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Gene Mutation Predicts Cancer Drug's Success

Studies explain why Iressa works wonders for some

THURSDAY, April 29, 2004 (HealthDayNews) -- Scientists have discovered a gene mutation that appears to identify those lung cancer patients who will respond well to the drug Iressa.

The results of two studies, conducted independently but with similar results, are being published early in the May 20 issue of the New England Journal of Medicine and in the April 30 issue of Science.

Investigators would not reveal exactly why the two studies were conducted separately in the same town (Boston), but the story hinted at being almost as interesting as the scientific findings.

"People have been saying that this is a great drug if we just knew who to use it in," said Dr. Thomas Lynch, co-author of the New England Journal article and director of the Thoracic Oncology Center at Massachusetts General Hospital in Boston. "This study doesn't just tell us how to use the drug; it also gives us a window into the biology of lung cancer."

As such, the findings have implications not only for the treatment of lung cancer with existing drugs, but for the development of new drugs.

The U.S. Food and Drug Administration approved the use of Iressa one year ago to treat advanced non-small cell lung cancer, which represents about 85 percent of all lung cancers and which is the leading cause of cancer deaths in the United States. This type of cancer is notoriously difficult to treat. However, in a clinical trial, Iressa had dramatic results in slightly more than 13 percent of patients.

The question has been: Why does the drug work so well in some patients and not in others?

The Science article pointed out that in the United States, better responses were seen more frequently in women, nonsmokers and patients with adenocarcinomas (a certain type of cancer cell). Also, Japanese patients were more likely to respond than American patients.

The New England Journal authors looked at tumor samples from patients at Mass General who had participated in the Iressa trial. Specifically, they were looking for mutations in the EGFR (epidermal growth factor receptor) gene.

The Science authors also looked for EGFR mutations in non-small cell lung tumors in both Japanese and American patients, some who had responded to Iressa and some who had not.

Epidermal growth factors bind to specific receptors in a lock-and-key manner and stimulate the cells to grow, Lynch explained. In some cases, such as when a wound needs to heal, this can be good. When there's a mutation in the receptor, however, the growth factor can go into overdrive, sending thousands upon thousands of messages telling the cell to grow. Iressa works by shutting off this out-of-control signal.

Both sets of scientists found a particular EGFR mutation was associated with response to Iressa. "This will have to be proven prospectively, but this is one of the strongest retrospective data I've seen," said Dr. Bruce E. Johnson, a co-author of the Science article and director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute in Boston. "The association is strong enough that we can publish the results in some of the fanciest medical journals with fewer than 50 patients put together."

In the immediate future, the information will let physicians test patients with advanced lung cancer to see who is likely to respond well to Iressa. These patients may then be started on the drug earlier, instead of trying chemo first. "Having a negative test doesn't mean you won't benefit, but it means that we would probably still use chemo, then use Iressa afterwards," Lynch said. "It allows us to give some rational thought to how we select treatment."

The drug may also be helpful to prevent recurrences in individuals who have had surgery for early-stage lung cancer.

Finally, the findings provide leads as to how to develop new drugs.

There is no commercial test for this particular mutation, and Lynch thinks that genetic testing will probably be available in hospitals first. "We think it's going to be a matter of weeks before we can do it here [Mass General]," he said. "It may be six months to a year for commercial testing."

Cost and coverage are still big unknowns, although insurance companies tend not to cover new tests in the beginning, Lynch added.

More information

The U.S. Food and Drug Administration has information on Iressa. The National Cancer Institute has more on non-small cell lung cancer.

SOURCES: Thomas Lynch, M.D., director, Thoracic Oncology Center, Massachusetts Hospital, Boston; Bruce E. Johnson, M.D., director, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston; May 20, 2004, New England Journal of Medicine; April 30, 2004, Science
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