Commentary on Chenet al. (2014): Another step on the road to clinical utility of pharmacogenetics for smoking cessation?

Abstract

Tobacco smoking continues to be the leading cause of preventable death in the world 1, and yet the most efficacious behavioral and pharmacological treatments are ineffective in the majority of treatment-seeking smokers. While social and other environmental determinants are major contributors to tobacco use, twin and family studies over decades confirm that additive genetic factors contribute substantially to smoking behavior and smoking-attributable disease 2. Converging research on the molecular genetics of smoking has pointed to at least two biologically plausible genetic loci contributing to nicotine dependence: cigarette consumption and smoking cessation. The α5–α3–β4 (CHRNA5–CHRNA3–CHRNB4) nicotinic acetylcholine receptor gene cluster on chromosome 15q24–25.1 has been associated with cigarette consumption 3, lung cancer and chronic obstructive pulmonary disease 4, 5 and smoking cessation 6-9. The cytochrome p450 2A6 enzyme inactivates approximately 80% of nicotine to cotinine and other metabolites through oxidative hepatic metabolism 10, and variations in its highly polymorphic gene (CYP2A6) on chromosome 19q13.2 or the nicotine metabolic 3-hydroxycotinine/cotinine ratio (NMR) have been associated with cigarette consumption, lung and other aerodigestive cancers and smoking cessation 3, 5, 11, 12. Both loci include multiple genes and/or alleles with complex pharmacology and mechanisms underlying nicotine dependence, smoking behavior and disease pathogenesis, but these mechanisms are the subject of a parallel translational research literature, with equally impressive breakthroughs from ‘mice to men’ 11, 13-15. In this issue of Addiction 16, Chen and colleagues extend their analyses of the CHRNA5–CHRNA3–CHRNB4 rs16969968–rs680244 haplotype and smoking cessation 9 to report analyses of the joint contribution CYP2A6 genotype-defined metabolic status and CHRNA5 genotype and pharmacotherapy response for smoking cessation in a randomized clinical trial of 709 European-ancestry smokers. The investigation found that combination (patch and lozenge) nicotine replacement therapy (NRT) is more effective in individuals with CYP2A6 genotype-defined fast metabolizer status compared to placebo, but not in slow metabolizers, and that the combined effects of CYP2A6 and CHRNA5 haplotype produces a number-needed-to-treat (NNT) of 2.6 for high-risk/high-risk genotype status versus 1000 for low-risk/low-risk genotype status. The report also indicated that CYP2A6-defined metabolic status was not informative for predicting bupropion response for smoking cessation. The strengths of this investigation include the design of the multi-arm trial, well-justified hypothesis-driven analyses and the clinical relevance of the NNT metric. The limitation is the small effective sample size and resulting limited statistical power from multiple genotype/drug subgroups. A recent White Paper by the National Institute on Drug Abuse on smoking cessation biomarkers endorsed a three-step process for development of genetic tests to guide translation to practice, consisting of (1) ‘analytical validation’ (determination of whether or not a biomarker is able to be measured accurately, precisely and reliably); (2) ‘qualification’ (assessment of available evidence on associations between the biomarker and disease states); and (3) ‘utilization’ (determination of adequate evidence to support applying the biomarker for a specific use) 17. Evidence cited above suggests that analytical validation and qualification of the genetic and non-genetic biomarkers for CHRNA5–CHRNA3–CHRNB4 and CYP2A6 may be within reach. However, utilization (or demonstration of clinical utility) may require that several remaining gaps in translation be filled before genetically informed personalized medicine for smoking cessation becomes realistic as part of the multi-faceted tobacco use treatment arsenal used in real-world clinical settings. Remaining translational gaps include the need to (1) demonstrate improved smoking cessation or other clinical outcomes from prospectively genetically tailored treatment compared to usual care (comparative effectiveness); (2) replicate drug-selective (biomarkers specific to bupropion, NRT, varenicline or other pharmacotherapies); (3) produce evidence from studies of non-European-ancestry populations; (4) develop and validate robust additive genetic scores to account for more of the phenotypical variation in drug response; and (5) illustrate the relative value proposition of genetic testing using cost-effectiveness analyses and evidence-based medicine metrics such as the NNT 18. The results of the present study may be the first to demonstrate the combined predictive value of the most robust pharmacodynamic (CHRNA5–CHRNA3–CHRNB4) 6, 8, 9 and pharmacokinetic (CYP2A6) 12, 19 loci for NRT. Hypothetically, the prospect of avoiding costly treatment that is unlikely to be effective, or even necessary, for 99.9% of the smokers in the lowest-risk genetic stratum would seem to be a powerful argument to clinicians and health-care organizations for exploration of its clinical implementation, whereas identification of subgroups of patients at conspicuously high risk for continued smoking and its health consequences would be of great value from clinical and public health perspectives. While these findings will need to be replicated independently by other investigators, this paper represents an important translational step in the pathway towards personalized medicine for smoking cessation, but many additional leaps will be needed to confirm the clinical utility of these and other (probably additive) genetic tests on the practice of evidence-based medicine. None.