April 30, 2004

Gene mutations predict which lung cancers will respond to Iressa

MGH Cancer Center researchers have discovered a molecular marker that identifies lung cancer patients whose tumors will respond to treatment with the drug Iressa. Their findings, to be published in the May 20 New England Journal of Medicine (NEJM), were released online April 29. "This discovery will help us significantly improve the treatment of many lung cancer patients and also is an important next step in the molecular targeting of cancer drugs," says Daniel Haber, MD, PhD, director of the MGH Cancer Center (left) and senior author of the paper.

Approved a year ago for deadly non-small-cell lung cancer, Iressa causes tumors to shrink significantly in a small percentage of patients, but some of those responses are rapid and dramatic. The drug acts by disabling the epidermal growth factor receptor (EGFR) on the surface of lung cancer cells, halting signals that can lead to the uncontrolled growth of a malignant tumor. To understand why the drug worked so well for some patients but not others, the MGH team screened samples from patients who participated in an Iressa clinical trial to search for mutations in the EGFR gene.

In eight of nine patients that had responded to Iressa, the researchers found genetic mutations affecting the same area of the EGFR protein. No mutations were seen in patients that did not respond. Further tests confirmed that cultured cells with two of the mutations responded more powerfully and for a longer time to growth factor and were 10 times more sensitive to disruption by Iressa than were tumor cells without the mutation.

Thomas Lynch, MD, director of the MGH Thoracic Oncology Center and a co-lead author of the paper, says, "These findings will help determine which patients will benefit from Iressa and which should not receive it. In addition, if we know a patient is likely to respond, we might be able to start treatment earlier with this drug that is more effective and has fewer side effects than standard chemotherapy."