Cetuximab is a novel anticancer agent that inhibits the actions of the epidermal growth factor receptor (EGFR). EGFR plays an important role in the growth, survival, and spread of some forms of cancer.
The KRAS gene encodes for small guanosine nucleotide-binding proteins that are important signal transducers for many cellular receptors, including EGFR. If there is a mutation in this KRAS gene, the drugs that inhibit EGFR, including cetuximab, fail to act. There are 7 possible mutations at the KRAS region and these are present on codons 12 and 13.
In July 2009, the United States Food and Drug Administration upgraded the labels of two approved EGFR antagonist monoclonal antibodies, cetuximab and panitumumab, to include information about KRAS mutations. These drugs are only effective in the non-mutated or "wild type" KRAS genotype.
KRAS mutational analysis can be performed in the laboratory using a variety of techniques such as allele-specific PCR, real-time PCR, and DNA sequencing. If KRAS gene mutation is detected in a patient, they are unlikely to respond to EGFR inhibitors such as cetuximab or panitumumab. Therefore, genetic testing for mutation is now performed routinely as part of standard practice, before such agents are administered.
Sixty percent of patients express wild type KRAS tumors and data demonstrates that there is a significantly greater likelihood of these patients benefitting from cetuximab therapy. Studies have shown significantly improved response and survival rates in patients with wild type KRAS tumors who added cetuximab to their chemotherapy regimen compared with those who received chemotherapy alone.