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
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.
For information about cancer, please visit the NCI home page at
http://cancer.gov or call the NCI's
Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
* 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.