Background:

While cigarette smoking is the leading cause of lung cancer, the majority of smokers do not develop the disease over their lifetime. The inter-individual differences in risk among smokers may in part be due to variations in exposure to smoking-related toxicants.

Methods:

Using data from a subcohort of 2,309 current smokers at the time of urine collection from the Multiethnic Cohort Study, we prospectively evaluated the association of ten urinary biomarkers of smoking-related toxicants (total nicotine equivalents [TNE], a ratio of total trans-3’-hydroxycotinine [3-HCOT]/cotinine [a phenotypic measure of CYP2A6 enzymatic activity], 4-(methylnitrosamino)-1–3-(pyridyl)-1-butanol [NNAL], S-phenylmercapturic acid [SPMA], 3-hydroxypropyl mercapturic acid [3-HPMA], phenanthrene tetraol [PheT], 3-hydroxyphenanthrene [PheOH], the ratio of PheT/PheOH, cadmium (Cd), and (Z)-7-(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]cyclopenyl]hept-5-enoic acid [8-iso-PGF2α]) with lung cancer risk (n=140 incident lung cancer cases over an average of 13.4 years of follow-up). Lung cancer risk was estimated using Cox proportional hazards models.

Results:

After adjusting for decade of birth, sex, race/ethnicity, body mass index, self-reported pack-years, creatinine, and urinary TNE (a biomarker of internal smoking dose), a one standard deviation increase in log total 3-HCOT/cotinine (HR=1.33, 95% CI:1.06–1.66), 3-HPMA (HR=1.41, 95% CI:1.07–1.85), and Cd (HR=1.45, 95% CI: 1.18–1.79) were each associated with increased lung cancer risk.

Conclusion:

Our study demonstrates that urinary total 3-HCOT/cotinine, 3-HPMA, and Cd are positively associated with lung cancer risk. These findings warrant replication and consideration as potential biomarkers for smoking-related lung cancer risk.

Impact:

These biomarkers may provide additional information on lung cancer risk that is not captured by self-reported smoking history or TNE.