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ACF in the colon have been the focus of many mechanistic and preclinical, and a few epidemiologic, studies (3) since their initial description (4). Given the potential value of ACF as an early and readily identifiable change that might indicate colorectal cancer risk or response to preventive measures, the specifics of the Lance and Hamilton Perspective require close scrutiny.
The authors' statement (regarding the first description of ACF in humans) that "at least one ACF was found in each left colon of the 13 autopsy patients without colorectal cancer" (1) is factually incorrect. Table 1 of the original article (5) clearly states that 13 patients had "left colon from autopsy," only 1 of whom had ACF (one in this case). More important, two key references that very strongly link human ACF to colon tumorigenesis (6, 7) were omitted from the Perspective. In the first, all human ACF were monoclonal proliferations (i.e., the earliest identified neoplastic lesions in the colon; ref. 6). In the second, it seems that Wnt signaling was constitutively active in more than 90% of human ACF through promoter methylation of the genes for secreted frizzled-related protein 1 or 2 (7). In addition, a number of recent molecular and genetic analyses have shown that ACF of each histologic subtype have characteristic aberrations found in colorectal cancer (e.g., ref. 8).
There is a long, impressive history of preclinical animal studies showing that ACF suppression by a wide variety of dietary factors is associated with reduced cancer incidence (9).1 In rodent studies, larger ACF and/or crypt multiplicity often correlates with tumors better than does the number of ACF (10).
The clinical evidence is provocative but limited (10) and the Cho et al. study (2) is the first and only prospective randomized trial. Although innovative, it alone cannot be taken as strong evidence against human ACF as a suitable surrogate end point. The study was based on only 45 patients (of whom 10 were regular aspirin users), who were evaluated at five different sites with five different investigators. These investigators found that "the mean number of ACF at baseline was... not different between those with and without advanced adenomas," in contrast to several other reports (10). Most important, the 45 patients in the Cho et al. study did not provide evidence that celecoxib reduced the incidence of adenomas: Adenoma detection was 37.5% in the placebo group and 45.7% in the celecoxib group at "year 1 and/or year 3." If this study did not have the statistical power to detect a protective effect of celecoxib, it certainly did not have the power to make any definitive conclusion about ACF as a surrogate end point.
We view the Perspective by Lance and Hamilton (1) as an example of "jury nullification." They present the evidence with clarity and scholarship, but then render a verdict that is strikingly inconsistent with that evidence. Our position is not that ACF should now be accepted as a surrogate end point for human chemoprevention trials, but rather that the existing direct evidence is woefully inadequate to render a verdict at this time. In other words, more research is needed.
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References |
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2. Cho NL, Redston M, Zauber AG et al . Aberrant crypt foci in the Adenoma Prevention with Celecoxib trial. Cancer Prev Res 2008;1:21–31Available from: http://cancerpreventionresearch.aacrjournals.org/cgi/reprint/1/1/21.[CrossRef]
3. Stevens RG, Swede H, Rosenberg DW. Epidemiology of colonic aberrant crypt foci: review and analysis of existing studies. Cancer Lett 2007;252:171–83.[CrossRef][Medline]
4. Bird RP. Observation and quantification of aberrant crypts in the murine colon treated with a colon carcinogen: preliminary findings. Cancer Lett 1987;37:147–51.[CrossRef][Medline]
5. Pretlow TP, Barrow BJ, Ashton WS et al . Aberrant crypts: putative preneoplastic foci in human colonic mucosa. Cancer Res 1991;51:1564–7.
6. Siu I-M, Robinson DR, Schwartz S et al . The identification of monoclonality in human aberrant crypt foci. Cancer Res 1999;59:63–6.
7. Suzuki H, Watkins DN, Jair K-W et al . Epigenetic inactivation of SFRP genes allows constitutive Wnt signaling in colorectal cancer. Nat Genet 2004;36:417–22.[CrossRef][Medline]
8. Rosenberg DW, Yang S, Pleau DC et al . Mutations in BRAF and KRAS differentially distinguish serrated versus non-serrated hyperplastic aberrant crypt foci in humans. Cancer Res 2007;67:3551–4.
9. Corpet DE Pierre F. How good are rodent models of carcinogenesis in predicting efficacy in humans? A systematic review and meta-analysis of colon chemoprevention in rats, mice, and men. Eur J Cancer 2005;41:1911–22.[CrossRef][Medline]
10. Gupta AK, Pretlow TP, Schoen RE. Aberrant crypt foci: what we know and what we need to know. Clin Gastroenterol Hepatol 2007;5:526–33.[CrossRef][Medline]
Department of Community Medicine, University of Connecticut Health Center, Farmington, Connecticut
Department of Pathology, Case Western Reserve University, Cleveland, Ohio
Gastroenterology and Liver Unit, Royal Hallamshire Hospital, University of Sheffield Medical School, Sheffield, United Kingdom
Department of Molecular and Cell Biology, University of Connecticut, Storrs, Connecticut
Center for Molecular Medicine, Colon Cancer Prevention Program, University of Connecticut Health Center, Farmington, Connecticut
Key Words: aberrant crypt foci • chemoprevention trials • colorectal cancer
To the Editor: We believe that the enthusiasm of Lance and Hamilton (1) in embracing the study by Cho et al. (2) as "seminal" and their finality in dismissing aberrant crypt foci (ACF) as a surrogate end point for chemoprevention trials are misplaced. We are concerned that the Perspective of Lance and Hamilton (1) may have overlooked important evidence in arriving at these conclusions, which the authors state were based on their "diverse perspectives of gastroenterology and clinical chemoprevention and of gastrointestinal and molecular pathology."
ACF in the colon have been the focus of many mechanistic and preclinical, and a few epidemiologic, studies (3) since their initial description (4). Given the potential value of ACF as an early and readily identifiable change that might indicate colorectal cancer risk or response to preventive measures, the specifics of the Lance and Hamilton Perspective require close scrutiny.
The authors' statement (regarding the first description of ACF in humans) that "at least one ACF was found in each left colon of the 13 autopsy patients without colorectal cancer" (1) is factually incorrect. Table 1 of the original article (5) clearly states that 13 patients had "left colon from autopsy," only 1 of whom had ACF (one in this case). More important, two key references that very strongly link human ACF to colon tumorigenesis (6, 7) were omitted from the Perspective. In the first, all human ACF were monoclonal proliferations (i.e., the earliest identified neoplastic lesions in the colon; ref. 6). In the second, it seems that Wnt signaling was constitutively active in more than 90% of human ACF through promoter methylation of the genes for secreted frizzled-related protein 1 or 2 (7). In addition, a number of recent molecular and genetic analyses have shown that ACF of each histologic subtype have characteristic aberrations found in colorectal cancer (e.g., ref. 8).
There is a long, impressive history of preclinical animal studies showing that ACF suppression by a wide variety of dietary factors is associated with reduced cancer incidence (9).1 In rodent studies, larger ACF and/or crypt multiplicity often correlates with tumors better than does the number of ACF (10).
The clinical evidence is provocative but limited (10) and the Cho et al. study (2) is the first and only prospective randomized trial. Although innovative, it alone cannot be taken as strong evidence against human ACF as a suitable surrogate end point. The study was based on only 45 patients (of whom 10 were regular aspirin users), who were evaluated at five different sites with five different investigators. These investigators found that "the mean number of ACF at baseline was... not different between those with and without advanced adenomas," in contrast to several other reports (10). Most important, the 45 patients in the Cho et al. study did not provide evidence that celecoxib reduced the incidence of adenomas: Adenoma detection was 37.5% in the placebo group and 45.7% in the celecoxib group at "year 1 and/or year 3." If this study did not have the statistical power to detect a protective effect of celecoxib, it certainly did not have the power to make any definitive conclusion about ACF as a surrogate end point.
We view the Perspective by Lance and Hamilton (1) as an example of "jury nullification." They present the evidence with clarity and scholarship, but then render a verdict that is strikingly inconsistent with that evidence. Our position is not that ACF should now be accepted as a surrogate end point for human chemoprevention trials, but rather that the existing direct evidence is woefully inadequate to render a verdict at this time. In other words, more research is needed.
No potential conflicts of interest were disclosed.
1http://www.inra.fr/reseau-nacre/sci-memb/corpet/indexan.html
Received for publication May 7, 2008.
Revision received June 10, 2008.
Accepted July 2, 2008
2. Cho NL, Redston M, Zauber AG et al . Aberrant crypt foci in the Adenoma Prevention with Celecoxib trial. Cancer Prev Res 2008;1:21–31Available from: http://cancerpreventionresearch.aacrjournals.org/cgi/reprint/1/1/21.[CrossRef]
3. Stevens RG, Swede H, Rosenberg DW. Epidemiology of colonic aberrant crypt foci: review and analysis of existing studies. Cancer Lett 2007;252:171–83.[CrossRef][Medline]
4. Bird RP. Observation and quantification of aberrant crypts in the murine colon treated with a colon carcinogen: preliminary findings. Cancer Lett 1987;37:147–51.[CrossRef][Medline]
5. Pretlow TP, Barrow BJ, Ashton WS et al . Aberrant crypts: putative preneoplastic foci in human colonic mucosa. Cancer Res 1991;51:1564–7.
6. Siu I-M, Robinson DR, Schwartz S et al . The identification of monoclonality in human aberrant crypt foci. Cancer Res 1999;59:63–6.
7. Suzuki H, Watkins DN, Jair K-W et al . Epigenetic inactivation of SFRP genes allows constitutive Wnt signaling in colorectal cancer. Nat Genet 2004;36:417–22.[CrossRef][Medline]
8. Rosenberg DW, Yang S, Pleau DC et al . Mutations in BRAF and KRAS differentially distinguish serrated versus non-serrated hyperplastic aberrant crypt foci in humans. Cancer Res 2007;67:3551–4.
9. Corpet DE Pierre F. How good are rodent models of carcinogenesis in predicting efficacy in humans? A systematic review and meta-analysis of colon chemoprevention in rats, mice, and men. Eur J Cancer 2005;41:1911–22.[CrossRef][Medline]
10. Gupta AK, Pretlow TP, Schoen RE. Aberrant crypt foci: what we know and what we need to know. Clin Gastroenterol Hepatol 2007;5:526–33.[CrossRef][Medline]
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