Targeted therapy in metastatic colorectal cancer -- an example of personalised medicine in action

Abstract

In metastatic colorectal cancer (mCRC), an improved understanding of the underlying pathology and molecular biology has successfully merged with advances in diagnostic techniques and local/systemic therapies as well as improvements in the functioning of multidisciplinary teams, to enable tailored treatment regimens and optimized outcomes. Indeed, as a result of these advancements, median survival for patients with mCRC is now in the range of 20-24months, having approximately tripled in the last 20years. The identification of KRAS as a negative predictive marker for activity of epidermal growth factor receptor (EGFR)-targeted monoclonal antibodies (mAbs), such as panitumumab (Amgen, Thousand Oaks, USA) and cetuximab (ImClone, Branchburg, USA), has perhaps had the greatest impact on patient management. This meant that, for the first time, mCRC patients unlikely to respond to a targeted therapy could be defined ahead of treatment. Ongoing controversies such as whether patients with KRAS G13D- (or BRAF V600-) mutated tumours can still respond to EGFR-targeted mAbs and the potential impact of inter- and intra-tumour heterogeneity on tumour sampling show that the usefulness of KRAS as a biomarker has not yet been exhausted, and that other downstream biomarkers should be considered. Conversely, a predictive biomarker for anti-angiogenic agents such as bevacizumab (Genentech, San Francisco, USA) in the mCRC setting is still lacking. In this review we will discuss the discovery and ongoing investigation into predictive biomarkers for mCRC as well as how recent advances have impacted on clinical practice and ultimately the overall cost of treatment for these patients.