Nonsmokers who develop lung cancer are more likely than their smoking counterparts to have a mutation in a gene called EGFR, a new study shows. The discovery could be good news for these nonsmokers because tumors that have this genetic defect—which fosters aberrant cell growth—appear highly responsive to a drug called gefitinib.
The findings have already triggered genetic screening to identify which patients might benefit from the drug. Roughly 10 percent of people who develop lung cancer have never smoked. And, in the new study, almost half of such patients showed a mutation in some part of EGFR.
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The Food and Drug Administration approved gefitinib as a lung cancer treatment in May 2003, even though the drug benefited only a small proportion of patients. In one study, 10 percent of people with advanced lung cancer experienced tumor shrinkage while taking gefitinib. Patients in another trial showed no gains from it. The FDA approved the drug as a “third-line treatment,” to be used only after at least two standard chemotherapy cycles had failed. Gefitinib is marketed as Iressa by AstraZeneca in Wilmington, Del.
EGFR encodes a molecule that acts as a docking station on cell surfaces for a protein called epidermal growth factor (EGF). When EGF binds, the receptor jump-starts cell division. EGF and its receptor have legitimate roles in development, but a cell strewn with receptors encoded by a mutated EGFR gene can start dividing uncontrollably. Previous research had established that gefitinib neutralizes these rogue receptors.
In the study published in the Sept. 7 Proceedings of the National Academy of Sciences, scientists determined which lung cancer patients had a mutated EGFR gene. Among 81 smokers, only 4 had lung tumors with mutated EGFR, and 3 of those people were light smokers. In contrast, 7 of 15 nonsmokers’ tumors had mutated EGFR, says study coauthor William Pao of Memorial Sloan-Kettering Cancer Center in New York. Researchers are now reviewing the earlier gefitinib trials to see how many of the patients who benefited were nonsmokers.
Cancers are driven by mutations that either activate growth-inducing genes or sabotage genes that stop growth. In a separate study reported in the Aug. 20 Science, researchers show that mutated EGFR falls into the latter category. If normal cells’ growth runs amok, the EGF receptor follows its cell-division signals with a self-destruct message, says study coauthor Daniel A. Haber of Harvard Medical School and Massachusetts General Hospital in Boston. Cells with mutant EGF receptors don’t employ this failsafe signal, he says.
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All these findings support a hypothesis championed by I. Bernard Weinstein of Columbia University, who maintains that tumor cells become dependent on growth-promoting mutations. “It’s quite fascinating to see [the effect of EGFR mutations] sorted out at the molecular level,” Weinstein says.
The clinical benefits could show up soon. Doctors at both the Memorial Sloan-Kettering Cancer Center and Massachusetts General Hospital are already screening lung cancer patients for the EGFR mutation. That might identify patients likely to benefit from gefitinib or a similar but still-unapproved drug called erlotinib (Tarceva).
Meanwhile, the cause of the EGFR mutation remains obscure, although research so far indicates that the genetic defects are not inherited but acquired, Haber says.
“We think it’s some kind of environmental factor [causing the mutation], so the hunt is on to find what it is,” Pao says.