INTRODUCTION

Colorectal cancer (CRC) is the third most frequently diagnosed cancer in the United States (1). From 2000 to 2014, CRC death rate has decreased by 34% in the population over 50 years of age, in part due to the implementation of screening techniques and improvement in the treatment of stages III (preoperative chemotherapy) and IV (treatment of metastases with monoclonal antibodies)(1). However, the decline in CRC mortality rates seems to be less important in patients who carried any mutation in the EFGR pathway. These mutations seem to be poor prognostic biomarkers, as recently reviewed (2,3). The epidermal growth factor receptor (EGFR) is widely expressed in CRC, among other tumors (1). Its ligand, the epidermal growth factor (EFG), activates MAPK/ERK (RAS-BRAF-MEK-ERK) and PIK3CA/AKT, two distinct signaling cascades implicated in cell proliferation and differentiation (1,2). Associations between CRC survival and mutations in some of these signaling pathway mediators have been reported (3–7). There are three oncogenes inRAS family: Harvey RAS (HRAS) , Kirsten RAS (KRAS ) and neuroblastoma RAS (NRAS ) (4). The KRAS gene, whose mutation is the most frequent in CRC, mainly occurring in codons 12, 13 and 61 (7), is the one preferentially activated by the MAPK/ERK route (5,6). Patients who present mutations in KRAS have a 50% lower overall survival than patients with KRAS wild type and approximately 33% less progression-free survival (8). Mutation in another RAS gene, NRAS , has also been associated with approximately 50% loss of overall survival (8). V600E mutation inBRAF , described in 12% of CRC (9), is also considered a risk factor for progression and death, increasing the risk of death up to three times (8,10). Although these studies show a promising usefulness of mutations in EFGR pathway (KRAS , NRAS and BRAF ) as biomarkers of survival in CRC (8,10), other studies of similar power have failed to find such association (12–14); therefore, the utility of EGFR pathway biomarkers on CRC survival is still under debate (2,3). Other signaling pathways, such as PIK3CA-AKT, involved in activation ofRAS oncogenes (2,7), have also been proposed as potential biomarkers. Alterations on this signaling pathway have been observed in 60-70% of CRC cases (11). An approximate 33% decrease in overall survival has been reported in patients with a mutation in exon 20 ofPIK3CA gene (8). Therefore, mutations in several components of different pathways may have a contribution in the survival of CRC patients.
The aim of this study was to evaluate the influence of mutations in the EGFR pathway (KRAS , NRAS , BRAF and PIK3CA ) on overall survival in CRC.