1. Epidemiology of Bladder Cancer Jennifer Prescott, PhD Epidemiology and Molecular Pathology of Cancer: Bootcamp Course Thursday, January 12, 2012

2. Learning Objectives To review descriptive epidemiology of bladder cancer To understand etiology behind established bladder cancer risk factors To recognize opportunities for epidemiologic research of bladder cancer

3. Descriptive Epidemiology

4. Global Incidence

5. ASR per 100,000

6. United States, 2011 Siegel et. al. 2011 CA: A Cancer Journal for Clinicians #12 Urinary bladder 17,230 2% #13 Urinary bladder 4,320 2%

7. Trend in US Incidence Rates http://seer.cancer.gov/

8. Trend in US Mortality Rates http://seer.cancer.gov/

9. Subtype Distribution in US population >90% transitional cell carcinoma (TCC) 5% squamous cell carcinoma (SCC) 1% adenocarcinoma Other rare subtypes

10. Survival by SEER Stage http://seer.cancer.gov/

11. Established Risk Factors

12. Crude Age-specific Incidence Rates http://seer.cancer.gov/

13. Incidence by Race and Sex http://seer.cancer.gov/

14. Carcinogen exposure and TCC Occupation ▫Workers in dye and rubber industries ▫Accounts for 5 to 10% of cases Smoking ▫Most important risk factor ▫Same effect in males and females ▫Accounts for 1/2 male, 1/3 female cases Aromatic amines induce DNA adducts ▫4-aminobiphenyl, 2-naphthylamine, benzidine

15. Urogenous-contact hypothesis Ureters Bladder Urethra

16. Smoking and Bladder Cancer in Men Pooled analysis ▫11 case-control studies ▫European countries 2,600 Cases ▫Histologically confirmed ▫Incident (recruited within short time after dx) 5,524 Controls ▫3 population-based, 7 hospital-based, 1 both ▫Hospital controls with non-smoking related diseases Brennan et. al. 2000 International Journal of Cancer

17. Smoking Dose Number of cigarettes/day Brennan et. al. 2000 International Journal of Cancer

18. Smoking Duration Years of smoking Brennan et. al. 2000 International Journal of Cancer

19. Smoking Cessation Years since quitting Brennan et. al. 2000 International Journal of Cancer

20. Chronic Inflammation and SCC Schistosoma haematobium ▫Endemic in Middle East and parts of Africa ▫Ova found in bladder wall ▫Infestation control -> lower rates of SCC Indwelling catheters ▫Patients with spinal cord injury Reactive oxygen and nitrogen species

21. Suspected Risk/Protective Factors

22. Reduce effect of carcinogen Ureters Bladder Urethra DNA adducts - OR -

23. Health Professionals Follow-up Study (HFPS) 1986 (51,000 men) 198819901992199419961998200020022004200620082010 Diet

24. Fluid Intake in HPFS men Michaud et. al. 1999 New England Journal of Medicine*Literature not consistent Table 4.

25. Coffee In 1991, classified as possible bladder carcinogen by International Agency for Research on Cancer

26. Coffee Pooled analysis ▫10 case-control studies ▫European countries 564 Cases ▫Histologically confirmed ▫Incident ▫Never smokers 2929 Controls ▫3 population-based, 6 hospital-based, 1 both ▫Never smokers Sala et. al. 2000 Cancer Causes and Control

27. Coffee Cups per day Sala et. al. 2000 Cancer Causes and Control Table 4. from Michaud et. al. 1999 New England Journal of Medicine

28. Fruits & Vegetables Source of phytochemicals Induce detox enzymes Antioxidants

29. Fruits & Vegetables Michaud et. al. 1999 Journal of the National Cancer Institute

30. Fruits & Vegetables Published literature ▫Overall associated with reduced risk ▫No consistent association with subcategories ▫No consistent association with micronutrients

31. Gonorrhoea Michaud et. al. 2007 British Journal of Cancer Consistent with 2 case-control studies of invasive TCC

32. Non-Steroidal Anti-Inflammatory Drugs Genkinger et. al. 2007 International Journal of Cancer

33. Genetic Epidemiology

34. Genetic Contribution Family history ▫~2 fold risk ▫Bladder cancer families rare No high-penetrance mutations

35. Candidate Detoxification Genes N-acetyltransferase 2 ▫N-acetylation of aromatic amines ▫50% of whites are ‘slow acetylators’  Higher levels of adducts  Potential interaction with smoking Glutathione S-transferase mu 1 ▫Considered to have wide range of substrates ▫50% of whites are GSTM1 null Lipophilic Toxins Reactive Intermediates Water-soluble compound Phase IPhase II

36. Blood subcohorts 1986 (51,000 men) 19881990199219941996 18,000 Blood 200820101998 1976 (120,000 women)1978 19801982 198419861988 19901992199419961998 33,000 Blood 20082010 HPFS NHS

37. Bladder Cancer GWAS Study Design Rothman et. al. 2010 Nature Genetics

38. Confirm prior GWAS results Rothman et. al. 2010 Nature Genetics

39. Novel GWAS loci Rothman et. al. 2010 Nature Genetics

40. NAT2-smoking interaction Rothman et. al. 2010 Nature Genetics

41. Urea transporter locus Garcia-Closas et. al. 2011 Human Molecular Genetics (above table) Rafnar et. al. 2011 Human Molecular Genetics

42. Gene-gene interaction? Garcia-Closas et. al. 2011 Human Molecular Genetics

43. Recurrence and Progression

44. Survival by SEER Stage http://seer.cancer.gov/

45. Recurrence and Progression Non-muscle invasive bladder cancer (NMIBC) ▫50 – 70% with at least 1 recurrence  Most within 3 years ▫10 – 30% progress

46. Surveillance Guidelines (NMIBC) Clinical visits ▫Frequent schedule  3 months for first 2 years  6 months for additional 2-3 years  Annually thereafter ▫Symptoms, urinalysis, cystoscopy, urine cytology Lifelong follow-up $$$

47. Risk factors for recurrence/progression None have been established Smoking ▫Risk factor most investigated ▫May have worse prognosis, but inconclusive Fruits & vegetables ▫Broccoli intake Tang 2010 Cancer Epidemiology, Biomarkers & Prevention Genetic variants ▫rs798766[T] (4p16.3; FGFR3 locus) associated with recurrence Kiemeney 2010 Nature Genetics

48. Future Directions Which risk factors vary by stage/aggressiveness of disease? Additional gene-environment/gene interactions? What are risk factors for recurrence/progression? ▫Pre-diagnosis ▫Post-diagnosis Risk factors by tumor tissue markers? ▫Stratify tumors into different etiologic groups ▫Etiologic evidence for risk factor associations

49. Harvard Cohorts Health Professionals Follow-up Study ▫http://www.hsph.harvard.edu/hpfs/http://www.hsph.harvard.edu/hpfs/ Nurses’ Health Study I and II ▫http://www.channing.harvard.edu/nhs/http://www.channing.harvard.edu/nhs/ Nurses’ Health Study III (NEW!) ▫http://www.nhs3.org/http://www.nhs3.org/