ASPIRIN/FOLATE PREVENTION OF LARGE BOWEL POLYPS
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
- Ornithine decarboxylase polymorphism modification of response to aspirin treatment for colorectal adenoma preventionElizabeth 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...
- Circulating folate, vitamin B12, homocysteine, vitamin B12 transport proteins, and risk of prostate cancer: a case-control study, systematic review, and meta-analysisSimon 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...
- Baseline plasma total homocysteine and adenoma recurrence: results from a double blind randomized clinical trial of aspirin and folate supplementationA 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...
- Association between folate levels and CpG Island hypermethylation in normal colorectal mucosaKristin 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...
- Folic acid and prevention of colorectal adenomas: a combined analysis of randomized clinical trialsJane 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...
- Variants downstream of the ornithine decarboxylase gene influence risk of colorectal adenoma and aspirin chemopreventionElizabeth 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...
- Aspirin in the chemoprevention of colorectal neoplasia: an overviewAndrew 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...
- CYP2C9 variants increase risk of colorectal adenoma recurrence and modify associations with smoking but not aspirin treatmentElizabeth 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)...
- One-year risk for advanced colorectal neoplasia: U.S. versus U.K. risk-stratification guidelinesMaria 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...
- Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50,000 individualsStein 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...
- Antagonistic effects of aspirin and folic acid on inflammation markers and subsequent risk of recurrent colorectal adenomasGloria 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...
- Cyclooxygenase-2 polymorphisms, aspirin treatment, and risk for colorectal adenoma recurrence--data from a randomized clinical trialElizabeth 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...
- 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...
- Folic acid for the prevention of colorectal adenomas: a randomized clinical trialBernard 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...
- Vitamins B2, B6, and B12 and risk of new colorectal adenomas in a randomized trial of aspirin use and folic acid supplementationJane 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...
- MTHFR genotype and colorectal adenoma recurrence: data from a double-blind placebo-controlled clinical trialA 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...
- Colorectal adenomas in a randomized folate trial: the role of baseline dietary and circulating folate levelsJane 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...
- Association between body mass index and colorectal neoplasia at follow-up colonoscopy: a pooling studyElizabeth 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...
- A pooled analysis of advanced colorectal neoplasia diagnoses after colonoscopic polypectomyMaria 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...
- Folic acid and risk of prostate cancer: results from a randomized clinical trialJane 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...
- Global DNA hypomethylation (LINE-1) in the normal colon and lifestyle characteristics and dietary and genetic factorsJane 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...
- Using the results of a baseline and a surveillance colonoscopy to predict recurrent adenomas with high-risk characteristicsDouglas 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...
- The association of lifestyle and dietary factors with the risk for serrated polyps of the colorectumKristin 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...
- Identification and characterization of functional risk variants for colorectal cancer mapping to chromosome 11q23.1Michela 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. ..
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