Epidemiology of Bladder CancerJennifer Prescott, PhDEpidemiology 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

•To recognize opportunities for epidemiologic research of bladder cancer

Descriptive Epidemiology

Global Incidence

Global Incidence

ASR per 100,000

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%

Trend in US Incidence Rates

http://seer.cancer.gov/

19751977

19791981

19831985

19871989

19911993

19951997

19992001

20032005

20070

5

10

15

20

25

30

35

40

Male Female

Year of Diagnosis

Rat

e pe

r 10

0,00

0

Trend in US Mortality Rates

http://seer.cancer.gov/

19751977

19791981

19831985

19871989

19911993

19951997

19992001

20032005

20070

2

4

6

8

10

12

Male (mortality) Female (mortality)

Year of Diagnosis

Rat

e pe

r 10

0,00

0

Subtype Distribution in US population

•>90% transitional cell carcinoma (TCC)

•5% squamous cell carcinoma (SCC)

•1% adenocarcinoma

•Other rare subtypes

In situ Localized Regional Distant Unknown0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100% 96.6%

70.7%

34.6%

5.4%

49.1%

5-year Relative Survival

Survival by SEER Stage

http://seer.cancer.gov/

Established Risk Factors

Crude Age-specific Incidence Rates

15-1920-24

25-2930-34

35-3940-44

45-4950-54

55-5960-64

65-6970-74

75-7980-84 85+

0

50

100

150

200

250

300

350

400

Male Female

Age at Diagnosis

Rat

e pe

r 10

0,00

0

http://seer.cancer.gov/

Incidence by Race and Sex

Male Female0.0

5.0

10.0

15.0

20.0

25.0

30.0

35.0

40.0

45.0

White

Black

Hispanic

Asian / Pacific Is-lander

American Indian / Alaska NativeR

ate

per

100,

000

http://seer.cancer.gov/

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

Urogenous-contact hypothesisUreters

Bladder

Urethra

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

Smoking Dose

Never 1-2 3-4 5-910-14

15-1920-24

25-2930-34

35-3940+

0.00

0.50

1.00

1.50

2.00

2.50

3.00

3.50

4.00

4.50

5.00

1.04

1.80

2.75

3.44

4.50 4.514.74

4.61

3.99

4.29

Odd

s R

atio

Number of cigarettes/dayBrennan et. al. 2000 International Journal of Cancer

Never

1-4 5-9 10-14

15-19

20-24

25-29

30-34

35-39

40-44

45-49

50-54

55-59

60+0.00

1.00

2.00

3.00

4.00

5.00

6.00

7.00

1.21

1.66

2.21

3.81

4.684.96

6.14

Odd

s R

atio

Smoking Duration

Years of smokingBrennan et. al. 2000 International Journal of Cancer

Smoking Cessation

Years since quittingBrennan et. al. 2000 International Journal of Cancer

Current 1-4 5-9

10-1415-19

20-2425+

Never0.00

0.20

0.40

0.60

0.80

1.00

1.20

0.6500000000000010.6700000000000010.610000000000001

0.46 0.45

0.37

0.2

Odd

s R

atio

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

Suspected Risk/Protective Factors

Reduce effect of carcinogenUreters

Bladder

UrethraDNA adducts

- OR -

Health Professionals Follow-up Study (HFPS)

1986 (51,000 men)

19881990

19921994

19961998

20002002

20042006

20082010

Diet

Fluid Intake in HPFS men

Michaud et. al. 1999 New England Journal of Medicine *Literature not consistent

Table 4.

Coffee•In 1991, classified as possible bladder carcinogen

by International Agency for Research on Cancer

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

Coffee

Cups per dayNever 1-2 3-5 6-9 10+

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

1.0 1.0 1.0

1.8

Odd

s R

atio

Sala et. al. 2000 Cancer Causes and Control

Table 4. from Michaud et. al. 1999 New England Journal of Medicine

Fruits & Vegetables

•Source of phytochemicals

•Induce detox enzymes

•Antioxidants

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

Fruits & Vegetables

•Published literature▫Overall associated with reduced risk

▫No consistent association with subcategories

▫No consistent association with micronutrients

Gonorrhoea

Michaud et. al. 2007 British Journal of Cancer

Consistent with 2 case-control studies of invasive TCC

Non-Steroidal Anti-Inflammatory Drugs

Genkinger et. al. 2007 International Journal of Cancer

Genetic Epidemiology

Genetic Contribution•Family history

▫~2 fold risk▫Bladder cancer families rare

•No high-penetrance mutations

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

LipophilicToxins

ReactiveIntermediates Water-soluble

compoundPhase I Phase II

Blood subcohorts

1986 (51,000 men)

19881990

19921994

1996

18,000Blood

20082010

1998

1976 (120,000 women)

19781980

19821984

19861988

19901992

19941996

1998

33,000Blood

20082010

HPFS

NHS

Bladder Cancer GWASStudyDesign

Rothman et. al. 2010 Nature Genetics

Confirm prior GWAS results

Rothman et. al. 2010 Nature Genetics

Novel GWAS loci

Rothman et. al. 2010 Nature Genetics

NAT2-smoking interaction

Rothman et. al. 2010 Nature Genetics

Urea transporter locus

Garcia-Closas et. al. 2011 Human Molecular Genetics (above table)Rafnar et. al. 2011 Human Molecular Genetics

Gene-gene interaction?

Garcia-Closas et. al. 2011 Human Molecular Genetics

Recurrence and Progression

In situ Localized Regional Distant Unknown0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100% 96.6%

70.7%

34.6%

5.4%

49.1%

5-year Relative Survival

Survival by SEER Stage

http://seer.cancer.gov/

Recurrence and Progression

•Non-muscle invasive bladder cancer (NMIBC)▫50 – 70% with at least 1 recurrence

Most within 3 years

▫10 – 30% progress

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

•$$$

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

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

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/