Molecular biology of colorectal cancer & Antiepidermal growth factor receptor therapies

Colorectal cancer (CRC) results from the progressive accumulation of genetic and epigenetic alterations that lead to the transformation of normal colonic epithelium to colon adenocarcinoma and can have different prognoses and different responses to treatment. The morphology of tumors and the pattern of molecular abnormalities vary depending on their anatomical location, with a probable gradual change in molecular characteristics between the right and left side of the bowel. There are thought to be at least three main mechanisms by which CRC occurs. The majority of cancers start as adenomas, which then undergo other mutational events such as loss of the adenomatous polyposis coli (APC) gene and p53 mutations and result in the chromosome instability (CIN) phenotype. In contrast, patients with Lynch syndrome (hereditary nonpolyposis CRC) have germline loss of DNA mismatch repair genes, most commonly MLH1 and MLH2. This results in the accumulation of DNA defects, predominantly in microsatellite areas and leads to the microsatellite instability high (MSI-high) phenotype. The Cancer Genome Atlas Network has recently published a comprehensive molecular characterization of CRC [Cancer Genome Atlas Network, 2012]. Specific signaling pathways or genes have been found to be commonly affected in CRC. Tumor heterogeneity means that it is challenging to elucidate the roles of individual mutations and poses significant challenges to personalized medicine. There may be significant differences not only within the primary tumor, but also between the primary tumor and metastases. Furthermore, anticancer treatment can affect tumor heterogeneity due to selection pressures. One of the major advances in the treatment of CRC has been the development of targeted therapies. Amongst the most well-established of these are the monoclonal antibodies cetuximab and panitumumab, which target the EGFR. Cetuximab has been shown to have efficacy both as monotherapy and in combination with chemotherapy for patients with pretreated metastatic CRC