Search

ObjectiveVaccines against antigens expressed on adenomas could prevent new adenoma formation. We assessed whether a MUC1 peptide vaccine produces an immune response and prevents subsequent colonic adenoma formation.DesignMulticenter, double blind, placebo-controlled randomized trial in individuals age 40-70 with diagnosis of an advanced adenoma ≤1 year from randomization. Vaccine was administered at 0, 2, and 10 weeks with a booster injection at week 53. Adenoma recurrence was assessed ≥1 year from randomization. The primary endpoint was vaccine immunogenicity at 12 weeks defined by anti-MUC1 ratio ≥2.0.Results53 participants received the MUC1 vaccine and 50 placebo. 13/52 (25%) of MUC1 vaccine recipients had a ≥2-fold increase in MUC1 IgG (range 2.9-17.3) at week 12 vs. 0/50 placebo recipients (1-sided Fisher’s exact PConclusionAn immune response was observed only in vaccine recipients. Overall adenoma recurrence was not different than placebo, but a 38% absolute reduction in adenoma recurrence was observed in immune responders.ClinicalTrials.gov Identifier: NCT02134925.https://clinicaltrials.gov/ct2/show/NCT02134925Key PointsWhat is already knownAntigens expressed on colonic adenomas are potential targets for immunopreventive vaccines. An effective vaccine could prevent subsequent adenoma formation.What this Study AddsIn this multicenter, double blind, placebo-controlled randomized trial, MUC1 vaccine recipients developed an immune response. Overall adenoma recurrence was not different than placebo, but a 38% absolute reduction in adenoma recurrence was observed in immune responders.How this study might affect research, practice or policyVaccine immunoprevention is a potential new frontier to colorectal cancer prevention.

Chronic hepatitis C can lead to cirrhosis and hepatocellular carcinoma. We studied the safety and immunogenicity of a novel therapeutic hepatitis C virus (HCV) genotype 1a/1b consensus DNA vaccine, INO-8000, encoding HCV NS3, NS4A, NS4B, and NS5A proteins alone or co-administered with DNA-encoding IL12 (INO-9012), a human cytokine that stimulates cellular immune function, in individuals with chronic hepatitis C. This was a phase I, multisite dose-escalation trial with an expansion cohort evaluating doses of 0, 0.3, 1.0, and 3.0 mg of INO-9012 (IL12 DNA) as an addition to 6.0 mg of (INO-8000; HCV DNA vaccine). Vaccines were administered by intramuscular injection followed by electroporation at study entry and at weeks 4, 12, and 24. HCV-specific CD4+ and CD8+ T-cell immune responses were measured by IFNγ ELISpot and flow cytometry–based assays. Transient, mild-to-moderate injection site reactions unrelated to IL12 DNA dose were common. Increases in HCV-specific IFNγ production occurred in 15/20 (75%) participants. Increases in the frequency of HCV-specific CD4+ and CD8+ T cells occurred at all dose levels, with the greatest increases seen at 1.0 mg of INO-9012. HCV-specific CD8+ and CD4+ T-cell activities increased in 16/18 (89%) and 14/17 (82%) participants with available data, respectively. The vaccine regimen was safe and induced HCV-specific CD4+ and CD8+ cellular immune responses of modest magnitude in most HCV-infected participants. The addition of 1.0 mg of IL12 DNA provided the best enhancement of immune responses. The vaccine regimen had little effect on controlling HCV viremia.Prevention Relevance:The administration of IL12 DNA along with a hepatitis C viral antigen DNA vaccine enhanced the HCV-specific immune responses induced by the vaccine in individuals with chronic hepatitis C, an important cause of hepatocellular carcinoma. IL12 could be an effective adjuvant in vaccines targeting HCV and other oncogenic viruses.

ImportancePatients with familial adenomatous polyposis (FAP) are at markedly increased risk for duodenal adenomas and cancer. Combination sulindac and erlotinib was previously shown to reduce duodenal polyp burden but was associated with a relatively high adverse event (AE) rate. Objective: To evaluate if a once weekly dosing schedule for erlotinib intervention improves the AE profile, while still providing efficacy with respect to reduced polyp burden, in participants with FAP. Design, setting and participants: Single-arm trial, enrolling 46 participants with FAP, conducted from October 2017 to September 2019 in eight academic cancer centres.ExposuresParticipants self-administered 350 mg of erlotinib by mouth, one time per week for 6 months. Main outcomes and measures: Duodenal polyp burden (sum of polyp diameters) was assessed in the proximal duodenum by esophagogastroduodenoscopy performed at baseline and 6 months, with mean per cent change defined as the primary efficacy outcome of interest. Rate of grade 2–3 AEs was evaluated as a co-primary outcome. Secondary outcomes included changes in total duodenal polyp count, along with changes in lower gastrointestinal (GI) polyp burden and count (for participants examined by optional lower endoscopy).ResultsForty-six participants (mean age, 44.1 years (range, 18–68); women, 22 (48%)) were enrolled; 42 participants completed 6 months of intervention and were included in the per-protocol analysis. Duodenal polyp burden was significantly reduced after 6 months of weekly erlotinib intervention, with a mean per cent change of −29.6% (95% CI, −39.6% to −19.7%; pConclusionIn this single-arm, multi-centre trial of participants with FAP, erlotinib one time per week resulted in markedly lower duodenal polyp burden, and modestly reduced lower GI polyp burden, after 6 months of intervention. While AEs were still reported by nearly three-quarters of all participants, these events were generally lower grade and well-tolerated. These findings support further investigation of erlotinib as an effective, acceptable cancer preventive agent for FAP-associated GI polyposis.Trial registration numberNCT02961374.

Purpose:To assess whether MUC1 peptide vaccine produces an immune response and prevents subsequent colon adenoma formation.Patients and Methods:Multicenter, double-blind, placebo-controlled randomized trial in individuals age 40 to 70 with diagnosis of an advanced adenoma ≤1 year from randomization. Vaccine was administered at 0, 2, and 10 weeks with a booster injection at week 53. Adenoma recurrence was assessed ≥1 year from randomization. The primary endpoint was vaccine immunogenicity at 12 weeks defined by anti-MUC1 ratio ≥2.0.Results:Fifty-three participants received the MUC1 vaccine and 50 placebo. Thirteen of 52 (25%) MUC1 vaccine recipients had a ≥2-fold increase in MUC1 IgG (range, 2.9–17.3) at week 12 versus 0/50 placebo recipients (one-sided Fisher exact P < 0.0001). Of 13 responders at week 12, 11 (84.6%) responded to a booster injection at week 52 with a ≥2-fold increase in MUC1 IgG measured at week 55. Recurrent adenoma was observed in 31 of 47 (66.0%) in the placebo group versus 27 of 48 (56.3%) in the MUC1 group [adjusted relative risk (aRR), 0.83; 95% confidence interval (CI), 0.60–1.14; P = 0.25]. Adenoma recurrence occurred in 3/11 (27.3%) immune responders at week 12 and week 55 (aRR, 0.41; 95% CI, 0.15–1.11; P = 0.08 compared with placebo). There was no difference in serious adverse events.Conclusions:An immune response was observed only in vaccine recipients. Adenoma recurrence was not different than placebo, but a 38% absolute reduction in adenoma recurrence compared with placebo was observed in participants who had an immune response at week 12 and with the booster injection.

Background Information on Advanced Adenoma

supplementary methods: Detailed laboratory methods

Endpoint titers of plasma antibodies at week 12 amongst vaccine responders

Matched demographics of the selected SEER-Medicare population.

Significant morbidity and expense result from frequent recurrences of nonmuscle-invasive bladder cancer (NMIBC) after standard treatment, and carcinoma in situ (Tis) is a poor prognostic factor. Predicated on observational and preclinical data strongly supporting cyclooxygenase-2 (COX-2) in the pathogenesis, and the activity of COX-2 inhibitors, in bladder cancer, we conducted a randomized, double-blind, placebo-controlled trial to determine whether celecoxib could reduce the time-to-recurrence (TTR) in NMIBC patients at high risk for recurrence. A total of 146 patients were randomized to celecoxib (200 mg) or placebo orally twice daily for at least 12 months. The average treatment duration was 1.25 years. Primary intent-to-treat analysis revealed celecoxib did not statistically significantly prolong TTR compared with placebo (P = 0.17, log rank) with a median follow-up of 2.49 years. The recurrence-free rate at 12 months with celecoxib was 88% (95% CI: 0.81–0.96) versus 78% (95% CI: 0.69–0.89) with placebo. After controlling for covariates with Cox regression analysis, recurrence rates did not differ between the two study arms (HR = 0.69; 95% CI: 0.37–1.29). However, celecoxib had a marginally significant effect on reducing metachronous recurrences (vs. placebo) with HR of 0.56 (95% CI: 0.3–1.06; P = 0.075). Celecoxib was well tolerated, with similar adverse events and quality-of-life in both arms. Our clinical trial results do not show a clinical benefit for celecoxib in preventing NMIBC recurrence but further investigation of COX-2 inhibitors in this setting is warranted. Cancer Prev Res; 4(10); 1580–9. ©2011 AACR.

Perspective on This Article from A Randomized Controlled Trial of Celecoxib to Prevent Recurrence of Nonmuscle-Invasive Bladder Cancer

Supplemental Figure 1. Metformin effects on insulin, AMPK, mTOR

legend for supplementary figure 1

In animal models of hepatocellular carcinoma (HCC), deficiency of S-adenosylmethionine (SAMe) increased the risk of HCC whereas administration of SAMe reduced HCC. The aim of this trial was to determine whether oral SAMe administration to patients with hepatitis C cirrhosis would decrease serum α-fetoprotein (AFP) level, a biomarker of HCC risk in hepatitis C. This was a prospective, randomized, placebo-controlled, double-blind trial of SAMe, up to 2.4 g/d, for 24 weeks as compared with placebo among subjects with hepatitis C cirrhosis and a mildly elevated serum AFP. Primary outcome was change in AFP between baseline and week 24. Secondary outcomes included changes in routine tests of liver function and injury, other biomarkers of HCC risk, SAMe metabolites, markers of oxidative stress, and quality of life. One hundred ten subjects were randomized and 87 (44 SAMe and 43 placebo) completed treatment. There was no difference in the change in AFP during 24 weeks among subjects receiving SAMe as compared with placebo. Changes in markers of liver function, liver injury, and hepatitis C viral level were not significantly different between groups. Similarly, SAMe did not change markers of oxidative stress or serum glutathione level. SAMe blood level increased significantly among subjects receiving SAMe. Changes in quality of life did not differ between groups. Overall, this trial did not find that SAMe treatment improved serum AFP in subjects with advanced hepatitis C cirrhosis and a mildly elevated AFP. SAMe did not improve tests of liver function or injury or markers of oxidative stress or antioxidant potential. Cancer Prev Res; 8(9); 864–72. ©2015 AACR.

Supplemental Table 1: Change from Week 0 to Week 24 for routine blood tests of liver function or injury. Supplemental Table 2: Compliance with study medicine among 87 subjects who completed the study. Supplemental Table 3: Change from Week 0 to Week 24 in quality of life as assessed with SF-36 and CLDQ.

Supplementary Table Legends

Supplemental Figure 1a: SF-36. SF-36 mental component score among subjects randomized to SAMe or placebo, at baseline, Week 12 and Week 24. Supplemental Figure 1b: SF-36 physical component score among subjects randomized to SAMe or placebo, at baseline, Week 12 and Week 24. Only subjects with SF-36 at all three time points were included in the analysis. Supplemental Figure 2: CLDQ. Chronic liver disease questionnaire among subjects randomized to SAMe or placebo, at baseline, Week 12 and Week 24. Only subjects with CLDQ at all three time points were included in the analysis.

Supplementary Materials from Phase IIA Trial Testing Erlotinib as an Intervention against Intraductal Pancreatic Mucinous Neoplasms

Barrett's esophagus (BE), a recognized risk factor for esophageal adenocarcinoma (EAC), is routinely managed with proton pump inhibitors (PPIs) when symptomatic. Several lines of evidence suggest that PPIs may prevent malignant transformation. Chronic use of other common drugs, namely, statins nonsteroidal anti-inflammatory drugs (NSAIDs) and metformin, may also interfere with BE carcinogenesis, but confirmatory evidence is lacking. We identified 1,943 EAC cases and 19,430 controls (matched 10:1) between 2007 and 2013 that met our specified inclusion criteria in the SEER–Medicare database. Conditional logistic regression was used to generate odds ratios (OR) and 95% confidence intervals (95% CI). Wald χ2 tests were used to assess significance of covariates. Compared with controls, EAC cases had a higher prevalence of BE (26.2%). Use of PPIs, NSAIDs, statins, or metformin reduced the odds of EAC (PPIs: 0.10; 95% CI, 0.09–0.12; NSAIDs: 0.62; 95% CI, 0.51–0.74; statins: 0.15; 95% CI, 0.13–0.17; metformin: 0.76; 95% CI, 0.62–0.93). When stratified by BE, these associations persisted, though no association was found between NSAID use and EAC risk for participants with BE. Dual use of PPIs with NSAIDs or statins, and NSAID, statin, or metformin use alone also showed significant EAC risk reduction among all participants and those without BE. Use of PPIs alone and with NSAIDs, statins, or metformin was associated with reduced risk of EAC; however, a history of BE may diminish drug efficacy. These results indicate that common pharmacologic agents alone or in combination may decrease EAC development.Prevention Relevance: The use of common drugs, such as proton pump inhibitors, statins, non-steroidal anti-inflammatory drugs, or metformin, may reduce one's risk of developing esophageal adenocarcinoma. These results suggest that repurposing agents often used for common chronic conditions may be a new strategy for cancer prevention efforts.

Obesity is associated with risk of colorectal adenoma (CRA) and colorectal cancer. The signaling pathway activated by metformin (LKB1/AMPK/mTOR) is implicated in tumor suppression in ApcMin/+ mice via metformin-induced reduction in polyp burden, increased ratio of pAMPK/AMPK, decreased pmTOR/mTOR ratio, and decreased pS6Ser235/S6Ser235 ratio in polyps. We hypothesized that metformin would affect colorectal tissue S6Ser235 among obese patients with recent history of CRA. A phase IIa clinical biomarker trial was conducted via the U.S. National Cancer Institute-Chemoprevention Consortium. Nondiabetic, obese subjects (BMI ≥30) ages 35 to 80 with recent history of CRA were included. Subjects received 12 weeks of oral metformin 1,000 mg twice every day. Rectal mucosa biopsies were obtained at baseline and end-of-treatment (EOT) endoscopy. Tissue S6Ser235 and Ki-67 immunostaining were analyzed in a blinded fashion using Histo score (Hscore) analysis. Among 32 eligible subjects, the mean baseline BMI was 34.9. Comparing EOT to baseline tissue S6Ser235 by IHC, no significant differences were observed. Mean (SD) Hscore at baseline was 1.1 (0.57) and 1.1 (0.51) at EOT; median Hscore change was 0.034 (P = 0.77). Similarly, Ki-67 levels were unaffected by the intervention. The adverse events were consistent with metformin's known side-effect profile. Among obese patients with CRA, 12 weeks of oral metformin does not reduce rectal mucosa pS6 or Ki-67 levels. Further research is needed to determine what effects metformin has on the target tissue of origin as metformin continues to be pursued as a colorectal cancer chemopreventive agent.

The Chinese natural product, berberine, has biological properties that support its potential efficacy as a colon cancer prevention agent. Its longstanding use in China to treat gastrointestinal tract and rheumatologic disorders is generally regarded as safe, supporting initial investigations in an at-risk population, such as individuals with ulcerative colitis. However, the safety of berberine in this population is not established. Individuals living in China with biopsy-proven ulcerative colitis, ≤grade 2 dysplasia, and with a ulcerative colitis disease activity index (UCDAI) score ≤1 on mesalamine, were randomized 3:1 in a double-blind phase I trial to berberine 900 mg/day or placebo for 3 months, with the primary objective of assessing safety. Blood samples and biopsies of the colorectum, from prespecified locations, were collected prior to and following therapy. Secondary endpoints included changes in UCDAI score, and in tissue and plasma markers of inflammation. Of toxicities at least possibly related, one episode of grade 3 elevation in transaminases and one episode of grade 1 nausea were observed among 12 individuals on berberine, and none were observed among 4 on placebo. The mean plasma berberine concentration was 3.5 nmol/L after berberine treatment, significantly higher than 0.5 nmol/L with placebo. Berberine significantly decreased the Geboes grade in colonic tissue, but had a nonsignificant effect on other tissue or blood biomarkers related to cell growth and inflammation. The combination of berberine and mesalamine is well tolerated in Chinese with ulcerative colitis and may enhance mesalamine's anti-inflammatory effects in colonic tissue.

Objective Patients with Lynch syndrome (LS) are at markedly increased risk for colorectal cancer. It is being increasingly recognised that the immune system plays an essential role in LS tumour development, thus making an ideal target for cancer prevention. Our objective was to evaluate the safety, assess the activity and discover novel molecular pathways involved in the activity of naproxen as primary and secondary chemoprevention in patients with LS. Design We conducted a Phase Ib, placebo-controlled, randomised clinical trial of two dose levels of naproxen sodium (440 and 220 mg) administered daily for 6 months to 80 participants with LS, and a co-clinical trial using a genetically engineered mouse model of LS and patient-derived organoids (PDOs). Results Overall, the total number of adverse events was not different across treatment arms with excellent tolerance of the intervention. The level of prostaglandin E2 in the colorectal mucosa was significantly decreased after treatment with naproxen when compared with placebo. Naproxen activated different resident immune cell types without any increase in lymphoid cellularity, and changed the expression patterns of the intestinal crypt towards epithelial differentiation and stem cell regulation. Naproxen demonstrated robust chemopreventive activity in a mouse co-clinical trial and gene expression profiles induced by naproxen in humans showed perfect discrimination of mice specimens with LS and PDOs treated with naproxen and control. Conclusions Naproxen is a promising strategy for immune interception in LS. We have discovered naproxen-induced gene expression profiles for their potential use as predictive biomarkers of drug activity. Trial registration number gov Identifier: NCT02052908

Background and Aims: Current guidelines recommend surveillance for patients with nondysplastic Barrett's esophagus (NDBE) but do not include a recommended age for discontinuing surveillance. This study aimed to determine the optimal age for last surveillance of NDBE patients stratified by sex and level of comorbidity. Methods: We used 3 independently developed models to simulate patients diagnosed with NDBE, varying in age, sex, and comorbidity level (no, mild, moderate, and severe). All patients had received regular surveillance until their current age. We calculated incremental costs and quality-adjusted life-years (QALYs) gained from 1 additional endoscopic surveillance at the current age versus not performing surveillance at that age. We determined the optimal age to end surveillance as the age at which incremental cost-effectiveness ratio of 1 more surveillance was just less than the willingness-to-pay threshold of $100,000/QALY. Results: The benefit of having 1 more surveillance endoscopy strongly depended on age, sex, and comorbidity. For men with NDBE and severe comorbidity, 1 additional surveillance at age 80 years provided 4 more QALYs per 1000 patients with BE at an additional cost of $1.2 million, whereas for women with severe comorbidity the benefit at that age was 7 QALYs at a cost of $1.3 million. For men with no, mild, moderate, and severe comorbidity, the optimal ages of last surveillance were 81, 80, 77, and 73 years, respectively. For women, these ages were younger: 75, 73, 73, and 69 years, respectively. Conclusions: Our comparative modeling analysis illustrates the importance of considering comorbidity status and sex when deciding on the age to discontinue surveillance in patients with NDBE.

Barrett's esophagus (BE), a recognized risk factor for esophageal adenocarcinoma (EAC), is routinely managed with proton pump inhibitors (PPIs) when symptomatic. Several lines of evidence suggest that PPIs may prevent malignant transformation. Chronic use of other common drugs, namely, statins nonsteroidal anti-inflammatory drugs (NSAIDs) and metformin, may also interfere with BE carcinogenesis, but confirmatory evidence is lacking. We identified 1,943 EAC cases and 19,430 controls (matched 10:1) between 2007 and 2013 that met our specified inclusion criteria in the SEER–Medicare database. Conditional logistic regression was used to generate odds ratios (OR) and 95% confidence intervals (95% CI). Wald χ2 tests were used to assess significance of covariates. Compared with controls, EAC cases had a higher prevalence of BE (26.2%). Use of PPIs, NSAIDs, statins, or metformin reduced the odds of EAC (PPIs: 0.10; 95% CI, 0.09–0.12; NSAIDs: 0.62; 95% CI, 0.51–0.74; statins: 0.15; 95% CI, 0.13–0.17; metformin: 0.76; 95% CI, 0.62–0.93). When stratified by BE, these associations persisted, though no association was found between NSAID use and EAC risk for participants with BE. Dual use of PPIs with NSAIDs or statins, and NSAID, statin, or metformin use alone also showed significant EAC risk reduction among all participants and those without BE. Use of PPIs alone and with NSAIDs, statins, or metformin was associated with reduced risk of EAC; however, a history of BE may diminish drug efficacy. These results indicate that common pharmacologic agents alone or in combination may decrease EAC development. Prevention Relevance: The use of common drugs, such as proton pump inhibitors, statins, non-steroidal anti-inflammatory drugs, or metformin, may reduce one's risk of developing esophageal adenocarcinoma. These results suggest that repurposing agents often used for common chronic conditions may be a new strategy for cancer prevention efforts.

Background ASPirin in Reducing Events in the Elderly, a randomized, double-blind, placebo-controlled trial of daily low-dose aspirin (100 mg) in older adults, showed an increase in all-cause mortality, primarily due to cancer. In contrast, prior randomized controlled trials, mainly involving younger individuals, demonstrated a delayed cancer benefit with aspirin. We now report a detailed analysis of cancer incidence and mortality. Methods 19 114 Australian and US community-dwelling participants aged 70 years and older (US minorities 65 years and older) without cardiovascular disease, dementia, or physical disability were randomly assigned and followed for a median of 4.7 years. Fatal and nonfatal cancer events, a prespecified secondary endpoint, were adjudicated based on clinical records. Results 981 cancer events occurred in the aspirin and 952 in the placebo groups. There was no statistically significant difference between groups for all incident cancers (hazard ratio [HR] = 1.04, 95% confidence interval [CI] = 0.95 to 1.14), hematological cancer (HR = 0.98, 95% CI = 0.73 to 1.30), or all solid cancers (HR = 1.05, 95% CI = 0.95 to 1.15), including by specific tumor type. However, aspirin was associated with an increased risk of incident cancer that had metastasized (HR = 1.19, 95% CI = 1.00 to 1.43) or was stage 4 at diagnosis (HR = 1.22, 95% CI = 1.02 to 1.45), and with higher risk of death for cancers that presented at stages 3 (HR = 2.11, 95% CI = 1.03 to 4.33) or 4 (HR = 1.31, 95% CI = 1.04 to 1.64). Conclusions In older adults, aspirin treatment had an adverse effect on later stages of cancer evolution. These findings suggest that in older persons, aspirin may accelerate the progression of cancer and, thus, suggest caution with its use in this age group.

Background & Aims: Endoscopic treatment is recommended for patients with Barrett's esophagus (BE) with high-grade dysplasia, yet clinical management recommendations are inconsistent for patients with BE without dysplasia (NDBE) or with low-grade dysplasia (LGD). We used a comparative modeling analysis to identify optimal management strategies for these patients. Methods: We used 3 independent population-based models to simulate cohorts of 60-year-old individuals with BE in the United States. We followed up each cohort until death without surveillance and treatment (natural disease progression), compared with 78 different strategies of management for patients with NDBE or LGD. We determined the optimal strategy using cost-effectiveness analyses, at a willingness-to-pay threshold of $100,000 per quality-adjusted life-year (QALY). Results: In the 3 models, the average cumulative incidence of esophageal adenocarcinoma was 111 cases, with costs totaling $5.7 million per 1000 men with BE. Surveillance and treatment of men with BE prevented 23% to 75% of cases of esophageal adenocarcinoma, but increased costs to $6.2 to $17.3 million per 1000 men with BE. The optimal strategy was surveillance every 3 years for men with NDBE and treatment of LGD after confirmation by repeat endoscopy (incremental cost-effectiveness ratio, $53,044/QALY). The average results for women were consistent with the results for men for LGD management, but the optimal surveillance interval for women with NDBE was 5 years (incremental cost-effectiveness ratio, $36,045/QALY). Conclusions: Based on analyses from 3 population-based models, the optimal management strategy for patient with BE and LGD is endoscopic eradication, but only after LGD is confirmed by a repeat endoscopy. The optimal strategy for patients with NDBE is endoscopic surveillance, using a 3-year interval for men and a 5-year interval for women.

Difluoromethylornithine (DFMO), an inhibitor of polyamine synthesis, was shown to act synergistically with a NSAID for chemoprevention of colorectal neoplasia. We determined the efficacy and safety of DFMO plus aspirin for prevention of colorectal adenomas and regression of rectal aberrant crypt foci (ACF) in patients with prior advanced adenomas or cancer. A double-blinded, placebo-controlled trial was performed in 104 subjects (age 46–83) randomized (1:1) to receive daily DFMO (500 mg orally) plus aspirin (325 mg) or matched placebos for one year. All polyps were removed at baseline. Adenoma number (primary endpoint) and rectal ACF (index cluster and total) were evaluated at a one year colonoscopy. ACF were identified by chromoendoscopy. Toxicity was monitored, including audiometry. Eighty-seven subjects were evaluable for adenomas or ACF modulation (n = 62). At one year of treatment, adenomas were detected in 16 (38.1%) subjects in the DFMO plus aspirin arm (n = 42) versus 18 (40.9%) in the placebo arm (n = 44; P = 0.790); advanced adenomas were similar (n = 3/arm). DFMO plus aspirin was associated with a statistically significant reduction in the median number of rectal ACF compared with placebo (P = 0.036). Total rectal ACF burden was also reduced in the treatment versus the placebo arm relative to baseline (74% vs. 45%, P = 0.020). No increase in adverse events, including ototoxicity, was observed in the treatment versus placebo arms. While adenoma recurrence was not significantly reduced by one year of DFMO plus aspirin, the drug combination significantly reduced rectal ACF number consistent with a chemopreventive effect.

Prior research strongly implicates gastric acid and bile acids, two major components of the gastroesophageal refluxate, in the development of Barrett's esophagus and its pathogenesis. Ursodeoxycholic acid (UDCA), a hydrophilic bile acid, has been shown to protect esophageal cells against oxidative stress induced by cytotoxic bile acids. We conducted a pilot clinical study to evaluate the clinical activity of UDCA in patients with Barrett's esophagus. Twenty-nine patients with Barrett's esophagus received UDCA treatment at a daily dose of 13 to 15 mg/kg/day for 6 months. The clinical activity of UDCA was assessed by evaluating changes in gastric bile acid composition and markers of oxidative DNA damage (8-hydroxydeoxyguanosine), cell proliferation (Ki67), and apoptosis (cleaved caspase-3) in Barrett's esophagus epithelium. The bile acid concentrations in gastric fluid were measured by liquid chromatography/mass spectrometry. At baseline, UDCA (sum of unchanged and glycine/taurine conjugates) accounted for 18.2% of total gastric bile acids. After UDCA intervention, UDCA increased significantly to account for 93.4% of total gastric bile acids (P < 0.0001). The expression of markers of oxidative DNA damage, cell proliferation, and apoptosis was assessed in the Barrett's esophagus biopsies by IHC. The selected tissue biomarkers were unchanged after 6 months of UDCA intervention. We conclude that high-dose UDCA supplementation for 6 months resulted in favorable changes in gastric bile acid composition but did not modulate selected markers of oxidative DNA damage, cell proliferation, and apoptosis in the Barrett's esophagus epithelium. Cancer Prev Res; 9(7); 528–33. ©2016 AACR. See related article by Brian J. Reid, p. 512

Patients diagnosed with germline mutations in MMR genes (Lynch Syndrome, LS) have up to 70-80% lifetime risk of colorectal cancer. Therefore, this high-risk population has the potential to benefit from effective chemopreventive strategies. Naproxen is an NSAID widely used for pain treatment with an excellent safety profile that has demonstrated to be more efficacious preventing colorectal cancer compared to aspirin in vivo using an intestinal tissue-specific mouse model of LS (VC-Msh2-LoxP). The ‘Naproxen trial' was designed to evaluate the modulation of PGE2 levels in colorectal mucosa, evaluate safety and tolerability, and discover novel molecular pathways involved in the chemopreventive activity of naproxen in LS patients. Methods: Participants were randomized to naproxen 440 mg (HD), 220 mg (LD) and placebo by mouth daily for 6 months. Modulation of prostaglandin levels, number of adverse events (AEs) observed in each treatment arm and gene expression profiles by next-generation sequencing (mRNAseq) in normal colorectal mucosa of LS patients after 6 months of intervention were examined. Results: Eighty participants diagnosed with LS were randomized, 25 participants to HD, 27 to LD, and 28 to placebo. From these patients, 54 were considered evaluable per-protocol analysis: 16 in the HD group, 15 in the LD and 23 in placebo. The level of prostaglandin E2 in the colorectal mucosa decreased significantly after treatment with both LD and HD naproxen when compared to placebo (-91.2%±14.1, -93.6%±7.9, and 23.8%±108.4, P-value Citation Format: Laura Reyes Uribe, Wenhui Wu, Ozkan Gelincik, Prashant V. Bommi, Alejandro Francisco-Cruz, Luisa M. Solis, Patrick M. Lynch, Ramona Lim, Elena Stoffel, Priyanka Kanth, N. Jewel Samadder, Maureen E. Mork, Melissa W. Taggart, Ginger L. Milne, Lawrence J. Marnett, Lana Vornik, Diane D. Liu, Maria Revuelta, Kyle Chang, Y. Nancy You, Levy Kopelovich, Ignacio I. Wistuba, J. Jack Lee, Shizuko Sei, Robert H. Shoemaker, Eva Szabo, Ellen Richmond, Asad Umar, Marjorie Perloff, Powell H. Brown, Steven M. Lipkin, Eduardo Vilar. Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT111.

The incidence of esophageal adenocarcinoma (EAC), a debilitating and highly lethal malignancy, has risen dramatically over the past 40 years in the United States and other Western countries. To reverse this trend, EAC prevention and early detection efforts by clinicians, academic researchers and endoscope manufacturers have targeted Barrett's esophagus (BE), the widely accepted EAC precursor lesion. Data from surgical, endoscopic and pre-clinical investigations strongly support the malignant potential of BE. For patients with BE, the risk of developing EAC has been estimated at 11- to 125-fold greater than that of the individual at average risk. Nevertheless, screening for BE in symptomatic patients (ie, with symptoms of reflux) and surveillance in patients diagnosed with BE have not had a substantial impact on the incidence, morbidity or mortality of EAC; the overwhelming majority of EAC patients are diagnosed without a pre-operative diagnosis of BE. This article will discuss the current state of the science of esophageal adenocarcinoma prevention, including ideas about carcinogenesis and its underlying genomic and molecular level mechanisms, and suggest strategies for a systems approach to targeted preventive management.

Objective A major impediment to translating chemoprevention to clinical practice has been lack of intermediate biomarkers. We previously reported that rectal interrogation with low-coherence enhanced backscattering spectroscopy (LEBS) detected microarchitectural manifestations of field carcinogenesis. We now wanted to ascertain if reversion of two LEBS markers spectral slope (SPEC) and fractal dimension (FRAC) could serve as a marker for chemopreventive efficacy. Design We conducted a multicentre, prospective, randomised, double-blind placebo-controlled, clinical trial in subjects with a history of colonic neoplasia who manifested altered SPEC/FRAC in histologically normal colonic mucosa. Subjects (n=79) were randomised to 325 mg aspirin or placebo. The primary endpoint changed in FRAC and SPEC spectral markers after 3 months. Mucosal levels of prostaglandin E2 (PGE2) and UDP-glucuronosyltransferase (UGT)1A6 genotypes were planned secondary endpoints. Results At 3 months, the aspirin group manifested alterations in SPEC (48.9%, p=0.055) and FRAC (55.4%, p=0.200) with the direction towards non-neoplastic status. As a measure of aspirin9s pharmacological efficacy, we assessed changes in rectal PGE2 levels and noted that it correlated with SPEC and FRAC alterations (R=−0.55, p=0.01 and R=0.57, p=0.009, respectively) whereas there was no significant correlation in placebo specimens. While UGT1A6 subgroup analysis did not achieve statistical significance, the changes in SPEC and FRAC to a less neoplastic direction occurred only in the variant consonant with epidemiological evidence of chemoprevention. Conclusions We provide the first proof of concept, albeit somewhat underpowered, that spectral markers reversion mirrors antineoplastic efficacy providing a potential modality for titration of agent type/dose to optimise chemopreventive strategies in clinical practice. Trial Number NCT00468910

Background and aim Although Non-steroidal anti-inflammatory drugs reduce colorectal adenoma burden in familial adenomatous polyposis (FAP), the utility of combining chemopreventive agents in FAP is not known. We conducted a randomised trial of celecoxib (CXB) versus CXB+diflouromethylornithine (DFMO) to determine the synergistic effect, if any. Methods The primary endpoint was % change in adenoma count in a defined field. Secondary endpoints were adenoma burden (weighted by adenoma diameter) and video review of entire colon/rectal segments. Adverse event (AEs) were monitored by National Cancer Institution toxicity criteria. Results 112 subjects were randomised: 60 men and 52 women at a mean age of 38 years. For the 89 patients who had landmark-matched polyp counts available at baseline and 6 months, the mean % change in adenoma count over the 6 months of trial was −13.0% for CXB+DFMO and −1.0% for CXB (p=0.69). Mean % change in adenoma burden was −40% (CXB+DFMO) vs −27% (CXB) (p=0.13). Video-based global polyp change was −0.80 for CXB+DFMO vs −0.33 for CXB (p=0.03). Fatigue was the only significant AE, worse on the CXB arm (p=0.02). Conclusions CXB combined with DFMO yielded moderate synergy according to a video-based global assessment. No significant difference in adenoma count, the primary endpoint, was seen between the two study arms. No evidence of DFMO-related ototoxicity was seen. There were no adverse cardiovascular outcomes in either trial arm and no significant increase in AEs in the CXB+DFMO arm of the trial. Differences in outcomes between primary and secondary endpoints may relate to sensitivity of the endpoint measures themselves. Trial registration number ClinicalTrials.gov number N01-CN95040.

Chemoprevention represents an attractive modality against colorectal cancer (CRC) although widespread clinical implementation of promising agents (e.g. aspirin/NSAIDS) have been stymied by both suboptimal efficacy and concerns over toxicity. This highlights the need for better agents. Several groups, including our own, have reported that the over-the-counter laxative polyethylene glycol (PEG) has remarkable efficacy in rodent models of colon carcinogenesis. In this study, we undertook the first randomized human trial to address the role of PEG in prevention of human colonic neoplasia. This was a double-blind, placebo-controlled, three-arm trial where eligible subjects were randomized to 8g PEG-3350 (n = 27) or 17g PEG-3350 (n = 24), or placebo (n = 24; maltodextrin) orally for a duration of six months. Our initial primary endpoint was rectal aberrant crypt foci (ACF) but this was changed during protocol period to rectal mucosal epidermal growth factor receptor (EGFR). Of the 87 patients randomized, 48 completed study primary endpoints and rectal EGFR unchanged PEG treatment. Rectal ACF had a trend suggesting potentially reduction with PEG treatment (pre-post change 1.7 in placebo versus -0.3 in PEG 8+ 17g doses, p = 0.108). Other endpoints (proliferation, apoptosis, expression of SNAIL and E-cadherin), previously noted to be modulated in rodent models, appeared unchanged with PEG treatment in this clinical trial. We conclude that PEG was generally well tolerated with the trial failing to meet primary efficacy endpoints. However, rectal ACFs demonstrated a trend (albeit statistically insignificant) for suppression with PEG. Moreover, all molecular assays including EGFR were unaltered with PEG underscoring issues with lack of translatability of biomarkers from preclinical to clinical trials. This data may provide the impetus for future clinical trials on PEG using more robust biomarkers of chemoprevention. Trial registration: ClinicalTrials.gov NCT00828984

The incidence of esophageal adenocarcinoma (EAC) has been increasing steadily over the past few decades,1 despite widespread recognition of the problem and a vast body of research. This disease is believed to originate in the broadest sense from Barrett’s Esophagus (BE), the recognized precursor of EAC, but current methods for surveillance have not been found to be effective in defining patients at risk. While a number of molecular and cellular mechanisms that underlie the transformation of BE to EAC have been outlined, their utility in understanding and preventing the progression of this cancer or in managing the intervention-resistant clones has not been demonstrated in a number of proposed models. As the rate of progression of BE to EAC is very low, estimated at

Background: Immunoprevention via targeting antigens aberrantly expressed on colorectal cancers and adenomatous polyps offers the potential for a less invasive prevention strategy than endoscopic surveillance. Specificity of the immune response and long-term memory provide the potential for prolonged protection. Leveraging the infrastructure of the NCI-funded Cancer Prevention Network (CPN) consortium, we are conducting a double-blind randomized trial in individuals with a diagnosis of advanced colorectal adenomas within the previous year. We are evaluating MUC1 vaccine with the TLR-3 agonist polyICLC as an adjuvant, for its immunogenicity, ability to elicit immune memory and prevent recurrence of colorectal adenomas. Aims: We previously reported on the vaccine immunogenicity at week 12 (vaccine administered at 0, 2, and 10 weeks) compared to placebo. Here we report the ability of the vaccine to elicit long-term memory by measuring increase in anti-MUC1 antibody levels following a booster administered at one year. Methods: Subjects with endoscopically resected advanced adenoma (defined as ≥1cm, tubululovillous or villous histology, or with high grade dysplasia) were randomized. The primary endpoint was the response to the vaccine at week 12 assessed by monitoring anti-MUC1 IgG antibody titer ratio defined as t12/t0, where t0 was the titer pre-vaccination, and t12 was the titer at week 12. The key secondary endpoint was to assess anti-MUC1 IgG response at week 55 to a booster at week 52 in the vaccine arm compared to placebo. Results: 102 eligible subjects were randomized at 6 centers, 52 received MUC1 vaccine and 50 placebo. The mean age was 59.4±7.0 (range 40-70), 60.8% male, 88.2% white, and 18.6% Hispanic or Latino ethnicity. At 12 weeks the IgG ratio was ≥2.0 in 13/52 (25%) of individuals receiving vaccine (ratio range -0.5-17.3), vs. 0/50 in placebo group (2-sided p=.0001), and was ≥1.5 in 19/52 (36.5%) individuals receiving vaccine compared to 1/50 (2%) in placebo group (P Conclusions: Subjects with a recent history of advanced adenoma receiving a MUC1 vaccine compared with a placebo were significantly more likely to develop an immune response at week 12, confirming the vaccine’s immunogenicity, and to respond again at week 55 to a booster injection on week 52, confirming the vaccine’s ability to elicit immune memory. Follow-up colonoscopy to evaluate the vaccine’s potential to lower adenomatous polyp recurrence rates are in progress. Citation Format: Olivera J. Finn, Lisa Boardman, Marcia Cruz-Correa, Ajay Bansal, David Kastenberg, Chin Hurr, Sharon Kaufman, Colleen Akerley, Lynda Dzubinski, April Felt, Karrie Fursa, L.M. Rodriguez, Ellen Richmond, Asad Umar, Eva Szabo, John McKolanis, Ryan McMurray, Nathan Foster, Andres Salazar, Paul Limburg, Robert Schoen. Randomized, double-blind, placebo-controlled trial of preventative MUC1 vaccine in patients with newly diagnosed advanced adenomas: Results from one-year booster [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT236.

The clinical trials investigative team faces a number of challenges during the execution of a chemoprevention protocol that often depend on the phase of the trial. Phase II chemoprevention trials test promising agents for biomarker modulation in cohorts of 30 to 200 participants at greater than average risk of the cancer being studied who meet strict eligibility criteria. By contrast, phase III trials test agents for their efficacy in cancer prevention in thousands of participants who are generally healthy or may be at slightly elevated risk. Consideration must be given to accruing a very large cohort or a smaller but relatively rare group of participants, and to maintaining vigilance over the toxicity profile of the agent, which may be taken for a lengthy period of time. Additional considerations include clear communication to the participants of the risks and benefits associated with participating on the trial, as well as the need for their long-term commitment. In light of the layer of complexities that chemoprevention research adds to clinical trials, one or more team members need a unique set of skills and knowledge, beyond understanding the scientific aspects of the trial.

Background: Patients diagnosed with Lynch Syndrome (LS) have an approximately 70% lifetime risk of colorectal cancer (CRC) due to the presence of germline mutations in the mismatch repair (MMR) genes. Cyclooxygenases (COX) are key enzymes in the metabolism of Prostaglandins (PGs) being COX-2 induced at sites of inflammation as well as in ~85% of CRC and 50% of premalignant adenomas. Non-steroidal anti-inflammatory drugs (NSAIDs) such as Aspirin and Naproxen exert their therapeutic effects through the inhibition of both COX-1 and COX-2, which causes a reduction in PGs. However, other known non-canonical effects include inhibition of cell growth, induction of cell cycle arrest, and apoptosis. Aspirin has demonstrated chemopreventive properties in LS patients at high doses. Naproxen is widely used for the treatment of pain with an excellent safety profile. In addition, pre-clinical in vivo data using a genetically-engineered mouse model of Lynch Syndrome (Villin-Cre;Msh2LoxP/LoxP) has demonstrated that Naproxen is the most effective NSAID in preventing colorectal tumors and has shown to be superior to Aspirin. The present clinical trial was designed to assess the safety and tolerability of long-term chemoprevention with Naproxen in LS and also to discover novel biomarkers of drug activity. Methods: LS patients at 4 participating sites (The University of Texas MD Anderson Cancer Center, Dana Farber Cancer Institute, The University of Michigan Comprehensive Cancer Center, and Huntsman Cancer Institute) were randomly assigned to Naproxen 440 mg, 220 mg, or placebo once daily for 6 months. To determine the safety profile and tolerability of Naproxen, adverse events (AEs) were reported using CTCAE V4.03. To assess the activity of the drug intervention we measured Prostaglandin E2 (PGE2) levels in normal colorectal mucosa, its metabolite in urine (PGE-M), levels of Naproxen in plasma and colorectal mucosa at baseline and 6 months after treatment. Response to treatment was defined as 30% reduction in PGE2 levels. Results: A total of 86 patients were registered to this study, 28 randomized to Placebo, 25 to Naproxen 440 mg, and 27 to Naproxen 220 mg. Mean age was 44.6 years, 64% of the patients were females, 53% were unaffected carriers, and MLH1 and MSH2 were the most frequently mutated genes. Fifty-eight completed the study (67%). A total of 183 AEs were recorded in 61 patients, 77% were unrelated or unlikely related to the treatment, only 8 were reported as grade 3 AEs and none of these were related to Naproxen. In the group that received Naproxen at 440 mg, the levels of Naproxen in plasma and normal colorectal mucosa were the highest and the levels of PGE2 and PGE-M were significantly lower when compared to patients in the Placebo arm (P=0.027). In addition, the response rate was the highest among patients receiving Naproxen at 440 mg daily compared to Naproxen at 220 mg and Placebo (87.5% vs 75% vs 13%, respectively). Conclusions: The tolerance and safety of long-term chemoprevention with Naproxen at a dose of 440 mg for 6 months was excellent. There was evidence of decreased inflammatory activity among LS patients treated with high dose Naproxen compared to Placebo. Biomarker studies to discover novel non-canonical effects of Naproxen via modulation of miRNA and mRNA profiles using next-generation sequencing approaches are currently ongoing. Citation Format: Laura Reyes Uribe, Ramona Lin, Elena M. Stoffel, N. Jewel Samadder, Patrick Lynch, Priyanka Kanth, Ginger Milne, Lawrence J. Marnett, Valerie Sepeda, Diane D Liu, Y. Nancy You, Lana A. Vornik, J. Jack Lee, Ellen Richmond, Asad Umar, Marjorie Perloff, Steven M. Lipkin, Powel H. Brown, Eduardo Vilar-Sanchez. A phase Ib biomarker trial of naproxen in patients at risk for DNA mismatch repair deficient colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT065.

TPS1594Background: Colorectal cancer (CRC) remains the 4th most common cancer in the United States. Thus the identification of effective and safe prevention methods remains important. While long-te...

The Selenium and Vitamin E Cancer Prevention Trial (SELECT) was conducted to assess the efficacy of selenium and vitamin E alone and in combination on the incidence of prostate cancer. In this randomized, double-blind, placebo-controlled, 2×2 factorial design clinical trial, neither selenium nor vitamin E reduced the incidence of prostate cancer after seven years, and in fact, vitamin E was associated with a 17% increased risk of prostate cancer compared to placebo. The null findings were initially surprising given the preclinical and clinical evidence suggesting chemopreventive activity of selenium. These findings suggest that selenium and vitamin E do not prevent prostate cancer. Other potential explanations for the null findings include the agent formulation and dose, the characteristics of the cohort, and the study design. It is likely that only specific subpopulations may benefit from selenium supplementation; therefore, future studies should consider the baseline selenium status of the participants, age of the cohort, and genotype of specific selenoproteins, among other characteristics, in order to determine the activity of selenium in cancer prevention.

In animal models of hepatocellular carcinoma (HCC), deficiency of S-adenosylmethionine (SAMe) increased the risk of HCC whereas administration of SAMe reduced HCC. The aim of this trial was to determine whether oral SAMe administration to patients with hepatitis C cirrhosis would decrease serum α-fetoprotein (AFP) level, a biomarker of HCC risk in hepatitis C. This was a prospective, randomized, placebo-controlled, double-blind trial of SAMe, up to 2.4 g/d, for 24 weeks as compared with placebo among subjects with hepatitis C cirrhosis and a mildly elevated serum AFP. Primary outcome was change in AFP between baseline and week 24. Secondary outcomes included changes in routine tests of liver function and injury, other biomarkers of HCC risk, SAMe metabolites, markers of oxidative stress, and quality of life. One hundred ten subjects were randomized and 87 (44 SAMe and 43 placebo) completed treatment. There was no difference in the change in AFP during 24 weeks among subjects receiving SAMe as compared with placebo. Changes in markers of liver function, liver injury, and hepatitis C viral level were not significantly different between groups. Similarly, SAMe did not change markers of oxidative stress or serum glutathione level. SAMe blood level increased significantly among subjects receiving SAMe. Changes in quality of life did not differ between groups. Overall, this trial did not find that SAMe treatment improved serum AFP in subjects with advanced hepatitis C cirrhosis and a mildly elevated AFP. SAMe did not improve tests of liver function or injury or markers of oxidative stress or antioxidant potential. Cancer Prev Res; 8(9); 864–72. ©2015 AACR.