1. Epidemiology of Colorectal Cancer Edward Giovannucci, M.D., Sc.D. Harvard School of Public Health Brigham and Women’s Hospital and Harvard Medical School Boston, MA USA

2. 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

4. Risk of Colorectal Carcinoma in General Population and 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.

5. Colorectal Cancer: Natural History Process takes several decades Molecular lesions fairly well characterized Empirical stages:small adenoma large adenoma carcinoma

7. APC mutation K-ras mutation COX-2 over- expression MLH1 hypermethylation MSI p27 loss p53 mutation Increased Cell Growth Adenoma I Cancer Adenoma II Adenoma III Normal Cell Small Large >30 - 40 years

8. Sub-Type Classification of CRC Clinical:proximal vs. distal Pathological: mucinous vs. non-mucinous poorly vs. well-differentiated Molecular:chromosomal instability (CIN) microsatellite instability (MSI) CpG island methylation phenotype (CIMP) Ogino S & Goel A, J Mol Diagn 2008

9. 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

10. Screening American Cancer Society Guidelines For average risk persons, screening is recommended beginning at age 50 yrs Colonoscopy is recommended every 10 years (if no polyps are found)

11. Primary Prevention

12. 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

13. Smoking and Alcohol

14. Smoking and Colorectal Cancer NHS and HPFS Years Since Starting Smoking  Giovannucci et al., JNCI 1994 Multivariate Relative Risk

15. Alcohol and Colorectal Cancer Analysis of 8 Cohort Studies Cho e et al., Ann Intern Med 2004 Intake (g / day) Multivariate Relative Risk

16. Why are colon cancer rates invariably high in populations that undergo “Westernization”?

17. 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

18. 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

19. Pituitary GH Secretion Tallness Insulin Resistance Diabetes Red & Processed Meats, Saturated Fat, Sweets, Refined Grains  Insulin  IGF-1 Competent  -Cells Insulin Treatment Physical Inactivity Abdominal Obesity Energy, Protein, Minerals Acromegaly  Colon Tumor Growth  Proliferation;  Apoptosis

20. Risk Factors* for Colon Cancer and Adenoma Compatible 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

21. Tertile 1 Tertile 3 IGF-1 / IGFBP-3: Physicians’ Health Study Colon Cancer Ma et al., 2004

22. 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.

23. Meta-Analysis of Risk of CRC for an Increase for 1 Portion of Red Meat Sandhu et al., CEBP 2001

24. Meta-Analysis of Risk of CRC for an Increase of 1 Portion of Processed Meat Sandhu et al., CEBP 2001

25. Factors That Decrease Risk Physical activity Calcium (  1000 mg/day)* Vitamin D Multivitamins (folate, B6?) Aspirin* Hormone replacement therapy* Fiber ? * Randomized trial evidence

26. Most studies, including randomized clinical trials of adenomas, indicate a benefit of calcium intake A recent pooled analysis of major cohort studies found a non-linear inverse association

27. Cho et al., JNCI 2004 Nonparametric Regression Curve for the Relationship between Total Calcium Intake and Colorectal Cancer Pooled Cohort Analysis

29. NCI, National Cancer Mortality Maps & Graphs

30. Plasma 25(OH) Vitamin D and Colorectal Cancer Nurses’ Health Study P trend = 0.02 Feskanich D. et al., CEBP 2004

31. Colorectal Cancer Risk (NHS, HPFS) Total Folate Intake (mg/day) Multivariate RR 0-4 year lag (P=0.19) 12-16 year lag (P=0.01) Lee JE et al., submitted

32. Alcohol is an antagonist of folate and vitamin B6 Risk of CRC is particularly high when alcohol is high and folate is low

33. Inflammation is a risk factor for CRC  inflammatory markers  expression of COX-2 aspirin / NSAIDs  risk

34. RR and 95% CI of CRC according to Years of Aspirin Use NHS Giovannucci et al., NEJM 1995

35. Summary of Results for Colon Cancer  increases risk  decreases risk

36. smokingaspirin (–) folate (–) alcohol vitamin D (–) calcium (–) physical activity (–) body size Western diet insulin, IGF estrogens (–) SCHMTC: Normal cell to cancer - environmentSCHMTC: Normal cell to cancer - environment Increased Cell Growth Adenoma I Cancer Adenoma II Adenoma III Normal Cell

37. smokingaspirin (–) folate (–) alcohol vitamin D (–) calcium (–) physical activity (–) body size Western diet insulin, IGF estrogens (–) APC mutation K-ras mutation COX-2 over- expression MSI p27 loss p53 mutation Increased Cell Growth Adenoma I Cancer Adenoma II Adenoma III Normal Cell

38. Primary vs. Secondary Prevention

39. Wei E.K., et al. Am J Epidemiol, 2009 Age-specific incidence per 100,000 person-years of colon cancer determined by: smoking body weight exercise processed meat intake multivitamin use Nurses’ Health Study NOTE: Does not account for alcohol, vitamin D, calcium, hormone use, aspirin/NSAIDs