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Chemoprevention of hereditary colon cancers: time for new strategies

Key Points

  • Colon cancer can be prevented through chemoprevention

  • The highest return from chemopreventive strategies is in patients with a hereditary predisposition for developing colorectal cancer

  • Clinical trials have yielded conflicting results and currently no chemopreventive agent is approved in hereditary colorectal cancer syndromes

  • Chemoprevention should ultimately be aimed at delaying colectomy, reducing endoscopies and polypectomies, and preventing cancer development

  • Future trials must be carefully designed and conducted to be successful, with an effort to avoid wasting resources and time

Abstract

Colorectal cancer (CRC) is potentially preventable. Chemoprevention, a focus of research for the past three decades, aims to prevent or delay the onset of cancer through the regression or prevention of colonic adenomas. Ideal pharmacological agents for chemoprevention should be cheap and nontoxic. Although data indicate that aspirin can reduce the risk of CRC in the general population, the highest return from chemopreventive strategies would be expected in patients with the highest risk of developing the disease, particularly those with a defined hereditary predisposition. Despite compelling data showing that a large number of chemopreventive agents show promise in preclinical CRC models, clinical studies have yielded conflicting results. This Review provides a historical and methodological perspective of chemoprevention in familial adenomatous polyposis and Lynch syndrome, and summarizes the current status of CRC chemoprevention in humans. Our goal is to critically focus on important issues of trial design, with particular attention on the choice of appropriate trial end points, how such end points should be measured, and which patients are the ideal candidates to be included in a chemopreventive trial.

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Figure 1: Timeline of selected published chemopreventive clinical trials for FAP.
Figure 2: A new approach for drug development in chemopreventive trials for FAP.

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Acknowledgements

L.R. is supported by the Italian Association for Cancer Research (AIRC) IG Investigator Grant N. 14281 and the European Community's Seventh Framework Program FP7/2007–2013 under grant agreement 311876, Pathway-27.

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L.R. researched the data for the article and drafted the manuscript. D.J.A. and P.M.L. edited and reviewed the manuscript and provided a critical contribution to discussions of the content.

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Correspondence to Luigi Ricciardiello.

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L.R. has received an unrestricted research grant from SLA Pharma UK. D.J.A. serves on the Scientific Advisory Boards for EXACT Sciences and Cancer Prevention Pharmaceuticals. P.M.L. declares no competing interests.

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Selected clinical randomized, placebo-controlled trials in FAP and Lynch syndrome, and limits in their end point evaluation (PDF 183 kb)

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Ricciardiello, L., Ahnen, D. & Lynch, P. Chemoprevention of hereditary colon cancers: time for new strategies. Nat Rev Gastroenterol Hepatol 13, 352–361 (2016). https://doi.org/10.1038/nrgastro.2016.56

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