Clinical Information

Strategies that focus on early detection and prevention effectively decrease the risk of mortality associated with cancer. In addition, an increase in survival rate for individuals with advanced stage disease 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 an area of targeted therapy for patients with colorectal and non-small cell lung cancer (NSCLC). However, studies have shown that not all individuals with colorectal cancer or NSCLC 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.

Epidermal growth factor receptor 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 cancer, in particular, colorectal cancer and NSCLC.

One of the most common somatic mutations in colon cancer and NSCLC is the presence of activating mutations in the protooncogene KRAS. KRAS is recruited by ligand-bound (active) EGFR to initiate the signaling cascade induced by the RAS/MAPK pathway. Because altered 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 altered KRAS. Current data suggest that the efficacy of EGFR-targeted therapies in colon cancer and NSCLC is confined to patients with tumors lacking KRAS mutations. An exception is the KRAS G12C variant, which is targetable with variant-specific inhibitors.

This test uses DNA extracted from tumor tissue to evaluate for the presence of KRAS (G12A, G12C, G12D, G12R, G12S, G12V, G13D, Q61K, Q61L, Q61R, Q61H, and A146T) mutations. A positive result indicates the presence of an activating KRAS mutation and can be a useful marker by which patients are selected for EGFR-targeted therapy.