Adenoma Prevention Research Articles

Aspirin in the Chemoprevention of Colorectal Neoplasia: An Overview

Considerable evidence supports the effectiveness of aspirin for chemoprevention of colorectal cancer (CRC) in addition to its well-established benefits in the prevention of vascular disease. Epidemiologic studies have consistently observed an inverse association between aspirin use and risk of CRC. A recent pooled analysis of a long-term posttrial follow-up of nearly 14,000 patients from four randomized, cardiovascular disease prevention trials showed that daily aspirin treatment for about five years was associated with a 34% reduction in 20-year CRC mortality. A separate metaanalysis of nearly 3,000 patients with a history of colorectal adenoma or cancer in four randomized adenoma prevention trials showed that aspirin reduced the occurrence of advanced adenomas by 28% and any adenoma by 17%. Aspirin has also been shown to be beneficial in a clinical trial of patients with Lynch syndrome, a hereditary CRC syndrome; in those treated with aspirin for at least two years, there was a 50% or more reduction in the risk of CRC commencing five years after randomization and after aspirin had been discontinued. A few observational studies have shown an increase in survival among patients with CRC who use aspirin. Taken together, these findings strengthen the case for consideration of long-term aspirin use in CRC prevention. Despite these compelling data, there is a lack of consensus about the balance of risks and benefits associated with long-term aspirin use, particularly in low-risk populations. The optimal dose to use for cancer prevention and the precise mechanism underlying aspirin's anticancer effect require further investigation.

Determinants of bile acids.

632 Background: Several epidemiological studies have demonstrated an association between bile acids (BA) and colorectal cancer. Despite this evidence, there are limited studies that examine the determinants of bile acids in humans. We conducted a secondary, cross-sectional analysis on 735 adenoma formers from a phase III adenoma prevention trial of ursodeoxycholic acid (URSO) who provided a fecal sample at their baseline visit. Methods: Fecal measures of primary bile acids cholic acid (CA) and chenodoxycholic acid (CDCA), as well as secondary bile acids, deoxycholic acid (DCA), lithocholic (LCA) were the outcome variables of interest. Dietary, non-dietary, medication use, genetic variation in the CYP7A1 gene (as single nucleotide polymorphisms (SNPs) and haplotypes), and physical activity, and characteristics of baseline adenoma were evaluated as correlates of fecal BAs. We used maximum likelihood methods to incorporate left-censoring in the BAs that had concentrations below the detection limit (BDL). These log-normal parametric survival models were used to fit potential predictors of fecal BA levels, stratifying by sex. The Akaike information criterion (AIC) was used to choose the best predictive model from each BA outcome. Model accuracy was assessed using leave-one-out cross validation and a likelihood-based measure of R2 and the Brier score. Results: LDL and cholesterol were predictors for primary bile acid CDCA in men and women, as was the use of pain medication (use of medication lowered BA levels). Genetic variation in CYP7A1 (as haplotypes and individual SNP's) was a significant determinant of CA level in both men and women. BMI was an important predictor for both men and women for DCA and CA. Presentation with tubular-villous histology was associated with LCA levels whereas proximal adenoma was an important predictor for CA levels, in men and women. Conclusions: This secondary analysis of a uniquely large dataset validates previous studies that suggest lifestyle and genetic factors influence colonic exposure to carcinogenic BAs. These findings also importantly highlight gender-specific differences in BA determinants that may explain colorectal cancer incidence differences between men and women.

Bowel cancer chemoprevention - ready for the clinic?

In 1988 Gabriel Kune of Melbourne published a seminal paper reporting a negative association of the use of non-steroidal anti-inflammatory drugs such as aspirin and colorectal cancer. This prompted a deluge of case control and cohort studies, all but one of which confirmed the finding. The conclusion of these observational studies was that regular aspirin users had half as many cancers. Four randomised controlled trials (RCTs) using adenoma prevention as their endpoint gave a more mixed result but meta-analysis supported benefit though at a more modest level. Rothwell and colleagues returned to the cancer registry to look up people who took part in the early vascular disease prevention trials using aspirin and found that about 7 years after starting the trial, those who had been given aspirin started to show a reduced cancer rate and a reduced cancer mortality. The CAPP1 study recruited and followed 133 carriers of Familial Adenomatous Polyposis to test 600mg aspirin and showed a weak effect on adenoma formation and evidence of fewer large polyps. CAPP2 recruited 1009 carriers of Lynch syndrome resulting from a germline defect in a mismatch repair gene, and tested 600mg aspirin and/or 30g Novelose, a resistant starch, over four years. Australia was a key contributor to this international trial. At the end of intervention phase there was no difference in overall colorectal neoplasia in any of the groups. Double blind post trial follow-up has revealed a dramatic effect; at a mean of 5 years from randomisation, those who had been taking the active aspirin have significantly fewer colorectal cancers. Confining analysis to the primary endpoint of colorectal cancer after a minimum of 2 years on aspirin revealed 60% fewer cancers. A similar effect was evident when all Lynch syndrome cancers were considered (paper in press). All people at risk of Lynch syndrome should be advised to take aspirin and their physicians should take usual measures to reduce the recognised burden of side effects. This should include consideration of eradication of H. pylori and use of a regular proton pump inhibitor if there is evidence of gastric erosion. CAPP3 will compare three different doses of enteric coated aspirin: 100mg, 300mg and 600mg in proven gene carriers between 18 and 60 with treatment for a minimum of 5 years and unlimited follow-up. In our present state of knowledge a pragmatic position is to recommend immediate introduction of a low dose daily aspirin (75-100mg) and encouragement to log on to the new CAPP3 website to keep abreast of the emerging story. This dose will not preclude joining the RCT in 2012 and will allow us to explore methods to personalise the aspirin dose in future by assessment of the genetic basis of aspirin sensitivity and resistance.

Aspirin for the prevention of colorectal adenomas: a systematic review

Objective To assess the effect of aspirin for the chemoprevention of colorectal adenomas by meta analysis of the published literature.Methods Cochrane strategy in combination with manual search was used to identify previously published randomized controlled trials by searching PubMed,EMBase,Cochrane Library,China Journal Full-text Database(CNKI),Chinese Scientific Journal Full-text Database (CSJD) and Chinese Biomedical Literature Database (CBM).Results Six randomized controlled trials involving a total of 2 858 patients were studied.Of the six trials,two trials were performed in China,four trials were in the Europe and the United States.Some sufficient evidence were found to support that aspirin could prevent of colorectal adenomas compared with placebo group ( P =0.003,RR =0.66,95％ CI:0.50-0.86).No adaquate evidence supported the role of aspirin in the prevention of development of colorectal cancer ( P =0.29,RR =0.65,95％ CI:0.30-1.44).High-dose aspirin ( P =0.10,RR =0.85,95％ CI:0.71-1.30 ) and low-dose aspirin could prevent colorectal adenomas compared with placebo group( P =0.02,RR =0.57,95％ CI:0.36-0.90),and a dose-dependent associtation was found.The risk of stroke was higher in any dose of aspirin compared with placebo group ( P =0.04),and the risks of adverse events had no significant differences in all groups.Conclusion Aspirin might prevent the development of colorectal adenomas in individuals,but could not prevent the colorectal cancer. Key words: Aspirin; Chemprevention; Colorectal neoplasms; Meta-analysis

Abstract CN01-03: Moving from molecular biology to clinical prevention in colorectal cancer

Abstract Cancers of the gastrointestinal tract are among the most common cancers affecting people around the world. Colorectal cancer, stomach cancer, and liver cancer are the most prevalent GI cancers and are not effectively treated with currently available medical therapies, which has led to intense efforts to try to prevent these cancers from occurring. These efforts have led to a better understanding of the molecular and cellular biology of the tumors and to the identification of clinically effective chemoprevention agents for at least some of these cancers. Our understanding of the molecular biology of colorectal cancer and how it interfaces with prevention strategies is arguably more advanced than it is for most other tumors types. Thus, the focus of this session will be on colorectal adenoma and cancer prevention. The molecular biology related to clinically effective primary and secondary chemoprevention will be discussed as will promising future strategies based on our understanding of the molecular pathogenesis of colorectal cancer. Colorectal cancer is known to evolve through a series of histologic progression steps called the polyp cancer sequence. These histologic steps include early adenomas, advanced adenomas, early adenocarcinomas and advanced adenocarcinomas. These steps result from the accumulation of genetic and epigenetic alterations in colon epithelial cells, which drive the initiation and progression of colorectal cancers. Genes identified to be mutant early in the polyp-cancer sequence include APC, KRAS, and BRAF, and these mutant genes are logical targets for chemoprevention strategies. With regards to epigenetic alterations, aberrant DNA CpG island hypermethylation has been shown to occur at the earliest steps of polyp formation. The consequence of the genetic and epigenetic alterations is to deregulate a number of signaling pathways, including the Wnt-APC-ß-catenin pathway, KRAS-MAPK pathway, TGF-ß pathway, and PI3K pathway, and to disrupt metabolic processes in the cells, including glycolysis, proliferation, apoptosis and senescence, and differentiation. Although a large number of drugs, nutritional supplements, and whole foods (ie vegetables, fiber, green tea) have been assessed for their chemoprevention properties, the most robust data is available for NSAIDs, anti-oxidants, calcium, vitamin D, DMFO, and folate. NSAID's inhibit COX-2, an enzyme involved with conversion of arachidonic acid to tumor-promoting prostaglandins that is expressed at high levels in the majority of colon adenomas and cancers. COX-2 is presumably a major target of NSAID's although other non-COX-2 related mechanisms also likely play a role in NSAID mediated chemoprevention. Vitamin D and calcium inhibit cell proliferation and induce differentiation and apoptosis. The effects on the molecular biology of nascent tumor cells is less clear for these agents than it is for NSAID's. The most recent agent shown to be clinically effective for secondary adenoma prevention is DFMO, which inhibits ornithine decarboxylase and affects polyamine production. Folate's role in chemoprevention is unclear at this time in light of data that suggests the timing of its use in relation to tumor initiation may play a major role in whether it inhibits or promotes colon cancer formation. Lastly, anti-oxidants presumably mediate their effects through reducing DNA-damaging free radicals, although clinically they do not appear to be effective chemoprevention agents. The clinical efficacy of some of these candidate agents suggests further efforts to target the molecular mediators of these agents will enhance future chemoprevention strategies. In addition, advances in our understanding of the molecular pathogenesis of colorectal cancer has suggested additional strategies for colorectal cancer chemoprevention, such as drugs that inhibit ß-catenin induced gene expression, etc., that may be effective and selective for the early neoplastic cells. Citation Information: Cancer Prev Res 2011;4(10 Suppl):CN01-03.

C-reactive protein and risk of colorectal adenoma according to celecoxib treatment.

Inflammation, as measured by the circulating inflammatory marker high-sensitivity C-reactive protein (hsCRP), has been associated with cardiovascular disease. However, data about CRP and risk of colorectal cancer have been conflicting. The Adenoma Prevention with Celecoxib (APC) trial showed that the anti-inflammatory drug celecoxib prevents recurrence of colorectal adenoma but increases risk of cardiovascular events. We examined whether serum hsCRP modified these results. We measured hsCRP from serum specimens provided at study entry by patients enrolled in the APC trial. Patients were stratified according to use of low-dose aspirin, randomized to receive 3 years of treatment with placebo, 200-mg-bid celecoxib, or 400-mg-bid celecoxib, and underwent follow-up colonoscopies at years 1 and 3. Among 1,680 patients, the estimated 3-year cumulative incidence of adenoma was 42% for patients with hsCRP <1 mg/L, compared with 43% [relative risk (RR) = 1.02; 95% CI = 0.85-1.22] for hsCRP 1-3 mg/L, and 41% (RR = 1.10; 95% CI = 0.90-1.34) for hsCRP >3 mg/L. The effect of celecoxib on adenoma recurrence did not vary among patients with high (>3 mg/L) compared with low (≤3 mg/L) hsCRP. However, among patients with high hsCRP, the RR of cardiovascular events compared with placebo was 2.27 (95% CI = 0.72-7.14) for those randomized to celecoxib 200-mg-bid and 3.28 (95% CI = 1.09-9.91) for 400-mg-bid. In contrast, among patients with low hsCRP, the corresponding RRs were 0.99 (95% CI = 0.53-1.83) and 1.11 (95% CI = 0.61-2.02). hsCRP may predict risk of celecoxib-associated cardiovascular toxicity but not adenoma recurrence or celecoxib treatment efficacy. Patients with low hsCRP may be a subgroup with a favorable risk-benefit profile for celecoxib chemoprevention.

Chemoprevention – History and general principles

Our current understanding of tumourigenesis suggests that cancer develops as a series of cumulative genetic and epigenetic derangements across time culminating in a clone of cells differing from its population of origin in terms of cellular identity, growth control, and its contextual relationship to its environment. Our increasing knowledge of the timing, sequence, frequency, and specific implications of these changes provides unique opportunities for earlier identification of aberrations and preventive interventions. Here we discuss the fundamentals of cancer prevention including the targets, cohorts, agents, endpoints, mechanistic biomarkers, designs, and strategies employed in preventive drug development. There have been many notable successes in this field such as the identification and development of tamoxifen and raloxifene for breast cancer risk reduction, instillational BCG and valrubicin for treatment of preinvasive bladder cancer, and a variety of topical and systemic agents that effectively treat preinvasive neoplastic lesions of the skin. A variety of null or negative developmental endeavours have occurred as well, including trials of beta-carotene for lung cancer prevention, nutritional modifications for colorectal adenoma prevention, and most recently, selenium and alpha-tocopherol for prostate cancer prevention. A third category of prevention trials can be summarized as investigationally successful, but not achieving regulatory success. The development of finasteride and dutasteride for prostate cancer prevention, and celecoxib for colorectal neoplasia prevention fall into this category. In less than four decades, cancer chemoprevention has transformed from a concept to an achievable reality.

Aspirin and Familial Adenomatous Polyposis: Coming Full Circle

This perspective discusses the clinical trial reported by Burn and colleagues in this issue of the journal (beginning on page 655), which assessed aspirin and resistant starch for the prevention of colorectal adenomas in patients with familial adenomatous polyposis (FAP). The findings are examined in the context of previous clinical trials of aspirin in patients with sporadic adenomas and of sulindac or celecoxib in patients with FAP. This newly reported work raises important considerations of a role for aspirin in the clinical management of FAP patients and adds to considerations of a role for aspirin in the chemoprevention of colorectal cancer among broader populations.

Dietary Patterns and the Risk of Colorectal Adenomas: the Black Women's Health Study

Colorectal adenomas are benign lesions that may be precursors to colorectal cancer. No studies of African American women have investigated dietary patterns and the risk of developing colorectal adenomas. We examined data from the Black Women's Health Study to determine whether dietary patterns are associated with the risk of developing colorectal adenomas. This is a prospective cohort study of 59,000 participants followed biennially since 1995. During 155,414 person-years of follow-up from 1997 to 2007 among women who had had at least one screening colonoscopy, 620 incident cases of colorectal adenomas were identified. By using Cox regression models, we obtained incidence rate ratios (IRR) for colorectal adenoma in relation to quintiles of each of two dietary patterns, adjusting for other colorectal adenoma risk factors. Two dietary patterns, Western and prudent, were utilized to assess the association between dietary intake and adenoma risk. The highest quintile of prudent diet, relative to the lowest quintile, was significantly associated with 34% lower colorectal adenoma risk overall (IRR = 0.66; 95% CI, 0.50-0.88; P(trend) < 0.01). Higher scores on the Western pattern were associated with a higher risk of developing colorectal adenoma (IRR = 1.42; 95% CI, 1.09-1.85 for the highest quintile relative to the lowest; P(trend) = 0.01). Our findings suggest that African American women may be able to reduce their risk of developing colorectal adenomas by following a prudent dietary pattern and avoiding a more Western pattern. A dietary modification could have a strong impact in colorectal adenoma prevention in African American women.

Folic acid and prevention of colorectal adenomas: A combined analysis of randomized clinical trials

Observational data suggest that lower folate status is associated with an increased risk of colorectal neoplasia, implying that folate may be useful as a chemopreventive agent. We conducted a combined analysis of three large randomized trials of folic acid supplementation for the prevention of metachronous adenomas in patients with an adenoma history. Participants included 2,632 men and women who had a history of adenomas randomized to either 0.5 or 1.0 mg/day of folic acid or placebo and who had a follow-up endoscopy 6 to 42 months after randomization [mean = 30.6 (standard deviation = 8.1) months]. We used random-effects meta-analysis to estimate risk ratios (RRs) and 95% confidence intervals (CIs). The RR comparing folic acid versus placebo was 0.98 (95% CI = 0.82-1.17) for all adenomas and 1.06 (95% CI = 0.81-1.39) for advanced lesions. Folic acid was associated with a nonsignificant decreased risk of any adenoma among subjects in the lowest quartile of baseline plasma folate (≤ 11 nmol/L) and no effect among individuals in the highest quartile (> 29 nmol/L, p for trend = 0.17). There was a nonsignificant trend of decreasing risk of any adenoma associated with folic acid supplements with increasing alcohol intake. During the early follow-up reported here, more deaths occurred in the placebo group than in the folic acid group (1.7% 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.

Serum Salicylate Levels and Risk of Recurrent Colorectal Adenomas

Intake of aspirin is associated with reduction in risk of colorectal adenoma and carcinoma. Some plants contain salicylates, and individuals not taking aspirin may have measurable salicylate levels. However, the association between serum salicylate level and recurrence of adenoma in nonusers of aspirin has not been studied. We measured serum salicylate levels in participants in a randomized controlled trial with calcium supplementation for the prevention of colorectal adenomas. Generalized linear models were used to assess the association between serum levels and adenoma risk during the follow-up period of the trial. We did not find an association with recurrence of adenomas or advanced adenomas with serum salicylate levels at year 1 among nonusers of aspirin. There was no effect modification of the chemopreventive effect of calcium supplementation in reducing risk of recurrent adenomas or advanced adenomas. Among nonusers of ASA, serum salicylate levels are not associated with risk of recurrence of adenomas. Serum salicylate levels can be detected in individuals not taking aspirin, but the levels may be too low to confer protection from risk of recurrent adenomas.

Leptin acts as a growth factor for colorectal tumours at stages subsequent to tumour initiation in murine colon carcinogenesis

Background and aimsObesity increases the risk of colorectal cancer (CRC). Serum leptin levels are markedly elevated in obese individuals, but the involvement of leptin in CRC growth remains unclear. We...

Role of obesity in a randomized placebo-controlled, double-blind trial of difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas.

374 Background: Chemoprevention with difluoromethylornithine (DFMO) plus sulindac markedly reduces risk of recurrence in colorectal adenoma (CRA) patients. Obesity is associated with risk of CRA and colorectal cancer (CRC). This study investigates how obesity influences CRA characteristics at baseline and risk of recurrence after treatment with DFMO plus sulindac vs. placebo. Methods: Our analysis included subjects enrolled in a phase III CRA prevention clinical trial investigating DFMO plus sulindac vs. placebo. Patients were classified by obesity (BMI &gt; 30 kg/m2) status at baseline. Pearson's χ2 statistic or Fisher's exact test and Mann-Whitney U test were used to compare baseline characteristics with regard to obesity status. Log-binomial regression analysis was used to determine the relative risk of metachronous adenoma, adenoma with advanced histology, or multiple adenomas, adjusted for covariates. Results: At baseline, obesity was associated with increased adenoma number (p =0.017), size (p =0.003), advanced histology (p =0.042), high-risk adenomas (p =0.0002), and distal adenomas (p =0.038). Obesity did not modify adenoma recurrence after treatment with DFMO plus sulindac or placebo (p =0.80). Conclusions: Our results provide supporting evidence for the association of obesity with high-risk adenoma features at baseline; however, obesity does not substantially modify CRA risk reduction after treatment with DFMO plus sulindac vs. placebo. [Table: see text] [Table: see text]

Stepwise Relationship Between Components of Metabolic Syndrome and Risk of Colorectal Adenoma in a Taiwanese Population Receiving Screening Colonoscopy

Metabolic syndrome (MS) is a cluster of diseases related to insulin resistance and is an important cardiovascular risk factor. In addition, MS has been linked to some malignancies, including colorectal cancer. Colon adenoma is a well-established pre-malignant lesion of colorectal cancer. The aim of this study was to determine the effect of various components of MS on the risk of colorectal adenoma. From October 2004 to April 2006, 3106 subjects who had undergone complete colonoscopy for health examinations at the hospital were enrolled. MS was defined according to the modified National Cholesterol Education Program Adult Treatment Panel III definition for South Asians and Chinese. Multivariate logistic regression was used to analyze the association between components of MS and colorectal adenoma. Of the 3106 subjects, the mean age was 47.1 ± 10.8 years and there were 397 (13%) subjects with pathologically proven colorectal adenoma. Male sex, old age (=50 years), current smokers, and abdominal obesity were associated with increasing risk of colorectal adenoma. MS was associated with increased risk of colorectal adenoma (odds ratio: 1.71, 95% confidence interval: 1.34-2.71), and this risk increased with the number of metabolic components. Multiple and synchronous adenomas of the proximal and distal colon were positively associated with MS. Subjects with metabolic syndrome have increased risk of developing colorectal adenoma. Screening colonoscopy for prevention of colorectal adenoma might be warranted when abdominal obesity or more than three components of MS are present.

Emerging role of bioflavonoids in gastroenterology: Especially their effects on intestinal neoplasia

Flavonoids, secondary plant products which could be essential for normal physiology in humans and animals, may be the vitamins of the next century. Flavonoids belong to the polyphenols and possess antioxidative, anti-inflammatory, antimutagenic and anticarcinogenic properties. Among the various flavonoid species, tea flavonoids such as apigenin (from camomile) and epigallocatechin gallate (EGCG from green tea) can be used for the prevention of intestinal neoplasia, especially for adenoma and cancer prevention in the gastrointestinal tract. Numerous experimental studies with molecular and biological end points support the therapeutic efficacy of bioflavonoids. Clinical studies with cohorts and case-control trials suggest that flavonoids are effective in tertiary bioprevention but, as yet, there are no controlled randomized clinical trials. Flavonoids can inhibit inflammatory pathways and could be useful for chronic inflammatory bowel diseases. Flavonoid deficiency syndromes could be therapeutic targets in the future.

Abstract PL01-04: ODC genotype as prognostic and predictive factors in colorectal carcinogenesis and prevention

Abstract Polyamines are increased in many intraepithelial neoplasia, which are risk factors for cancer in humans (1). Ornithine decarboxylase (ODC1), the first enzyme in polyamine synthesis, is regulated in part by Ebox transcription factors including MYC and MAD family members. The ODC1 gene contains several single nucleotide polymorphisms (SNPs) which are associated with risk of colorectal neoplasia. A SNP located 316 nucleotides from the start of transcription (rs2302615) has functional consequences for Ebox transcription factor binding and promoter activity. Both the transcription activator MYC and transcriptional repressors in the MAD family preferentially bind the ODC promoter element containing the minor A allele, which is flanked by two canonical E-boxes, resulting in allele-specific expression (2, 3). This SNP is associated with both risk of metachronous colorectal adenoma (CRA), in several independent studies (2, 4), and survival of patients with stages I-III colon cancer (3). The ODC1 SNP was also found to be predictive of reduced risk of CRA in association with aspirin use by three independent groups (2, 4, 5). The mechanism underlying the relationship between the ODC1 SNP and aspirin appears to involve the action of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) on polyamine catabolism and export. NSAIDs, including aspirin and sulindac, and celecoxib transcriptionally activate SAT1, a spermidine/spermine acetyltransferase, by unique mechanisms (6-8). Acetylation targets these polyamines for export by an SLC3A2-dependent arginine antiporter (9). Thus, NSAIDs and celecoxib, by activating polyamine export, complement ODC1 inhibitors, which suppress polyamine synthesis, to reduce tissue polyamine contents. In a prospective, randomized, placebo-controlled clinical trial of difluoromethylornithine (DFMO), a selective ODC1 inhibitor, and the NSAID sulindac for three years, combination treatment was associated with a 70% reduction of all, and over a 90% reduction of advanced and/or multiple CRAs, in patients with prior colon polyps (10). The 30% rate of non-advanced CRA development in the treatment arm was strongly associated with both the ODC1 SNP and dietary polyamines (11). Consideration of homeostatic regulatory processes, supported by measurements of tissue polyamine contents in participants in this trial, support the interpretation that decreased ODC transcription, resulting from the ODC1 SNP, is associated with altered polyamine transport. Treatment-associated toxicities were rare and associated with pretreatment clinical and genetic risk factors. The ODC1 SNP was predictive of ototoxicity in this trial (11). These studies identify genetic variability in ODC1, a MYC target gene, as a prognostic factor for colorectal carcinogenesis and as a predictive factor for treatments targeting this pathway. The role(s) of other ODC1 SNPs in colorectal or other cancers remains to be established.

Abstract SS01-01: View from the NCI: NCI's Division of Cancer Prevention

Abstract The Division of Cancer Prevention (DCP) was established in 1997 with the mission to plan and direct cancer prevention research including chemoprevention, nutritional science, genetic and infectious agent studies, early detection including biomarker development and validation, risk stratification, and biometry; and to coordinate community-based clinical research in cancer prevention and supportive care. Since then, there have been 42 new INDs and more than 200 publications about new prevention agents, including new classes of agents such as statins, HDAC inhibitors, NONSAIDs, p53 modulators and vaccines. One recent success is the finding that a combination of the anti-inflammatory sulindac and DFMO, pioneered by DCP, can reduce adenoma return by &amp;gt;95% reduction. In addition more than 50 early phase prevention trials have been conducted, expanding critical knowledge and stimulating science. More than one-third of all people in NCI's prevention, control, supportive care, and treatment trials enroll through DCP's Community Clinical Oncology Program (CCOP) network. The CCOP network initiated four large-scale phase III chemoprevention trials enrolling 87,560 participants over a 15-year period to establish the proof-of-principle that an agent can reduce a person's risk for developing cancer. Two of the trials resulted in the Food and Drug Administration drug approvals: tamoxifen and raloxifene for use in breast cancer risk reduction. A third agent, finasteride for use in prostate cancer risk reduction, is under consideration. The Early Detection Research Network, created in 2000 has made significant progress in: developing an organized effort for biomarker discovery and validation; building resources to support this effort; demonstrating the capabilities of several genomic and proteomic platforms; identifying candidate biomarkers; and undertaking multi-center validation studies. In its first 10 years, the Early Detection Research Network (EDRN) went from a ground-breaking concept to an operational success. To date, EDRN has developed more than 127 biomarkers; has launched 5 validation studies; three of which are completed, and has a number of prioritized markers ready for prevalidation and validation studies. More than 600 publications, more than 28 patents and more than 14 licenses have been generated. The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial enrolled 154,934 people to evaluate the effectiveness of various screening modalities on cancer-specific mortality and created the PLCO Biorepository, an invaluable resource of data and samples that precede cancer diagnosis. Data from the screening arms of the trial have been published, providing critical data on the ability of these tests to detect cancer. Mortality data from the prostate arm was published in the NEJM in 2009. The Biorepository has been available to the entire research community since 2005, through the Etiologic and Early Markers Program (EEMS). Over 100 research projects have been approved for use of PLCO biospecimens including genome-wide association studies and environmental and life style risk association studies. The National Lung Screening Trial (NLST) was launched in 2002 and enrolled 53,456 individuals within 18 months. Participants who were current or former smokers, aged 55 to 74, were randomized to screening with either low-dose helical CT or chest x-ray. Three rounds of screening were completed by 2007 with a compliance rate of approximately 90% in both arms. Results are expected in 2011. DCP also has a robust portfolio of nutritional science research that addresses the critical need to unravel the fundamental role of food components in cancer related processes.

Abstract A98: Prevention of gastrointestinal adenomas in the ApcMin mouse by high-fiber rice bran

Abstract Consumption of dietary bran has been considered to be beneficial to health. It has also been linked to a lower risk of developing malignancies, most notably, colorectal cancer. Rice bran (containing 23-35% dietary fiber) at 30% in the diet interfered with adenoma development in the ApcMin mouse, a preclinical model of colorectal cancer (Verschoyle et al., Br J Cancer 2007). Here we used a high fiber rice bran extract (Nutracea, USA), with a fiber content of 40-50% to explore whether an increase in fiber imparts higher efficacy in the ApcMin mouse. The bran was mixed in with the diet at three concentrations: 5, 15 and 30% (n=19-22 per group) and administered to ApcMin mice from 4 weeks of age until termination of study at 16 weeks. Adenoma numbers were reduced by 12, 26, 74 % and adenoma burden by 30, 26 and 84 %, respectively, in the treatment groups in comparison to control mice, with reduction being significant only at the highest dose (p&amp;lt;0.05). The high fiber rice bran seems to be more efficacious than the rice bran used in the previous study in which 30% rice bran reduced adenoma numbers by 51% (Verschoyle et al., Br J Cancer 2007). Plasma samples from each experimental group were collected and undergo proteomic analysis using liquid chromatography-mass spectrometry to identify potential biomarkers of efficacy. This study highlights the potential health benefit of high-fiber rice bran, but further investigations are warranted to better understand the role of fiber in colorectal cancer prevention. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A98.

Association between Folate Levels and CpG Island Hypermethylation in Normal Colorectal Mucosa

Gene-specific promoter methylation of several genes occurs in aging normal tissues and may predispose to tumorigenesis. In the present study, we investigate the association of blood folate levels and dietary and lifestyle factors with CpG island (CGI) methylation in normal colorectal mucosa. Subjects were enrolled in a multicenter chemoprevention trial of aspirin or folic acid for the prevention of large bowel adenomas. We collected 1,000 biopsy specimens from 389 patients, 501 samples from the right colon and 499 from the rectum at the follow-up colonoscopy. We measured DNA methylation of estrogen receptor alpha (ERα) and secreted frizzled related protein-1 (SFRP1), using bisulfite pyrosequencing. We used generalized estimating equations regression analysis to examine the association between methylation and selected variables. For both ERα and SFRP1, percentage methylation was significantly higher in the rectum than in the right colon (P = 0.001). For each 10 years of age, we observed a 1.7% increase in methylation level for ERα and a 2.9% increase for SFRP1 (P < 0.0001). African Americans had a significantly lower level of ERα and SFRP1 methylation than Caucasians and Hispanics. Higher RBC folate levels were associated with higher levels of both ERα (P = 0.03) and SFRP1 methylation (P = 0.01). Our results suggest that CGI methylation in normal colorectal mucosa is related to advancing age, race, rectal location, and RBC folate levels. 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.

Role of dietary polyamines in a phase III clinical trial of DFMO and sulindac for prevention of metachronous colorectal adenomas.

1523 Background: Our group has previously demonstrated that polyamine-inhibitory regimen difluoromethylornithine (DFMO) plus sulindac vs. placebo has marked efficacy in preventing metachronous colorectal adenomas in a phase-III trial. Polyamines are synthesized endogenously but also obtained from diet. Here we investigate the role of dietary polyamines in the phase III placebo controlled colorectal adenoma prevention trial with DMFO + sulindac. Methods: Dietary polyamine data were available for 222 of 375 baseline study patients, and for 188 of 267 patients completing the study. A dietary questionnaire completed by each patient was collected at the initiation of the study. Total dietary polyamine content was derived by the sum of dietary putrescine, spermine and spermidine values and further categorized into highest (75%-100%) quartile group vs. a group with lower three quartiles (0-25, 25-50 and 50%-75%). Baseline tissue polyamine concentration was determined using HPLC methodology. Linear and logistic regression analyses were used for risk estimation. Results: A significant direct association was observed between dietary polyamine intake and tissue spermidine (p = 0.02) and spermine concentrations (p = 0.04) at baseline. Higher dietary polyamine group at baseline was associated with adenomas > 1 cm (43.6 % vs. 26.4 %; p = 0.01),high grade adenomas (32.7% vs. 20.4 %; p = 0.06) and advanced adenomas (52.7% vs. 35.9 %; p = 0.02). Among all patients, a significant interaction was observed between treatment, dietary polyamines and the risk of metachronous adenomas (p = 0.01). Therefore we stratified the final analyses (n = 188) by polyamine intake groups. We observed a significant risk reduction of metachronous adenomas from treatment with DFMO+sulindac in the lower dietary polyamine group (RR = 0.19 [0.09-0.40] p < 0.0001) and no benefit in the higher dietary polyamine group (RR = 1.04 [0.32-3.36] p = 0.94). Conclusions: Controlling dietary polyamines may be an effective strategy for preventing the occurrence of colorectal adenomas and colorectal cancer. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Cancer Prevention Pharmaceuticals Cancer Prevention Pharmaceuticals