Chemoprevention in Hereditary Colorectal Cancer Syndromes

  • Reagan M. Barnett
  • Ester Borras
  • N. Jewel Samadder
  • Eduardo Vilar


Patients and families diagnosed with hereditary colorectal cancer syndromes present with an accelerated carcinogenesis. In this scenario, screening measures and preventive interventions play a crucial role in modulating the cancer risk by decreasing its incidence and mortality. In this chapter we will provide an overview of the clinical evidence of chemopreventive interventions developed in Familial Adenomatous Polyposis and Lynch Syndrome. Specifically, we will present the use of non-steroidal anti-inflammatory drugs (NSAIDs), which have been the most commonly studied agents in this field. Finally, we will discuss the latest clinical trials deploying targeted agents and modern NSAIDs in the context of prevention of hereditary colorectal cancer syndromes.


Chemoprevention Hereditary colorectal cancer syndromes Nonsteroidal anti-inflammatory drugs Aspirin COX-2 inhibitors Familial adenomatous polyposis Lynch syndrome 



CpG island methylator phenotype


Chromosomal instability




COX-2 inhibitor


Colorectal cancer




Familial adenomous polyposis




Lynch syndrome


Mismatch repair


Microsatellite instability


Nuclear factor-kappa B


Nonsteroidal anti-inflammatory drug




Conflict of Interest

The authors declare no conflicts of interest.


  1. 1.
    Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9–29.CrossRefGoogle Scholar
  2. 2.
    Hawk ET, Levin B. Colorectal cancer prevention. J Clin Oncol. 2005;23(2):378–91.CrossRefGoogle Scholar
  3. 3.
    Taylor DP, Burt RW, Williams MS, Haug PJ, Cannon-Albright LA. Population-based family history-specific risks for colorectal cancer: a constellation approach. Gastroenterology. 2010;138(3):877–85.CrossRefGoogle Scholar
  4. 4.
    Fearon ER. Molecular genetics of colorectal cancer. Annu Rev Pathol. 2011;6:479–507.CrossRefGoogle Scholar
  5. 5.
    Sporn MB, Dunlop NM, Newton DL, Smith JM. Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids). Fed Proc. 1976;35(6):1332–8.PubMedGoogle Scholar
  6. 6.
    Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759–67.CrossRefGoogle Scholar
  7. 7.
    Barker N, Ridgway RA, van Es JH, van de Wetering M, Begthel H, van den Born M, et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature. 2009;457(7229):608–11.CrossRefGoogle Scholar
  8. 8.
    Bonasio R, Tu S, Reinberg D. Molecular signals of epigenetic states. Science. 2010;330(6004):612–6.CrossRefGoogle Scholar
  9. 9.
    Pancione M, Remo A, Colantuoni V. Genetic and epigenetic events generate multiple pathways in colorectal cancer progression. Pathol Res Int. 2012;2012:509348.CrossRefGoogle Scholar
  10. 10.
    Issa J-P. Colon cancer: it’s CIN or CIMP. Clin Cancer Res off J am Assoc Cancer Res. 2008;14(19):5939–40.CrossRefGoogle Scholar
  11. 11.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.CrossRefGoogle Scholar
  12. 12.
    Grady WM, Carethers JM. Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology. 2008;135(4):1079–99.CrossRefGoogle Scholar
  13. 13.
    Aaltonen LA, Peltomäki P, Leach FS, Sistonen P, Pylkkänen L, Mecklin JP, et al. Clues to the pathogenesis of familial colorectal cancer. Science. 1993;260(5109):812–6.CrossRefGoogle Scholar
  14. 14.
    Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature. 1993;363(6429):558–61.CrossRefGoogle Scholar
  15. 15.
    González-García I, Moreno V, Navarro M, Martí-Ragué J, Marcuello E, Benasco C, et al. Standardized approach for microsatellite instability detection in colorectal carcinomas. J Natl Cancer Inst. 2000;92(7):544–9.CrossRefGoogle Scholar
  16. 16.
    Pedroni M, Tamassia MG, Percesepe A, Roncucci L, Benatti P, Lanza G, et al. Microsatellite instability in multiple colorectal tumors. Int J Cancer. 1999;81(1):1–5.CrossRefGoogle Scholar
  17. 17.
    Vilar E, Gruber SB. Microsatellite instability in colorectal cancer-the stable evidence. Nat Rev Clin Oncol. 2010;7(3):153–62.CrossRefGoogle Scholar
  18. 18.
    Toyota M, Ahuja N, Suzuki H, Itoh F, Ohe-Toyota M, Imai K, et al. Aberrant methylation in gastric cancer associated with the CpG island methylator phenotype. Cancer Res. 1999;59(21):5438–42.PubMedGoogle Scholar
  19. 19.
    Ballestar E, Esteller M. SnapShot: the human DNA methylome in health and disease. Cell. 2008;135(6):1144. e1.CrossRefGoogle Scholar
  20. 20.
    Liu Y, Siegmund KD, Laird PW, Berman BP. Bis-SNP: combined DNA methylation and SNP calling for Bisulfite-seq data. Genome Biol. 2012;13(7):R61.CrossRefGoogle Scholar
  21. 21.
    Hinoue T, Weisenberger DJ, Lange CPE, Shen H, Byun H-M, Van Den Berg D, et al. Genome-scale analysis of aberrant DNA methylation in colorectal cancer. Genome Res. 2012;22(2):271–82.CrossRefGoogle Scholar
  22. 22.
    Tsujii M, DuBois RN. Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell. 1995;83(3):493–501.CrossRefGoogle Scholar
  23. 23.
    Sawaoka H, Kawano S, Tsuji S, Tsujii M, Murata H, Hori M. Effects of NSAIDs on proliferation of gastric cancer cells in vitro: possible implication of cyclooxygenase-2 in cancer development. J Clin Gastroenterol. 1998;27(Suppl 1):S47–52.CrossRefGoogle Scholar
  24. 24.
    Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S, DuBois RN. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology. 1994;107(4):1183–8.CrossRefGoogle Scholar
  25. 25.
    Gupta RA, Dubois RN. Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat Rev Cancer. 2001;1(1):11–21.CrossRefGoogle Scholar
  26. 26.
    Fritsche E, Baek SJ, King LM, Zeldin DC, Eling TE, Bell DA. Functional characterization of cyclooxygenase-2 polymorphisms. J Pharmacol Exp Ther. 2001;299(2):468–76.PubMedGoogle Scholar
  27. 27.
    Smith CE, Soti S, Jones TA, Nakagawa A, Xue D, Yin H. Non-steroidal anti-inflammatory drugs are caspase inhibitors. Cell Chem Biol. 2017;24(3):281–92.CrossRefGoogle Scholar
  28. 28.
    Jana NR. NSAIDs and apoptosis. Cell Mol Life Sci CMLS. 2008;65(9):1295–301.CrossRefGoogle Scholar
  29. 29.
    Yin MJ, Yamamoto Y, Gaynor RB. The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature. 1998;396(6706):77–80.CrossRefGoogle Scholar
  30. 30.
    Waddell WR, Loughry RW. Sulindac for polyposis of the colon. J Surg Oncol. 1983;24(1):83–7.CrossRefGoogle Scholar
  31. 31.
    Giardiello FM, Hamilton SR, Krush AJ, Piantadosi S, Hylind LM, Celano P, et al. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med. 1993;328(18):1313–6.CrossRefGoogle Scholar
  32. 32.
    Giardiello FM, Yang VW, Hylind LM, Krush AJ, Petersen GM, Trimbath JD, et al. Primary chemoprevention of familial adenomatous polyposis with sulindac. N Engl J Med. 2002;346(14):1054–9.CrossRefGoogle Scholar
  33. 33.
    Labayle D, Fischer D, Vielh P, Drouhin F, Pariente A, Bories C, et al. Sulindac causes regression of rectal polyps in familial adenomatous polyposis. Gastroenterology. 1991;101(3):635–9.CrossRefGoogle Scholar
  34. 34.
    Barry ELR, Baron JA, Grau MV, Wallace K, Haile RW. K-ras mutations in incident sporadic colorectal adenomas. Cancer. 2006;106(5):1036–40.CrossRefGoogle Scholar
  35. 35.
    Brosens LAA, Iacobuzio-Donahue CA, Keller JJ, Hustinx SR, Carvalho R, Morsink FH, et al. Increased cyclooxygenase-2 expression in duodenal compared with colonic tissues in familial adenomatous polyposis and relationship to the -765G -> C COX-2 polymorphism. Clin Cancer Res Off J Am Assoc Cancer Res. 2005;11(11):4090–6.CrossRefGoogle Scholar
  36. 36.
    Bertoni G, Sassatelli R, Bedogni G, Nigrisoli E. Sulindac-associated ulcerative pouchitis in familial adenomatous polyposis. Am J Gastroenterol. 1996;91(11):2431–2.PubMedGoogle Scholar
  37. 37.
    Lanza LL, Walker AM, Bortnichak EA, Dreyer NA. Peptic ulcer and gastrointestinal hemorrhage associated with nonsteroidal anti-inflammatory drug use in patients younger than 65 years. A large health maintenance organization cohort study. Arch Intern Med. 1995;155(13):1371–7.CrossRefGoogle Scholar
  38. 38.
    Patrono C. Cardiovascular effects of nonsteroidal anti-inflammatory drugs. Curr Cardiol Rep. 2016;18(3):25.CrossRefGoogle Scholar
  39. 39.
    Anwar A, Anwar IJ, Delafontaine P. Elevation of cardiovascular risk by non-steroidal anti-inflammatory drugs. Trends Cardiovasc Med. 2015;25(8):726–35.CrossRefGoogle Scholar
  40. 40.
    Steinbach G, Lynch PM, Phillips RK, Wallace MH, Hawk E, Gordon GB, et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med. 2000;342(26):1946–52.CrossRefGoogle Scholar
  41. 41.
    Phillips RKS, Wallace MH, Lynch PM, Hawk E, Gordon GB, Saunders BP, et al. A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis. Gut. 2002;50(6):857–60.CrossRefGoogle Scholar
  42. 42.
    Higuchi T, Iwama T, Yoshinaga K, Toyooka M, Taketo MM, Sugihara K. A randomized, double-blind, placebo-controlled trial of the effects of rofecoxib, a selective cyclooxygenase-2 inhibitor, on rectal polyps in familial adenomatous polyposis patients. Clin Cancer Res Off J Am Assoc Cancer Res. 2003;9(13):4756–60.Google Scholar
  43. 43.
    Hallak A, Alon-Baron L, Shamir R, Moshkowitz M, Bulvik B, Brazowski E, et al. Rofecoxib reduces polyp recurrence in familial polyposis. Dig Dis Sci. 2003;48(10):1998–2002.CrossRefGoogle Scholar
  44. 44.
    Arber N, Eagle CJ, Spicak J, Rácz I, Dite P, Hajer J, et al. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med. 2006;355(9):885–95.CrossRefGoogle Scholar
  45. 45.
    Garcia Rodriguez LA, Cea-Soriano L, Tacconelli S, Patrignani P. Coxibs: pharmacology, toxicity and efficacy in cancer clinical trials. Recent Results Cancer Res Fortschritte Krebsforsch Progres Dans Rech Sur Cancer. 2013;191:67–93.CrossRefGoogle Scholar
  46. 46.
    Lynch PM, Ayers GD, Hawk E, Richmond E, Eagle C, Woloj M, et al. The safety and efficacy of celecoxib in children with familial adenomatous polyposis. Am J Gastroenterol. 2010;105(6):1437–43.CrossRefGoogle Scholar
  47. 47.
    Burn J, Mathers J, Bishop DT. Genetics, inheritance and strategies for prevention in populations at high risk of colorectal cancer (CRC). Recent Results Cancer Res Fortschritte Krebsforsch Progres Dans Rech Sur Cancer. 2013;191:157–83.CrossRefGoogle Scholar
  48. 48.
    Burn J, Mathers JC, Bishop DT. Chemoprevention in Lynch syndrome. Familial Cancer. 2013;12(4):707–18.CrossRefGoogle Scholar
  49. 49.
    Giardiello FM, Hamilton SR, Hylind LM, Yang VW, Tamez P, Casero RA. Ornithine decarboxylase and polyamines in familial adenomatous polyposis. Cancer Res. 1997;57(2):199–201.PubMedGoogle Scholar
  50. 50.
    Celano P, Baylin SB, Casero RA. Polyamines differentially modulate the transcription of growth-associated genes in human colon carcinoma cells. J Biol Chem. 1989;264(15):8922–7.PubMedGoogle Scholar
  51. 51.
    Celano P, Berchtold CM, Giardiello FM, Casero RA. Modulation of growth gene expression by selective alteration of polyamines in human colon carcinoma cells. Biochem Biophys Res Commun. 1989;165(1):384–90.CrossRefGoogle Scholar
  52. 52.
    Casero RA. Say what? The activity of the polyamine biosynthesis inhibitor difluoromethylornithine in chemoprevention is a result of reduced thymidine pools? Cancer Discov. 2013;3(9):975–7.CrossRefGoogle Scholar
  53. 53.
    Witherspoon M, Chen Q, Kopelovich L, Gross SS, Lipkin SM. Unbiased metabolite profiling indicates that a diminished thymidine pool is the underlying mechanism of colon cancer chemoprevention by alpha-difluoromethylornithine. Cancer Discov. 2013;3(9):1072–81.CrossRefGoogle Scholar
  54. 54.
    Meyskens FL, McLaren CE, Pelot D, Fujikawa-Brooks S, Carpenter PM, Hawk E, et al. Difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas: a randomized placebo-controlled, double-blind trial. Cancer Prev Res Phila Pa. 2008;1(1):32–8.CrossRefGoogle Scholar
  55. 55.
    Jacoby RF, Seibert K, Cole CE, Kelloff G, Lubet RA. The cyclooxygenase-2 inhibitor celecoxib is a potent preventive and therapeutic agent in the min mouse model of adenomatous polyposis. Cancer Res. 2000;60(18):5040–4.PubMedGoogle Scholar
  56. 56.
    Rao CV, Tokumo K, Rigotty J, Zang E, Kelloff G, Reddy BS. Chemoprevention of colon carcinogenesis by dietary administration of piroxicam, alpha-difluoromethylornithine, 16 alpha-fluoro-5-androsten-17-one, and ellagic acid individually and in combination. Cancer Res. 1991;51(17):4528–34.PubMedGoogle Scholar
  57. 57.
    Erdman SH, Ignatenko NA, Powell MB, Blohm-Mangone KA, Holubec H, Guillén-Rodriguez JM, et al. APC-dependent changes in expression of genes influencing polyamine metabolism, and consequences for gastrointestinal carcinogenesis, in the Min mouse. Carcinogenesis. 1999;20(9):1709–13.CrossRefGoogle Scholar
  58. 58.
    Meyskens FL, Gerner EW. Development of difluoromethylornithine (DFMO) as a chemoprevention agent. Clin Cancer Res Off J Am Assoc Cancer Res. 1999;5(5):945–51.Google Scholar
  59. 59.
    Love RR, Jacoby R, Newton MA, Tutsch KD, Simon K, Pomplun M, et al. A randomized, placebo-controlled trial of low-dose alpha-difluoromethylornithine in individuals at risk for colorectal cancer. Cancer Epidemiol Biomark Prev Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol. 1998;7(11):989–92.Google Scholar
  60. 60.
    Meyskens FL, Emerson SS, Pelot D, Meshkinpour H, Shassetz LR, Einspahr J, et al. Dose de-escalation chemoprevention trial of alpha-difluoromethylornithine in patients with colon polyps. J Natl Cancer Inst. 1994;86(15):1122–30.CrossRefGoogle Scholar
  61. 61.
    Meyskens FL, Gerner EW, Emerson S, Pelot D, Durbin T, Doyle K, et al. Effect of alpha-difluoromethylornithine on rectal mucosal levels of polyamines in a randomized, double-blinded trial for colon cancer prevention. J Natl Cancer Inst. 1998;90(16):1212–8.CrossRefGoogle Scholar
  62. 62.
    Samadder NJ, Neklason DW, Boucher KM, Byrne KR, Kanth P, Samowitz W, et al. Effect of sulindac and erlotinib vs placebo on duodenal neoplasia in familial adenomatous polyposis: a randomized clinical trial. JAMA. 2016;315(12):1266–75.CrossRefGoogle Scholar
  63. 63.
    Vrhovac B. Placebo and its importance in medicine. Int J Clin Pharmacol Biopharm. 1977;15(4):161–5.PubMedGoogle Scholar
  64. 64.
    Ricciardiello L, Ahnen DJ, Lynch PM. Chemoprevention of hereditary colon cancers: time for new strategies. Nat Rev Gastroenterol Hepatol. 2016;13(6):352–61.CrossRefGoogle Scholar
  65. 65.
    Burn J, Gerdes A-M, Macrae F, Mecklin J-P, Moeslein G, Olschwang S, et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet Lond Engl. 2011;378(9809):2081–7.CrossRefGoogle Scholar
  66. 66.
    Mathers JC, Movahedi M, Macrae F, Mecklin J-P, Moeslein G, Olschwang S, et al. Long-term effect of resistant starch on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet Oncol. 2012;13(12):1242–9.CrossRefGoogle Scholar
  67. 67.
    Burn J, Bishop DT, Mecklin J-P, Macrae F, Möslein G, Olschwang S, et al. Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome. N Engl J Med. 2008;359(24):2567–78.CrossRefGoogle Scholar
  68. 68.
    Liljegren A, Barker G, Elliott F, Bertario L, Bisgaard ML, Eccles D, et al. Prevalence of adenomas and hyperplastic polyps in mismatch repair mutation carriers among CAPP2 participants: report by the colorectal adenoma/carcinoma prevention programme 2. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26(20):3434–9.CrossRefGoogle Scholar
  69. 69.
    Movahedi M, Bishop DT, Macrae F, Mecklin J-P, Moeslein G, Olschwang S, et al. Obesity, aspirin, and risk of colorectal cancer in carriers of hereditary colorectal cancer: a prospective investigation in the CAPP2 Study. J Clin Oncol Off J Am Soc Clin Oncol. 2015;33(31):3591–7.CrossRefGoogle Scholar
  70. 70.
    Glebov OK, Rodriguez LM, Lynch P, Patterson S, Lynch H, Nakahara K, et al. Celecoxib treatment alters the gene expression profile of normal colonic mucosa. Cancer Epidemiol Biomark Prev Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol. 2006;15(7):1382–91.CrossRefGoogle Scholar
  71. 71.
    Nissen SE, Yeomans ND, Solomon DH, Lüscher TF, Libby P, Husni ME, et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med. 2016;375(26):2519–29.CrossRefGoogle Scholar
  72. 72.
    You YN, Vilar E. Classifying MMR variants: time for revised nomenclature in Lynch syndrome. Clin Cancer Res Off J Assoc Cancer Res. 2013;19(9):2280–2.CrossRefGoogle Scholar
  73. 73.
    Boland CR. Recent discoveries in the molecular genetics of Lynch syndrome. Familial Cancer. 2016;15(3):395–403.CrossRefGoogle Scholar
  74. 74.
    Chen Y, Peate M, Kaur R, Meiser B, Wong T, Kirk J, et al. Exploring clinicians’ attitudes about using aspirin for risk reduction in people with Lynch syndrome with no personal diagnosis of colorectal cancer. Familial Cancer. 2017;16(1):99–109.CrossRefGoogle Scholar
  75. 75.
    Spira A, Disis ML, Schiller JT, Vilar E, Rebbeck TR, Bejar R, et al. Leveraging premalignant biology for immune-based cancer prevention. Proc Natl Acad Sci U S A. 2016;113(39):10750–8.CrossRefGoogle Scholar
  76. 76.
    Spira A, Yurgelun MB, Alexandrov L, Rao A, Bejar R, Polyak K, et al. Precancer atlas to drive precision prevention trials. Cancer Res. 2017;77(7):1510–41.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Reagan M. Barnett
    • 1
  • Ester Borras
    • 1
  • N. Jewel Samadder
    • 2
  • Eduardo Vilar
    • 1
  1. 1.Department of Clinical Cancer PreventionThe University of Texas MD Anderson Cancer CenterHoustonUSA
  2. 2.Department of Internal MedicineUniversity of Utah College of MedicineSalt Lake CityUSA

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