ASPIRIN/FOLATE PREVENTION OF LARGE BOWEL POLYPS

Summary

Principal Investigator: JOHN ANTHONY BARON
Abstract: DESCRIPTION (provided by applicant): This application is for the renewal of CA059005, supporting a multicenter, randomized, double blind, placebo controlled trial of aspirin and/or folate supplementation for the prevention of colorectal adenomas. The study was motivated by extensive epidemiological and preclinical data suggesting the efficacy of these interventions. The treatment phase of the trial has been completed, and we now propose final clinical follow- up of subjects and biological measurements that will help clarify the study findings. At enrollment, each study subject had a recent large bowel adenoma, with no known polyps remaining in the bowel. Subjects were randomized in a 2 x 3 factorial manner to folic acid (1 mg or placebo daily) and to aspirin (325 mg, 81 mg or placebo daily). Follow-up colonoscopies were scheduled for approximately 3 years after study entry;subsequent examinations followed clinician recommendations (typically 3 or 5-years later). Aspirin treatment was for three years;subjects were invited to maintain randomized folic acid treatment for an additional colonoscopic surveillance cycle. (74% of subjects agreed.) Over the 3-year treatment period, 81 mg aspirin reduced the risk of all adenomas (RR = 0.83 (95% CI, 0.70-0.98) and of advanced lesions (tubulovillous or villous adenomas, those at least 1 cm in diameter, or with severe dysplasia or invasive cancer, RR = 0.59, 95% CI 0.38-0.92). However, 325 mg aspirin did not have significant effects. The reasons for this dose-response pattern are not clear, but may relate to the broad effect of aspirin in reducing production of both pro-carcinogenic and anti-carcinogenic prostaglandins at various doses. Folic acid supplementation had no effect during the first three years of treatment, but showed some evidence of harm during the next surveillance cycle, when the RR for advanced lesions was 1.67 (95% CI 1.00-2.80) and the RR for 3 or more adenomas was 2.32 (95% CI 1.23-4.35). Risk of prostate cancer was also increased. These findings could be a consequence of the high folate intake in subjects randomized to folic acid or could reflect differences between the biological effects of the natural, dietary folates and those of the synthetic, unmetabolized folic acid used in supplements and food fortification. We now propose to investigate the evolution of the increased adenoma risks associated with folic acid supplementation by following subjects for at least one colonoscopic surveillance cycle after randomized folic acid treatment ended. Using blood specimens drawn about 3 years after study entry, we will assay unmetabolized folic acid as well as the main natural folate, 5-methyl-tetrahydrofolate, to assess their separate effects on adenoma risk. To study the aspirin effects, we will assay urinary PGE-M (the main metabolite of PGE2, strongly associated with carcinogenesis in the large bowel) and urinary PGI-M (the main metabolite of prostacyclin, a likely anti-carcinogenic prostaglandin). We will also explore whether aspirin-triggered lipoxins - recently identified anti-inflammatory eicosanoids - played a role in the chemopreventive effects of aspirin.
Funding Period: 1993-09-30 - 2014-07-31
more information: NIH RePORT

Top Publications

  1. ncbi Ornithine decarboxylase polymorphism modification of response to aspirin treatment for colorectal adenoma prevention
    Elizabeth L R Barry
    Department of Community and Family Medicine, Dartmouth Medical School, 46 Centerra Parkway, Ste 300, Lebanon, NH 03766, USA
    J Natl Cancer Inst 98:1494-500. 2006
  2. pmc Circulating folate, vitamin B12, homocysteine, vitamin B12 transport proteins, and risk of prostate cancer: a case-control study, systematic review, and meta-analysis
    Simon M Collin
    Department of Social Medicine, University of Bristol, Bristol, United Kingdom
    Cancer Epidemiol Biomarkers Prev 19:1632-42. 2010
  3. pmc Baseline plasma total homocysteine and adenoma recurrence: results from a double blind randomized clinical trial of aspirin and folate supplementation
    A Joan Levine
    USC Keck School of Medicine, Department of Preventive Medicine, Genetic Epidemiology, NRT 1450 Biggy Street Room 1509A, Los Angeles, CA 90033, USA
    Cancer Epidemiol Biomarkers Prev 19:2541-8. 2010
  4. pmc Association between folate levels and CpG Island hypermethylation in normal colorectal mucosa
    Kristin Wallace
    Department of Medicine, Dartmouth Medical School, Evergreen Center, Lebanon, NH 03756, USA
    Cancer Prev Res (Phila) 3:1552-64. 2010
  5. pmc Folic acid and prevention of colorectal adenomas: a combined analysis of randomized clinical trials
    Jane C Figueiredo
    Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
    Int J Cancer 129:192-203. 2011
  6. pmc Variants downstream of the ornithine decarboxylase gene influence risk of colorectal adenoma and aspirin chemoprevention
    Elizabeth L Barry
    Department of Community and Family Medicine, Dartmouth Medical School, 46 Centerra Parkway, Suite 300, Lebanon, NH 03766, USA
    Cancer Prev Res (Phila) 4:2072-82. 2011
  7. pmc Aspirin in the chemoprevention of colorectal neoplasia: an overview
    Andrew T Chan
    Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit St, Boston, MA 02114, USA
    Cancer Prev Res (Phila) 5:164-78. 2012
  8. pmc CYP2C9 variants increase risk of colorectal adenoma recurrence and modify associations with smoking but not aspirin treatment
    Elizabeth L Barry
    Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
    Cancer Causes Control 24:47-54. 2013
  9. pmc One-year risk for advanced colorectal neoplasia: U.S. versus U.K. risk-stratification guidelines
    Maria Elena Martinez
    Moores Cancer Center, University of California, San Diego, 3855 Health Sciences Drive 0901, La Jolla, CA 92093 0901, USA
    Ann Intern Med 157:856-64. 2012
  10. pmc Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50,000 individuals
    Stein Emil Vollset
    Norwegian Institute of Public Health and Department of Public Health and Primary Health Care, University of Bergen, Bergen, Norway
    Lancet 381:1029-36. 2013

Research Grants

Detail Information

Publications26

  1. ncbi Ornithine decarboxylase polymorphism modification of response to aspirin treatment for colorectal adenoma prevention
    Elizabeth L R Barry
    Department of Community and Family Medicine, Dartmouth Medical School, 46 Centerra Parkway, Ste 300, Lebanon, NH 03766, USA
    J Natl Cancer Inst 98:1494-500. 2006
    ..Previous research suggests that the G315A single-nucleotide polymorphism in the ornithine decarboxylase (ODC) gene may be a genetic marker for risk of colorectal neoplasia and may also modify the association of aspirin use with risk...
  2. pmc Circulating folate, vitamin B12, homocysteine, vitamin B12 transport proteins, and risk of prostate cancer: a case-control study, systematic review, and meta-analysis
    Simon M Collin
    Department of Social Medicine, University of Bristol, Bristol, United Kingdom
    Cancer Epidemiol Biomarkers Prev 19:1632-42. 2010
    ..Disturbed folate metabolism is associated with an increased risk of some cancers. Our objective was to determine whether blood levels of folate, vitamin B(12), and related metabolites were associated with prostate cancer risk...
  3. pmc Baseline plasma total homocysteine and adenoma recurrence: results from a double blind randomized clinical trial of aspirin and folate supplementation
    A Joan Levine
    USC Keck School of Medicine, Department of Preventive Medicine, Genetic Epidemiology, NRT 1450 Biggy Street Room 1509A, Los Angeles, CA 90033, USA
    Cancer Epidemiol Biomarkers Prev 19:2541-8. 2010
    ..It is uncertain whether plasma tHcy is associated with risk at the low levels common in a folate-fortified population...
  4. pmc Association between folate levels and CpG Island hypermethylation in normal colorectal mucosa
    Kristin Wallace
    Department of Medicine, Dartmouth Medical School, Evergreen Center, Lebanon, NH 03756, USA
    Cancer Prev Res (Phila) 3:1552-64. 2010
    ..These data have important implications regarding the safety of supplementary folate administration in healthy adults, given the hypothesis that methylation in normal mucosa may predispose to colorectal neoplasia...
  5. pmc Folic acid and prevention of colorectal adenomas: a combined analysis of randomized clinical trials
    Jane C Figueiredo
    Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
    Int J Cancer 129:192-203. 2011
    ..7% vs. 0.5%, p = 0.002). In conclusion, after up to 3.5 years of folic acid use, there is no clear decrease or increase in the occurrence of new adenomas in patients with a history of adenoma...
  6. pmc Variants downstream of the ornithine decarboxylase gene influence risk of colorectal adenoma and aspirin chemoprevention
    Elizabeth L Barry
    Department of Community and Family Medicine, Dartmouth Medical School, 46 Centerra Parkway, Suite 300, Lebanon, NH 03766, USA
    Cancer Prev Res (Phila) 4:2072-82. 2011
    ..Our findings suggest that common genetic variants located downstream (3') of the ODC gene influence risk of colorectal adenoma and may also impact the efficacy of aspirin chemoprevention...
  7. pmc Aspirin in the chemoprevention of colorectal neoplasia: an overview
    Andrew T Chan
    Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit St, Boston, MA 02114, USA
    Cancer Prev Res (Phila) 5:164-78. 2012
    ..The optimal dose to use for cancer prevention and the precise mechanism underlying aspirin's anticancer effect require further investigation...
  8. pmc CYP2C9 variants increase risk of colorectal adenoma recurrence and modify associations with smoking but not aspirin treatment
    Elizabeth L Barry
    Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
    Cancer Causes Control 24:47-54. 2013
    ..Two common nonsynonymous polymorphisms in CYP2C9 are associated with reduced enzyme activity: CYP2C9*2 (rs1799853, R144C) and CYP2C9*3 (rs1057910, I359L)...
  9. pmc One-year risk for advanced colorectal neoplasia: U.S. versus U.K. risk-stratification guidelines
    Maria Elena Martinez
    Moores Cancer Center, University of California, San Diego, 3855 Health Sciences Drive 0901, La Jolla, CA 92093 0901, USA
    Ann Intern Med 157:856-64. 2012
    ..Guidelines from the United Kingdom and the United States on risk stratification after polypectomy differ, as do recommended surveillance intervals...
  10. pmc Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50,000 individuals
    Stein Emil Vollset
    Norwegian Institute of Public Health and Department of Public Health and Primary Health Care, University of Bergen, Bergen, Norway
    Lancet 381:1029-36. 2013
    ..We aimed to assess any effects on site-specific cancer rates in the randomised trials of folic acid supplementation, at doses higher than those from fortification...
  11. pmc Antagonistic effects of aspirin and folic acid on inflammation markers and subsequent risk of recurrent colorectal adenomas
    Gloria Y F Ho
    Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    J Natl Cancer Inst 101:1650-4. 2009
    ..Low-dose aspirin (325 mg/d) is beneficial in stabilizing CRP levels, which may be abrogated by folate. Nevertheless, inflammation markers do not mediate the chemopreventive effect of aspirin on colorectal adenomas...
  12. pmc Cyclooxygenase-2 polymorphisms, aspirin treatment, and risk for colorectal adenoma recurrence--data from a randomized clinical trial
    Elizabeth L Barry
    Department of Community and Family Medicine, Dartmouth Medical School, Suite 300, Evergreen Center, 46 Centerra Parkway, Lebanon, NH 03756, USA
    Cancer Epidemiol Biomarkers Prev 18:2726-33. 2009
    ..These results support the hypothesis that COX-2 plays a role in the etiology of colon cancer and may be a target for aspirin chemoprevention and warrant further investigation in other colorectal adenoma and cancer populations...
  13. ncbi Aspirin may be more effective in preventing colorectal adenomas in patients with higher BMI (United States)
    Sangmi Kim
    Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC 27599 7555, USA
    Cancer Causes Control 17:1299-304. 2006
    ..The more pronounced effect of 325 mg aspirin in individuals with higher BMI suggests a possible protective role of anti-inflammatory aspirin against increased adipose-driven cytokines among obese subjects...
  14. ncbi Folic acid for the prevention of colorectal adenomas: a randomized clinical trial
    Bernard F Cole
    Department of Community and Family Medicine, Dartmouth Medical School, Hanover, NH, USA
    JAMA 297:2351-9. 2007
    ..Laboratory and epidemiological data suggest that folic acid may have an antineoplastic effect in the large intestine...
  15. pmc Vitamins B2, B6, and B12 and risk of new colorectal adenomas in a randomized trial of aspirin use and folic acid supplementation
    Jane C Figueiredo
    Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Harlyne J Norris Cancer Research Tower, 1450 Biggy Street Room 1509B, Los Angeles CA 90033, USA
    Cancer Epidemiol Biomarkers Prev 17:2136-45. 2008
    ..In this study, we examined the associations between dietary and circulating plasma levels of vitamins B(2), B(6), and B(12) and risk colorectal adenomas...
  16. pmc MTHFR genotype and colorectal adenoma recurrence: data from a double-blind placebo-controlled clinical trial
    A Joan Levine
    Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
    Cancer Epidemiol Biomarkers Prev 17:2409-15. 2008
    ..Our findings indicate that the MTHFR genotype does not change adenoma risk in a manner similar to its effect on colorectal cancer, and does not modify the effect of folate supplementation on metachronous adenoma risk...
  17. pmc Colorectal adenomas in a randomized folate trial: the role of baseline dietary and circulating folate levels
    Jane C Figueiredo
    Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA
    Cancer Epidemiol Biomarkers Prev 17:2625-31. 2008
    ..Our findings support the idea that although moderate doses of folate may be protective compared with deficiency, at some point of sufficiency, supplementation provides no additional benefit...
  18. pmc Association between body mass index and colorectal neoplasia at follow-up colonoscopy: a pooling study
    Elizabeth T Jacobs
    Arizona Cancer Center, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ 85724 5024, USA
    Am J Epidemiol 169:657-66. 2009
    ..Our results provide further support for the association between BMI and metachronous colorectal adenomas, particularly among men, thereby indicating that body size may affect colorectal carcinogenesis at comparatively early stages...
  19. pmc A pooled analysis of advanced colorectal neoplasia diagnoses after colonoscopic polypectomy
    Maria Elena Martinez
    Arizona Cancer Center, University of Arizona, Tucson, Arizona, USA
    Gastroenterology 136:832-41. 2009
    ..Limited data exist regarding the actual risk of developing advanced adenomas and cancer after polypectomy or the factors that determine risk...
  20. pmc Folic acid and risk of prostate cancer: results from a randomized clinical trial
    Jane C Figueiredo
    Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, USA
    J Natl Cancer Inst 101:432-5. 2009
    ..These findings highlight the potential complex role of folate in prostate cancer and the possibly different effects of folic acid-containing supplements vs natural sources of folate...
  21. pmc Global DNA hypomethylation (LINE-1) in the normal colon and lifestyle characteristics and dietary and genetic factors
    Jane C Figueiredo
    Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
    Cancer Epidemiol Biomarkers Prev 18:1041-9. 2009
    ..Little is known about the relationships between global hypomethylation and lifestyle, demographics, dietary measures, and genetic factors...
  22. pmc Using the results of a baseline and a surveillance colonoscopy to predict recurrent adenomas with high-risk characteristics
    Douglas J Robertson
    Veterans Affairs Outcomes Group, Veterans Affairs Medical Center, Section of Gastroenterology, White River Junction, Vermont 05009, USA
    Ann Intern Med 151:103-9. 2009
    ..Suggested intervals for postpolypectomy surveillance colonoscopy are currently based on the adenoma findings from the most recent examination...
  23. pmc The association of lifestyle and dietary factors with the risk for serrated polyps of the colorectum
    Kristin Wallace
    Department of Community and Family Medicine, Dartmouth Medical School, Hanover, New Hamsphire, USA
    Cancer Epidemiol Biomarkers Prev 18:2310-7. 2009
    ..Our results suggest that several common lifestyle and dietary variables are associated with risk for serrated polyps, and some of these may differ for the right and left colorectum...
  24. pmc Identification and characterization of functional risk variants for colorectal cancer mapping to chromosome 11q23.1
    Michela Biancolella
    Department of Preventive Medicine
    Hum Mol Genet 23:2198-209. 2014
    ..These data imply that rs10891246 and rs7130173 are functional SNPs mapping to 11q23.1 and that C11orf53, C11orf92 and C11orf93 represent novel candidate target genes involved in CRC etiology. ..

Research Grants30

  1. Biomathematical Evaluation of Colon Cancer Screening and Prevention
    GEORG E LUEBECK; Fiscal Year: 2013
    ..The goal of this renewal is to further explore, via a biomathematical description of the natural history of CRC, how screening and interventions can be applied most effectively to reduce the mortality associated with CRC ..
  2. Inflammation and Colorectal Neoplasia
    Andrew T Chan; Fiscal Year: 2013
    ..S., its optimal use in light of its toxicities remains uncertain. We will investigate the role of inflammation in colorectal carcinogenesis to define predictors of susceptibility for tailored preventative strategies. ..
  3. Colorectal Chemoprevention with Calcium and Vitamin D
    JOHN ANTHONY BARON; Fiscal Year: 2013
    ....
  4. Methods for Pathway Modeling with Application to Folate
    Duncan C Thomas; Fiscal Year: 2013
    ....
  5. A Cohort Study of Sessile Serrated Polyps and Subsequent Colorectal Neoplasia
    Polly A Newcomb; Fiscal Year: 2013
    ....
  6. Personalized Prevention of Colorectal Cancer
    Chang Yu; Fiscal Year: 2013
    ....
  7. Comparative Mechanisms of Cancer Chemoprevention
    Roderick H Dashwood; Fiscal Year: 2013
    ..This application is innovative and timely in bridging basic mechanisms, preclinical models, and human studies of epigenetics and diet. ..
  8. DRUG ABUSE RESEARCH CENTER
    Solomon H Snyder; Fiscal Year: 2013
    ....
  9. A MULTILEVEL APPROACH TO ENERGY BALANCE AND CANCER ACROSS THE LIFECOURSE
    Graham A Colditz; Fiscal Year: 2013
    ..To address these aims, we propose four research projects and five cores that form a cohesive, transdisciplinary center focused on research, training/career development, and dissemination. ..
  10. Selenium Colorectal Cancer Chemoprevention Trials
    PATRICIA ANN THOMPSON; Fiscal Year: 2013
    ..In secondary analyses, we will investigate whether or not baseline Se levels, genetic background, and/or use of low-dose aspirin modify Se effects on CRA occurrence or risk for T2D. ..
  11. Aspirin-PC for Chemoprevention of Colorectal Cancer
    Lenard M Lichtenberger; Fiscal Year: 2013
    ..These studies, therefore will establish the feasibility of using PL2200 for chemoprevention while lowering the risk of adverse GI events, resulting in the development of an efficacious and safe drug for prevention of colorectal cancer. ..
  12. PACIFIC OVARIAN CANCER RESEARCH CONSORTIUM
    NICOLE DENISE URBAN; Fiscal Year: 2013
    ..abstract_text> ..