Lung cancer patients who have never smoked are more likely than smokers to harbor one of two genetic mutations that researchers at UT Southwestern Medical Center have now linked to the disease.
"This study describes the first known mutation to occur in lung cancer patients who have never smoked," said 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. "These findings may help explain why certain lung cancer patients respond dramatically to a specific form of targeted therapy while others have little or no response."
Mutations in the epidermal growth factor receptor (EGFR) gene are present mainly in adenocarcinomas, the most common form of lung cancer found in smokers and non-smokers, as well in women and people under 45. These mutations have shown increased sensitivity to gefitinib (Iressa) and erlotinib (Tarceva), drugs targeting the gene.
To understand better 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).
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 smokers.
As a result, it appears that two distinct molecular pathways are involved in formation of lung cancer, Dr. Gazdar said. The pathway in smokers involves KRAS gene mutations, while the pathway in people who never smoked involves EGFR gene mutations.
The next step is to move these findings toward development of 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 the gefitinib drug.
"These lines will prove invaluable in understanding both the response to gefitinib and erlotinib and the mechanisms by which resistance eventually develops," Dr. Gazdar said. "The cell lines may help identify strategies to overcome this drug resistance that eventually develops in most responders."