Setting future standards for KRAS testing in colorectal cancer

predictive biomarker that is available, and it is now widely accepted that KRAS testing needs to be performed before EGFR targeting therapy is administered in patients with metastasized colorectal cancer [2]. Research into the EGF pathway has gone from bench to bedside. The EGFR receptor is a growth receptor expressed on many cells and overexpression occurs in many different forms of cancer, especially carcinomas. Overexpression can be due to amplification of the gene, mutations in the gene or post-translational factors. Binding of a ligand (EGF, TGF-α, epiregulin) to the receptor leads to dimerization of EGFR and stimulation of intracellular signal transduction pathways ultimately resulting in the stimulation of cell growth and proliferation and the inhibition of apoptosis. Therefore, EGFR is an attractive target for therapeutic strategies. Several approaches using either small molecules or monoclonal antibodies have become available and have shown effect in a variety of tumor types, including cancer of the epithelia of the oropharynx and larynx [9], lung cancer [8] and colorectal cancer [3,4]. Since not all patients respond to this treatment studies into predictive factors were initiated, comparing responding to nonresponding patients. An obvious target for study was the EGFR itself but the response to EGFR targeting agents appeared not to be limited to patients expressing EGFR on their tumors [10] and also, many patients with EGFR expression on the tumor cells did not respond. An increased EGFR gene copy-number, however, is associated with increased responsiveness to cetuximab in patients with advanced colorectal cancer [11], but is an uncommon event and many patients without EGFR gene amplification do respond. Mutations in the intracellular domain of the EGFR are observed in non-small-cell lung cancer and associated with response to the EGFR small molecules gefitinib and erlotinib [8] but in colorectal cancer these mutations are only very Selection of patients with metastasized colorectal cancer, who do not benefit from treatment directed against the epidermal growth factor receptor (EGFR) is now feasible. Since the start of the new millennium, the outlook for patients with metastasized colorectal cancer has improved significantly, mainly thanks to the introduction of new, biological treatments that targets the vascular endothelial growth factor receptor (VEGFR) or the EGFR. However, not all patients benefit from these treatments and much effort is undertaken to identify predictive markers that can be used to select patients most likely to benefit from these expensive and potentially toxic agents. The most relevant and recent development in this field is the discovery that in patients with metastasized colorectal cancer EGFR targeting treatment is only effective in those patients that have wild-type KRAS [1,2], a discovery that has attracted wide publicity.