WASHINGTON — In a step toward more tailored cancer therapy, scientists have discovered some lung cancer patients harbor gene mutations that make a new drug dramatically help them — even as it fails most.
Now the race is on to develop a test to figure out in advance whom Iressa will help, so patients who need it might benefit sooner and others won’t waste time and money and risk unnecessary side effects.
The discovery, by two teams of Boston scientists, ultimately could benefit thousands battling the nation’s top cancer killer. And it points the way toward more targeted therapy of other cancers.
'The beginning of personalized medicine'
“It’s incredibly important,” said Vanderbilt University lung cancer specialist Dr. David Johnson, president-elect of the American Society of Clinical Oncology. “This is just the beginning of personalized medicine.”
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But it also raises some intriguing questions: The mutations aren’t inherited, they just occasionally arise inside the cancer itself — yet they seem more common among Japanese patients, women and nonsmokers. Why? No one knows.
Iressa, which began selling a year ago, was designed to target “epidermal growth factor receptor,” or EGFR, growth-spurring signaling posts for lung cancer cells. The idea was that lung cancer might make excess EGFR, and blocking it might slow growth with less toxicity than chemotherapy.
Doctors have reported terminally ill patients who lived months or even years longer than expected on Iressa. But they were rare: Only about 10 percent of U.S. patients respond to the drug, frustrating doctors who felt they had to offer it to most advanced-stage patients to find the fraction it helps.
Gene mututations influence response to drug
Now scientists working separately at Massachusetts General Hospital and the Dana-Farber Cancer Institute have made the same discovery: Blocking excess EGFR didn’t matter. Instead, Iressa works in people whose lung tumors harbor certain gene mutations that make abnormal EGFR.
This growth protein contains a little pocket to capture an energy-spurring molecule called ATP, said Dr. Daniel Haber, who led the Mass General team. Iressa apparently targets that pocket — and when the protein is mutated, Iressa fits inside the pocket much better, blocking ATP from getting in and thus inhibiting cancer-cell growth, he explained.
“This was a targeted therapy before the target was really known,” added Dr. Matthew Meyerson, who co-led the Dana-Farber team.
The teams report their research Thursday in the journals Science and the New England Journal of Medicine.
The discovery won’t immediately help patients — there is no commercial test. The Mass General scientists are negotiating with companies to create one, and large hospitals might also eventually offer in-house laboratory testing. Once testing is available, patients would need tumor samples on file after their initial lung surgery to get it.
In the next step, researchers will begin studies to see whether mutation-harboring patients fare better if given Iressa early in the disease, maybe even before chemotherapy, instead of receiving it as a last-ditch treatment.
Larger studies needed
Helping even a subset of lung cancer patients is important because the killer disease is so prevalent, cancer specialists stress. Some 170,000 Americans will be diagnosed with lung cancer this year, and it kills more than 150,000 annually.
Still, they caution the studies were small and need confirmation.
Learn more about lung cancerAt Mass General, eight of nine patients who had responded to Iressa had mutation-containing tumors; seven patients not helped by Iressa didn’t.
The one other responder suggests there may be other Iressa-susceptible mutations to discover.
In 25 tumors from patients not given Iressa, Mass General found only two had the mutations. Laboratory studies of cancer cells found the mutated receptors were 10 times more sensitive to Iressa than were normal receptors.
The Dana-Farber team first scanned tumors from 58 Japanese and 61 U.S. patients and found the mutations in 15 of the Japanese and just one American. Then they looked at tumors from nine Iressa users, and found the mutations in all five who responded to the drug and no mutations in the four Iressa didn’t help.
The Japanese findings were intriguing because 20 percent to 25 percent of patients there respond to Iressa, much higher than the 10 percent U.S. response rate, Meyerson said.
Also, the mutations were more common in women, people who had never or not recently smoked, and people who had a subtype called bronchoalveolar cancer — characteristics doctors already had noticed.
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