Theoretical basis validation and oxidative stress markers for cancer prevention clinical trials of aspirin.

Aspirin, a nonsteroidal anti-inflammatory drug, has been proven effective in a clinical trial of carcinogenesis blockade. However, various modes of action have been reported for these effects. Thus, in this study, we aimed to present reasonable mode of actions as a proof of concept for human trials, especially trials for patients with familial adenomatous polyposis (FAP). Aspirin treatment at 1000 ppm inhibited intestinal tumorigenesis in FAP model Min mice. As a mode of action, aspirin regulated ß-catenin signaling, inflammation, and oxidative stress both in vivo and in vitro. Furthermore, we examined novel markers predictive of aspirin treatment based on liquid biopsy. Here, we demonstrated that aspirin reduced the levels of reactive carbonyl species in the serum of Min mice. These data are expected to be of use for proof of concept of aspirin human trials and implied for the prediction of aspirin efficacy.

Azithromycin induces read-through of the nonsense Apc allele and prevents intestinal tumorigenesis in C3B6F1 ApcMin/+ mice.

Therapeutic strategies that promote read-through of a mutant gene have proved effective for certain non-neoplastic diseases. However, the efficacy of this approach is unproven regarding neoplastic diseases with germline nonsense mutations, including familial adenomatous polyposis. Here we examined the cancer-preventive efficacy of the macrolide antibiotic azithromycin, with a reported read-through effect, on intestinal tumorigenesis in C3B6F1 ApcMin/+ mice harboring a nonsense Apc mutation resulting in a truncated Apc protein. Mice were given drinking water lacking azithromycin or containing 0.0125-0.2 mg/mL azithromycin from 3 weeks of age. The small intestine and cecum were analyzed for pathological changes and alterations of intestinal flora. Azithromycin suppressed the number of tumors and the proportion of adenocarcinomas, with the most effective drinking-water concentration being 0.0125 mg/mL. Furthermore, azithromycin recovered the cellular level of full-length Apc, resulting in downregulation of ß-catenin and cyclin D1. Conversely, the effect of azithromycin on the diversity of the intestinal microbiota depended on the drinking-water concentration. These results suggest that the balance between azithromycin-mediate read-through of mutant Apc mRNA and antibacterial effects influences intestinal tumorigenesis. Thus, azithromycin is a potential anticancer agent for familial adenomatous polyposis patients harboring nonsense mutations.

Primary and Secondary Prevention Interventions to Reduce Risk Factors Associated with Colorectal Cancer in High-Risk Groups: a Systematic Literature Review.

In the USA, colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths. Certain groups in the USA are at an increased risk of developing CRC, including those with a genetic risk and family history. The purpose of this project was to synthesize primary and secondary prevention interventions for individuals who are at high risk of CRC due to family history or genetic predisposition. This study systematically reviewed articles from PubMed, Google Scholar, and EBSCO using specific search terms to find relevant articles. Sixteen articles were identified for full-text review, which were categorized as non-drug interventions (n = 7) and drug interventions (n = 9). Non-drug interventions focused primarily on increasing screening in those with a first-degree relative (FDR) with CRC or those with Lynch syndrome (LS). Interventions that increased CRC screening often had a tailored component and were otherwise varied in study designs and intervention type. Drug interventions focused on the use of NSAIDs on patients with familial adenomatous polyposis (FAP). Studies showed very little racial and ethnic diversity. Findings suggest that tailored interventions are particularly effective in increasing CRC screening, and greater diversity of sample is needed with respect to race and ethnicity.

[Risk and protective factors for colorectal cancer]. / Facteurs de risque et de protection du cancer colorectal.

RISK AND PROTECTIVE FACTORS FOR COLORECTAL CANCER Behaviour and environment play a more important role than heredity in colorectal carcinogenesis. The proportion of colorectal cancers (CRCs) attributable to occupational exposure, pollution or poor socio- economic status is low. The risk levels on which the French CRC screening recommendations are based are obsolete and need to be updated. An individual with one or two non-advanced adenomas resected at colonoscopy is at low risk of CRC. Only a first-degree family history of CRC in one parent before age 50 or in two parents at any age confers a significant increased risk. Certain diseases or situations that are sources of an increased risk of CRC were not previously considered: cystic fibrosis, radiotherapy and paediatric cancer survivors. New inherited predisposition syndromes associated with a very high risk of CRC have been described in addition to Lynch syndrome and familial adenomatous polyposis: MUTYH-associated polyposis, constitutional MMR deficiency, Lynch-like, PPAP and X syndromes. Half of all CRCs are related to modifiable risk factors associated with westernized lifestyle such as physical inactivity, junk food and obesity. There is nothing specific about dietary recommendations for the primary prevention of CRC: physical activity, limitation of red and processed meat, increase in dietary fibre and dairy products, limitation of alcohol and avoidance of tobacco. Finally, it is premature to use aspirin in primary prevention of CRC outside of Lynch syndrome and associated significant cardiovascular risk.

FACTEURS DE RISQUE ET DE PROTECTION DU CANCER COLORECTAL Comportement et environnement jouent un rôle plus important que l'hérédité dans la carcinogenèse colorectale. La part des cancers colorectaux (CCR) attribuable à une exposition professionnelle, à la pollution ou à un statut socio-économique défavorable est faible. Les niveaux de risque sur lesquels reposent les recommandations françaises de dépistage du CCR sont obsolètes et doivent être actualisés. Un individu ayant un ou deux adénomes non avancés réséqués lors d'une coloscopie est à risque faible de CCR. Seuls les antécédents familiaux au 1er degré de CCR chez un parent avant 50 ans ou chez deux parents quel que soit l'âge confèrent un surrisque significatif. Certaines maladies ou situations sources d'un sur-risque de CCR n'étaient pas prises en compte précédemment : mucoviscidose, radiothérapie et survivant de cancer pédiatrique. De nouveaux syndromes de prédisposition héréditaire associés à un risque très élevé de CCR ont été décrits en sus du syndrome de Lynch et de la polypose adénomateuse familiale : polypose associée à MUTYH, syndromes de déficience constitutionnelle du système MMR, Lynch-like, PPAP et X. La moitié des CCR sont liés à des facteurs de risque modifiables associés au mode de vie occidental tels que sédentarité, malbouffe et obésité. Les recommandations hygiéno-diététiques destinées à la prévention primaire du CCR n'ont rien de spécifique : activité physique, limitation des viandes rouges et charcuteries, augmentation des fibres alimentaires et produits laitiers, limitation de l'alcool et éviction du tabac. Enfin, il est prématuré d'utiliser l'aspirine en prévention primaire du CCR en dehors du syndrome de Lynch et d'un risque cardiovasculaire significatif associé.

The CHAMP-study: the CHemopreventive effect of lithium in familial AdenoMatous Polyposis; study protocol of a phase II trial.

BACKGROUND: Familial adenomatous polyposis (FAP) is a rare autosomal dominant disease characterized by germline mutations in the Adenomatous Polyposis Coli (APC) gene, resulting in the development of numerous colorectal adenomas. As these patients have a high risk of developing colorectal cancer (CRC), guidelines suggest prophylactic colectomy during early adulthood, however, adenoma development is still observed in the remaining intestinal tract. Therefore, FAP patients would benefit from chemoprevention strategies reducing the development of adenomas. Recent work in mice reveals a chemopreventive effect of lithium on the development of adenomas by inhibiting the expansion of Apc mutated intestinal stem cells (ISCs) within the crypts of normal intestinal mucosa. Here, we aim to investigate the effect of lithium on the spread of APC mutant cells within the human intestinal epithelium. METHODS: This prospective phase II single arm trial has a duration of 18 months. FAP patients (18-35 years) with a genetically confirmed APC mutation who did not undergo colectomy will be treated with lithium carbonate orally achieving a serum level of 0.2-0.4 mmol/l between month 6 and 12. Colonoscopy with biopsies of normal intestinal mucosa will be performed at baseline and every six months. The primary endpoint is the effect of lithium on the spread of APC mutant cells within intestinal crypts over time by using APC specific marker NOTUM in situ hybridization. Secondary endpoints include change in adenoma burden, patient reported side effects and safety-outcomes. Total sample size is 12 patients and recruitment will take place in the Amsterdam UMC, location AMC in the Netherlands. DISCUSSION: The outcome of this study will function as a proof-of-concept for the development of novel chemoprevention approaches that interfere with the competition between normal and mutant ISCs. TRIAL REGISTRATION: ClinicalTrials.gov ( https://clinicaltrials.gov/ ): NCT05402891 (June 1, 2022) and the EU Clinical Trials Register: EuraCT 2022-000240-30 (January 1, 2022).

Long-term chemoprevention in patients with adenomatous polyposis coli: an observational study.

Prospective short-term studies on effectiveness of non-steroidal anti-inflammatory drugs (NSAIDs) point towards a decrease in the number and size of polyps. Effectiveness and safety in the prevention of progression in familial polyposis with NSAIDs in long-term use, which is the prerequisite for therapeutic evaluation in prospective studies, is unknown. The total absolute observation period of 54 patients under sulindac was 399 patient years with a mean of 7.4 (2-19) years per patient. 36 patients (66.7%) showed a fast decrease of polyp burden, 8 (14.8%) were slow responders, and 9 (16.7%) had stable disease; one patient had a slow progression. Upper gastrointestinal (GI) polyp burden remained stable in 47% patients, increased in 31%, and improved in 22%. Advanced adenomas were found in 8 patients only within the first 5 years of chemoprevention, no patient developed desmoid disease, anamnestically evaluated on every follow-up. There were no life-threatening side-effects. Dosage and delivery pattern were essential for effectiveness. This study provides evidence that chemoprevention with sulindac is effective and safe and can, either alone or in combination with other drugs, become a long-term management option in cases of adenomatous polyposis. These results justify further long-term prospective chemoprevention studies to elaborate treatment protocols and guidelines.

Efficacy of Low-Dose Aspirin in Colorectal Cancer Risk Prevention is Dependent on ADH1B and ALDH2 Genotype in Japanese Familial Adenomatous Polyposis Patients.

Aspirin has gained great attention as a cancer preventive agent. Our previous study revealed that the low-dose aspirin prevents colorectal tumor recurrence in Japanese patients with colorectal adenomas and/or adenocarcinomas, whereas aspirin increases risks in smokers and has no effects on regular drinkers. Our recent study revealed that aspirin reduces polyp growth in Japanese patients with familial adenomatous polyposis (FAP). In this study, we have studied the association of genotypes of alcohol metabolizing enzymes (ADH1B and ALDH2) on aspirin's efficacy of suppressing polyp growth (≥5 mm) in a total of 81 Japanese patients with FAP. Our study revealed that aspirin showed significant preventive effects for patients with ADH1B-AA and AA+GA types [OR = 0.21; 95% confidence interval (CI), 0.05-0.95, and OR = 0.31; 95% CI, 0.10-0.95, respectively], and for patients with ALDH2-GG and GG+GA types (OR = 0.10; 95% CI, 0.01-0.92, and OR = 0.29; 95% CI, 0.09-0.94, respectively), but not for patients with ADH1B-GG and GA+GG types, and ALDH2-AA and GA+AA types. In addition, substantial preventive effects of aspirin were seen for patients with ADH1B-AA type who do not drink regularly (<3 times/week, OR = 0.11; 95% CI, 0.02-0.78), where a statistically significant interaction between aspirin and ADH1B was observed (P interaction = 0.036). Results from this exploratory study strongly indicate that aspirin is beneficial in prevention of polyp growth for patients with FAP with ADH1B-AA and AA+GA types, and ALDH2-GG and GG+GA types. Taken together, we propose ADH1B and ALDH2 as candidate markers for the personalized prevention by aspirin. Significance: Aspirin is beneficial to patients with FAP with ADH1B-AA and AA+GA types or ALDH2-GG and GG+GA types. ADH1B and ALDH2 genotypes can be the markers for the personalized prevention of colorectal cancer by aspirin.

Celecoxib Colorectal Bioavailability and Chemopreventive Response in Patients with Familial Adenomatous Polyposis.

Why celecoxib exerts chemopreventive activity in only some familial adenomatous polyposis (FAP) patients remains poorly understood. We conducted a phase II clinical study to identify potential predictive biomarkers for celecoxib chemopreventive activity in FAP. Twenty-seven patients with FAP completed a 6-month oral course of 400 mg of celecoxib twice a day; they underwent colonoscopies before and after celecoxib treatment to assess colorectal polyp tumor burden and to obtain normal and polyp colorectal biopsies to measure celecoxib, 13-S-hydroxyoctadecadienoic acid (13-HODE), 15-HETE, 12-HETE, and LTB4 levels by LC/MS-MS. Celecoxib levels in sera from those patients were also measured before treatment and after 2, 4, and 6 months of treatment. Nineteen of the 27 patients experienced a response to celecoxib, with a ≥ 28% reduction of colonic polyp burden on the basis of a reproducible quantitative assessment of colonoscopy results. Celecoxib levels were significantly lower in polyp tissues than in normal colorectal tissues. Celecoxib levels in sera and normal colorectal tissues were correlated in patients who experienced a response to celecoxib but not in those who did not. Among the measured lipoxygenase products, only 13-HODE levels were significantly lower in polyp tissues than in normal tissues. Our findings demonstrate the differential bioavailability of celecoxib between normal and polyp tissues and its potential effects on clinical response in patients with FAP. PREVENTION RELEVANCE: This study evaluated potential predictive biomarkers for celecoxib chemopreventive activity in patients with FAP. Our findings demonstrated the differential bioavailability of celecoxib between normal and polyp tissues and its potential effects on clinical chemopreventive response in patients with FAP. See related Spotlight, p. 205.

Artesunate inhibits intestinal tumorigenesis through inhibiting wnt signaling.

Artesunate (ART) is a clinically approved antimalarial drug and was revealed as a candidate of colorectal cancer chemopreventive agents in our drug screening system. Here, we aimed to understand the suppressive effects of ART on intestinal tumorigenesis. In vitro, ART reduced T-cell factor/lymphoid enhancer factor (TCF/LEF) promoter transcriptional activity. In vivo, ART inhibited intestinal polyp development. We found that ART reduces TCF1/TCF7 nuclear translocation by binding the Ras-related nuclear protein (RAN), suggesting that ART inhibits TCF/LEF transcriptional factor nuclear translocation by binding to RAN, thereby inhibiting Wnt signaling. Our results provide a novel mechanism through which artesunate inhibits intestinal tumorigenesis.

Chemoprevention in familial adenomatous polyposis: past, present and future.

Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer syndrome characterized by colorectal adenomas and a near 100% lifetime risk of colorectal cancer (CRC). Prophylactic colectomy, usually by age 40, is the gold-standard therapy to mitigate this risk. However, colectomy is associated with morbidity and fails to prevent extra-colonic disease manifestations, including gastric polyposis, duodenal polyposis and cancer, thyroid cancer, and desmoid disease. Substantial research has investigated chemoprevention medications in an aim to prevent disease progression, postponing the need for colectomy and temporizing the development of extracolonic disease. An ideal chemoprevention agent should have a biologically plausible mechanism of action, be safe and easily tolerated over a prolonged treatment period, and produce a durable and clinically meaningful effect. To date, no chemoprevention agent tested has fulfilled these criteria. New agents targeting novel pathways in FAP are needed. Substantial preclinical literature exists linking the molecular target of rapamycin (mTOR) pathway to FAP. A single case report of rapamycin, an mTOR inhibitor, used as chemoprevention in FAP patients exists, but no formal clinical studies have been conducted. Here, we review the prior literature on chemoprevention in FAP, discuss the rationale for rapamycin in FAP, and outline a proposed clinical trial testing rapamycin as a chemoprevention agent in patients with FAP.

Silymarin, boswellic acid and curcumin enriched dietetic formulation reduces the growth of inherited intestinal polyps in an animal model.

BACKGROUND: Some substances of plant origin have been reported to exert an effect in reducing intestinal neoplasm development, especially in animal models. Adenomatous polyposis coli multiple intestinal neoplasia - ApcMin/+ is the most studied murine model of genetic intestinal carcinogenesis. AIM: To assess whether an enriched nutritional formulation (silymarin, boswellic acid and curcumin) with proven "in vitro" and "in vivo" anti-carcinogenetic properties may prevent inherited intestinal cancer in animal model. METHODS: Forty adenomatous polyposis coli multiple intestinal neoplasia - ApcMin/+ mice were used for the study of cancer prevention. They were divided into two groups: 20 assumed standard and 20 enriched diet. At the 110th d animals were sacrificed. In each group, four subgroups received intraperitoneal bromodeoxyuridine injection at different times (24, 48, 72 and 96 h before the sacrifice) in order to assess epithelial turnover. Moreover, we evaluated the following parameters: Intestinal polypoid lesion number and size on autoptic tissue, dysplasia and neoplasia areas by histological examination of the whole small intestine, inflammation by histology and cytokine mRNA expression by real-time polymerase chain reaction, bromodeoxyuridine and TUNEL immuno-fluorescence for epithelial turnover and apoptosis, respectively. Additionally, we performed western blotting analysis for the expression of estrogen alpha and beta receptors, cyclin D1 and cleaved caspase 3 in normal and polypoid tissues. RESULTS: Compared to standard, enriched diet reduced the total number (203 vs 416) and the mean ± SD/animal (12.6 ± 5.0 vs 26.0 ± 8.8; P < 0.001) of polypoid lesions. In enriched diet group a reduction in polyp size was observed (P < 0.001). Histological inflammation and pro-inflammatory cytokine expression were similar in both groups. Areas of low-grade dysplasia (P < 0.001) and intestinal carcinoma (IC; P < 0.001) were significantly decreased in enriched diet group. IC was observed in 100% in standard and 85% in enriched formulation assuming animals. Enriched diet showed a faster epithelial migration and an increased apoptosis in normal mucosa and low-grade dysplasia areas (P < 0.001). At western blotting, estrogen receptor beta protein was well expressed in normal mucosa of enriched and standard groups, with a more marked trend associated to the first one. Estrogen receptor alpha was similarly expressed in normal and polypoid mucosa of standard and enriched diet group. Cleaved caspase 3 showed in normal mucosa a stronger signal in enriched than in standard diet. Cyclin D1 was more expressed in standard than enriched diet group of both normal and polypoid tissue. CONCLUSION: Our results are suggestive of a chemo-preventive synergic effect of the components (silymarin, boswellic acid and curcumin) of an enriched formulation in inherited IC. This effect may be mediated by the reduction of epithelial proliferation, the increase of apoptosis and the acceleration of villous cell renewal due to dietary formulation intake.

Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG).

Heritable factors account for approximately 35% of colorectal cancer (CRC) risk, and almost 30% of the population in the UK have a family history of CRC. The quantification of an individual's lifetime risk of gastrointestinal cancer may incorporate clinical and molecular data, and depends on accurate phenotypic assessment and genetic diagnosis. In turn this may facilitate targeted risk-reducing interventions, including endoscopic surveillance, preventative surgery and chemoprophylaxis, which provide opportunities for cancer prevention. This guideline is an update from the 2010 British Society of Gastroenterology/Association of Coloproctology of Great Britain and Ireland (BSG/ACPGBI) guidelines for colorectal screening and surveillance in moderate and high-risk groups; however, this guideline is concerned specifically with people who have increased lifetime risk of CRC due to hereditary factors, including those with Lynch syndrome, polyposis or a family history of CRC. On this occasion we invited the UK Cancer Genetics Group (UKCGG), a subgroup within the British Society of Genetic Medicine (BSGM), as a partner to BSG and ACPGBI in the multidisciplinary guideline development process. We also invited external review through the Delphi process by members of the public as well as the steering committees of the European Hereditary Tumour Group (EHTG) and the European Society of Gastrointestinal Endoscopy (ESGE). A systematic review of 10 189 publications was undertaken to develop 67 evidence and expert opinion-based recommendations for the management of hereditary CRC risk. Ten research recommendations are also prioritised to inform clinical management of people at hereditary CRC risk.

Identification of a Novel Candidate Gene for Serrated Polyposis Syndrome Germline Predisposition by Performing Linkage Analysis Combined With Whole-Exome Sequencing.

OBJECTIVES: Serrated polyposis syndrome (SPS) is a complex disorder with a high risk of colorectal cancer for which the germline factors remain largely unknown. Here, we combined whole-exome sequencing (WES) and linkage studies in families with multiple members affected by SPS to identify candidate genes harboring rare variants with higher penetrance effects. METHODS: Thirty-nine affected subjects from 16 extended SPS families underwent WES. Genome-wide linkage analysis was performed under linear and exponential models. The contribution of rare coding variants selected to be highly pathogenic was assessed using the gene-based segregation test. RESULTS: A significant linkage peak was identified on chromosome 3p25.2-p22.3 (maxSNP = rs2293787; LODlinear = 2.311, LODexp = 2.11), which logarithm of the odds (LOD) score increased after fine mapping for the same marker (maxSNP = rs2293787; LODlinear = 2.4, LODexp = 2.25). This linkage signal was replicated in 10 independent sets of random markers from this locus. To assess the contribution of rare variants predicted to be pathogenic, we performed a family-based segregation test with 11 rare variants predicted to be deleterious from 10 genes under the linkage intervals. This analysis showed significant segregation of rare variants with SPS in CAPT7, TMEM43, NGLY1, and FBLN2 genes (weighted P value > 0.007). DISCUSSION: Protein network analysis suggested FBLN2 as the most plausible candidate genes for germline SPS predisposition. Etiologic rare variants implicated in disease predisposition may be identified by combining traditional linkage with WES data. This powerful approach was effective for the identification of a new candidate gene for hereditary SPS.

Lower Gastrointestinal Conditions: Colorectal Cancer Screening and Prevention.

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second most common cause of cancer mortality worldwide. It was estimated that approximately 50,630 mortalities due to CRC would occur in the United States in 2018. Seventy percent of CRC originates from adenomatous polyps that become dysplastic over time. Risk factors for CRC include genetic syndromes, such as familial polyposis syndromes and Lynch syndrome; inflammatory bowel disease; dietary and lifestyle factors; and family history of advanced adenomas. The U.S. Preventive Services Task Force and the U.S. Multi-Society Task Force on CRC recommend screening beginning at age 50 years for patients at average risk. Multiple screening tools may be offered based on availability and patient comorbid conditions, personal preferences, and risk factors. In the United States, colonoscopy continues to be the screening modality of choice but is not without risks and adverse effects. Currently, genetic testing has no role in the screening of patients at average risk. Research into CRC prevention is ongoing but there currently are no recommended strategies other than adequate screening.

Hereditary Polyposis Syndromes: Opportunities for Early Detection in Individuals and Families

People with multiple polyps may have a germline mutation that places them at higher risk for developing colorectal, gastrointestinal, and other cancers. Genetic testing can often identify the specific polyposis syndrome and provide insight into appropriate recommendations for cancer prevention and early detection. Individuals with hereditary polyposis syndromes often begin developing polyps in their teenage years and require aggressive gastrointestinal surveillance to remove polyps. For some, the polyp burden will be too high to manage endoscopically and will require risk-reducing colectomies. Identification of individuals with hereditary polyposis syndromes may help to reduce morbidity and mortality.
.

Cyclic-GMP-Elevating Agents Suppress Polyposis in ApcMin mice by Targeting the Preneoplastic Epithelium.

The cGMP signaling axis has been implicated in the suppression of intestinal cancers, but the inhibitory mechanism and the extent to which this pathway can be targeted remains poorly understood. This study has tested the effect of cGMP-elevating agents on tumorigenesis in the ApcMin/+ mouse model of intestinal cancer. Treatment of ApcMin/+ mice with the receptor guanylyl-cyclase C (GCC) agonist linaclotide, or the phosphodiesterase-5 (PDE5) inhibitor sildenafil, significantly reduced the number of polyps per mouse (67% and 50%, respectively). Neither of the drugs affected mean polyp size, or the rates of apoptosis and proliferation. This was possibly due to increased PDE10 expression, as endogenous GCC ligands were not deficient in established polyps. These results indicated that the ability of these drugs to reduce polyp multiplicity was primarily due to an effect on nonneoplastic tissues. In support of this idea, ApcMin/+ mice exhibited reduced levels of endogenous GCC agonists in the nonneoplastic intestinal mucosa compared with wild-type animals, and this was associated with crypt hyperplasia and a loss of goblet cells. Administration of either sildenafil or linaclotide suppressed proliferation, and increased both goblet cell numbers and luminal apoptosis in the intestinal mucosa. Taken together, the results demonstrate that targeting cGMP with either PDE5 inhibitors or GCC agonists alters epithelial homeostasis in a manner that reduces neoplasia, and suggests that this could be a viable chemoprevention strategy for patients at high risk of developing colorectal cancer. Cancer Prev Res; 11(2); 81-92. ©2018 AACR.

Chemoprevention with Cyclooxygenase and Epidermal Growth Factor Receptor Inhibitors in Familial Adenomatous Polyposis Patients: mRNA Signatures of Duodenal Neoplasia.

To identify gene expression biomarkers and pathways targeted by sulindac and erlotinib given in a chemoprevention trial with a significant decrease in duodenal polyp burden at 6 months (P < 0.001) in familial adenomatous polyposis (FAP) patients, we biopsied normal and polyp duodenal tissues from patients on drug versus placebo and analyzed the RNA expression. RNA sequencing was performed on biopsies from the duodenum of FAP patients obtained at baseline and 6-month endpoint endoscopy. Ten FAP patients on placebo and 10 on sulindac and erlotinib were selected for analysis. Purity of biopsied polyp tissue was calculated from RNA expression data. RNAs differentially expressed between endpoint polyp and paired baseline normal were determined for each group and mapped to biological pathways. Key genes in candidate pathways were further validated by quantitative RT-PCR. RNA expression analyses of endpoint polyp compared with paired baseline normal for patients on placebo and drug show that pathways activated in polyp growth and proliferation are blocked by this drug combination. Directly comparing polyp gene expression between patients on drug and placebo also identified innate immune response genes (IL12 and IFNγ) preferentially expressed in patients on drug. Gene expression analyses from tissue obtained at endpoint of the trial demonstrated inhibition of the cancer pathways COX2/PGE2, EGFR, and WNT. These findings provide molecular evidence that the drug combination of sulindac and erlotinib reached the intended tissue and was on target for the predicted pathways. Furthermore, activation of innate immune pathways from patients on drug may have contributed to polyp regression. Cancer Prev Res; 11(1); 4-15. ©2017 AACRSee related editorial by Shureiqi, p. 1.

Randomized Controlled Trials in Hereditary Cancer Syndromes.

Conducting randomized controlled trials (RCTs) in patients with germline mutations in genes that predispose to adult-onset cancer is hampered by the rarity of these mutations, barriers to their identification, and challenges inherent to randomizing high-risk individuals as part of a clinical trial. Most of the clinically relevant RCTs have been conducted in 3 syndromes in only some of the high-risk genes for which clinical testing is currently available. This article reviews the surgical, screening, and chemoprevention RCTs in each of the syndromes in clinically relevant studies conducted in the past 10 years.

Chemoprevention of colorectal neoplasia.

BACKGROUND: Colorectal cancer is a common and often fatal malignancy. Currently, the modifications that alter disease outcome include early symptom recognition, population screening as well as improved surgical and adjuvant treatments. Preventative strategies have been limited with little evidence that lifestyle changes significantly alter risk. There is however a growing awareness of a potential role for chemoprevention in some patient groups. This study aimed to review the literature associated with chemoprevention in colorectal cancer. METHODS: An electronic literature search of MEDLINE and Embase databases was performed on PubMed for studies detailing the use of chemoprevention agents in colon and rectal cancer. The search was limited to clinical trials on adult humans (>16 years of age) published in English since 1990. RESULTS: The strongest evidence is for non-steroidal anti-inflammatory drugs slowing polyp progression, notably Sulindac and aspirin in patients with familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer, respectively. There is also increasing evidence that continuing use of low-dose aspirin reduces long-term incidence of colorectal cancers. Cyclooxygenase 2 inhibitors also have a potential role but cardiac toxicity currently limits their use. Folic acid, statins, antioxidants, calcium and 5-aminosalicylic acid lack evidence to support their use at present. CONCLUSIONS: Currently, there is not enough evidence to support the implementation of a chemopreventative agent for general use. However, there appears to be a role for aspirin in selected subgroups.