The Question: The drug Iressa shows a rapid and often dramatic response in only a minority of people (about 10%) with the most common type of lung cancer -- non-small-cell lung cancer. Why is this drug only effective for just a few people, but not most?
The Answer: It appears that people with lung cancer who respond well to Iressa have a mutation in the gene for epidermal growth factor receptor (EGFR).
Explanation: Many cells have receptors on their surfaces for epidermal growth factor (EGF), a protein that promotes cell growth. When EGF attaches to the epidermal growth factor receptor (EGFR), it stimulates cells to grow. Iressa attaches to EGFR and thereby inhibits the attachment of EGF and stops cell growth. The mutation in EGFR corresponds to an increased signal that there is enough growth factor and this makes the cells susceptible to the drug Iressa.
Comment: This remarkable finding has already been confirmed as correct. In addition to the report in Science (see below), the same result has been from a separate study in the New England Journal of Medicine.
Barbara K. Hecht,
Frederick Hecht, M.D.
Medical Editors, MedicineNet.com
- Lung Cancer (Main Article)
- Lung Cancer Center
Presence of Gene Mutation Tightly Linked to Drug Effectiveness in Lung Cancer
Mutation of a gene involved in non-small cell lung cancer (NSCLC) increases the likelihood that the drug gefitinib (Iressa™) will show a beneficial response, researchers at the Dana-Farber Cancer Institute, the National Cancer Institute (NCI) - part of the National Institutes of Health - and two other institutions announced today in the online version of Science. Previously, gefitinib had been shown to cause tumor regression in certain patients, but researchers had not been able to predict which patients would be responsive to the drug. With this discovery, doctors will be able to select those lung cancer patients who could most benefit from gefitinib and may identify additional patients with other types of cancer who may respond to similar treatments.
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.
* 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.
Source: National Cancer Institute (NCI) Press Release, April 29, 2004.