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Epidemiology of Colorectal Cancer

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. Colorectal Cancer (CRC). Second leading cause of cancer death in the United States  10% of cancer deaths

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Epidemiology of Colorectal Cancer

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  1. EpidemiologyofColorectal 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

  3. 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.

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

  5. MLH1 hypermethylation MSI COX-2 over- expression APC mutation K-ras mutation p27 loss p53 mutation IncreasedCellGrowth AdenomaI AdenomaII AdenomaIII Normal Cell Cancer Small Large >30 - 40 years

  6. 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

  7. 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

  8. ScreeningAmerican 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)

  9. Primary Prevention

  10. 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

  11. Smoking and Alcohol

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

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

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

  15. 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

  16. 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

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

  18. 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

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

  20. 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.

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

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

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

  24. 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

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

  26. NCI, National Cancer Mortality Maps & Graphs

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

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

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

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

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

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

  33. IncreasedCellGrowth AdenomaI AdenomaII AdenomaIII Normal Cell Cancer SCHMTC: Normal cell to cancer - environment smoking aspirin (–) folate (–) alcohol vitamin D (–) calcium (–) physical activity (–) body size Western diet insulin, IGF estrogens (–)

  34. COX-2 over- expression MSI APC mutation K-ras mutation p27 loss p53 mutation IncreasedCellGrowth AdenomaI AdenomaII AdenomaIII Normal Cell Cancer smoking aspirin (–) folate (–) alcohol vitamin D (–) calcium (–) physical activity (–) body size Western diet insulin, IGF estrogens (–)

  35. Primary vs. Secondary Prevention

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

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