Clinical Information

Colorectal cancer is currently among the most common malignancies diagnosed each year. Strategies that focus on early detection and prevention effectively decrease the risk of mortality associated with the disease. In addition, an increase in survival rate for individuals with advanced stage colorectal cancer has been observed as a result of advancements in standard chemotherapeutic agents and the development of specialized targeted therapies. Monoclonal antibodies against epidermal growth factor receptor (EGFR), such as cetuximab and panitumumab, represent a new area of targeted therapy for such patients. However, studies have shown that not all individuals with colorectal cancer respond to EGFR-targeted molecules. Because the combination of targeted therapy and standard chemotherapy leads to an increase in toxicity and cost, strategies that help to identify the individuals most likely to benefit from such targeted therapies are desirable.

EGFR is a growth factor receptor that is activated by the binding of specific ligands (epiregulin and amphiregulin), resulting in activation of the RAS/MAPK pathway. Activation of this pathway induces a signaling cascade ultimately regulating a number of cellular processes including cell proliferation. Dysregulation of the RAS/MAPK pathway is a key factor in tumor progression. Targeted therapies directed to EGFR, which inhibit activation of the RAS/MAPK pathway, have demonstrated some success (increased progression-free and overall survival) in patients with colorectal cancer.

One of the most common somatic alterations in colon cancer is the presence of activating mutations in the proto-oncogene KRAS. KRAS is recruited by ligand-bound (active) EGFR to initiate the signaling cascade induced by the RAS/MAPK pathway. Because mutant KRAS constitutively activates the RAS/MAPK pathway downstream of EGFR, agents such as cetuximab and panitumumab, which prevent ligand-binding to EGFR, do not appear to have any meaningful inhibitor activity on cell proliferation in the presence of mutant KRAS. Current data suggest that the efficacy of EGFR-targeted therapies in colon cancer is confined to patients with tumors lacking KRAS mutations. As a result, the mutation status of KRAS can be a useful marker by which patients are selected for EGFR-targeted therapy.

At this time, this test is approved specifically for colorectal tumors and metastatic lesions from a colorectal primary. Please refer to KRASO / KRAS Mutation Analysis, 7 Mutation Panel, Other (Non-Colorectal) for KRAS testing in noncolorectal tumors.