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Epidemiology of Bladder Cancer

Epidemiology of Bladder Cancer. Jennifer Prescott, PhD Epidemiology and Molecular Pathology of Cancer: Bootcamp Course Thursday, January 12, 2012. Learning Objectives. To review descriptive epidemiology of bladder cancer To understand etiology behind established bladder cancer risk factors

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Epidemiology of Bladder Cancer

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  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. Global Incidence ASR per 100,000

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

  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 - OR - Urethra DNA adducts

  23. Health Professionals Follow-up Study (HFPS) 1986 (51,000 men) 2000 2008 2004 2006 2002 2010 1988 1990 1998 1994 1996 1992 Diet

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

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

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

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

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

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

  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 Reactive Intermediates Lipophilic Toxins Phase I Phase II Water-soluble compound • 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

  36. Blood subcohorts 1986 (51,000 men) 2008 2008 2010 2010 1988 1990 1998 1994 1996 1992 HPFS Blood 18,000 1976 (120,000 women) 1990 1998 1994 1996 1992 1978 1980 1988 1984 1986 1982 Blood 33,000 NHS

  37. Bladder Cancer GWASStudyDesign 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/ • Nurses’ Health Study I and II • http://www.channing.harvard.edu/nhs/ • Nurses’ Health Study III (NEW!) • http://www.nhs3.org/

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