Download - Epidemiology of Colorectal Cancer
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Epidemiologyof
Colorectal Cancer
Edward Giovannucci, M.D., Sc.D.
Harvard School of Public HealthBrigham and Women’s Hospital
and Harvard Medical SchoolBoston, MA USA
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Colorectal Cancer (CRC)
• Second leading cause of cancer death in the United States
10% of cancer deaths
105,000 colon cancer and 42,000 rectal cancer cases annually in U.S.
57,000 people die annually of CRC in the U.S.
1,000,000 cases annually worldwide
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Group Approximate lifetime cancer risk (%)
Normal population 5 Past history of breast or female genital cancer 7-20 Past history of colorectal cancer 15 Family history of colorectal cancer 15 a Adenomas 10-20 b Ulcerative colitis 5-50 c Cancer family syndrome (HNCC) 50 Familial polyposis coli 100
Risk of Colorectal Carcinoma in General Populationand in High-Risk Groups
a Risk increases with number of relatives affected.b Risk depends on number, size, and histology of adenomas.c Risk depends on extent and duration of disease; the 50 percent figure applies to subjects with universal colitis of >30 years duration.
Modified from Ron & Lubin, 1986.
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Colorectal Cancer: Natural History
• Process takes several decades
• Molecular lesions fairly well characterized
• Empirical stages:small adenomalarge adenomacarcinoma
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APCmutation
K-rasmutation
COX-2 over-expression
MLH1 hypermethylation
MSI
p27 lossp53 mutation
IncreasedCell
Growth
AdenomaI
CancerAdenoma
IIAdenoma
IIINormal
Cell
Small Large
>30 - 40 years
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Sub-Type Classification of CRC
Clinical: proximal vs. distal
Pathological: mucinous vs. non-mucinouspoorly vs. well-differentiated
Molecular: chromosomal instability (CIN)microsatellite instability (MSI)CpG island methylation
phenotype (CIMP)
Ogino S & Goel A, J Mol Diagn 2008
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Prevention of Colorectal Cancer
• Primary:Prevent cancers from occurring through diet, lifestyle, drugs
• Secondary: Prevent cancers by removing precursor lesions (adenomas)
Prevent mortality by discovering cancers at early treatable stage
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ScreeningAmerican Cancer Society Guidelines
• For average risk persons, screeningis recommended beginning at age 50 yrs
• Colonoscopy is recommended every10 years (if no polyps are found)
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Primary Prevention
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Factors That Increase Risk
• Smoking (esp. at early ages)
• Alcohol (>2 drinks/day)
• Red or processed meats
• Obesity (esp. central adiposity)
• Sedentary lifestyle
• “Western” diet in general
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Smoking and Alcohol
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Smoking and Colorectal CancerNHS and HPFS
Years Since Starting Smoking
0
0.5
1
1.5
2
2.5
3
3.5
4
NeverSmokers
1-19 Yrs 20-29 Yrs 30-34 Yrs 35-39 Yrs 40-44 Yrs 45 Yrs
Giovannucci et al., JNCI 1994
Mul
tivar
iate
Rel
ativ
e R
isk
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Alcohol and Colorectal CancerAnalysis of 8 Cohort Studies
Cho e et al., Ann Intern Med 2004
Intake (g / day)
0.5
1
1.5
2
0 >0-<5 5-<15 15-<30 30-<45 >45
Mul
tivar
iate
Rel
ativ
e R
isk
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Why are colon cancer rates invariably high
in populations that undergo “Westernization”?
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Factors That Increase Risk
• Smoking (esp. at early ages)
• Alcohol (>2 drinks/day)
Red or processed meats
Obesity (esp. central adiposity)
Sedentary lifestyle
“Western” diet in general
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Increased risk of colon cancer in Western countries
is primarily due to hyperinsulinemia and corresponding
increase in insulin and insulin-like growth factor-1 (IGF-1)
resulting from excess energy intake, central obesity,
physical inactivity, and Western dietary pattern.
Giovannucci, CCC 1995; JNCI 2002
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Pituitary GH SecretionTallness
Insulin ResistanceDiabetes
Red & Processed Meats,Saturated Fat, Sweets,
Refined Grains
Insulin IGF-1
Competent -CellsInsulin Treatment
Physical InactivityAbdominal Obesity
Energy,Protein, Minerals
Acromegaly
Colon Tumor Growth
Proliferation; Apoptosis
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Risk Factors* for Colon Cancer and AdenomaCompatible with Insulin/IGF Hypothesis
• circulating C-peptide / insulin• circulating IGF-1 or IGF-1/BP-3• Acromegaly ( IGF, insulin)• Type 2 diabetes• Metabolic syndrome ( insulin)• BMI• waist circumference• physical activity• Western diet ( insulin)• Tallness ( IGF-1)
* based on meta-analyses
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1.01.4
3.0
1.8
2.3
4.7
3.63.3
3.5
0.0
1.0
2.0
3.0
4.0
5.0O
dds
Ratio
Tertile 1 Tertile 2 Tertile 3
C-Peptide
Tertile 1 Tertile 1 Tertile 3IGF-1 / IGFBP-3:
Physicians’ Health StudyC
olon
Can
cer
Ma et al., 2004
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In the Physicians’ Health Study,
80% of colon cancers
were attributed to being
above the low tertile of
C-peptide (insulin) and of IGF-1.
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Meta-Analysis of Risk of CRC for an Increase for 1 Portion of Red Meat
Sandhu et al., CEBP 2001
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Meta-Analysis of Risk of CRC for an Increase of 1 Portion of Processed Meat
Sandhu et al., CEBP 2001
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Factors That Decrease Risk
• Physical activity• Calcium (1000 mg/day)*• Vitamin D• Multivitamins (folate, B6?)
• Aspirin*• Hormone replacement therapy*• Fiber ?
* Randomized trial evidence
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• Most studies, including randomizedclinical trials of adenomas, indicatea benefit of calcium intake
• A recent pooled analysis of majorcohort studies found a non-linearinverse association
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Cho et al., JNCI 2004
Nonparametric Regression Curve for the Relationship between Total Calcium Intake and Colorectal Cancer
Pooled Cohort Analysis
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NCI, National Cancer Mortality Maps & Graphs
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Plasma 25(OH) Vitamin D and Colorectal CancerNurses’ Health Study
0
0.25
0.5
0.75
1
1.25
1.5
1.75
13 20 24 28 35
Median (ng/mL)
Mul
tivar
iabl
e O
R
P trend = 0.02
Feskanich D. et al., CEBP 2004
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Colorectal Cancer Risk(NHS, HPFS)
0.88
0.65
0.921.000.961.0
0.80 0.790.69
0.0
0.2
0.4
0.6
0.8
1.0
1.2
<250 250-399 400-499 600-799 >800
Total Folate Intake (mg/day)
Mu
ltiva
ria
te R
R
0-4 year lag (P=0.19)
12-16 year lag (P=0.01)
Lee JE et al., submitted
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• Alcohol is an antagonist
of folate and vitamin B6
• Risk of CRC is particularly high
when alcohol is high and
folate is low
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Inflammation is a risk factor for CRC
• inflammatory markers
• expression of COX-2
• aspirin / NSAIDs risk
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RR and 95% CI of CRCaccording to Years of Aspirin Use
NHS
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
0 1-4 5-9 10-19 > 20
Years of Regular Use
Mu
ltiv
ari
ate
Re
lati
ve
Ris
k
Giovannucci et al., NEJM 1995
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Adenoma Cancer <1 cm 1 cm Latency
Smoking > 35-40 yr Aspirin > 10 yr Folate/vitamin B6 > 10 yr Alcohol > 10 yr Calcium/vitamin D > 10 yr Physical inactivity 0 < 10 yr Central adiposity 0 < 10 yr IGF-1/insulin 0 < 10 yr Estrogens 0 < 10 yr
Summary of Results for Colon Cancer
increases risk decreases risk
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smoking aspirin (–)
folate (–)
alcohol
vitamin D (–)
calcium (–)
physical activity (–)
body size
Western diet
insulin, IGF
estrogens (–)
SCHMTC: Normal cell to
cancer - environment
IncreasedCell
Growth
AdenomaI
CancerAdenoma
IIAdenoma
IIINormal
Cell
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smoking aspirin (–)
folate (–)
alcohol
vitamin D (–)
calcium (–)
physical activity (–)
body size
Western diet
insulin, IGF
estrogens (–)
APCmutation
K-rasmutation
COX-2 over-expression MSI
p27 lossp53 mutation
IncreasedCell
Growth
AdenomaI
CancerAdenoma
IIAdenoma
IIINormal
Cell
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Primary vs. Secondary
Prevention
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Wei E.K., et al. Am J Epidemiol, 2009
Age-specific incidenceper 100,000 person-yearsof colon cancer determinedby:
smokingbody weightexerciseprocessed meat intakemultivitamin use
Nurses’ Health Study
NOTE: Does not account for alcohol, vitamin D, calcium, hormone use, aspirin/NSAIDs
0
50
100
150
200
250
30 35 40 45 50 55 60 65 70
Age
Inc
ide
nc
e
High risk - neverscreened
High risk - screenedfrom age 50-70
Moderate risk -never screened
Low risk - neverscreened