1. Epidemiology and Global Trend of Adenocarcinoma Professor Tony Mok Dept of Clinical Oncology The Chinese University of Hong Kong

2. Rising incidence in adenocarcinoma?

3. Age Adjusted Incidence Rate of Adenocarcinoma in USA (per 100,000) Wu JNCI 1986, Dodds JNCI 1986, Travis Cancer 1995 More so in patients<65 year old

4. Age Adjusted Incidence Rate of Squamous Cell Carcinoma in USA (per 100,000) Wu JNCI 1986, Dodds JNCI 1986, Travis Cancer 1995

5. Change in ratio of adenocarcinoma vs SCC

6. Change in Percentage of Adenocarcinoma Subtype in Asia Japan Hong Kong

7. Change in Percentage of Squamous Cell Carcinoma Subtype in Asia Japan Hong Kong

8. Percentage of Adenocarcinoma in Female European (80’)

9. A global trend towards an increase in both the total number and proportion of adenocarcinoma. WHY?

10. Adenocarcinoma in smoker

11. Cigarette Filters Invented in 1935 Popularized in the 60’ In the 50’, filters were manufactured from crocidolite asbestosis. Banned since the association with lung cancer and mesothelioma Now made from acetalated cellulose Claims to reduce larger particles including tars and nicotine

12. Cancer Cell Type and Lung Airway Compartments Modified from Sun, Schiller, and Gazdar, Nat Rev Cancer, 7:778, 2007 Squamous Ca SCLC Adenocarcinoma © 2007 Nature Publishing Group Less large particle may Imply less exposure of Carcinogen in larger airways Less large particle may Imply less exposure of Carcinogen in larger airways

13. Filtered cigarette in USA Market 95%

14. Smoking-Related Lung Cancer Cell Type (Male) Morabia A Cancer 68:2074, 1991

15. Smoking-Related Lung Cancer Cell Type (Female) At a history of 40 pack-years relative to lifelong nonsmoking, the odds ratio for women was 27.9 (95% confidence interval (CI) 14.9-52.0) and that for men was 9.60 (95% CI 5.64-16.3). Morabia A Cancer 68:2074, 1991

16. Increase in tobacco consumption with filtered cigarette At a history of 40 pack-years relative to lifelong nonsmoking, the odds ratio for women was 27.9 (95% confidence interval (CI) 14.9-52.0) and that for men was 9.60 (95% CI 5.64-16.3). Higher consumption of tobacco in female who switched from non-filtered to filtered cigarette. Risch H Am J Epidermiol 138:281, 1993

17. Changes in nature of cigarette High nitrate content –Enhances combustion –Increase N-nitrosamines Favor –Impact of combusted flavorants is unknown Larger puffs with low-yield cigarettes –Inhale more deeply –Puff volume at 55ml at 5 times per minutes

18. Summary on smoking-related adenocarcinoma A trend toward increase in adenocarcinoma of lung in smoker Cigarette filter and modified tobacco contributed to the higher incidence –Exposure of carcinogens to lower airway –Deeper and larger puffs

19. Adenocarcinoma in non-smoker

20. Lung Cancer in Never Smokers Squamous Cell Ca (~35%) Adenocarcinoma (~45%) Predominance of Adenocarcinoma Histology SCLC (~20%) Percentage 0 20 40 60 80 Smokers (n = 21,853) Never Smokers (n = 5,144) Adenocarcinoma Squamous Cell Ca Modified from Sun, Schiller and Gazdar, Nat Rev Cancer, 7:778, 2007 0.4:13.4:1

21. Change in cigarette consumption in USA Rise in incidence of adenocarcinoma despite the decline in tobacco consumption

22. Adenocarcinoma in non-smoker USA –Rising incidence in non-smoker but histologic subtype were not available –Detection bias not clear from older studies Asia –Denial of smoking history in female population –Only two small studies suggested a rise in incidence of adenocarcinoma Wu JNCI 74:747, 1985; Kabat G Cancer 755, 1984; Koo Int J Epidermiol S14, 1990 SmokerNon-smoker Male (USA)25-33%31-54% Female (USA)33-43%49-73% Female (Asia)29%64-80%

23. Impact of rising incidence of adenocarcinoma in China: 2000–2005 No. of new cases% of change Age-standardised mortality rates (per 100,000) 2000200520002005 Male261,839332,28626.943.049.0 Female119,648165,62238.419.122.9 64-80% non-smoker Yang et al Can Epi Bio Prv 14(1):243<2005 Parkin et al CA Cancer 55:74, 2005

24. Lung Cancer not related to smoking in China 25% of male lung cancer were not smoking related 72% of female lung cancer were not smoking related Wang et al Cancer Causes and Control 21:959, 2010

25. Majority of lung cancer in non-smokers are adenocarcinoma and total number of lung cancer is increasing, but there is no definite evidence of increase in proportion of adenocarcinoma

26. Carcinogenesis of adenocarcinoma in non-smoker: Atypical adenomatous hyperplasia (AAH) Modified from Gazdar et al, in press Lancet Oncology 2009 AAH in 23-35% of adenocarcinomas vs. 3-7% of squamous cell ca (Nakanishi et al Br J Cancer, 1990; Chapman et al, Br J Cancer, 2000) BAC Adenocarcinoma Atypical Adenomatous Hyperplasia (AAH)

27. Lung Cancer in Never Smokers Different Molecular Pathways 0 10 20 30 40 50 60 70 80 TP53 (n=137) KRAS (n=846) Mutations 1 Percentage Smokers Non Smokers 71% 48% 21% 4% 1 Modified from Sun et al, Nat Rev 7:778, 2007 2 Modified from Riely et al, Clin Cancer Res 14:5731, 2008 0 5 10 15 20 25 30 35 40 45 50 G-T and A-G at CpG sites G-A Transition Percentage TP53 Mutations (n=137) 1 0 10 20 30 40 50 60 70 80 90 100 G-A Transition G-T / G-C Transversion Percentage KRAS Mutations (n=482) 2

28. EGFR versus KRAS Driven Lung Cancer Sun et al Nat Rev Cancer, 7:778, 2007 Never Smoker EGFR Signaling Pathway Smoker KRAS Signaling Pathway

29. Oncogene in Chinese Patients with NSCLC An SJ,…Wu YL Plos ONE 7(6):e40109

30. Genome profile of smoker vs non- smoker adenocarcinoma in China

31. Meta-analysis of Risk Factors in Never Smokers Risk FactorRisk (Hazard Ratio with 95% CI) Meta-analysis Cooking Fume2.12 (1.81 to 2.47)7 studies from China/Taiwan Environmental Tobacco Smoking 1.21 (1.13-1.30)44 case-control studies Coal burning2.66 (1.39 to 5.07)7 studies from China/Taiwan Family History1.51 (1.11 to 2.06)28 case control studies Report of US Surgeon General 2006, Zhao Total Environ 366:500, 2006 Matakidou et al Br J Can 93:825, 2006 What is the genetic factor that predispose non-smokers to develop adenocarcinoma of lung??

32. What are other potential explanations for change in incidence of adenocarcinoma in non-smoker?

33. Change in Environmental Tobacco Smoking Increase in tobacco consumption from 60’ to 80’ may indirectly increase spousal exposure to environmental tobacco smoking Non-smoking female spouse of male smoker had about 30% increase in risk of lung cancer (OR 1.30) No difference between adenocarcinoma (OR 1.29) and non-adenocarcinoma (OR 1.37) Fontham JAMA 271:1752, 1997

34. Change in classification and pathological technique Charloux et al Int J Epidemiology 26:14, 1997

35. Change in diagnostic procedure Adenocarcinoma is previously under-diagnosis –43 of 153 lung cancer only diagnosed post mortem (30% in non-smoker vs 8% in smoker) Advances in fibro-optic bronchoscopy and needle aspiration –53-75% of adenocarcinoma present a peripheral nodule, and routine needle biopsy started only in 1980 1961 Rigid Bronchoscopy SurgeryAutopsy Adenocarcinoma2%10%28% Squamous cell carcinoma 42%54%35% Theros AM Roentgen 128:893, 1983; Whitewell BJC 15:440, 1961

36. Summary Global trend in increase in incidence of adenocarcinoma Increase in adenocarcinoma in smokers –Cigarette filter and higher consumption contribute to the increase Increase in adenocarcinoma in non-smokers –Major of non-smoker lung cancer is adenocarcinoma but no definite evidence on rising proportion –Etiology and carcinogenesis of adenocarcinoma involve distinguish molecular change –Environmental factors contribute the increase but real reason is not known –Diagnostic bias exists