Biomarker May Predict Best Smoking Cessation Treatment

A genetic biomarker may help predict response to specific smoking cessation treatments, new research suggests.

A multicenter, randomized controlled trial (RCT) of more than 1200 smokers showed that those who had a normal nicotine metabolite ratio had significantly higher quit rates after receiving varenicline (Chantix, Pfizer Inc) for 11 weeks than those receiving a nicotine patch.

Although for those who metabolized nicotine slowly, the efficacy of both treatments was equivalent, there were significantly more overall side effects with varenicline.

"Our findings show that a simple biomarker...can tell us who responds well to nicotine patch, a low-cost medication available over the counter, vs those who require more intensive treatment," lead author Caryn Lerman, PhD, professor of psychiatry and deputy director of the Abramson Cancer Center at the University of Pennsylvania, in Philadelphia, told Medscape Medical News.

"Taken together, the data suggest a simple algorithm for treatment," said Dr Lerman.

She added that it is important for clinicians to recognize that tobacco dependence is a very heterogeneous condition. "And a one-size-fits-all approach is not likely to be effective."

The study was published online January 12 in Lancet Respiratory Medicine.

Quest for Improved Outcomes

The investigators note that because effectiveness and adverse effects vary widely among pharmacotherapies for treating tobacco dependence, they wanted to examine whether biomarkers in individual smokers could improve outcomes.

"We tested whether a genetically informed biomarker of nicotine clearance, the nicotine metabolite ratio (NMR; 3'-hydroxycontinine:cotinine), predicts response to nicotine patch or varenicline for smoking cessation," they write.

"The NMR reflects the activity of the liver enzyme CYP2A6, the major nicotine-metabolizing and cotinine-metabolizing enzyme," the researchers report, adding that NMR also reflects both environmental and genetic effects ― unlike CYP2A6 genotyping.

The RCT included 1246 adult smokers seeking treatment at one of four North American sites between November 2010 and September 2014. NMR status was determined at baseline through blood samples; 662 of the participants were found to be slow metabolizers of nicotine, and 584 found to be normal metabolizers.

The slow metabolizers were less likely than normal metabolizers to be white (P < .0001) and more likely to be male (P = .001), younger (P = .02), and to smoke fewer cigarettes per day (P < .001).

"Sex differences in NMR groups are expected because of estrogen effects...and the difference in ethnicity is expected because of differences in the frequency of reduced or inactive CYP2A6 alleles," note the investigators.

All participants were randomly assigned to receive one of three treatments for 11 weeks. The treatment groups included nicotine patch (active patch plus placebo pill, n = 418), varenicline (active pill plus placebo patch, n = 420), or placebo (placebo pill plus placebo patch, n = 408). They also received behavioral counseling.

The study's primary endpoint was biochemically verified 7-day point prevalence abstinence at the end of treatment to estimate the pharmacologic effect of treatment by NMR.

After treatment, all patients were followed for up to 12 months.

Tailored Treatment

Results showed that normal metabolizers had more success with varenicline than with the patch at end of treatment (odds ratio [OR], 2.17; 95% confidence interval, 1.38 - 3.42; P = .001) and 6 months later (OR, 1.81; 95% CI, 1.05 - 3.11; P = .03).

Quit rates at end of treatment in this group were 38.5% and 22.5%, respectively; at 6 months, the rates were 22.0% and 13.6%.

There was no difference between varenicline and patch for the slow metabolizers at any time point. Although the quit rates were 30.4% and 27.7%, respectively, at end of treatment and 19.1% and 21.6, respectively, at 6 months, these were not significant.

However, according to NMR-by-treatment interactions, for the slow metabolizers, side effects were more severe overall with varenicline than with placebo (P = .04). These differences included increases in nausea (P = .0003) and abnormal dreams (P = .005).

The NMR-by-treatment interaction was not significant for side effects from the patch vs placebo.

Finally, the number needed to treat was 4.9 for varenicline and 26.0 for nicotine patch in the normal metabolizers and 8.1 vs 10.3 in the slow metabolizers.

"An improved understanding of the mechanisms underlying NMR associations with treatment response could help to refine the use of this biomarker in clinical practice," write the investigators.

They add that "our data suggest that treating normal metabolizers with varenicline and slow metabolizers with nicotine patch could provide a viable clinical approach." And extending the duration of use "could potentially sustain the benefits of tailored treatment."

The researchers write that the assay results cost $50 per sample and were reported in less than 1 week. Although the development of a point-of-care test could be helpful to clinicians, they note that using the NMR could result in additional costs and time.

"There are some steps needed before this can be fully translated into practice. But hopefully we're not too far off," said Dr Lerman.

For now, "it's important to consider the patient's history and to obtain the data necessary to be able to make a treatment choice based on their individual characteristics."

Important Advance

"The results reported by Lerman and colleagues are an important scientific advance," Jennifer J. Ware, PhD, from the MRC Integrative Epidemiology Unit at the University of Bristol, United Kingdom, and colleagues write in an accompanying editorial.

The editorialists note that if the findings can be replicated, they could potentially lead to changes in clinical practice.

However, "the extent to which tailoring treatment by a biomarker such as NMR is a cost-effective approach will depend on doing a full health economic assessment, including consideration of the relevant national context," they write.

"The cost-effectiveness ratio was included as a secondary outcome in the trial protocol, therefore we look forward to reading the results of this analysis in due course."

They add that the effect of warnings "stipulated by national regulatory bodies on prescribing rates of varenicline" will also need to be considered.

The US Food and Drug Administration (FDA) mandated black box warnings to varenicline labeling in 2009. In the United Kingdom, it is considered a black triangle medication. Although this means it is subject to additional monitoring, prescriptions for varenicline continue to increase steadily there.

"Thus, the personalized biomarker-based approach proposed by Lerman and colleagues might therefore prove to more effective (and cost-effective) in reducing overall smoking prevalence in the USA, where there are barriers to the prescription of varenicline, than in the UK, where [it] is prescribed widely," write the editorialists.

The study authors and editorialists have reported several financial relationships, which are fully listed in the original articles.

Lancet Respir Med. Published online January 12, 2015. Abstract, Editorial

Medscape Medical News © 2015  WebMD, LLC

Send comments and news tips to news@medscape.net.

Cite this: Biomarker May Predict Best Smoking Cessation Treatment - Medscape - Jan 15, 2015.