Erlotinib (Tarceva) was approved for treatment of progressive non-small cell lung cancer (NSCLC) after the BR21 study that showed that tarceva not only improved survival but also improved lung cancer symptoms and quality of life. This study and others have also taught us that the benefit of tarceva is much better in those who had never smoked and less effective in current smokers. It is important to note, however, that even those who currently smoke obtain a benefit from treatment with tarceva, albeit smaller. In the wake of the BR.21 trial, it became known that certain EGFR mutations in the tumor are associated with a dramatic benefit with tarceva, as well as the other EGFR tyrosine kinase inhibitor (TKI) gefitinib (Iressa).We also began to realize that these EGFR mutations were found most commonly in never smokers and rarely in current smokers. There it was: the reason why tarceva worked better in never smokers. But in fact that was not the whole story. Tarceva, like many other drugs, is broken down in the body by an enzyme group called CYP 1A1/1A2. Enzymes are proteins that help to break down and digest our food, but enzymes can break down and digest many other things as well. The products in inhaled tobacco smoke stimulate this enzyme CYP, which then further breaks down tarceva in the body before it has a chance to work.

So it is possible that smokers may not have enough amount of tarceva in their body, explaining the lack of effectiveness of tarceva. A recent publication in the Journal of Clinical Oncology described the attempt to increase blood levels of tarceva in patients who smoke. Two groups of patients were evaluated. Those taking the normal dose of drug (D) and those taking twice the normal dose (2D). Blood tests were done to measure the amount of tarceva in the blood. Those in the 2D group had higher blood levels of drug and lived longer than those in the D group. So how do I interpret this study? POSITIVES: Tarceva may work better even in those who currently smoke just by increasing the dose of this drug. NEGATIVE: This was a small study and more work will need to be done on this issue. WARNINGS: This study does not provide a license to smoke just because it provides us with a way to get around the harmful effects of smoking on tarceva. FUTURE: To quote the authors, “The potential benefit of higher erlotinib doses in current smokers warrants further investigation.” Importantly, CYP enzymes not only modulate the effect of treatment: they appear to play a role in development of lung cancer as well. In those who smoke, CYP activates the products of cigarette smoke. In women, those who smoke have been found to have high levels of CYP1A1 than women who don’t smoke. GSTM1 is an enzyme that converts the activated tobacco smoke products into breakdown products that can be disposed of by the body. Women are more likely than men to have variations in the genes controlling this enzyme, such that this enzyme functions lower than normal, thereby again increasing risk for developing lung cancer. This may explain why women are more susceptible to developing lung cancer from smoking than men. In conclusion, enzymes not only affect one’s susceptibility to cancer, they may also affect how we respond to treatment. Ongoing investigations will continue to add to our understanding of this very complex dynamic.