Incident Adenoma Research Articles

A157 FIT-POSITIVE COLONOSCOPY FINDINGS IN NOVA SCOTIA STRATIFIED BY SEX, RACE, AND REGIONAL POPULATION DENSITY

Abstract Background Population-based colorectal cancer (CRC) screening programs aim to minimize disparities in CRC rates through universal access. However, Canadian CRC mortality rates remain inversely associated with socioeconomic status and rural residence. In the United States some racialized groups have higher rates of advanced adenomas and CRC. Little is known about pre-cancerous findings or CRC mortality amongst racialized groups in Canada because race and ethnicity data are not routinely collected. Purpose To determine whether FIT-positive colonoscopy incident adenomas and CRC differ on the basis of sex, race, and regional population density in a provincial CRC screening program. Method In this retrospective cohort study drawn from the Nova Scotia Colon Cancer Prevention Program database, we identified adults who had a positive FIT from 2011 to 2021. This report describes incident adenomas and CRC, stratified by sex, race (white vs. racialized groups), and regional population density (urban vs. rural). Racialized groups included those who self-identified as Black/African Canadian, Asian, Middle Eastern and Indigenous. Urban was defined as population centers with more than 5000 individuals. Colonoscopy findings were categorized as no findings, low-risk adenoma (LRA), high-risk adenoma (HRA), or CRC. Comparison between categorical variables was performed with a chi-square test and a t-test for continuous variables. P-value <0.05 was considered significant. Result(s) 41,209 adults (mean age 63.9) had a positive FIT and 34,636 went on to have a colonoscopy offered by the screening program. The FIT-positive colonoscopy participation rate was 84%. Of the 16% overall with a positive FIT but no screening program colonoscopy, 83% had a program consultation but did not proceed with endoscopy for unspecified reasons, 9% declined, and 8.2% are unknown. The overall rate of CRC was 2.4% (n=825) and the adenoma-detection rate was 60.4% (n=20,932). CRC (mean age 65.4) and HRA (mean age 64.6) were associated with older age (p <0.01). Males were more likely to have HRA (38.4% of males) or LRA (26.6% of males) identified compared to females, and females were more likely to have no colonoscopy findings (47.8% of females). CRC was more likely to be identified in urban (2.8%) than rural sub-populations (2.0%). No difference in adenomas or CRC incident rates were noted between white and racialized sub-groups. Image Conclusion(s) This analysis of a provincial CRC screening program suggests that males and urban sub-populations had more high-risk findings during FIT-positive colonoscopies. In the first reported Canadian data, incident rates of adenomas and CRC were similar in white and racialized sub-groups. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared

Inflammatory potential of diet and colorectal carcinogenesis: a prospective longitudinal cohort.

Acknowledging the role of inflammation in colorectal carcinogenesis, this study aimed to evaluate the associations between diet-associated inflammation, as measured by the energy-adjusted dietary inflammatory index (E-DIITM), and distinct stages of colorectal carcinogenesis. The Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial enrolled participants without a colorectal cancer history, who were asked to complete baseline questionnaires and food frequency questionnaires. To estimate the associations between the E-DII and risks of newly incident colorectal adenoma, recurrent adenoma, and colorectal cancer, multivariable-adjusted Cox proportional hazards regression models were employed. Among 101,680 participants, with an average age of 65 years, a total of 1177 incident colorectal adenoma cases, 895 recurrent adenoma cases and 1100 colorectal cancer cases were identified. Higher E-DII scores from food and supplement (HRQ5 vs Q1: 0.86 [0.69-1.06], Ptrend: 0.27) or from food only (HRQ5 vs Q1: 0.82 [0.64-1.05], Ptrend: 0.06) were not associated with higher risks of incident adenoma. However, the elevated risk of recurrent adenoma was found in the highest category of E-DII from food plus supplement (HRQ5 vs Q1: 1.63 [1.28-2.03], Ptrend: < 0.001) when compared with the lowest category. A significant association between colorectal cancer risk and E-DII from food plus supplement (HRQ5 vs Q1: 1.34 [1.09-1.65], Ptrend: 0.009) was found, where this association was only pronounced in distal colorectal cancer. Higher E-DII scores from diet plus supplement but not from diet only were associated with a higher risk of recurrent adenoma and distal colorectal cancer. The role of nutrient supplements on cancer risk, especially when combined with diet, needs to be elucidated in future studies.

Adenoma and colorectal cancer risks in Lynch syndrome, Lynch-like syndrome and familial colorectal cancer type X.

Lynch syndrome (LS), Lynch-like syndrome (LLS) and familial colorectal cancer type X (FCCX) are different entities of familial cancer predisposition leading to an increased risk of colorectal cancer (CRC). The aim of this prospective study was to characterise and to compare the risks for adenoma and CRC in these three risk groups. Data was taken from the registry of the German Consortium for Familial Intestinal Cancer. Patients were prospectively followed up in an intensified colonoscopic surveillance programme that included annual examinations. Cumulative risks for adenoma and CRC were calculated separately for LS, LLS and FCCX, and then for males and females. Multivariate Cox regression was used to analyse the independent contributions of risk group, mismatch repair gene (within LS), sex and previous adenoma. The study population comprised 1448 individuals (103 FCCX, 481 LLS and 864 LS). The risks were similar for colorectal adenomas, but different for first and metachronous CRC between the three risk groups. CRC risk was highest in LS, followed by LLS and lowest in FCCX. Male sex and a prevalent adenoma in the index colonoscopy were associated with a higher risk for incident adenoma and CRC. In patients with LS, CRC risks were particularly higher in female MSH2 than MLH1 carriers. Our study may support the development of risk-adapted surveillance policies in LS, LLS and FCCX.

Oral Antibiotics and Risk of New Colorectal Adenomas During Surveillance Follow-up.

Antibiotics may increase colorectal neoplasia risk by modifying the gut microbiome. It is unknown whether use is associated with the risk of new colorectal adenomas among individuals with prior adenomas. We performed a secondary analysis of four randomized clinical trials for the chemoprevention of colorectal adenomas. Participants self-reported all currently used prescription drugs shortly after an initial colorectal adenoma diagnosis and two or three times a year thereafter over 3 to 5 years of follow-up. We estimated adjusted risk ratios (RR) with 95% confidence intervals (CI) for incident adenomas, analyzing the four trials together. Cumulatively, the four trials enrolled 5,174 participants (3,491 men and 1,683 women), of whom 4,769 (92%) completed ≥1 follow-up colonoscopy. A total of 763 (15%) participants reported using oral antibiotics on ≥2 occasions. Overall, 39% of those using oral antibiotics at least twice developed new colorectal adenomas compared with 40% of those with no use or a single report of use (RR, 0.99; 95% CI, 0.90-1.10). No statistically significant associations were found in study-specific analyses, and results were similar for high- and low-risk adenoma findings, antibiotic class, anatomic location of adenomas, and analyses excluding those with interim colorectal exams. Oral antibiotic use during colonoscopic surveillance after an initial adenoma diagnosis was not associated with risk of these polyps. Any changes to the gut microbiome as a consequence of oral antibiotic use during surveillance may not affect the development of metachronous colorectal adenomas.

Aspirin, ibuprofen, and reduced risk of advanced colorectal adenoma incidence and recurrence and colorectal cancer in the PLCO Cancer Screening Trial.

Studying the differential impact of aspirin and other nonsteroidal anti-inflammatory drugs across the stages of colorectal neoplasia from early adenoma to cancer is critical for understanding the benefits of these widely used drugs. With 13 years of follow-up, the authors prospectively evaluated the association between aspirin and ibuprofen use and incident distal adenoma (1221 cases), recurrent adenoma (862 cases), and incident colorectal cancer (CRC; 2826 cases) among men and women in the population-based Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. With multivariable-adjusted models, odds ratio (ORs) and 95% confidence intervals (CIs) for adenoma incidence and recurrence and hazard ratios (HRs) and 95% CIs for incident CRC were determined. The authors observed a significantly reduced risk of incident adenoma with ibuprofen use (≥30 vs <4 pills per month: OR, 0.76 [95% CI, 0.60-0.95]; Ptrend = .04), particularly advanced adenoma (OR, 0.48 [95% CI, 0.28-0.83]; Ptrend = .005). Among those with a previous adenoma detected through screening, aspirin use was associated with a decreased risk of advanced recurrent adenoma (≥30 vs <4 pills per month: OR, 0.56 [95% CI, 0.36-0.87]; Ptrend = 0.006). Both aspirin (HR, 0.88 [95% CI, 0.81-0.96]; Ptrend <.0001) and ibuprofen use (HR, 0.81 [95% CI, 0.70-0.93); Ptrend = 0.003) ≥30 versus <4 pills per month were significantly associated with reduced CRC risk. In this large prospective study with long-term follow-up, a beneficial role for not only aspirin, but also ibuprofen, in preventing advanced adenoma and curbing progression to recurrence and cancer among older adults was observed.

Increasing changes in visceral adiposity is associated with higher risk for colorectal adenoma: Multilevel analysis in a prospective cohort.

While many studies demonstrated an association between visceral adiposity and colorectal adenoma (CRA), the effect of longitudinal changes in body fat composition on CRA is unclear. We investigated the longitudinal association between changes in visceral adiposity and CRA occurrence. Between 2006 and 2018, 732 (62.8%) of the 1165 subjects in a prospective cohort voluntarily underwent follow-up abdominal fat computed tomography and colonoscopy. We defined incident and recurrent CRA as adenoma detected at follow-up colonoscopy from negative and positive adenoma at baseline colonoscopy, respectively. Multilevel survival analysis examined the longitudinal association between changes in visceral fat and CRA. During a median follow-up of 7.4years, 400 (54.6%) subjects developed CRA. In multivariable analysis, increasing changes in visceral adipose tissue (VAT) area were associated with higher risk of incident adenoma (hazard ratio [HR] 1.21, 95% confidence interval [CI] 1.00-1.46 for change per 10cm2 increase; HR 1.79, 95% CI 1.08-2.97 for highest vs lowest quartile, P values for trend=0.045). Likewise, increasing changes in VAT area were independently associated with a higher risk of recurrent adenoma (HR 1.35, 95% CI 1.13-1.62 for change per 10cm2 increase; HR 1.62, 95% CI 1.04-2.52 for highest vs lowest quartile, P values for trend=0.001). Changes in subcutaneous adipose tissue area were not independently associated with CRA. Increasing changes in VAT area were longitudinally associated with a higher risk of incident and recurrent CRA, independent of risk factors, suggesting that visceral adiposity may be an important target in CRA prevention.

Blunted PTH response to vitamin D insufficiency/deficiency and colorectal neoplasia risk

In contrast to many observational studies, large-scale randomized trials do not support the protective role of vitamin D for the prevention of colorectal neoplasia. However, in previous studies, individuals with blunted parathyroid hormone (PTH) response to vitamin D insufficiency/deficiency (BPRVID), were not differentiated from those with high PTH response to vitamin D insufficiency/deficiency (HPRVID). Individuals with BPRVID are responsive to magnesium treatment, particularly treatment of magnesium plus vitamin D while those with HPRVID are responsive to vitamin D treatment. We prospectively compared these two distinct groups (i.e. BPRVID and HPRVID) for risk of incident adenoma, metachronous adenoma, and incident colorectal cancer (CRC) METHODS: Three nested case-control studies in the Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial. We found optimal 25(OH)D levels were associated with a significantly reduced risk of CRC, primarily among women. The associations between 25(OH)D and CRC risk significantly differed by PTH levels, particularly among women. Compared to individuals with optimal levels for both 25(OH)D and PTH, all others were at an elevated risk of incident CRC, primarily in women. We found those with BPRVID had 2.56-fold significantly increased risk of CRC compared to 1.65-fold non-significantly increased risk for those with HPRVID. Among women, we observed those with BPRVID had 4.79-6.25-fold significantly increased risks of incident CRC and adenoma whereas those with HPRVID had 3.65-fold significantly increased risk of CRC. Individuals with BPRVID are at higher risks of incident adenoma and CRC compared to those with HPRVID, particularly among women.

Calcium: magnesium intake ratio and colorectal carcinogenesis, results from the prostate, lung, colorectal, and ovarian cancer screening trial

BackgroundWe aimed to evaluate the associations between calcium and various stages of colorectal carcinogenesis and whether these associations are modified by the calcium to magnesium (Ca:Mg) ratio.MethodsWe tested our hypotheses in the prostate lung, colorectal and ovarian cancer screening trial.ResultsCalcium intake did not show a dose–response association with incident adenoma of any size/stage (P-trend = 0.17), but followed an inverse trend when restricted to synchronous/advanced adenoma cases (P-trend = 0.05). This inverse trend was mainly in participants with Ca:Mg ratios between 1.7 and 2.5 (P-trend = 0.05). No significant associations were observed for metachronous adenoma. Calcium intake was inversely associated with CRC (P-trend = 0.03); the association was primarily present for distal CRC (P-trend = 0.01). The inverse association between calcium and distal CRC was further modified by the Ca:Mg ratio (P-interaction < 0.01); significant dose–response associations were found only in participants with a Ca:Mg ratio between 1.7 and 2.5 (P-trend = 0.04). No associations for calcium were found in the Ca:Mg ratio above 2.5 or below 1.7.ConclusionHigher calcium intake may be related to reduced risks of incident advanced and/or synchronous adenoma and incident distal CRC among subjects with Ca:Mg intake ratios between 1.7 and 2.5.

Different dietary fibre sources and risks of colorectal cancer and adenoma: a dose-response meta-analysis of prospective studies.

Dietary fibre is believed to provide important health benefits including protection from colorectal cancer. However, the evidence on the relationships with different dietary fibre sources is mixed and little is known about which fibre source provides the greatest benefits. We conducted a dose-response meta-analysis of prospective cohorts to summarise the relationships of different fibre sources with colorectal cancer and adenoma risks. Analyses were restricted to publications that reported all fibre sources (cereals, vegetables, fruits, legumes) to increase comparability between results. PubMed and Embase were searched through August 2018 to identify relevant studies. The summary relative risks (RR) and 95 % CI were estimated using a random-effects model. This analysis included a total of ten prospective studies. The summary RR of colorectal cancer associated with each 10 g/d increase in fibre intake were 0·91 (95 % CI 0·82, 1·00; I2 = 0 %) for cereal fibre, 0·95 (95 % CI 0·87, 1·03, I2 = 0 %) for vegetable fibre, 0·91 (95 % CI 0·78, 1·06, I2 = 43 %) for fruit fibre and 0·84 (95 % CI 0·63, 1·13, I2 = 45 %) for legume fibre. For cereal fibre, the association with colorectal cancer risk remained statistically significant after adjustment for folate intake (RR 0·89, 95 % CI 0·80, 0·99, I2 = 2 %). For vegetable and fruit fibres, the dose-response curve suggested evidence of non-linearity. All fibre sources were inversely associated with incident adenoma (per 10 g/d increase: RR 0·81 (95 % CI 0·54, 1·21) cereals, 0·84 (95 % CI 0·71, 0·98) for vegetables, 0·78 (95 % CI 0·65, 0·93) for fruits) but not associated with recurrent adenoma. Our data suggest that, although all fibre sources may provide some benefits, the evidence for colorectal cancer prevention is strongest for fibre from cereals/grains.

Polymorphisms in genes related to inflammation and obesity and colorectal adenoma risk.

We previously investigated the association between single nucleotide polymorphisms (SNPs) in genes related to obesity and inflammation and colorectal cancer in the CLUE II cohort. However, the relationships between these SNPs and colorectal adenomas have not been well evaluated. In a nested case-control study of 135 incident adenoma cases and 269 matched controls in the CLUE II cohort (1989-2000), we genotyped 17 candidate SNPs in 12 genes (PPARG, TCF7L2, ADIPOQ, LEP, IL10, CRP, TLR4, IL6, IL1B, IL8, TNF, RNASEL) and 19 tagSNPs in three genes (IL10, CRP, and TLR4). Conditional logistic regression was used to calculate odds ratios (OR) for adenomas (overall and by size, histology, location, number). Polymorphisms in the inflammatory-related genes CRP, ADIPOQ, IL6, and TLR4 were observed to be associated with adenoma risk. At rs1205 in CRP, T (minor allele) carriers had a higher risk (OR 1.67, 95%CI 1.07-2.60; reference: CC) of adenomas overall and adenomas with aggressive characteristics. At rs1201299 in ADIPOQ, the AC genotype had a higher risk (OR 1.58, 95%CI 1.00-2.49) of adenomas, while the minor AA genotype had a borderline inverse association (OR 0.44, 95%CI 0.18-1.08; reference: CC). At rs1800797 in IL6, the AA genotype had a borderline inverse association (OR 0.53, 95%CI 0.27-1.05; reference: GG). Three TLR4 tagSNPs (rs10116253, rs1927911, rs7873784) were associated with adenomas among obese participants. None of these SNPs were associated with colorectal cancer in our prior study in CLUE II, possibly suggesting a different genetic etiology for early colorectal neoplasia.

Visceral obesity as a risk factor for colorectal adenoma occurrence in surveillance colonoscopy

The aim of this study was to examine the prospective association between visceral obesity and the incidence and recurrence of colorectal adenoma. We conducted a cohort study involving 2244 participants between 2006 and 2007. The study participants were prospectively followed until 2014 according to the initial colonoscopy and histopathology findings. Incident and recurrent colorectal adenoma groups were defined as individuals with a positive follow-up colonoscopy result from the normal results and adenoma groups, respectively, at the baseline colonoscopy. Among the 1163 patients (51.8%) who received a follow-up colonoscopy, 509 (43.8%) and 654 (56.2%) were grouped into the normal and adenoma cohorts. Colorectal adenomas occurred in 592 patients (50.9%) during the median period of 43 months, with an incident adenoma prevalence of 39.1% and a recurrent adenoma prevalence of 60.1%. An increase in the visceral adipose tissue (VAT) area was associated with a higher incidence of adenoma (highest quintile vs lowest quintile of the VAT hazard ratios [HRs], 2.16; 95% confidence interval [CI], 1.26-3.71; HR 1.32 [per 1-standard deviation]; 95% CI, 1.10-1.60) in the multivariable analysis. Increases in body mass index and waist circumference were associated with recurrent adenomas (HR 1.33 [per 1 kg/m2], 95% CI, 1.18-1.46; HR 1.04 [per 1 cm], 95% CI, 1.01-1.07, respectively) in the multivariate analysis. A higher VAT area was dose-dependently associated with a higher risk of incident adenoma. Furthermore, increases in body mass index and waist circumference as surrogate markers of abdominal obesity were associated with a higher risk of recurrent adenoma.

Abstract 5003: Serum parathyroid hormone and risks of colorectal adenoma, adenoma recurrence and colorectal cancer, results from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

Abstract Background: Serum parathyroid hormone (PTH) may be related to risk of incident colorectal cancer. However, no study has prospectively examined whether serum PTH is differentially related to risks of different stages of colorectal carcinogenesis (incident adenoma and metachronous adenoma). Further, it is unclear if PTH is associated with risk of incident colorectal neoplasia in individuals receiving endoscopic screenings. To address these important scientific inquiries, we have conducted three nested case-control studies within the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial. Methods: The PLCO is a large, multicenter, population-based randomized trial designed to determine the effects of screening on cancer-related mortality with a median of 12.5 years of follow up. We evaluated the associations between serum PTH and the risks of incident colorectal adenoma (755 cases and 514 controls), metachronous adenoma (755 cases and 755 controls) and incident colorectal cancer (755 cases and 514 controls) within PLCO participants aged 55 to 74 years. Odds ratios (OR) and 95% confidence intervals (95%CIs) were estimated using unconditional logistic regression models after adjusting for potential confounding factors. Results: Compared to low serum PTH (&amp;lt;30 ng/L), higher concentrations of serum PTH were associated with significantly reduced risk of incident colorectal cancer with the ORs (95% CIs) being 0.65(0.48-0.88) and 0.52(0.35-0.76) for PTH ≥30 ng/L and PTH≥65 ng/L (p for trend, 0.001). The inverse associations appeared significant for both women and men. However, overall, serum PTH was not related to risk of incident adenoma and metachronous adenoma. Conclusion: In conclusion, compared to the lowest PTH levels, higher serum PTH were related to reduced risks of incident colorectal cancer among an US population who received endoscopy, but not incident colorectal adenoma and metachronous adenoma. Citation Format: Xiangzhu Zhu, Martha J. Shrubsole, Edward Giovannucci, Todd L. Edwards, Qi Dai. Serum parathyroid hormone and risks of colorectal adenoma, adenoma recurrence and colorectal cancer, results from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5003. doi:10.1158/1538-7445.AM2017-5003

Abstract 1739: Calcium to magnesium intake ratio and colorectal carcinogenesis, results from the Prostate, Lung, Colorectal, and Ovarian cancer screening trial

Abstract Background A recent randomized trial found no effect of calcium supplementation on reducing risk of colorectal adenoma recurrence. However, the role of calcium in carcinogenesis is yet unconfirmed. An earlier trial found calcium treatment only reduced recurrence when the baseline calcium: magnesium intake ratio was &amp;lt;2.6. Nor is it clear whether calcium intake is differentially related to risks of different stages of colorectal carcinogenesis (incident adenoma, adenoma recurrence and incident colorectal cancer). Further, it is unclear if calcium intake or supplementation confers additional protection against incident colorectal cancer in individuals receiving endoscopic screenings. To address these important scientific inquiries, we have conducted analyses within the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial. Methods The PLCO is a large, multicenter, population-based randomized trial designed to determine the effects of screening on cancer-related mortality with a median of 12.5 years of follow up. We evaluated the associations between calcium intake and the risks of incident colorectal adenoma (1,147 cases), recurrent adenoma (855 cases) and incident colorectal cancer (697 and 578 cases in intervention and control arms, respectively) among 108,563 PLCO participants aged 55 to 74 years. Odds ratios (OR) and 95% confidence intervals (95%CIs) for incident adenoma and recurrent adenoma, and hazard ratios (HR) and 95%CIs for colorectal cancer incidence were calculated using unconditional logistic regression models and Cox proportional hazard models after adjusting covariates. Results Compared to low calcium intake (&amp;lt;600 mg/day), higher intakes of calcium were not related to a reduced risk of incidence adenoma, but significantly associated with a reduced risk of advanced/multiple adenomas (p for trend, &amp;lt;0.05). Further, the significant inverse association only appeared when calcium:magnesiuim intake ratios between 1.7 and 2.5. No significant association was observed between Ca intake and risk of adenoma recurrence. In the control arm, we found, compared to low calcium intake, higher intakes of calcium were associated with significantly reduced risks of incident colorectal cancer, primarily distal cancer. Again, we found the inverse association may primarily appear in those with calcium:magnesiuim intake ratios between 1.7 and 2.5. In contrast, in the intervention arm (i.e. screening with flexible sigmoidoscopy), overall, we did not find any significant associations. Conclusion Intake of calcium may be more strongly related to reduced risks of incident advanced/multiple adenoma and incident colorectal cancer among those without active screening with flexible sigmoidoscopy than to recurrent adenoma and incident colorectal cancer risks among those with active screening with flexible sigmoidoscopy. Citation Format: Jing Zhao, Xiangzhu Zhu, Martha J. Shrubsole, Todd L. Edwards, Edward L. Giovannucci, Wei Zheng, Qi Dai, PLCO Project Team. Calcium to magnesium intake ratio and colorectal carcinogenesis, results from the Prostate, Lung, Colorectal, and Ovarian cancer screening trial. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1739.

Dietary fiber intake and risk of colorectal cancer and incident and recurrent adenoma in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

Dietary fiber has been associated with a reduced risk of colorectal cancer. However, it remains unclear at which stage in the carcinogenic pathway fiber may act or which food sources of dietary fiber may be most beneficial against colorectal cancer development. The objective was to prospectively evaluate the association between dietary fiber intake and the risk of incident and recurrent colorectal adenoma and incident colorectal cancer. Study participants were identified from the intervention arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Participants received flexible sigmoidoscopy at baseline and 3 or 5 y after. Dietary fiber intake was measured by using a self-reported dietary questionnaire. The colorectal cancer, incident adenoma, and recurrent adenoma analyses were based on 57,774, 16,980, and 1667 participants, respectively. Unconditional logistic regression was used to assess the risk of incident and recurrent adenoma, and Cox proportional hazards models were used to assess the risk of colorectal cancer across categories of dietary fiber intake, with adjustment for potential confounders. Elevated total dietary fiber intake was associated with a significantly reduced risk of incident distal colorectal adenoma (ORhighest vs. lowest tertile of intake: 0.76; 95% CI: 0.63, 0.91; P-trend = 0.003) but not recurrent adenoma (P-trend = 0.67). Although the association was not statistically significant for colorectal cancer overall (HR: 0.85; 95% CI: 0.70, 1.03; P-trend = 0.10), a reduced risk of distal colon cancer was observed with increased total fiber intake (HR: 0.62; 95% CI: 0.41, 0.94; P-trend = 0.03). Protective associations were most notable for fiber originating from cereals or fruit. This large, prospective study within a population-based screening trial suggests that individuals consuming the highest intakes of dietary fiber have reduced risks of incident colorectal adenoma and distal colon cancer and that this effect of dietary fiber, particularly from cereals and fruit, may begin early in colorectal carcinogenesis. This trial was registered at clinicaltrials.gov as NCT01696981.

Abstract 1875: Development of a dietary inflammation score and its association with incident, sporadic colorectal adenoma

Abstract It is now well established that inflammation is linked to colorectal carcinogenesis and other chronic diseases. The ability to characterize specific dietary and lifestyle components as having pro- or anti-inflammatory effects is a promising area of cancer prevention. We developed a “dietary inflammation score” based on associations of independent dietary components with plasma C-reactive protein (CRP) in the combined Markers of Adenomatous Polyps (MAPs) case-control studies, and investigated the association of the score with incident, sporadic colorectal adenoma in the same population. First, we excluded individuals who regularly took non-steroidal anti-inflammatory drugs (NSAIDs) and multivitamins, and among those remaining (n = 369) calculated the multivariable-adjusted associations of the individual dietary components with CRP, used the strengths of associations as weights, and summed the weighted dietary components to create an overall summary dietary inflammation score. Food components were included in the score based on biological plausibility and previous literature, and included four categories of meat, nuts, pepper, coffee, tea, high- and low-fat dairy products, refined and whole grains, and twelve botanical categories. The crude odds ratio (OR) for the association of the highest dietary score tertile with log-transformed CRP was 1.92 (95% confidence interval [CI]: 1.13, 3.27); after adjusting for age, sex, total energy intake, and lifestyle inflammation score category, the OR was 1.89 (95% CI: 1.06, 3.36). The association tended to be stronger among older individuals, males, and adenoma cases. The overall score was more strongly associated with CRP than was any individual dietary component. Next, to assess the association of the dietary inflammation score with adenomas, we used the entire MAPs population (n = 188 cases and 325 controls)– including the regular NSAID and multivitamin users. The crude OR for the association of the highest dietary score tertile with incident adenoma was 1.30 (95% CI: 0.84, 2.02), an association that tended to be stronger among men and those who regularly took aspirin or other NSAIDs. Multivariable adjustment did not appreciably change these estimates. The results from this pilot study suggest that diet may contribute to systemic levels of inflammation, and support further investigation of a dietary inflammation score with colorectal neoplasms and other chronic diseases in larger studies. Citation Format: Ashley C. Holmes, Roberd M. Bostick. Development of a dietary inflammation score and its association with incident, sporadic colorectal adenoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1875. doi:10.1158/1538-7445.AM2015-1875

A prospective evaluation of C-peptide levels and colorectal adenoma incidence

BackgroundObesity is a recognised positive risk factor for colorectal adenoma and colorectal cancer. Obesity is associated with insulin resistance and compensatory hyperinsulinaemia, and circulating insulin and C-peptide, a biomarker of insulin levels, have been positively associated with colorectal cancer risk. However, whether a similar relationship exists for colorectal adenomas, an established colorectal cancer precursor, is unclear. MethodsIn a nested case-control study of 273 colorectal adenoma cases and 355 matched controls from the screening arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, serum C-peptide levels were measured by a chemiluminescent immunometric assay. Multivariable unconditional logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (CI) for colorectal adenoma within quartiles of C-peptide. Further, to explore the temporal stability of C-peptide, repeat samples from the incident adenoma cases (n=50) and controls (n=30), over a 5-year period were assayed and the intra-class correlations (ICC) estimated. ResultsIn a multivariable model that included established colorectal adenoma risk factors, C-peptide levels were not associated with colorectal adenoma (Q4 vs. Q1, OR 0.83, 95% CI: 0.52–1.31; P-trend 0.32); similar null associations were observed by gender, by adenoma subsite and for advanced adenomas. Among control participants, the ICC value over a 5-year period was 0.66. ConclusionOur results suggest that higher C-peptide levels were not associated with colorectal adenoma incidence in this study population. Other biological pathways associated with obesity may be more relevant to the early stages of colorectal tumorigenesis.

Abstract 2159: A prospective study of non-steroidal anti-inflammatory drug use and colorectal adenoma and colorectal cancer

Abstract Background: Use of non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, has been shown to yield a chemopreventive effect against colorectal cancer. Whether NSAIDs protect against the initiation vs. the progression of colorectal cancer remains a debate. To explore its role in the course of colorectal carcinogenesis, we evaluated the associations of NSAIDs with incident adenoma, recurrent adenoma, and colorectal cancer in the context of a large population-based screening trial, where participants were randomized to undergo endoscopic examinations in a controlled setting. Methods: We prospectively evaluated the associations between self-reported baseline NSAIDs use and risk of incident distal adenoma (1,127 cases), recurrent adenoma (755 cases), and colorectal cancer (840 cases) among men and women, ages 55-74, enrolled between 1993-2001, and randomized to receive flexible sigmoidoscopy screening (n=77,445) as part of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Incident adenoma cases were those with a negative sigmoidoscopy at baseline, but then were found to have adenoma on a follow-up sigmoidoscopy 3 or 5 years later. Recurrent adenoma cases were identified via an ancillary study nested within the PLCO among participants who had an adenoma at baseline and another adenoma on a surveillance colonoscopy 6 months to 10 years after their baseline screen. Participants were followed for cancer incidence for the median of 11.9 years following the baseline screen. All diagnoses of colorectal adenoma and cancer were pathologically confirmed through medical record review. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for adenoma incidence and recurrence and hazard ratios (HRs) and 95% CIs for colorectal cancer incidence using multivariable-adjusted models. Results: Compared to no or infrequent use (&amp;lt;4 times/month), we found aspirin use ≥2 times/day to be associated with a reduced risk of incident adenoma (OR=0.72, 95% CI:0.52-1.00). Although not significantly associated with recurrent adenoma (OR=1.00) or colorectal cancer (OR=0.80), a marginally significant dose trend was observed for colorectal cancer (P=0.05). Similarly, ibuprofen use ≥2 times/day was associated with a reduced risk for incident adenoma (OR=0.72, 95% CI:0.54-0.97), but not associated with adenoma recurrence or cancer. No systematic differences in risk patterns were found by anatomic site, i.e., proximal colon, distal colon or rectum. Conclusion: Our data suggest that use of aspirin and ibuprofen significantly reduces adenoma initiation, but benefit against progression to adenoma recurrence or cancer growth may be weaker. Given the recognized adverse effects of NSAIDs, such as gastric ulcer perforation and upper gastrointestinal bleeding, any chemopreventive recommendations associated with NSAID use need to be tailored by individual cost-benefit assessment. Citation Format: Wen-Yi Huang, L. Joseph Su, Christine C. Johnson, Mark P. Purdue, Sonja I. Berndt. A prospective study of non-steroidal anti-inflammatory drug use and colorectal adenoma and colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2159. doi:10.1158/1538-7445.AM2014-2159

Prospective Investigation of Body Mass Index, Colorectal Adenoma, and Colorectal Cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

Obesity has consistently been linked to an increased risk of colorectal cancer, particularly among men. Whether body mass index (BMI) differentially influences the risk across the stages of colorectal cancer development remains unclear. We evaluated the associations of BMI with colorectal adenoma incidence, adenoma recurrence, and cancer in the context of a large screening trial, in which cases and controls had an equal chance for disease detection. We prospectively evaluated the association between baseline BMI and the risk of incident distal adenoma (1,213 cases), recurrent adenoma (752 cases), and incident colorectal cancer (966 cases) among men and women, ages 55 to 74 years, randomly assigned to receive flexible sigmoidoscopy screening as part of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. We calculated odds ratios (ORs) and 95% CIs for adenoma incidence and recurrence, and hazard ratios (HRs) and 95% CIs for colorectal cancer incidence, using multivariable-adjusted models. Compared with normal-weight men (18.5 to 24.9 kg/m(2)), obese men (≥ 30 kg/m(2)) had significantly higher risk of incident adenoma (OR, 1.32; 95% CI, 1.06 to 1.65) and colorectal cancer (HR, 1.48; 95% CI, 1.16 to 1.89) and a borderline increased risk of recurrent adenoma (OR, 1.50; 95% CI, 0.98 to 2.30). No associations were observed for either adenoma or cancer in women. Data from this large prospective study suggest that obesity is important throughout the natural history of colorectal cancer, at least in men, and colorectal cancer prevention efforts should encourage the achievement and maintenance of a healthy body weight in addition to regular screenings.

757 Impact of Metabolic Syndrome on Incident or Recurrent Advanced Adenoma After Colonoscopy

Background & Aims: Microbiota has been shown to play a critical role in colorectal cancer (CRC). Most of CRC mucosa-associated Escherichia coli harbor the pks genomic island (pks+ E. coli) responsible for the synthesis of colibactin, a genotoxic compound able to promote colon tumorigenesis in a genetically susceptible mouse model. Our aim was to investigate the mechanisms underlying the tumorigenic activity of E. coli. Methods: Human intestinal epithelial cells HCT116 were infected with pks+ or pksE. coli. Cellular senescence and proliferation were assessed by β-galactosidase activity and MTT assay, respectively. Effect of growth factors secreted from infected cells on the proliferation of uninfected cells was assessed using specific neutralizing antibodies and inhibitors in vitro and in a xenograft mouse model. Human biopsies isolated from CRC tumors colonized with pks+ or pksE. coli were used to validate the experimental data. Results: A transient infection of HCT16 cells with pks+ E. coli increased tumor growth in the xenograft mouse model compared to pksE. coli infection, and the conditioned media derived from pks+ E. coli-infected cells stimulated the growth of uninfected cells. A pretreatment of the conditioned media with an anti-HGF antibody and inhibition of HGF receptor in the xenograft mouse model abolished the pro-proliferative effect of pks+ E. coli, indicating the involvement of the growth factor HGF. HGF was produced by pks+ E. coli-induced senescent cells, which is driven by posttranslational modification of p53 involving small ubiquitin-like modifier (SUMO) peptides. The pks+ E. coli-infected cells displayed a modified pattern of SUMO-conjugated proteins and decreased expression of the SUMO peptidase SENP1, a key regulator of SUMOylation. Over-expression of SENP1 in HCT116 cells abolished the deregulated SUMOylation, cellular senescence, HGF production and the pro-proliferative effect induced by pks+ E. coli infection. Finally, the human CRC tumors colonized by pks+ E. coli expressed a higher level of HGF and decreased SENP1 expression compared to those colonized by pksE. coli, supporting the pathological relevance of the in vitro data. Conclusions: Our study elucidates a new paradigm for the mechanism underlying the carcinogenesis mediated by colibactin-producing bacteria. We propose that those bacteria modulate tumor microenvironment by favoring the emergence of senescent cells, which in turn promote tumor growth by the secretion of growth factors, notably HGF.

No Association between Circulating Levels and Genetic Variants of IL-6 and TNF-α and Colon Adenoma

BackgroundInterleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α), two important inflammatory cytokines, have been inconsistently associated with risk of colon neoplasia in epidemiological studies. However, research to date has not adequately assessed whether race-specific differences may exist in associations between biomarkers and genetic variants of these cytokines and colorectal adenoma - the precursor lesions of colorectal cancer. We sought to determine whether circulating levels of IL-6 and TNF-α, or genetic polymorphisms in IL-6and TNF-α were associated with colon adenoma and if so, whether that association differed by race.MethodsWe analyzed the associations of circulating levels and single nucleotide polymorphisms (SNPs) of IL-6 and TNF-α with risk of colon adenomas in a colonoscopy -based case-control study of 401 incident adenoma cases and 1,050 controls. We used multivariate unconditional logistic regression models to estimate the odds ratios (OR) and 95% confidence intervals (95% CI) for levels or genotypes (log additive models) of IL-6 and TNF-α.ResultsCompared to the bottom tertile of IL-6, the adjusted ORs were 1.06 (0.75 - 1.44) and 1.01 (0.72 - 1.40), respectively for the 2nd and 3rd tertiles (Ptrend = 0.10); the corresponding ORs for TNF-α were: 0.85 (0.63 - 1.15) and 1.01 (0.75 - 1.36), respectively (Ptrend = 0.39). Race-stratified analyses did not reveal any significant associations. There were also no statistically significant associations between IL-6 and TNF-α SNPs and colon adenoma.ConclusionsOur results do not support pre-diagnostic levels of IL-6, TNF-α or their genetic variants as significant risk factors for the development of colon adenoma.