1. Environmental Tobacco Smoke (ETS) and the Risk of Head and Neck Cancer: INHANCE Consortium Yuan-Chin Amy Lee Gene-Environmental Epidemiology Group International Agency for Research on Cancer JCCC Molecular Epidemiology Symposium, UCLA April 14, 2007

2. Background Metabolites of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were observed in the urine of non-smokers exposed to ETS (Hecht, 2006). About 7.5 million workers in 15 European Union countries and 24.6 million in the USA are exposed to ETS at work (Jaakkola, 2006). ETS is modifiable by public health intervention. ETS has not been fully investigated for head and neck cancer mainly because of the small number of cases who are never tobacco users.

3. Upper Respiratory Tract

4. The IARC Monograph concluded (Volume 83, 2004): ETS and Lung cancer: sufficient evidence ETS and Breast cancer and other cancer sites: inconsistent evidence US Surgeon General’s report concluded (2006): ETS and Lung cancer: sufficient evidence ETS and Breast cancer and nasal sinus cancer: suggestive but not sufficient evidence

5. Previous Literature Zhang et al. reported an OR of 2.4 (95% CI 0.9-6.8) for ETS and head and neck cancer risk, adjusting for age, sex, race, education, alcohol use, marijuana use, smoking (2000).  However, the analysis was not restricted to never tobacco users. Vineis et al. reported a HR of 1.21 (0.82-1.78) for ETS and respiratory diseases (lung, pharyngeal, laryngeal cancers and other pulmonary disease), adjusting for age, sex, smoking, country and school years (2005).  However, they included former smokers in the analysis.

6. International Head and Neck Cancer Epidemiology Consortium (http://inhance.iarc.fr) Collaboration of research groups leading large molecular epidemiology studies of head & neck cancer. Established in 2004 Aim to address research questions that are difficult to evaluate in individual level studies  never-tobacco users are a rare subgroup for head and neck cancer cases since tobacco smoking accounts for the majority of cases Data pooling projects are on-going  Current pooled data includes 15 case-control studies with ~10,000 cases and 15,000 controls

7. Summary of Studies with ETS Data in INHANCE Pooled Data v1.0

8. Statistical Methods ETS status (never/ever), duration and frequency variables for ETS were pooled across six studies.  Subjects were asked about ETS exposure at home and at work Never tobacco users: individuals who had not used cigarettes, cigars, pipes, snuff or chewing products. Odds ratios were adjusted for centers, age, sex, race/ethnicity, education and cumulative alcohol consumption, where appropriate. Stratified analyses were performed by cancer site, including oral cavity (n=146), pharynx (n=225), oral/pharynx NOS (n=98), and larynx (n=71).

9. Distribution of Demographic Characteristics among Never-Tobacco-Users

10. ETS at Home and the Risk of Head and Neck Cancer *Adjusted for centers, age, sex, race/ethnicity, education and alcohol drinking

11. ETS at Work and the Risk of Head and Neck Cancer *Adjusted for centers, age, sex, race/ethnicity, education and alcohol drinking

12. ETS and the Risk of Oral, Pharyngeal and Laryngeal Cancers among Never Tobacco Users *Adjusted for centers, age, sex, race/ethnicity, education and alcohol drinking

13. ETS and the Risk of Oral, Pharyngeal and Laryngeal Cancers among Never Tobacco/Never Alcohol Users *Adjusted for centers, age, sex, race/ethnicity, and education

14. Studies on ETS, Genetic Variants and Cancer

15. Studies with SNPs of Metabolic Genes

16. SNPs of Metabolic Genes Stratified ETS Status for Head and Neck Cancer *Adjusted for centers, age, sex, race/ethnicity, education and alcohol drinking

17. Limitations & Strengths Limitations  Comparability of ETS variables  Recall bias  Limited information on SNPs Strengths  Restriction to never tobacco users  More statistical power  Stratification by site

18. Summary I No association was observed for oral cancer. For pharyngeal cancer, we only observed an association with >15 years of ETS at home. For laryngeal cancer, we observed a dose- response trend in duration of ETS exposure at home and at work. Active smoking is thought to be a stronger risk factor for laryngeal cancer than pharyngeal and oral cancer. Perhaps ETS is also a stronger risk factor for laryngeal cancer.

19. Summary II We did not observe ETS modifying the effect of metabolic SNPs examined on the risk of head and neck cancer overall. If the effect of both ETS and genetic variants is moderate, the interaction may be moderate, which is difficult to detect.

20. Acknowledgements Investigators who have provided data:  Curado MP, Daudt AW, Fabianova E, Wünsch-Filho V, Hayes R, Koifman S, Lazarus P, Mates D, Matos E, Menezes A, Muscat J, Eluf-Neto J, Rudnai P, Sturgis EM, Szeszenia-Dabrowska N, Wei QY, Zaridze D, Zatonski W, Zhang ZF  Study participants IARC:  Mia Hashibe, Paolo Boffetta, Paul Brennan, Julien Berthiller, Manuela Marron, Gilles Ferro Support from US NCI grant (R03 CA113157)

21. Thank You!

22. ETS Variables Available by Study

23. Definitions of Never Tobacco User