1. Lung Cancer Molecular Pathology of Cancer Boot Camp January 4, 2012 Jennifer Rider, ScD

2. Learning objectives Basic descriptive epidemiology Major risk factors Historical perspective on establishing smoking as a causal agent Key differences in disease among smokers and non-smokers

9. Five-year survival rates ACS Cancer Facts & Figures 2011

10. Lung Cancer Epidemiology: Risk factors 1. Cigarette smoking 2. Environmental tobacco smoke 3. Radon 4. Occupational exposures a. Asbestos b. Asbestos x smoking interaction c. Cooking oil vapors and indoor coal burning 5. Ambient air pollution 6. Genetic factors

11. Smoking ▫Lung cancer risk depends on: ▫Years smoked ▫Age smoking initiated ▫Number of cigarettes smoked per day ▫Tar/Nicotine ▫Risk roughly proportional to yield (down to one-half risk) ▫BUT negated by compensation in numbers smoked ▫Risk elevated in cigar/pipe smokers ▫Amount smoked and inhaling contribute

12. Constituents of the cigarette 7000 chemicals ▫Carbon monoxide/vapor phase components ▫Nicotine ▫“Tar” = particulate – (nicotine + water) ▫60 carcinogens ▫Additives

13. Selected carcinogens in cigarette smoke Policyclic aromatic hydrocarbons (PAH): benzo[a]pyrene Tobacco-specific nitrosamines (TSNA) Aromatic amines: 4-aminobiphenyl Benzene Arsenic, Nickel, Chromium Polonium-210

14. Smoking Cessation Among individuals who have smoked less than 20 years Lung cancer risk reverts to non-smoker level after about 15 years of cessation. Among individuals who have already developed lung cancer Quitting reduces risks of developing a second cancer

15. Lung cancer incidence and trends, and smoking behavior among men – United States

16. Tobacco Use in the US, 1900-1999 *Age-adjusted to 2000 US standard population. Source: Death rates: US Mortality Public Use Tapes, 1960-1999, US Mortality Volumes, 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2001. Cigarette consumption: Us Department of Agriculture, 1900-1999. Per capita cigarette consumption Male lung cancer death rate Female lung cancer death rate

18. Smoking prevalence by sex

19. 1933: JAMA begins to accept advertising for cigarettes “Just as pure as the water you drink…and practically untouched by human hands.” --Chesterfield advertisement, NY State Journal of Medicine, 1933

20. “The following hints may prove helpful. In combination they are nearly perfect and 99 44/100% of the nicotine will go into the filter or your friends’ faces.” Consumer Reports, 1938

23. Barriers to acceptance of smoking-lung cancer relationship Ecologic data - other plausible alternatives Smoking common in scientific community Influence of tobacco companies Novelty of epidemiological techniques Strength of infectious disease model ▫Necessary and sufficient causes ▫Isolate and identify agent ▫Laboratory/animal evidence key ▫Smoking associated with multiple diseases

24. A new model of causality Bradford Hill’s guidelines ▫Strength of association ▫Consistency ▫Specificity ▫Temporal sequence ▫Dose-response/biologic gradient ▫Biological plausibility ▫Coherence ▫Experimental evidence ▫Analogy

25. Active smoking accounts for 90% of lung cancer deaths, but only 10% smokers develop lung cancer Smoking Genetic Polymorphisms Lung cancer risk

26. Lung Cancer Subtypes Squamous cell carcinoma Adenocarcinoma Large-cell carcinoma Small-cell undifferentiated carcinoma >90% of Lung Cancers in US

27. Primarily adenocarcinoma Primarily SCLC and squamous cell carcinoma Sun et al., Nature Reviews Cancer 2007

28. Lung Cancer in Never Smokers Estimated 25% of lung cancers not attributable to smoking ▫15% among men ▫53% among women 7 th leading cause of cancer death worldwide Only relatively weak risk factors identified Distinct histological, geographical and gender distribution

29. Sun et al., Nature Reviews Cancer 2007 Proportion of Lung Cancer in Never Smokers

31. Sun et al., Nature Reviews Cancer 2007

32. Mutation profile among smokers vs. nonsmokers Sun et al., Nature Reviews Cancer 2007

33. Gefitinib (Iressa) effectiveness among Asian patients with NSCLC Lim et al., Br J Cancer 2005