Issues & Insights

Caryn Lerman, Ph.D.
Mary W. Calkins Professor
Department of Psychiatry and Annenberg Public Policy Center
Deputy Director, Abramson Cancer Center
University of Pennsylvania
Philadelphia, Pennsylvania

Tobacco use is the greatest preventable cause of cancer mortality. Despite two decades of intensive tobacco control efforts and widespread knowledge of the health harms of tobacco use, approximately 22% of American men and women continue to smoke.

Given the public health significance of tobacco dependence, it is surprising that only a handful of medications have been approved by the FDA for a smoking cessation indication. Nicotine replacement therapies (NRT), such as nicotine gum, patch, spray, inhaler and lozenge, are among the first-line treatments for tobacco dependence. Bupropion (brand names Wellbutrin, Zyban) is an anti-depressant medication that was approved for the treatment of tobacco dependence in 1997. Although bupropion’s precise mode of action has yet to be determined, there is some evidence to suggest that it inhibits post-synaptic uptake of dopamine and norepinephrine by brain cells. Like the NRTs, bupropion doubles the odds of successful smoking cessation compared to placebo. In addition, the FDA recently approved varenicline (Chantix), a partial agonist at the α4β2 nicotinic acetylcholine receptor; this medication has superior efficacy to bupropion. However, even with the best treatments available, only 1 in 5 smokers are able to achieve and maintain long-term abstinence (1). Clearly, to reduce tobacco-related cancer morbidity and mortality, new approaches to tobacco dependence treatment are needed.

New investigations to improve the outcomes of tobacco dependence treatment are testing whether genetic information can be used to identify smokers most and least likely to benefit from particular therapies. While environmental factors exert critical influences on tobacco use, there is also extensive evidence supporting the role of genetic factors. Meta-analyses of data from studies of twins estimate that about 60-70% of the variability in nicotine dependence and smoking persistence is attributable to genetic factors (2). Further, about 50% of the variance in quitting success, given a quit attempt, is attributable to inherited factors (3).

These findings have stimulated a new field of research to elucidate the specific genetic variants that predict success in smoking cessation treatment. This research has been guided by increased understanding of the neurobiology of nicotine dependence (4). Nicotine dependence is a complex addictive disorder that involves several different neurobiological systems. Nicotine binds to neuronal nicotinic receptors (nAChRs), such as the α4β2 subtype located on dopaminergic neurons in the brain's ventral tegmental area (VTA), resulting in the release of dopamine (DA) in another brain area, the nucleus accumbens (NAC). Nicotine administration is also associated with release of natural opioid peptides, proteins that bind to mu-opioid receptors (MOR) on key neurons to weaken inhibitory control over dopamine release.

In addition, nicotine acts on the brain's serotonin and glutamate systems, further boosting its rewarding effects. Emerging research in pharmacogenetics -- the study of how genes affect our response to drugs -- is exploring the influence of inherited differences in drug metabolism (pharmacokinetics) and neurobiological drug targets (pharmacodynamics) on an individual's response to smoking cessation therapies (5).

For example, individual responses to the transdermal (skin) nicotine patch have been associated with gene variants that influence nicotine-metabolizing enzymes (e.g., CYP2A6) (6,7). There's evidence that people who are slower metabolizers of nicotine tend to be less dependent and have a higher likelihood of success with the nicotine patch compared to those who metabolize the drug more quickly.

Consistent with evidence that nicotine’s rewarding effects are mediated, in part, by dopamine-linked mechanisms in the brain, several genetic polymorphisms (variants) in the dopamine pathway have also been shown to predict response to the nicotine patch. These include the dopamine D2 receptor (DRD2) gene, the dopamine beta hydroxylase (DBH) gene, and the catechol-O-methyl-transferase (COMT) gene (8, 9, 10, 11). Response to bupropion has also been related to polymorphisms in the CYP2B6 gene(which codes for the enzyme that metabolizes the drug) (12), in DRD210 and in COMT (13). Validation of these findings in independent trials is necessary before doctors can ever use this data to tailor smoking-cessation treatments to particular patients.

Other key considerations include the preparedness of providers to deliver the service, patients’ willingness to undergo testing and their understanding of genetic test results, and the larger policy environment in which these new treatments would take place (14).

While there are many challenges associated with integrating genetic-based treatment strategies for smoking cessation, it is important to note that even a modest improvement in smoking cessation rates could have a significant public health impact. Addressing these broader policy and ethical concerns, in parallel to the scientific research, is an essential part of translating emerging genetics research on tobacco dependence treatment to practice and reducing tobacco-related cancer mortality.

References

1. Schnoll, R. A., & Lerman, C. (2006). Current and emerging pharmacotherapies for treating tobacco dependence. Expert Opin Emerg Drugs, 11(3), 429-444.
2. Sullivan, P. F., & Kendler, K. S. (1999). The genetic epidemiology of smoking. Nicotine & Tobacco Research, 1 Suppl 2, S51-57; discussion S69-70.
3. Xian, H., Scherrer, J. F., Madden, P. A., Lyons, M. J., Tsuang, M., True, W. R., et al. (2003). The heritability of failed smoking cessation and nicotine withdrawal in twins who smoked and attempted to quit. Nicotine & Tobacco Research, 5(2), 245-254.
4. Dani, J. A., & Harris, R. A. (2005). Nicotine addiction and comorbidity with alcohol abuse and mental illness. Nat Neurosci, 8(11), 1465-1470.
5. Lerman, C., Patterson, F., & Berrettini, W. (2005). Treating tobacco dependence: state of the science and new directions. Journal of Clinical Oncology, 23(2), 311-323.
6. Lerman, C., Tyndale, R., Patterson, F., Wileyto, E. P., Shields, P. G., Pinto, A., et al. (2006). Nicotine metabolite ratio predicts efficacy of transdermal nicotine for smoking cessation. Clinical Pharmacology & Therapeutics, 79(6), 600-608.
7. Malaiyandi, V., Lerman, C., Benowitz, N. L., Jepson, C., Patterson, F., & Tyndale, R. F. (2006). Impact of CYP2A6 genotype on pretreatment smoking behaviour and nicotine levels from and usage of nicotine replacement therapy. Mol Psychiatry, 11(4), 400-409.
8. Colilla, S., Lerman, C., Shields, P. G., Jepson, C., Rukstalis, M., Berlin, J., et al. (2005). Association of catechol-O-methyltransferase with smoking cessation in two independent studies of women. Pharmacogenetics & Genomics, 15(6), 393-398.
9. Johnstone, E. C., Yudkin, P. L., Hey, K., Roberts, S. J., Welch, S. J., Murphy, M. F., et al. (2004). Genetic variation in dopaminergic pathways and short-term effectiveness of the nicotine patch. Pharmacogenetics, 14(2), 83-90.
10. Lerman, C., Jepson, C., Wileyto, E. P., Epstein, L. H., Rukstalis, M., Patterson, F., et al. (2006). Role of functional genetic variation in the dopamine D2 receptor (DRD2) in response to bupropion and nicotine replacement therapy for tobacco dependence: results of two randomized clinical trials. Neuropsychopharmacology, 31(1), 231-242.
11. Yudkin, P., Munafo, M., Hey, K., Roberts, S., Welch, S., Johnstone, E., et al. (2004). Effectiveness of nicotine patches in relation to genotype in women versus men: randomised controlled trial. BMJ, 328(7446), 989-990.
12. Lee, A., Jepson, C., Hoffmann, E., Epstein, L., Hawk, L., Lerman, C., et al. (in press). CYP2B6 genotype alters abstinence rates in a bupropion smoking cessation trial. Biological Psychiatry.
13. Berrettini, W. H., Wileyto, E. P., Epstein, L., Restine, S., Hawk, L., Shields, P., et al. (2007). Catechol-O-methyltransferase (COMT) gene variants predict response to bupropion therapy for tobacco dependence. Biological Psychiatry, 61(1), 111-118.
14. Shields, A. E., Lerman, C., & Sullivan, P. F. (2004). Integrating genetics into smoking treatment: emerging ethical, social and legal issues. Nicotine & Tobacco Research, 6, 675-688.