Predictive Biomarkers and Targeted Therapies in Colorectal Cancer

Abstract

Colorectal cancer (CRC) so far has been found to have only a few biomarkers capable of being translated to patient care. These include RAS and BRAF mutation status, microsatellite instability (MSI) and CpG island methylator phenotype (CIMP). Of these, currently, the only biomarker used to predict response to a targeted therapy is the RAS mutation status. Accordingly tumours with a RAS mutation in exon 2 (codons 12 and 13) of KRAS (about 40% of cases) are not expected to respond to anti-EGFR therapy. In fact, only a small proportion of patients, with KRAS-wt status at exon 2, benefit from the monoclonal antibody therapy. For this reason recent clinical trials have focused on expanding the testing panel to include KRAS and NRAS exons 2, 3 and 4, as well as BRAF, yielding a further 30% of cases non-predictive of response to the antibody therapy. There is, therefore, the need to define potential driver events capable of being utilised as targets for effective predictive drug treatments. To this effect, a list of clinical trials in progress designed to define the novel therapeutic targets is given. A brief consideration is also given to the progress being made towards more accurate prognostic definition of CRC, using an integrated approach to molecular categorisation of colorectal tumours.