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Among patients with metastatic colorectal cancer, those whose cancers contain a mutation in the KRAS gene appear to be less likely than other patients to respond to treatment with Erbitux® (cetuximab) and chemotherapy. These results were published in the British Journal of Cancer.

Colorectal cancer remains the second leading cause of cancer-related death in the United States. Metastatic colorectal cancer refers to cancer that has spread from the colon to distant sites in the body.

The KRAS Oncogene

RAS is an oncogene—a gene that encodes proteins that function as switches to turn on various genes for cell growth and division. These genes are intricate players in the normal cell cycle, responding to cues both outside and inside the cell that regulate how fast a cell should grow and divide. Mutations in the RAS genes result in permanently “turned on” switches that in turn result in uninhibited cell division, which can lead to cancer.

There are three types of RAS oncogenes, designated NRAS, GRAS, and KRAS. Although mutations in all three can cause cancer, KRAS is the most frequently mutated oncogene in human colorectal cancer occurring i 40 to 50% of colorectal cancers.

Colon cancers that have non-mutated, or wild-type, KRAS are susceptible to a class of biologic agents called epidermal growth factor receptor (EGFR) inhibitors. EGFR is a receptor on the surface of the cell that binds to a growth factor called epidermal growth factor (EGF). This receptor activates cellular pathways that promote cell growth and division, with KRAS being one of the key players in the process. Blocking the EGF receptor removes this important signal for the continued growth of cancer cells. 

The two EGFR-targeting agents studied in colon cancer are Erbitux® (cetuximab) and panitumumab. Erbitux is a type of targeted therapy called a monoclonal antibody. It works by binding to EGFR and delays the spread of cancer.

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Response to Erbitux and other drugs may be influenced by mutations in specific genes. If gene mutations are found to predict response to treatment, information about a patient’s genetic status may help doctors select the best treatment for that patient. KRAS is a gene that may influence response to Erbitux.

To evaluate the relationship between KRAS mutations and response to treatment with a combination of chemotherapy and Erbitux, researchers conducted a study among 59 patients with metastatic colorectal cancer who had failed to respond to at least one previous chemotherapy regimen. All study participants were treated with a combination of Erbitux and chemotherapy.

  • A KRAS mutation in cancer tissue was detected in 22 out of 59 patients. None of the patients with a KRAS mutation experienced a reduction in cancer following treatment with Erbitux and chemotherapy.
  • Of the 37 patients without a KRAS mutation, 12 experienced a partial or complete disappearance of detectable cancer following treatment with Erbitux and chemotherapy.
  • Cancer progressed more quickly in patients with a KRAS mutation than in patients without a KRAS mutation.

In a larger clinical trial of Erbitux alone versus best supportive care in 572 patients in whom all prior therapies had failed, overall survival and quality of life were significantly improved in the Erbitux arm. The benefit of treatment, however, was limited to those patients who had the non-mutated KRAS gene. 

The researchers conclude that the presence of a KRAS mutation in cancer tissue reduces the likelihood that patients with metastatic colorectal cancer will respond to treatment with Erbitux and chemotherapy. The researchers note that larger studies are needed to confirm this finding.

Reference:

Di Fiore F, Blanchard F, Charbonnier F et al. Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. *British Journal of Cancer.*2007;96:1166-1169.