Researchers identify first known mutation to occur in lung cancer patients who have never smoked

Mar 2 2005

Researchers at UT Southwestern Medical Center have identified the first known mutation to occur in lung cancer patients who have never smoked.

Dr.Adi Gazdar, professor of pathology in the Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research and senior author of the study in today's issue of the Journal of the National Cancer Institute, explains that the findings may show why certain lung cancer patients respond dramatically to a specific form of targeted therapy while others have little or no response.

Mutations in the gene are present mainly in adenocarcinomas, the most common form of lung cancer found in people under 45. These mutations have shown increased sensitivity to the drugs Iressa and Tarceva used to target the gene.

To gain a better understanding of the role of the EGFR mutation in the development of lung cancer, Dr. Gazdar and his colleagues analyzed tissue samples from primary tumors of 519 patients in the United States, Japan, Taiwan and Australia. Mutations in the DNA of nonmalignant lung tissue from many of these patients and from other separate cancer tissues also were examined.

The researchers found mutations in the EGFR gene were much more common:

• in people with lung cancer who never smoked compared to smokers (51 percent vs. 10 percent, 85 of 166 non smokers vs. 35 of 353 smokers);
• in adenocarcinomas compared to other lung cancers (40 percent vs. 3 percent, 114 of 289 adenocarcinomas vs. 6 of 230 other cancers);
• in women compared to men (42 percent vs. 14 percent, 72 of 171 women vs. 48 of 348 men);
• in patients of Asian ancestry compared to other ethnicities (30 percent vs. 8 percent, 107 of 361 Asians vs. 13 of 158 in other ethnicities).

Two distinct molecular pathways appear to be involved in the formation of lung cancer; in smokers it involves KRAS gene mutations, while in people who never smoked it involves EGFR gene mutations.

The next step is to develop better treatments for lung cancer, said Dr. Gazdar.

He and Dr. John Minna, director of the W.A. "Tex" and Deborah Moncrief Jr. Center for Cancer Genetics and the Hamon Center for Therapeutic Oncology Research and a contributing author, have established eight lung cancer cell lines that harbor several types of EGFR mutations and are now establishing another line from a patient who relapsed after initially responding well to thedrug Iressa. This research will prove invaluable in understanding both the response to both drugs and the mechanisms by which resistance eventually develops; the cell lines may help show ways of overcoming resistance to the drug.

In a related study in the current issue of Cancer Research, Dr. Gazdar and his colleagues found that mutations in gene pathways is associated with certain cancers.

"Our work is very important because if you have a mutation in the EGFR gene in the tumor, a patient could have a dramatic response to a relatively nontoxic once-daily oral therapy," Dr. Minna said.Great variation regarding the sensitivity of the tumor to a drug was seen; they were also able to identify in advance a pattern of gene expression that tells whether a tumor is going to be resistant or sensitive to a particular drug. The ability to examine a patient's tumor,and profile each gene enabled the selection of the best current therapy.

Other research has found a lung cancer that initially was very sensitive to Iressa because of a mutation in the EGFR gene, developed resistance to the drug because of a second EGFR mutation.The enhanced understanding of EGFR and these mutations reported in the NEJM study will allow new drugs to be designed to combat these drug-resistant receptors, enabling effective second-line therapy to then be directed at the same target, Dr. Minna wrote.Mutations in the KRAS gene – a gene in the EGFR signaling pathway – were found in 8 percent of lung cancers but in none with the EGFR mutation. This mutation was more common in males, Caucasians, and current or former smoker.