Extended RAS testing in metastatic colorectal cancer—Refining the predictive molecular biomarkers

Mutations of exon 2 of Kirsten rat sarcoma viral oncogene homologue (KRAS) (exon 2 codons 12/13) lead to constitutive activation of the EGFR (epidermal growth factor receptor) mediated signal transduction pathway and been shown to be a negative predictive biomarker for EGFR-directed monoclonal antibodies among patients with colorectal cancer (CRC). As selection of patients is very important for administration of anti-EGFR therapy, this lone biomarker has proved to be insufficient for selecting the appropriate patients as more patients lacking exon 2 KRAS mutation were resistant to anti-EGFR therapy. The results of various randomized clinical trials have confirmed the presence of other RAS mutation including additional RAS mutations (KRAS exons 3/4 and NRAS exon 1/2/3/4). Extended RAS analysis should be considered before initiating anti-EGFR therapy to patients of metastatic CRC. This can help in proper selection of patients leading to tailored individualistic treatment, decreasing cost of treatment and the adverse effects related to use of monoclonal antibody therapy. The new evidence is supporting the need to make ‘Extended RAS’ analysis essential before start of treatment with anti-EGFR monoclonal antibody therapy. Prior to this the Extended RAS testing should be standardized.