When someone is diagnosed with lung cancer, the first question asked is almost always, “Did they smoke?” While this is an understandable reaction, based on the fact that 85% to 90% of lung cancer deaths in the U.S. are, at least in part, smoking-related, what accounts for the remaining 10% to 15%?
Some estimates show that as many as 20,000 Americans die from lung cancer each year even though they are classified as “never-smokers” (less than 100 cigarettes in a lifetime). Based on these figures, if never-smokers were placed in a separate category of lung cancer, they would place sixth among the top ten most lethal cancers in the U.S. Although secondhand smoke may have played a significant role in many of these cases, a large group of patients whose cancer cannot be connected to tobacco still remains.
Until recently, the medical community had little reason to believe that never-smokers could be considered as a separate entity from smokers. Regardless of their history, both groups were diagnosed and treated in exactly the same way. Response rates to treatment were similar, with the never-smoker group faring only slightly better than the smoker group. Now, however, there is more recognition that the two groups may harbor distinctly different diseases. Two cancer drugs, Iressa (gefitinib) and Tarceva (erlotinib) have proven to be more effective in people who never smoked, and researchers have identified genetic differences that may explain why.
Lung cancer in people who have never smoked differs in a number of ways from the same disease in smokers. For instance, never-smokers with lung cancer have different tumor tissue structure, gene mutations and demographic profiles than smokers with lung cancer. While lung cancer does run in families, a similar smoking history among family members is also common, so it does not necessarily follow that lung cancer is an inherited genetic condition. In 2006, however, researchers in Japan determined that family history proved to be a stronger risk factor among never-smokers than among smokers, suggesting that lung cancer in never-smokers may have an inherited component.
With the advent of “smart drugs” designed to target specific proteins found in cancer cells, the hope was that their selectivity would make them more effective while producing fewer side effects. Unfortunately, these drugs worked in some cancers, but had little, if any effect on others. Drugs such as Iressa, which targets epidermal growth factor receptors (EGFR) found in a host of different cancers, showed a disappointing 10% response rate in lung cancer patients who took the drug. The question then became why, given the same receptor, response rates were not similar for everyone. Further studies determined that cancers in certain populations were more likely to respond. Striking differences in response rates and outcomes were observed when patients with advanced non-small cell lung cancer who were lifelong never-smokers were treated with EGFR inhibitors such as Iressa and Tarceva compared with the outcomes using the same agents in patients who smoked and developed lung cancer.
As studies continued, it was found that various genetic mutations exist in a percentage of those diagnosed with the adenocarcinoma sub-type of non-small cell lung cancer. Clinical trials are currently in progress to test the efficacy of drugs that target several of these mutations. While results to date have yielded some success, it has also been determined that virtually all patients who initially respond to the drugs eventually develop resistance. Ongoing research is being conducted to find an agent capable of de-activating the resistance-causing genes.
At least in the near future, smoking will continue to be the primary cause of lung cancer, and programs to help people stop smoking will remain a priority. At the same time, the ever increasing population of never-smokers should be an reason enough for scientists to look beyond the smoking risk factor alone.
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