1. COPD AND LUNG CANCER Prof. Leonardo M. Fabbri Clinica di Malattie dell’Apparato Respiratorio Università di Modena e Reggio Emilia Modena, 12 Dicembre 2003 LA PNEUMOLOGIA NEL TERZO MILLENNIO

2. HIGHER RISK OF LUNG CANCER IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE 113 “cases” (FEV 1 85%) matched for age, sex, occupation and smoking 113 “cases” (FEV 1 85%) matched for age, sex, occupation and smoking All persons observed from 1973 through 1984 for a diagnosis of lung cancer, death from lung cancer and death from any cause All persons observed from 1973 through 1984 for a diagnosis of lung cancer, death from lung cancer and death from any cause Skillrud DM et al, Ann Intern Med 1986; 105: 503-7

3. 9/113 lung cancer diagnosis in “cases” group vs 2/113 in “controls“ (all lung cancers in smokers). 9/113 lung cancer diagnosis in “cases” group vs 2/113 in “controls“ (all lung cancers in smokers). Cumulative probability curves for developing lung cancer were significantly different (p=0.024) for the two groups. Cumulative probability curves for developing lung cancer were significantly different (p=0.024) for the two groups. The estimated cumulative probability of developing lung cancer by 10 years was 8.8% for “cases” and 2.0% for “controls”: 4.4 times increase in risk. The estimated cumulative probability of developing lung cancer by 10 years was 8.8% for “cases” and 2.0% for “controls”: 4.4 times increase in risk. COPD constituted a risk factor for lung cancer after matching for sex, smoking, age and occupation HIGHER RISK OF LUNG CANCER IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE Skillrud DM et al, Ann Intern Med 1986; 105: 503-7

4. Tockman MS et al, Ann Intern Med 1987; 106: 512-8 AIRWAYS OBSTRUCTION AND THE RISK FOR LUNG CANCER Patients with moderate to severe obstruction and a sample of patients with no obstruction to moderate obstruction from two different trials (a total of 4395 subjects) Patients with moderate to severe obstruction and a sample of patients with no obstruction to moderate obstruction from two different trials (a total of 4395 subjects) On follow-up, the risk of developing lung cancer was associated with age, smoking and ventilatory status On follow-up, the risk of developing lung cancer was associated with age, smoking and ventilatory status

5. Pack- years Reduced airflow lung cancer % Normal airflow lung cancer % 0 – 40 1.20.4 41 – 60 1.90.2 61 + 4.20.7 LUNG CANCER AND PACK-YEARS SMOKED Tockman MS et al, Ann Intern Med 1987; 106: 512-8

6. Age Reduced airflow lung cancer % Normal airflow lung cancer % 54 – 54 1.80.4 55 - 64 1.60.2 65 – 69 2.80.4 70 + 6.22.2 LUNG CANCER AND AGE Tockman MS et al, Ann Intern Med 1987; 106: 512-8

7. Lung cancer mortality rates of 11/1000 person-years (impaired lung function) vs 3.5/1000 person-years (normal lung function). Lung cancer mortality rates of 11/1000 person-years (impaired lung function) vs 3.5/1000 person-years (normal lung function). More than a 3-fold risk for lung cancer in those with abnormal spirometric findings. More than a 3-fold risk for lung cancer in those with abnormal spirometric findings. The presence of airways obstruction explains much of the contribution of age and pack-years to the risk for lung cancer Tockman MS et al, Ann Intern Med 1987; 106: 512-8 LUNG CANCER AND AIRFLOW LIMITATION

8. EFFECT OF SMOKING INTERVENTION AND THE USE OF AN INHALED ANTICHOLINERGIC BRONCHODILATOR ON THE RATE OF DECLINE OF FEV 1 : THE LUNG HEALTH STUDY 20 more lung cancer deaths than from cardiovascular disease or stroke and, in fact, lung cancer deaths exceeded all other deaths Anthonisen NR et al, JAMA 1994; 272: 1497-505

9. The patterns of familial clustering of pulmonary dysfunction in relatives of lung cancer patients and those of COPD cases are clearly consistent Lung cancer and COPD share a common familial component other than smoking Cohen BH et al, Lancet 1977; Sept 10: 523-6 A COMMON FAMILIAL COMPONENT IN LUNG CANCER AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE

10. Is COPD a genetic disorder? Only 15-20 % of smokers develops COPD Prevalence of COPD is different in different racial groups Increased prevalence of COPD in relatives of patients with COPD Lomas DA, Silverman EK. Respiratory Research 2001; 2: 20-26

11. COPD, a multifactorial disease (?) Enviroment Trauma Infections Diabetes Monogenic disorder Genes COPD with  1 AT deficit Kingston HM, Br Med J 1989;298:949-952 Congentital cardiomyopathy Schizofrenia Coronaropathy Teratogenic disorder

12. Candidate genes in COPD PROTEASEANTIPROTEASE IMBALANCE  1 antitrypsin (PI MA  1 anti-protease)  1 antitrypsin (PI MA  1 anti-protease)  1-antichimotrypsin  1-antichimotrypsin Catepepsin G Catepepsin G  2 macroglobulin  2 macroglobulin OXIDATIVE STRESS Extracellular superoxide dismutase Extracellular superoxide dismutase Glutathione – S – transferase Glutathione – S – transferase DETOXIFYING ENZYME microsomal epoxide hydrolase microsomal epoxide hydrolaseINFLAMMATION TNF  TNF  different cytokines (e.g. IL-8) different cytokines (e.g. IL-8) BRONCHIAL HYPERSECRETION Cystic fibrosis transmembrane regulator (CFTR) Cystic fibrosis transmembrane regulator (CFTR) Lomas DA, Silverman EK. Respiratory Research 2001; 2: 20-26

13. THE GENETICS OF COPD Many candidate genes have been assessed, but the data are often conflicting Lomas DA, Silverman EK. Respiratory Research 2001; 2: 20-26

14. Chronic Obstructive Lung Disease, NF Voelkel & W MacNee Eds. 2002 “The response of the body to a cancer is not a unique mechanism but has many parallels with inflammation and wound healing. … If genetic damage is the “match that lights the fire” of cancer, some types of inflammation may provide the “fuel that feeds the flames”.

15. Chronic Obstructive Lung Disease, NF Voelkel & W MacNee Eds. 2002 COMMON ELEMENTS IN THE PATHOGENESIS OF COPD AND LUNG CANCER Genetic predisposition (p53, Rb, K-ras) Genetic predisposition (p53, Rb, K-ras) Peptides and endopeptidases (bombesin-like) Peptides and endopeptidases (bombesin-like) Inflammation and oxidants (cigarette smoking) Inflammation and oxidants (cigarette smoking) Dysregulation of growth factor expression Dysregulation of growth factor expression

16. Balkwill and Mantovani, Lancet 2001; 357: 539-45 “The response of the body to a cancer is not a unique mechanism but has many parallels with inflammation and wound healing. … If genetic damage is the “match that lights the fire” of cancer, some types of inflammation may provide the “fuel that feeds the flames”.

17. Balkwill and Mantovani, Lancet 2001; 357: 539-45

18. Petty LT. Oncol Clin North Amer 1997; 11: 531-41 ADVICE FOR CLINICIACNS ! Always take a careful smoking history and look for airflow obstruction. Always take a careful smoking history and look for airflow obstruction. If patients are heavy smokers and have airflow limitation, standard posteroanterior and lateral chest roentgenographic films, sputum cytology, or both should be employed. If patients are heavy smokers and have airflow limitation, standard posteroanterior and lateral chest roentgenographic films, sputum cytology, or both should be employed.

19. COPD AND LUNG CANCER Prof. Leonardo M. Fabbri Clinica di Malattie dell’Apparato Respiratorio Università di Modena e Reggio Emilia Modena, 12 Dicembre 2003 LA PNEUMOLOGIA NEL TERZO MILLENNIO