1. Risk factors of non-smoking lung cancer Po-Yin Chang

2. Lung cancer in US The leading cause of cancer, estimated in 2009: – Estimated 219,440 new cases – Mortality: 1 st rank in both men and women – 2 nd rank in incidence (15%) in both genders Lung & bronchus30% Prostate9% Colon & rectum 9% Pancreas6% Leukemia4% Liver & intrahepatic bile duct4% Esophagus4% Urinary bladder3% Non-Hodgkin lymphoma 3% Kidney & renal pelvis3% All other sites 25% 26%Lung & bronchus 15%Breast 9%Colon & rectum 6%Pancreas 5% Ovary 4% Non-Hodgkin lymphoma 3%Leukemia 3%Uterine corpus 2% Liver & intrahepatic bile duct 2% Brain/ONS 25% All other sites Men 292,540 Women 269,800 Estimated Cancer Mortality, 2009 ONS: Other nervous system American Cancer Society, 2009.

3. Lung cancer worldwide The proportion of lung cancer patients in developing nations increased from 31% to 49.9% in the last two decades 15% of men and 53% of women with lung cancer worldwide are never smokers Geographic differences: the proportion of lung cancer of never smoking women: – 83% in Asian countries, 15% in US

4. Pathological features among non- smoking lung cancer patients Adenocarcinoma, especially bronchioloalveolar carcinoma Asian ethnicity Female Better response to Epithelium Growth Factor Receptor (EGFR) Tyrosine Kinase (TK) inhibitors, such as erlotinib and gefitinib

5. Etiologic factors and molecular features Several etiologic factors have been proposed: – Occupational and environmental factors: exposure to radon, asbestos, heavy metals – Cooking fumes – Environmental tobacco smoke – Human papilloma virus (HPV) infection – Inherited genetic susceptibility Molecular features – EGFR mutations, p53 mutations, K-ras mutations

6. Environmental tobacco smoke (ETS) ETS exposure from spouses and workplace resulted in an excess risk of 20% for developing lung cancer in never smokers 2 meta-analyses: never smokers with smoking spouses had greater risks of lung cancer than those with non-smokers spouses – ETS ↑35% lung cancer risk in men, 25% in women

7. Environmental tobacco smoke (ETS) Population-based prospective study, including 28,414 lifelong non-smoking Japanese women – Hazard ratio for LC incidence in women with a smoking husband was 1.34 [.81 – 2.21] – Lung adenocarcinoma: Current smoking husband: ↑risk of lung adenocarcinoma, current v.s. never: 2.03 [1.07–3.86] Dose-response relationships: both the intensity and the amount of the husband’s smoking are related to the increased risk

8. Exposure to cooking fumes A meta-analysis reported an increased risk of lung cancer in China – Exposure to domestic coal for heating and cooking – Indoor exposure to coal dust and chronic exposure to cooking oil vapor, though publication bias might affect these two factors More cooking dish-years, higher the OR of lung cancer – Different frying methods: deep-frying have the highest risk

9. EGFR mutations Somatic EGFR mutations: – Predictors of response to EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib, especially among non-smokers than smokers with NSCLC – Researchers found more activating mutations in the EGFR-TK domain in never smokers than smokers lung cancer patients

10. J Clin Oncol 2007;25:561

11. The EGFR-signaling pathway and potential sites for inhibitor activity Hodkinson P S et al. Chest 2008;133:1209-1216 © 2008 by American College of Chest Physicians Site 1: Cetuximab Site 2: Erlotinib Site 3: Downstream signaling inhibitors

12. Molecular features K-ras mutations: – More frequently seen in lung adenocarcinoma – More frequently detected among smokers – Less common in Asian patients – Never smokers: G to A transition; smokers: G to T or G to C transversion p53 mutations: – 40 to 60% of NSCLC, more frequently reported in smokers than never smokers

13. Inherited genetic susceptibility Family history of lung cancer was associated with higher risk for female non-smoking lung cancer, OR=5.7[1.9-16.9] – Higher risk was seen if the relative was a woman, younger than 60 yrs old, adenocarcinoma patients A Major susceptibility locus on chromosome 6q23-25 – Chromosome 6 includes more than 100 genes, and some of them are potential candidates for the role of a lung cancer susceptibility gene

14. Inherited genetic susceptibility White, non-smoking lung cancer: – Cytochrome P450 1A1 polymorphism Ile463Val: ↑3 folds of risk – The effect of 1A1 polymorphism is strong especially among adenocarcinoma patients and patients with glutathione-S-transferase M1 (GSTM1) null genotype Japan, non-smoking female lung cancer cases – GSTM1 null genotype: associated with an increased risk of lung cancer, OR=1.37[.9-2.09]

15. Hormonal status Estrogen receptor(ER) α and β are detected in lung normal and cancer tissue in both gender – ERβ is more frequently expressed in lung tissue, detected more commonly in never smokers than smokers, more in women than men Some studies show the higher intratumoral estradiol level in NSCLC, which increase the growth of ERα/β among these NSCLC patients Role of hormone replacement therapy (HRT)?

16. Hormonal status: Controversial role of HRT Interaction between estrogens and tobacco carcinogens – Lower median age at lung cancer diagnosis, a shorter median survival time in women with HRT around the time of diagnosis – The effect was more evident in smoking than nonsmoking women However, inverse relationship was observed between HRT use and NSCLC risk in post- menopausal women with ER positive lung tumor

17. HPV infection HPV 16/18 DNA was detected in 77(54.6%) of 141 lung cancer patients Higher prevalence of HPV DNA in lung cancer patients of Asian ethnicity, not in Caucasians HPV is acquired through the oral cavity by prenatal or sexual transmission

18. Summary Environmental tobacco smoke Cooking fumes Molecular features – EGFR mutations, p53 mutations, K-ras mutations Inherited genetic susceptibility Hormonal status Human papilloma virus (HPV) infection Occupational and environmental factors – exposure to radon, asbestos, heavy metals

19. Conclusion Lung cancer in never smokers is a distinct disease with unique molecular and biologic characteristics Incidences are different across the globe The unique genetic and epigenetic markers suggest a separate but overlapping carcinogenesis pathway Tobacco smoking should be discouraged for sure

20. References Subramanian J, and Govindan R. Lung cancer in never smokers: a review. J Clin Oncol 2007; 25: 561-70 Scagliotti GV, Longo M, and Novello S. Nonsmall cell lung cancer in never smokers. Curr Opin Oncol 2009; 21: 99-104

21. Thank you

22. 2009 Estimated US Cancer Cases* *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, 2009. Men 766,130 Women 713,220 27%Breast 14%Lung & bronchus 10%Colon & rectum 6%Uterine corpus 4%Non-Hodgkin lymphoma 4%Melanoma of skin 4% Thyroid 3%Kidney & renal pelvis 3%Ovary 3%Pancreas 22%All Other Sites Prostate25% Lung & bronchus15% Colon & rectum10% Urinary bladder7% Melanoma of skin5% Non-Hodgkin5% lymphoma Kidney & renal pelvis5% Leukemia 3% Oral cavity3% Pancreas3% All Other Sites19%