigoto , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Fenotipo , Modelos de Riesgos Proporcionales , Factores de Riesgo , Factores de Tiempo , Tokio , Resultado del TratamientoRESUMEN
AIM: We investigated whether the type of antibody [bevacizumab (bev) or cetuximab (cet)] added to neoadjuvant combination chemotherapy before curative liver resection was associated with histological response, the pattern of tumor destruction and clinical outcome in patients with colorectal liver metastases (CLM). METHODS: We investigated 138 patients with KRAS wild-type status (codon 12, 13 and 61) who received neoadjuvant chemotherapy including bev (n = 101) or cet (n = 37). The primary endpoint was histological response. Secondary endpoints were necrosis and fibrosis of metastases, radiological response, recurrence-free survival (RFS) and overall survival (OS). RESULTS: Histological response was not significantly different between the two groups (P = 0.19). A significantly higher fraction of patients in the bev group showed necrosis of the metastases of ≥ 50% (P < 0.001), while a higher fraction of patients in the cet group showed fibrosis of ≥ 40% (P = 0.030). Radiological response was not significantly different (P = 0.17). Median RFS was significantly shorter in the cet group in univariable analysis (HR 1.59 (95% CI 1.00, 2.51), P = 0.049), but this difference did not remain significant in multivariable analysis (P = 0.45). The 3-year OS rate was not significantly different (P = 0.73). CONCLUSIONS: The addition of bevacizumab to combination chemotherapy showed more necrosis but less fibrosis of metastases compared to cetuximab and a trend towards higher histological and radiological response and longer RFS. Further investigations of biological tumor characteristics are required to individualize treatment combinations.