Epidemiologyof

Colorectal Cancer

Edward Giovannucci, M.D., Sc.D.

Harvard School of Public HealthBrigham and Women’s Hospital

and Harvard Medical SchoolBoston, MA USA

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

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.

Colorectal Cancer: Natural History

• Process takes several decades

• Molecular lesions fairly well characterized

• Empirical stages:small adenomalarge adenomacarcinoma

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

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

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

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)

Primary Prevention

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

Smoking and Alcohol

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

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

Why are colon cancer rates invariably high

in populations that undergo “Westernization”?

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

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

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

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

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

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.

Meta-Analysis of Risk of CRC for an Increase for 1 Portion of Red Meat

Sandhu et al., CEBP 2001

Meta-Analysis of Risk of CRC for an Increase of 1 Portion of Processed Meat

Sandhu et al., CEBP 2001

Factors That Decrease Risk

• Physical activity• Calcium (1000 mg/day)*• Vitamin D• Multivitamins (folate, B6?)

• Aspirin*• Hormone replacement therapy*• Fiber ?

* Randomized trial evidence

• Most studies, including randomizedclinical trials of adenomas, indicatea benefit of calcium intake

• A recent pooled analysis of majorcohort studies found a non-linearinverse association

Cho et al., JNCI 2004

Nonparametric Regression Curve for the Relationship between Total Calcium Intake and Colorectal Cancer

Pooled Cohort Analysis

NCI, National Cancer Mortality Maps & Graphs

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

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

• Alcohol is an antagonist

of folate and vitamin B6

• Risk of CRC is particularly high

when alcohol is high and

folate is low

Inflammation is a risk factor for CRC

• inflammatory markers

• expression of COX-2

• aspirin / NSAIDs risk

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

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

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

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

Primary vs. Secondary

Prevention

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