You are here
Presence of Gene Mutation Tightly Linked to Drug Effectiveness in Lung Cancer
The mutation discovered was in the epidermal growth factor receptor (EGFR), a gene that codes for an enzyme in the tyrosine kinase family of proteins. Tyrosine kinases are a class of enzymes involved in cellular signaling that have been shown to undergo mutations in various cancers. Inhibition of this type of enzyme has recently been a focus for scientists, but gefitinib had not been as effective as some had expected based on earlier clinical trials conducted in Japan.
The gene mutations identified in this study cause the kinase to be overactive. The sensitivity to gefitinib in both patients entered into a clinical trial and to tumor cells grown in a lab was shown to be highly correlated with the presence of tumors that contained these EGFR mutations. While this type of drug sensitivity was shown earlier for the drug imatinib (Gleevec™), which is most effective against certain leukemias and gastrointestinal stromal tumors that possess specific genetic mutations, this is the first demonstration of a targeted therapy in a common adult malignancy.
"One of the more striking results we found in this study was the difference in response between Japanese and American patients, which raises the question of genetic variation in different ethnic, cultural, and geographic groups to this particular drug," said Bruce E. Johnson, M.D., Dana-Farber Cancer Institute, who led the Lung Cancer Biology Section at NCI before leaving for Dana-Farber.
To conduct the study, researchers examined 58 lung cancer tumors from Japan (Nagoya City University Hospital) and 61 tumors from the United States (Harvard Medical School). They also examined additional tumors from U.S. patients who had demonstrated a response to gefitinib. The presence of EGFR mutations and the best clinical response to gefitinib therapy occurred most frequently in women, non-smokers, and in patients with a certain type of lung cancer called adenocarcinoma.
Gene mutations were seen in 26 percent of Japanese NSCLC cancer patients vs. only 2 percent of American patients. Japanese women with adenocarcinoma showed the highest percentage of EGFR mutations (57 percent) and also showed the best clinical response to gefitinib. Lung cancer is the leading cause of cancer death in the United States and worldwide for both men and women.
"This is another example of successfully exploiting our ever-increasing understanding of the genetic aberrations of cancer," said Andrew C. von Eschenbach, M.D., director, NCI. Understanding how to maximize the benefits of anti-EGFR treatments should improve the outcome for many patients with lung cancer. In addition, the larger percentage of EGFR mutations in patients from Japan compared to the United States is striking and raises many unanswered questions, suggesting new avenues for basic research, as well as new considerations in the design of clinical trials.
An abstract in the New England Journal of Medicine is available for review.
Source: The National Institutes of Health
* Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson, BE, Meyerson M. EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy. Science, Online publication, April 29, 2004.