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Genetic Flaw May Streamline Cancer Treatment

Times Staff Writer

Researchers stepped closer toward the long-sought goal of tailoring cancer therapy to individuals, identifying a genetic defect that predicts response to a new drug called Iressa.

Two studies reported today indicate that about 15% of the 170,000 Americans who develop lung cancer each year have a specific genetic mutation that correlates with a potent, life-prolonging response to Iressa.

Those without the mutation aren’t helped by the drug and can be spared the $2,000- to $3,000-per-month treatment.

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“This is something very exciting that we have long hoped for, that we would have a way of predicting who would respond to a therapy and who would not,” said Dr. Ronald Blum, director of the Cancer Center at Beth Israel Hospital in New York.

For every 100 patients being treated with Iressa, only 10 are receiving a benefit, he said. “This way, you would benefit all that you treat,” he added.

“This will be very important for physicians considering giving Iressa to patients in the future,” predicted Dr. Harmon Eyre, chief medical officer of the American Cancer Society. After the tumor is initially removed from the lung, he said, its “gene mutation profile can be assessed, and the potential for Iressa to be effective can be evaluated.”

Therapy could also be started much earlier in the course of the disease, which would improve both the survival rate and quality of life, Blum said. Now, Iressa is approved only for use after two other chemotherapy agents have failed.

Experts cautioned that there was not yet a simple test available to determine if the mutation was present, but researchers were racing to develop one and it should be available within a year.

Similar mutations are also present in some patients with other cancers, including head and neck cancer and a brain tumor called glioblastoma. Researchers are trying to learn whether the drugs would work in those patients as well.

The finding also helps to explain why results from clinical trials with Iressa and similar drugs, such as Tarceva and Erbitux, have been so erratic. It seems clear that the average level of success seen in clinical trials correlates with the number of subjects in the trial who carry the mutation.

Iressa itself, for example, was almost rejected by the Food and Drug Administration because U.S. trials were not nearly as successful as earlier trials conducted in Japan. The new findings show, however, that Japanese lung cancer patients were three times as likely as Americans to carry the genetic defect that allows the drug to function.

The findings may also change the way clinical trials of cancer drugs are conducted in the future, Eyre said. By using genetic markers to identify patients who were most likely to benefit from new drugs, clinical trials could be conducted with fewer patients and new drugs could reach the market more quickly, he said.

Iressa, generically known as gefitinib, was developed by drug maker AstraZeneca to target a cellular protein that serves as the receptor for epidermal growth factor, or EGF, a naturally occurring compound that is associated with the proliferation of cancer cells in non-small cell lung cancer, the most common form of the disease.

Tarceva, developed by Genetech Inc., and Erbitux, produced by Imclone Systems Inc., target the same protein.

Researchers believed that there were abnormally high levels of EGF in the lung cancer patients promoting growth of the tumors, and thought that inhibiting the EGF receptor would slow or halt growth.

In an attempt to understand what was happening, Dr. Daniel Haber and his colleagues at Massachusetts General Hospital and Dr. William Sellers and his associates at the Dana-Farber Cancer Institute in Boston independently looked at tumor tissue taken from patients who responded to the drug and those who did not.

They then determined the DNA sequence of the EGF receptor gene.

The researchers found that nearly all of the patients who responded to therapy had a defective EGF receptor gene, while all of those who did not had a normal gene.

Instead of having unusually high levels of EGF, the people who responded to the drug had an abnormal receptor that made their tumor cells much more sensitive to the effects of normal levels of EGF.

The Dana-Farber results are reported in today’s issue of the journal Science. The Massachusetts General Hospital results will be reported in the May 20 issue of the New England Journal of Medicine, but were released today.

The researchers also found that the mutated EGF receptor was more common in women, Japanese, nonsmokers and people with a subtype of lung cancer called bronchoalveolar cancer. They don’t know why these groups were more likely to have the mutation, but physicians had already noted that people in those groups were more likely to respond to Iressa.


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