Correspondence

Effect of Aspirin or Resistant Starch on Colorectal Neoplasia in the Lynch Syndrome

N Engl J Med 2009; 360:1461-1463April 2, 2009

Article

To the Editor:

In their report on the Colorectal Adenoma/Carcinoma Prevention Programme 2 (CAPP2) study, Burn et al. (Dec. 11 issue)1 conclude that the use of aspirin, resistant starch, or both had no effect in reducing the risk of adenoma and carcinoma among carriers of the Lynch syndrome, on the basis of Cox proportional-hazards models adjusted for age and sex. However, the effect of the genotype-by-environment interaction on the risk of colorectal neoplasia was neglected.

According to two studies,2,3 germline mutations or polymorphisms in DNA mismatch-repair genes may be associated with a significant difference in the risk of colorectal cancer. The effectiveness of adjustment for age and sex in the study by Burn et al. may not be sufficient; the type of mutation should have been taken into account in the multivariable analysis of potential risk factors.

In addition, the authors provide no information about cigarette smoking in the study population. This may lead to bias if there is a difference in exposure between the groups, since cigarette smoking contributes to microsatellite instability in colon tumors and seems to increase the risk of Lynch syndrome–associated colorectal tumors.2,4,5 It would be more informative if cigarette smoking could be adjusted for in the statistical analysis.

Feng Yang, M.D., Ph.D.
Chen Jin, M.D., Ph.D.
Deliang Fu, M.D., Ph.D.
Huashan Hospital, Shanghai 200040, China

5 References

1. 1

   Burn J, Bishop DT, Mecklin JP, et al. Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome. N Engl J Med 2008;359:2567-2578
   Full Text | Web of Science | Medline

2. 2

   Watson P, Ashwathnarayan R, Lynch HT, Roy HK. Tobacco use and increased colorectal cancer risk in patients with hereditary nonpolyposis colorectal cancer (Lynch syndrome). Arch Intern Med 2004;164:2429-2431
   CrossRef | Web of Science | Medline

3. 3

   Campbell PT, Curtin K, Ulrich C, et al. Mismatch repair polymorphisms and risk of colon cancer, tumor microsatellite instability, and interactions with lifestyle factors. Gut 2008 June 3 (Epub ahead of print).
   

4. 4

   Slattery ML, Curtin K, Anderson K, et al. Associations between cigarette smoking, lifestyle factors, and microsatellite instability in colon tumors. J Natl Cancer Inst 2000;92:1831-1836
   CrossRef | Web of Science | Medline

5. 5

   Diergaarde B, Braam H, Vasen HF, et al. Environmental factors and colorectal tumor risk in individuals with hereditary nonpolyposis colorectal cancer. Clin Gastroenterol Hepatol 2007;5:736-742
   CrossRef | Web of Science | Medline

To the Editor:

Burn et al. report that resistant starch did not suppress colorectal neoplasms in patients with the Lynch syndrome. We suggest that this conclusion needs considerable qualification. Resistant starch is the fraction of ingested starch that reaches the large bowel, where it affects bacterial fermentation products in the colon, especially short-chain fatty acids.1 Laboratory studies indicate that resistant starch provides protection against experimental colorectal cancer2 and diet-induced colonocyte genetic damage3 through these acids. Burn et al. report that their subjects consumed 30 g of starch per day, implying that this was the resistant-starch intake. However, their article shows that the supplement provided only 9 g of resistant starch per day, and no data are given to assess its effect on the colon. Studies in humans (e.g., the study reported by Noakes et al.4) show that more than 20 g of resistant starch per day is needed to increase fecal levels of short-chain fatty acids. We suggest that resistant-starch consumption in the study by Burn et al. was insufficient to affect the production of short-chain fatty acids.

David L. Topping, Ph.D.
Anthony R. Bird, Ph.D.
Commonwealth Scientific and Industrial Research Organisation, Adelaide, SA 5000, Australia
david.topping@csiro.au

Graeme P. Young, M.D.
Flinders Medical Centre, Bedford Park, SA 5042, Australia

4 References

1. 1

   Topping DL, Clifton PM. Short-chain fatty acids and human colonic function: roles of resistant starch and nonstarch polysaccharides. Physiol Rev 2001;81:1031-1064
   Web of Science | Medline

2. 2

   Le Leu RK, Brown IL, Hu Y, Esterman A, Young GP. Suppression of azoxymethane-induced colon cancer development in rats by dietary resistant starch. Cancer Biol Ther 2007;6:1621-1626
   CrossRef | Web of Science | Medline

3. 3

   Toden S, Bird AR, Topping DL, Conlon MA. High red meat diets induce greater numbers of colonic DNA double-strand breaks than white meat in rats: attenuation by high-amylose maize starch. Carcinogenesis 2007;28:2355-2362
   CrossRef | Web of Science | Medline

4. 4

   Noakes M, Clifton PM, Nestel PJ, Le Leu R, McIntosh G. Effect of high-amylose starch and oat bran on metabolic variables and bowel function in subjects with hypertriglyceridemia. Am J Clin Nutr 1996;64:944-951
   Web of Science | Medline

Author/Editor Response

In response to Yang et al.: the basic concept of a randomized trial is to guard against imbalances of potential confounders such as smoking or differences in risks according to the type of mutation. To provide further protection against an imbalance, we performed block randomization according to geographic group, as we discuss in our report. Although we cannot absolutely guarantee that there is no imbalance of any measured or unmeasured confounder, the large sample size and absence of any evidence of a treatment effect argue against an important imbalance. In terms of different effects of germline mismatch-repair mutations on the risk of a neoplasm, analysis of screening histories before enrollment in CAPP2 showed no evidence of major mutation-specific differences, at least for the common (founder) mutations1 (and unpublished data).

In response to Topping et al.: the 30 g of resistant starch (Novelose, National Starch and Chemical) that we used is thought to deliver more than 13.2 g of resistant starch. This is in addition to the estimate of 4.1 g per day in the typical diet, or an estimated total of 17.3 g per day on average.

We were constrained by the pragmatic challenge of being able to deliver a powder supplement daily for up to 4 years. Novelose was used because it was relatively easy to mix with a variety of foods. The dose used was as much as we thought we could ask participants to add to their diet. There were 97 withdrawals on the basis of “minor disorders,” as compared with 76 among participants receiving placebo starch. The difference was attributable to symptoms of bloating, suggesting that we had delivered a clinically significant dose. Analysis of crypt-cell proliferation and dissected crypt dimensions in mucosal-biopsy specimens (unpublished data) revealed no difference between the placebo group and either of the treatment groups.

We agree that the literature supports the case for an antineoplastic effect of resistant starch. The lack of support for this hypothesis in our trial may simply reflect the major challenge of testing nutritional chemoprevention with the use of the traditional approach of a randomly assigned supplement.

D. Timothy Bishop, M.D.
Leeds University, Leeds LS9 7TF, United Kingdom

John Burn, M.D.
John C. Mathers, Ph.D.
Newcastle University, Newcastle upon Tyne NE1 3BZ, United Kingdom
john.burn@newcastle.ac.uk

1 References

1. 1

   Liljegren A, Barker G, Elliott F, 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 2008;26:3434-3439
   CrossRef | Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   Emily Steinhagen, Arnold J. Markowitz, José G. Guillem. (2010) How to Manage a Patient with Multiple Adenomatous Polyps. Surgical Oncology Clinics of North America 19:4, 711-723
   CrossRef