Risk factors and prevention of colorectal neoplasia

1. Risk factors and prevention of colorectal neoplasia Benoy Sebastian

2. High risk when… • Age > 50 yrs • DM,insulin resistance and hyperinsulinemia • Obesity • Physical inactivity

3. Dietary Factors • High fat low fiber diet • Red meat • Diet poor in multivitamins and minerals • Alcohol

4. Personal Hx of adenomas/carcinomas • Polyposis syndromes • Classic FAP, Gardner’s syndrome, Turcot syndrome • Muir Torre syndrome • Peutz Jegher’s syndrome • Familial juvenile polyposis • HNPCC • First degree relative with CRC

5. IBD Risk? • Ulcerative colitis 2% after 10yrs 8% after 20yrs 18% after 30 yrs • Crohn’s disease 4-20 times risk compared to unaffected

6. Predisposing conditions • Ureterosigmoidostomy sites • Acromegaly • Streptococcus bovis bactremia

7. Adenoma.. The villain!

8. Most CRC arise from adenomas • Risk depends on Size Number Villous architecture Degree of dysplasia • Actual risk of Ca unknown

9. Adenoma Carcinoma • Estimated annual conversion rate 3% for polyp > 1cm 17% for villous adenomas 37% for polyps with severe dysplasia

10. Adenoma carcinoma hypothesis The evidence • Epidemiological • Clinical and pathological • Molecular and genetic

11. Epidemiological evidence • Prevalence of adenomas and CRC parallels in a community • Prevalence of both increases with age

12. Clinicopathologic evidence • Inevitable cancer in FAP • Endoscopic screening and polyp removal decreases CRC incidence • Presence of remnant adenoma tissue in colon cancer • Synchronous adenomas

13. Molecular Genetic evidence Genomic instability; germline acquired Mutations Abnormal cell proliferation and neoplastic status

14. Three major genetic events • Activation of proto oncogenes • Inactivation of tumor suppressor genes • Mutations in ‘stability genes’

15. Activation of oncogenes • Normally regulate cell growth • Inappropriate activation leads to abnormal cell growth • k-ras mutation – most common in CRC • Seen in 47% carcinomas 58% adenomas > 1 cm 10% adenomas < 1 cm

16. Inactivation of tumor suppressor genes • APC gene – chr 5q • Gate keeper for colon carcinogenesis • Mutation of APC ;the crucial first step • Others DCC (18q) P53 (17p) Participates in later stages

17. APC Gene  Catenin WNT,TCF Signal Pathway Nucleus Proliferation APC protein binds to β catenin Nucleus APC Protein

18. Mutations in stability genes • Keep the genetic alterations to minimum • DNA mismatch repair genes (MMR genes) • hMLH1,hPMS1,hMSH2,hMSH6.. • Responsible for HNPCC

19. Evolution of CRC

20. Evolution of CRC Histology Endoscopy

21. Flat adenomas • Often missed during conventional endoscopy • Accounts for 7-36% of all adenomas • High grade dysplasia • ?evolve into polypoid adenomas • ?lead to de novo colon cancer

22. Serrated adenomas • Mixed hyperplastic and adenomatous picture • Malignant potential • Activation of Braf oncogene • mutation of hMLH1

23. Chemoprevention of Colorectal Cancer

24. Feasibility of Chemoprevention in CRC • Knowledge about molecular and genetic evolution • Precursor lesions • Long ‘incubation period’ • Opportunity for intervention at different levels • Population ‘ at risk ’ can be identified

25. Diet and Nutrients

26. Fiber Different mechanisms of action 50% risk reduction if fiber intake is more than 30gm/day Critical evaluation – AGA Benefit more for colon cancer Fruits and vegetables better than cereals

27. Vitamins E & C • Antioxidant vitamins • High serum levels associated with less risk of CRC • No strong experimental or clinical evidence

28. Folic Acid • 21 studies – relative risk of 0.8 • Protective role in ulcerative colitis • Folate deficiency induces DNA hypomethylation , which leads to activation of oncogenes

29. Calcium Binds luminal bile acids and fatty acids Cell regulatory effects Membrane stabilizing effects Modifies k-ras 2-3 gm CaCO3/day showed significant reduction in adenoma recurrence in two RCTs

30. Selenium • 200μgm/day showed 58% reduction in colon cancer incidence in patients treated for skin cancer • Inverse relation between environmental selenium levels and cancer risk

31. Aspirin and NSAIDs

32. Mechanism of action • Induction of apoptosis • Inhibition of COX-2 enzyme • Inhibition of angiogenesis • Inhibition of protein kinases

33. Three lines of evidence • Data from experimental animals • Data from epidemiological studies • Data from interventional trials

34. Animal data • Various NSAIDs prevent adenomas and CRC in both chemically and genetically induced animal models • Very convincing data

35. Epidemiological data • More than 35 studies • Aspirin/NSAID use – associated with 40-45% reduction of adenoma,cancer and CRC related mortality • Regardless of age,sex,race,health care setting or study design

36. Intervention Trials - FAP • Sulindac causes regression of adenomas in Gardner’s syndrome Waddel et al J Surg Onco 1983 • Several controlled trials since then -Regression of adenomas -Prevention of formation of new adenomas

37. Intervention Trials - FAP Celecoxib • Double blind placebo controlled trial • 83 pts; 400 mg bid x 6 months • 32% median reduction in polyp number • No significant side effects • FDA approval

38. Intervention trials - Sporadic Adenomas • Two trials with Sulindac – failed to detect a clear benefit • Two trials with Aspirin – only modest benefit

39. Concerns! • Optimum dose and duration of therapy • Re growth of polyps on stopping treatment • Limited data on sporadic adenomas • Side effects

40. Promising Agents • Difluromethylornithine (DFMC) • Ursodeoxycholic acid (UDCA) • Hormones – Estrogens • Statins – Pravastatin,Simvastatin Clear benefit in animal models and encouraging evidence in human studies

41. Natural COX-2 Inhibitors • Curcumin • Phenyl ethyl methyl caffeate • Omega 3 fatty acids All have shown benefit in experimental animals and in vitro carcinoma cell lines

42. Chemoprevention in IBD • 5 ASA & folic acid found to be beneficial • UDCA in patients with PSC • Steroids are beneficial,but not practical • No role for other immunosuppressive drugs

43. Summary • Adenoma carcinoma hypothesis is well established in CRC • Diet and environment likely to play a crucial role • Defined genetic syndromes – but rare • Chemoprevention is a novel concept • Ideal agent;still an enigma!