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KRAS Mutation a Strong Predictor of Response to Cetuximab Therapy in Colorectal Cancer: Presented at AACR

By Cameron Johnston

LOS ANGELES, CA -- April 19, 2007 -- Roughly 30% to 40% of patients with colorectal cancer fail to respond to cetuximab therapy.

But in a presentation here today at the American Association for Cancer Research (AACR) annual meeting, investigators from France discussed an interesting approach to determining which patients would respond to cetuximab therapy and which ones likely would not.

A wide variety of agents are now available to treat most forms of cancer, but determining which is going to be the most effective is a challenge for clinicians and is now more complicated than ever, according to presenter Pierre Laurent-Puig, MD, PhD, professor of oncology, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.

It has been hypothesised that the presence of a genetic variance known as a KRAS could predict a patient's response to cetuximab. Therefore, Dr. Laurent-Puig and colleagues planned a prospective study in which patients' tumours would be analysed for KRAS expression.

Among the 39 men and 27 women (mean age 60.1 years), 24 (31.5%) had an objective response to cetuximab. Complete response was seen in two patients, while partial response was seen in 22. Two patients received cetuximab as monotherapy, and the remainder received it in combination with either irinotecan, or irinotecan and 5-fluorouracil/leucovorin.

Of the 27 patients who had the KRAS mutation (35.5%) there were no responses. In a univariate analysis, progression-free survival was also found to be significantly better in patients who did not have the KRAS mutation compared with those who did (32 weeks vs 8.6 weeks). Patients who had the KRAS mutation were 3.5 times more likely to progress compared with patients who did not have the mutation.

The prognostic value of the KRAS mutation remained significant even when the data was controlled for age, sex and skin toxicity. This finding is particularly important, Dr. Laurent-Puig added, because a skin rash that develops following cetuximab use has been directly correlated to the success or failure of treatment -- the greater the rash, the more likely the patient will be to show a positive response.

Severe skin toxicity was more frequent in responders compared with nonresponders. Grade 2-3 skin toxicity was seen in all of the complete responders, in 64% of the partial responders, in 52% of the patients with stable disease, and in 35% of the patients who had progressive disease.

Skin toxicity was also found to be an independent risk factor for disease progression. Median survival was 15.6 months for patients with the skin toxicity and without a KRAS mutation, and 5.6 months among patients who had the mutation, but not skin toxicity.

According to Dr. Laurent-Puig, these results confirm the highly predictive value of the KRAS mutation for response to cetuximab in patients with colorectal cancer. Although many tests for the KRAS mutation are used in the research setting, regulatory bodies are withholding approval for such tests until they can all be validated for general medical practice.


[Presentation title: KRAS Mutations in Colorectal Cancer is a Predictive Factor of Response and Progression Free Survival in Patients Treated With Cetuximab. Abstract 5671]

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