K-Ras Mutation Status as a Predictive Biomarker in Metastatic Colorectal Cancer

Abstract

Colorectal cancer (CRC) is the third most common cancer worldwide, with approximately 1 million new cases diagnosed every year. It is estimated that approximately half of the patients with CRC will develop metastasis. Current use of irinotecan, oxaliplatin and bevacizumab, combined with the long-time standards 5-fluourouracil and leucovorin as firstor second-line treatment for metastatic CRC (mCRC), has resulted in median overall survival (mOS) figures of greater than 20 months. However, most patients develop resistance to these therapies and finally die owing to progression of their disease. Additional improvements in treatment are likely to be facilitated by the use of rationally selected therapeutic agents that target functionally important proteins in tumor cells, such as the EGF receptor (EGFR), expressed in 75–90% of mCRC specimens [1]. The activation of EGFR leads to the activation of intracellular effectors involved in intracellular signaling pathways such as the G-protein K-Ras. K-Ras is a self-inactivating signal transducer, cycling from a GDP-bound ‘off ’ state to GTP-bound ‘on’ state in response to receptor activation [2]. This response is transient owing to the intrinsic GTPase activity. Interestingly, K-Ras oncogene may harbor activating mutations yielding proteins with reduced GTPase activity. These activating K-Ras mutations are among the most common oncogenic alterations in cancer [3]. Monoclonal antibodies designed to bind to the ectodomain of the EGFR have shown activity in chemorefractory mCRC. Several Phase II studies have demonstrated the activity of cetuximab (a chimeric monoclonal IgG1 antibody) and panitumumab (a fully human monoclonal IgG2 antibody) in refractory mCRC. In a randomized Phase II study, increased activity with cetuximab plus irinotecan, compared with