Circulating cotinine concentrations and lung cancer risk in the Lung Cancer Cohort Consortium (LC3)

Abstract

Background: Self-reported smoking is the principal measure used to assess lung cancer risk in epidemiological studies. We evaluated if circulating cotinine-a nicotine metabolite and biomarker of recent tobacco exposure-provides additional information on lung cancer risk.

Methods: The study was conducted in the Lung Cancer Cohort Consortium (LC3) involving 20 prospective cohort studies. Pre-diagnostic serum cotinine concentrations were measured in one laboratory on 5364 lung cancer cases and 5364 individually matched controls. We used conditional logistic regression to evaluate the association between circulating cotinine and lung cancer, and assessed if cotinine provided additional risk-discriminative information compared with self-reported smoking (smoking status, smoking intensity, smoking duration), using receiver-operating characteristic (ROC) curve analysis.

Results: We observed a strong positive association between cotinine and lung cancer risk for current smokers [odds ratio (OR ) per 500 nmol/L increase in cotinine (OR500): 1.39, 95% confidence interval (CI): 1.32-1.47]. Cotinine concentrations consistent with active smoking (≥115 nmol/L) were common in former smokers (cases: 14.6%; controls: 9.2%) and rare in never smokers (cases: 2.7%; controls: 0.8%). Former and never smokers with cotinine concentrations indicative of active smoking (≥115 nmol/L) also showed increased lung cancer risk. For current smokers, the risk-discriminative performance of cotinine combined with self-reported smoking (AUCintegrated: 0.69, 95% CI: 0.68-0.71) yielded a small improvement over self-reported smoking alone (AUCsmoke: 0.66, 95% CI: 0.64-0.68) (P = 1.5x10-9).

Conclusions: Circulating cotinine concentrations are consistently associated with lung cancer risk for current smokers and provide additional risk-discriminative information compared with self-report smoking alone.

Figure 1

Forest plot showing odds ratios (OR) and 95% confidence intervals (95% CI) of lung cancer risk per 500 nmol/L increase in cotinine concentrations among all current smokers in the Lung Cancer Cohort Consortium (LC3). P_{heterogeneity} indicates differences in OR estimates between regions in the overall analysis and between men and women in the stratified analysis.

Figure 2

Odds ratios (OR) and 95% confidence intervals (CI) for lung cancer risk by cotinine concentration before and after adjustment for self-reported cigarettes per day (CPD) among all current smokers in the Lung Cancer Cohort Consortium (LC3). Where available, the CPD variable also included data on number of times per day the participant smoked cigars or pipes. Corresponding mean CPD for each category of cotinine concentration is given. Current smokers with cotinine levels below 115 nmol/L were used as the reference group.

Figure 3

Receiver operating characteristic (ROC) curve and area under the curve (AUC) for risk-discriminative performance of cotinine alone (AUC_cot), self-reported smoking alone (AUC_smoke), and cotinine combined with self-reported smoking (AUC_integrated) in current smokers overall, and stratified by sex in the Lung Cancer Cohort Consortium (LC3). This analysis includes current smokers with complete data on cotinine as well as self-reported smoking status, smoking intensity and smoking duration.

Figure 4

Forest plot showing odds ratios (OR) and 95% confidence intervals (95% CI) of lung cancer risk for former smokers, comparing participants having circulating cotinine concentrations 5-115 nmol/L with participants having circulating cotinine concentration below 5 nmol/L. P_{heterogeneity} indicates differences in OR estimates between regions in the overall analysis and between men and women in the stratified analysis.

Figure 5

Forest plot showing odds ratios (OR) and 95% confidence intervals (95% CI) of lung cancer risk for never smokers, comparing participants with circulating cotinine concentrations 5-115 nmol/L with participants with circulating cotinine concentrations below 5 nmol/L. P_{heterogeneity} indicates differences in OR estimates between regions in the overall analysis and between men and women in the stratified analysis.