Abstract
Barrett’s esophagus (BE) is an acquired disorder in which metaplastic columnar epithelium replaces the stratified squamous epithelium that normally lines the lower part of the esophagus. The disorder develops as a consequence of chronic gastroesophageal reflux disease and predisposes to the development of esophageal adenocarcinoma (EAC). EAC is strongly associated with BE and it has become increasingly common in developed countries over the last four decades. Endoscopic surveillance is one of the mainstays in the management of BE, however, whether only endoscopic surveillance leads to reduced mortality from EAC in patients with BE remains unclear. Since EAC is associated with poor outcomes even in earlier stages, BE represents an attractive target for chemoprevention. As gastric acid and duodenal bile reflux, obesity, diet and life, hypergastrinemia, Helicobacter pylori infection, and altered molecular mechanisms are possible important factors in pathogenesis of BE, they are also potential targets for chemoprevention to prevent or slow malignant transformation of BE. To date, different chemopreventive agents including proton pump inhibitors, aspirin/nonsteroid antiinflammatory steroids, ursodeoxycholic acid, statins, and metformin have been evaluated in preclinical and clinical studies. In the future, as our understanding of molecular mechanisms involved in BE oncogenesis improves, we hope to employ effective strategies in order to prevent or slow down neoplastic progression.
Keywords
Barrett’s esophagus, chemoprevention, aspirin, NSAID, statin, esophageal adenocarcinoma
14.1
Introduction
Barrett’s esophagus (BE) is an acquired condition in which a metaplastic columnar epithelium replaces the stratified squamous epithelium that normally lines the distal esophagus . Metaplasia commonly is a consequence of chronic inflammation, and intestinal metaplasia results from chronic reflux esophagitis caused by the gastroesophageal reflux of acid, bile, and other hazardous substances .
Approximately 5% of adult population in the United States is affected by BE . Esophageal adenocarcinoma (EAC) is strongly associated with BE and it has become increasingly common in developed countries over the last four decades. While the incidences of most malignancies are decreasing, incidence of EAC is increasing. Based on currently available data, the annual incidence of adenocarcinoma secondary to BE is estimated to range from 0.3% to 0.5% and the prognosis of EAC remains extremely poor, with a 5-year survival rates ranging from 15% to 39% . The lifetime risk of EAC in patients with BE was estimated as 10- to 125-fold higher than general population .
The most important risk factor for development of EAC is BE, and surveillance and early recognition of high-grade dysplasia (HGD) and/or EAC may improve survival .
Regular endoscopic surveillance is one of the mainstays in the management of BE . The aim of surveillance is to identify patients at a preclinical or asymptomatic early stage of cancer and initiate therapy leading to improved long-term outcomes. However, it is unclear whether only endoscopic surveillance leads to reduced mortality from EAC in patients with BE . Also, endoscopic surveillance of all patients with BE is expensive and more cost-effective methods are needed . Therefore, current strategies for improved management of EAC target identifying patients at high risk for progression to EAC and identifying chemopreventive agents. In light of the poor outcomes associated with EAC, combined with the presence of a readily identifiable precursor lesion, BE represents an attractive target for chemoprevention.
Chemoprevention refers to the use of chemical compounds to prevent the development and progression of dysplasia, as well as blocking the invasion of dysplastic epithelial cells throughout the basement membrane.
In contrast to the traditional therapeutic paradigms in EAC, chemoprevention is intended for generally healthy individuals. Therefore, several factors need to be considered prior to decision making. These factors include degree of dysplasia in BE, existing comorbidities, patient preferences, and local expertise. The risk of developing EAC increases progressively from 0.12% to 0.33% per year in nondysplastic to up to 20% chance of cancer per year in high-grade dysplastic BE . Thus, if the patient is relatively healthy with a low risk of progression, it is reasonable to use chemopreventive agents that have been considered safe for use. In this patient population, even a moderate reduction in cancer risk would translate into significant public health benefit as most patients with BE fall under this category. However, patients with preexisting HGD have a relatively higher risk of undergoing neoplastic transformation or a high probability that they may already have developed early EAC. In this patient group, it is important to use more effective chemopreventive treatment even if it carries a higher risk of adverse effects.
In this chapter, we will define suggested targets for chemoprevention of BE and review data about specific chemoprevention agents.
14.2
Suggested Targets and Strategies for Chemoprevention to Prevent or Slow Malignant Transformation of Barrett’s Esophagus
14.2.1
Gastric Acid and Bile Reflux
It is known that in patients with BE complicated with dysplasia and EAC, gastric acid and duodenal bile reflux are significantly more common than nondysplastic BE and GERD . Despite widespread use of acid-suppressing medications, the incidence of EAC is rising. This suggests that refluxed material other than acid might contribute to carcinogenesis . The controlling of reflux symptoms by medical or surgical (repair of lower esophageal sphincter (LES)) treatment do not prevent development of esophageal cancer . A probable explanation for this lack of efficacy is that despite medical treatment, bile reflux into the esophagus persists in approximately one out of three patients. Furthermore, reflux recurs within years of surgical fundoplication in a significant proportion of patients treated with fundoplication . More recently, in an ex vivo study , it was suggested that the pattern of gastric acid reflux may be an important determinant factor in the neoplastic progression of BE. In this study, it was shown that pulsed acid exposure increased cell proliferation but continuous acid exposure decreased cell proliferation .
In animal studies, it has been shown that the reflux of bilious intestinal juice alone is sufficient to cause esophageal cancer in rats . Studies in humans have shown that patients with BE have significantly more esophageal exposure to bile and significantly higher esophageal luminal concentrations of bile salts than patients who have GERD without BE .
In a study conducted on patients with BE , it was shown that deoxycholic acid (DCA) causes DNA damage and induces phosphorylation of proteins in the nuclear factor kappa B (NF-κB) signaling pathway in Barrett’s epithelial cells in vitro and in vivo. Authors also have reported that DCA-induced DNA damage and NF-κB pathway activation are mediated by the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). In addition, it was demonstrated that DCA-mediated activation of the NF-κB pathway allows Barrett’s epithelial cells to resist apoptosis in the setting of DNA injury, events which might contribute to neoplastic progression in BE.
Animal studies have shown that chronic gastric acid and/or bile exposure can lead to dysplasia and EAC. The mechanisms by which reflux causes chronic esophageal damage and induce carcinogenesis in BE are suggested as follows.
14.2.1.1
Chronic Injury and Inflammation
In animal model studies, it has been reported that normal cell volume regulatory mechanisms may be inhibited by gastric acid-induced mucosal injury . Reflux of duodenogastric contents (including bile acids) has been shown to cause esophageal damage in synergy with gastric acid in animal studies . These findings have also been confirmed in human studies . Reflux of bile parallels gastric acid and increases with the severity of GERD (BB). However, bile salts can cause esophageal damage in a wide range of pH. Glycine-conjugated bile salts cause damage in pH between 4 and 6, taurine-conjugated bile salts cause damage when the pH is lower than 4, while, unconjugated bile salts cause damage in neutral or alkaline pH states . Long-term use of PPIs lead to deconjugation of bile salts by bacterial colonization of the proximal intestine . In the alkaline pH state associated with PPI use, unconjugated bile salts cause chronic low-grade inflammation and induce carcinogenesis in BE .
14.2.1.2
Arachidonic Acid Pathway
Arachidonic acid pathway is a central regulator of inflammatory response. Gastric acid and duodenal bile acids may contribute to carcinogenesis in BE through activation of this pathway. Low pH and bile acids induce cyclooxygenase-2 (COX-2), which is a central enzyme of the arachidonic acid pathway both in the human BE ex vivo culture model and the EAC cell lines . Expression of COX-2 increases concomitantly with neoplastic progression in BE and this increase supports an association between the arachidonic acid pathway and the development of EAC . The COX-2 enzyme catalyzes conversion of arachidonic acid to different prostaglandins such as prostaglandin E2 (PGE2). PGE2 induces proliferation of Barret’s epithelial cells and its inhibition may slow their growth . PGE2-induced cell proliferation leads to accumulation of replicative errors in premalignant Barrett’s cells. Furthermore, it inhibits tumor surveillance through natural killer cell activity of PGE2. Chronic induction of PGE2 might facilitate accumulation of abnormal cells that have genomic instability and thus inhibition of components of arachidonic acid pathway probably will inhibit carcinogenesis .
14.2.1.3
Oxidative Stress
Bile acids can stimulate both esophageal squamous and Barrett’s epithelial cells to produce substances which can induce esophageal inflammation (ie, interleukin 8 (IL-8) and COX-2) and bile acids also can lead to oxidative stress and DNA damage in these cells .
Epidemiological, animal, and clinical studies suggest that BE develops as a result of injury induced by two major components of refluxate: gastric acid and bile acids. Bile acids in combination with gastric acid induce oxidative stress, DNA damage, and alterations in cell signaling. Moreover, bile acids may induce the expression of proteins associated with a phenotypic switch from normal squamous to intestinal phenotype such as Klf-4, villin, and CDX2 .
Gastric acid and bile salt injury induce ROS in BE . Moreover, decreased levels of glutation and vitamin C in the epithelium show that the antioxidant defense mechanisms are diminished in patients with BE . Low levels of antioxidant enzymes like glutathione- S -transferase and glutathione have been demonstrated in biopsies obtained from patients with BE and EAC. This change in oxidative tissue state promotes mutagenesis to induce neoplasia .
DNA damage incurred by free radicals causes mutations in key cell survival regulatory genes and induces carcinogenesis . In a normal individual, mutated cells do not further proliferate because they are forced to cell cycle arrest or apoptose by p53 . However, bile salts can inhibit this process via proteasome-mediated degradation of p53 . In conclusion, genetically abnormal cells accumulate and carcinogenesis progresses.
14.2.2
Obesity, Diet, and Lifestyle
In the last three decades, obesity has reached epidemic proportions in Western countries . Obese patients have a significantly increased risk of developing cancer . Approximately 14% of cancer-related deaths in men and 20% in women are partially attributed to obesity and the relative risk for EAC is increased in parallel to increased body mass index (BMI) (relative risk: 1.52 for each 5 kg/m 2 increase in BMI) . In a multicenter population-based case–control study, it was found that compared with subjects in the lowest 10% of usual BMI (<21.70 for men and <20.18 for women), risk of EAC increased fivefold among those in the highest decile (>29.54 for men and >31.25 for women) . There is a closer association between the risk of EAC and how the fat is distributed in the body, and the distribution of fat in the body is more important for EAC rather than only BMI . Risk of developing of EAC is higher in patients with increased waist to hip ratio, which is a surrogate measure of truncal obesity . In CT scan studies, it was reported that the excess visceral fat, compared to subcutaneous fat, more likely predict EAC risk . In diet studies, close association was reported between increased risk of EAC and higher consumption of dietary cholesterol and protein along with a decreased consumption of fiber, vitamins C, B6, E, folate, and beta-carotene .
Several mechanisms have been proposed through which obesity can facilitate carcinogenesis in BE .
14.2.2.1
Disruption of Antireflux Mechanisms
It has been suggested that by increasing abdominal or intraabdominal adiposity (representing visceral fat and other fats within the abdominal cavity), intraabdominal pressure increases in parallel to visceral obesity and this increase changes the relationship between gastroesophageal junction and diaphragmatic antireflux mechanisms. Studies conducted in obese patients reported that LES pressure is significantly lower compared to controls and obesity is associated with significant drop in LES pressure . Obese patients have also increased incidence of asymptomatic reflux . When the LES decreases below 10 mm Hg, this leads to reflux which causing injury, BE, and EAC .
14.2.2.2
Altered Composition of Refluxate and Mucosal Response to Reflux Injury
In a systematic review, it was reported that the concentration of carcinogenic bile acid in esophageal aspirate was higher in obese patients . In obesity, mucosal response to this reflux injury is changed along with the increased frequency of reflux episodes and alteration in composition of reflux .
Obesity causes a systemic and local proinflammatory condition where adipocytes release high concentration of inflammatory cytokines like tumor necrosis factor alpha (TNFα), IL6, IL1B, IL10, and CRP . Such cytokines lead to a proinflammatory state which has been suggested as an important association between obesity and different cancers including EAC .
14.2.2.3
Endocrine Disorders
Obesity is characterized by insulin resistance, high circulating levels of insulin, down regulation of adipokines like adiponectin and ghrelin as well as increased leptins . High-energy intake and excessive animal fat consumption and low fiber intake as well as physical inactivity contribute to insulin resistance and resulting hyperinsulinemia . Induction of the insulin/insulin-like growth factor (IGF) pathway in obese patients has been suggested in recent studies . Activation of IGF-1 receptors by insulin stimulates cellular proliferation and inhibits apoptosis via the oncogenic PI3K–AKT–mTOR–S6K1 signaling cascade which facilitates carcinogenesis in BE . Along with insulin/IGF, leptin also stimulates the proliferation of EAC cells and inhibits their apoptosis through PGE2-mediated activation of EGFR and activation of c-Jun NH2-terminal kinase . Adipokine signaling is also downregulated in metabolic syndrome and EAC has been correlated with the expression of adiponectin receptors .
14.2.3
Hypergastrinemia
Gastrin has trophic effects on gastric acid secretion and has been implicated in the regulation of cell survival as well as differentiation in the gastrointestinal tract . Gastrin-induced signaling by increasing COX-2 expression probably promotes carcinogenesis in BE . Compared to squamous epithelium of esophagus, Barrett’s mucosa expresses more CCK2 receptors and gastrin increases Barrett’s epithelial cell survival by inducing proliferation and inactivating proapoptotic factors to promote carcinogenesis .
Gastrin induces proliferation in Barrett’s metaplasia via prevention of apoptosis , activation of the cholecystokinin-2 receptor , and upregulation of COX-2 expression .
14.2.4
Helicobacter pylori Infection
Infection of the stomach with Helicobacter pylori causes chronic inflammation which can result in intestinal metaplasia and cancer in the stomach. However, H. pylori does not infect Barrett’s esophagus and there is no positive association between H. pylori infection and GERD. In contrast, studies have suggested that H. pylori infection may protect the esophagus from GERD and its complications like BE, perhaps by causing a chronic gastritis that interferes with acid production. H. pylori strains which express cytotoxin-associated gene A (cagA) appear to be important for damage to the stomach, and especially protective for the esophagus. However, a recent study that was controlled for potential confounders such as demographic factors, lifestyle factors, BMI, and smoking did not find a negative association between cagA positive H. pylori strains and EAC as had been expected . Despite the theoretical protective benefit, studies evaluating the association between BE and H. pylori infection have shown contradictory results . Although in vitro studies have shown that cagA expressing H. pylori strains leads to apoptosis in esophageal cancer cell lines , the clinical relevance of this finding remains unclear because H. pylori rarely colonize BE.
Therefore, protective role of H. pylori from EAC in BE remains uncertain. In EAC, the epidemiological evidence regarding the protective role of H. pylori is controversial.
H. pylori is also defined by World Health Organization (WHO) as a type I carcinogen for gastric cancer and therefore is not an optimal strategy for chemoprevention.
14.2.5
Molecular Alterations
The epigenetic alterations associated with the development of BE have been extensively studied. Caudal homeobox genes 1 (CDX1) and 2 (CDX2) are involved and are critical points in this process . Nuclear factor kappa B (NF-κB), fibroblast growth factor (FGF), bone morphogenetic protein 4 (Bmp4), and hedgehog and wnt pathways are related to CDX gene regulation . Moreover, p53 suppression which is a determinant of squamous phenotype may also be an important factor . There are multiple genes/pathways alterations in the BE and EAC development process. A partial list of altered genes/pathways in BE and EAC are shown in Table 14.1 .
| Barret’s Esophagus | Esophageal Adenocarcinoma |
|---|---|
| CDX1, CDX2 | |
| NF-κB targets | NF-κB targets |
| Genes in the mTOR pathway | Genes in the mTOR pathway |
| BMP4 | |
| RB pathway genes | |
| P53 | P53 |
| Ras pathway | Ras pathway |
| VEGF-related genes | VEGF-related genes |
| Cell cycle-related pathway genes | Cell cycle-related pathway genes |
| STAT-3 | STAT-3 |
| Sox 9 | Sox 9 |
| MMPs | MMPs |
| Wnt signaling | Wnt signaling |
| c-MET pathway | c-MET pathway |
14.3
Chemoprevention of Adenocarcinoma Associated with Barrett’s Esophagus
In light of the poor outcomes associated with EAC, combined with the presence of a readily identifiable precursor lesion, BE represents an attractive target for chemoprevention. Because the absolute risk of EAC is very low even in patients with BE , a viable chemoprevention strategy would have to be safe, inexpensive, and effective.
14.3.1
Proton Pump Inhibitors
GERD is a known primary risk factor for BE and EAC . PPIs, since the introduction of omeprazole in 1988, have been largely used for treatment of acid-related disorders, including BE. PPIs decrease secretion of gastric acid by inhibiting H + /K + ATPase of parietal cells and alleviate symptoms associated with acid reflux. Gastric acid suppression with PPI therapy plays a pivotal role in the management of symptoms in persons with chronic GERD and BE. Several epidemiologic studies suggest that acid suppression with PPIs has chemopreventive effects in patients with BE . In a meta-analysis, it was reported that PPI use in patients with BE was associated with a 71% reduced risk of progression to HGD or EAC . Although, clinical guidelines do not recommend gastric acid suppression as a means of cancer risk reduction for patients with BE, in daily clinical practice, PPIs have become de facto chemopreventive agents . Currently, almost all patients with BE under surveillance are prescribed PPIs .
Historically, PPIs have been considered safe medications. However, observational data suggest that chronic PPI use is associated with increased risks of bone fractures and of Clostridium difficile infection . Based on these data, the Food and Drug Administration has issued warnings regarding long-term use of PPIs and bone fracture and use of PPIs and C. difficile infection . However, given the observational nature of the data, physicians continue to prescribe PPIs to almost all patients with BE.
Although data obtained from clinical studies are lacking, epidemiologic studies suggest that PPI use in patients with BE has chemopreventive effects .
In a study, reported by El-Serag et al. , the development of dysplasia was compared in patients with BE treated with or without PPI or histamine 2 receptor antagonist (H2RA) over a 20-year time period. They found that the cumulative incidence of dysplasia was significantly lower among patients who received PPI after BE diagnosis than in those who received no therapy or H2RA. Furthermore, among those on PPIs, a longer duration of PPI use was associated with less frequent occurrence of dysplasia. In another study , Hillman et al. examined whether PPI therapy influences the incidence and progression of dysplasia in patients with BE. They found that ongoing PPI therapy appeared beneficial in the prevention of dysplasia and adenocarcinoma in patients with BE and suggested that all patients with this condition, even those with no esophagitis or symptoms, should be encouraged to continue long-term PPI therapy.
Many patients with BE have chronic reflux symptoms; PPIs have obvious therapeutic value in this group and therefore have benefits beyond potential EAC risk reduction. However, in two studies aimed at determining BE prevalence, approximately one half of patients with BE did not report a history of regular reflux symptoms . In a cost-effectiveness study, it was found that chemoprevention with PPIs in patients with BE without reflux is cost effective .
An important concern regarding long-term PPI use is that gastric acid suppression treatment with PPIs may lead to the bacterial overgrowth and increased reflux of toxic, unconjugated bile acids. This may result in increased cell DNA damage, mutations, and consequently to BE and EAC development . However, this issue remained uncertain and yet to be confirmed with epidemiological and randomized controlled trials. On the other hand, there is no significant association between EAC and the use of antisecretory agents per se .
In a retrospective observational study conducted on 344 patients with documented BE, authors performed COX regression analysis in order to examine the association between prescriptions for PPI, NSAID/aspirin or statins and the risk of developing esophageal dysplasia or EAC during follow-up (from 1982 to 2005). They found that after diagnosis of BE, 67.2% of the patients were prescribed PPI for a mean duration of 5.1 years. It was found that after BE diagnosis, PPI therapy was associated with a reduced risk of HGD or EAC and this association persisted after adjustment for gender, age, and the length of BE at time of diagnosis. They conclude that in patients with BE, PPI therapy reduces the risk of neoplasms. A nested case–control observational study in a cohort of patients with BE identified in a cohort of 11,823 patients with BE using PPI treatment might reduce the risk of developing EAC .
There are other additional observational studies which have demonstrated an association between PPI use and the reduced incidence of dysplasia in BE .
14.3.2
Aspirin/NSAIDs
The mechanism of EAC prevention is possibly related to inhibition of COX-2 production. Increased levels of COX-2 in esophageal epithelial cells have been observed in BE and noted to increase with disease progression from BE to EAC . In preclinical studies, COX-2 inhibitors inhibited the growth of BE cells, potentially through suppression of basic FGF . Another study confirmed that the end product of COX-2 conversion (prostaglandin E2) is reduced in patients with BE without HGD when using esomeprazole combined with higher doses of aspirin .
Epidemiologic data and animal studies suggest that aspirin and other NSAIDs which inhibit COX may protect against the development of BE or, in patients with established BE, the development of cancer in the chemoprevention of EAC. COX-2 inhibitors are a new class of NSAIDs that inhibit prostaglandin synthesis by selectively blocking the COX-2 enzyme. The COX-2 enzyme has been reported to be overexpressed in premalignant and malignant states, including BE and EAC . In BE-associated EAC cell lines, inhibition of COX-2 resulted in antiproliferative and proapoptotic effects . In a recent case–control study conducted on 434 patients with BE, patients who used aspirin were less likely to be diagnosed with BE compared with matched patients who did not use aspirin .
In a meta-analysis of published cohort studies that investigated the effect of aspirin on the development of EAC in patients with BE, it was estimated that there is an inverse association between aspirin use and EAC (OR 0.64, 95% CI 0.52–0.79) . A similar risk reduction was observed also for NSAIDs. With NSAID and/or aspirin use, reduced risk of EAC in patients with BE was shown in several observational studies and in a meta-analysis . Such observations provided the rational base for trials which have evaluated NSAIDs (also including COX-2 inhibitors) in EAC prevention in patients with BE . However, in a study investigating effect of celecoxib given for 48 weeks, no benefit was found regarding the progression of BE to dysplasia or cancer .
Although, NSAIDs are effective in preventing the progression of BE to EAC, it is not clear that the high cost and cardiovascular risks of the COX-2 selective NSAIDs will be justified for routine clinical use.
Aspirin is a cheap and nonselective NSAID that can prevent both cardiovascular and neoplastic complications, may be a useful chemopreventive agent if its protective effects can be demonstrated to outweigh its risks of gastrointestinal complications .
A phase III randomized study of aspirin and esomeprazole chemoprevention in BE (the ASPECT trial) is being conducted in the United Kingdom, however, the results are not expected to be available until after 2017.
It has been shown that aspirin with and without endoscopic surveillance is a cost-effective strategy . Choi et al. reported that chemoprevention with aspirin could be a cost-effective strategy when added to endoscopic surveillance for nondysplastic BE.
14.3.3
Ursodeoxycholic Acid
Reflux of bile acid into the esophagus induces esophagitis, inflammation-stimulated hyperplasia, BE, and EAC. Caudal-type homeobox 2 via NF-κB induced by bile acid is an important factor in the development of BE and EAC. Hydrophobic bile acids like DCA that cause oxidative DNA injury and activate NF-κB in Barrett’s metaplasia might contribute to carcinogenesis in BE .
A study conducted on Wistar rats , which underwent a duodenoesophageal reflux procedure, assessed whether UDCA may protect against the esophageal inflammation–metaplasia–carcinoma sequence by decreasing the overall proportion of the toxic bile acids. The rats were divided into two groups: one group was given commercial chow (control group) and the other was given experimental chow containing UDCA (UDCA group). After 40 weeks, the rats were sacrificed and their bile and esophagi were examined. They found that, in the UDCA group, the esophagitis was milder and the incidence of BE was significantly lower than in the control group, and EAC was not observed. Expression intensity of Cdx2 and NF-κB was found greater than in the UDCA group. Authors concluded that UDCA may be a chemopreventive agent against EAC by varying the bile acid composition.
In another study reported by Peng et al. , authors obtained biopsies of BE from 21 patients before and after esophageal perfusion with DCA at baseline and after 8 weeks of oral UDCA treatment. They found that UDCA increases expression of antioxidants that prevent toxic bile acids from causing DNA damage and NF-κB activation in Barrett’s metaplasia. In cells, they found that DCA-induced DNA damage and NF-κB activation were prevented by 24-hour pretreatment with UDCA, but not by mixing UDCA with DCA. They drew a conclusion that elucidation of the molecular pathway for UDCA protection provides rationale for clinical trials on UDCA for chemoprevention in BE.
14.3.4
Statins
Statins have antineoplastic effects through several pathways (both HMG-CoA reductase dependent and HMG-CoA reductase independent). The primary mechanism of action of statins on cholesterol reduction is by competitive inhibition of HMG-CoA reductase. This prevents posttranslational prenylation of the Ras/Rho superfamily, which is an important mediator of cell growth, differentiation, and survival . Due to obesity-associated lipid derangements, statins have also been studied for their potential role in chemoprevention in BE.
Statins, so-called 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are used for primary and secondary prevention of cardiovascular diseases. Recent observational data suggest that statins have protective effects against the development of cancers and may decrease the risk of cancers . In vitro and animal studies have shown that in addition to cholesterol reduction, statins have antiproliferative, proapoptotic, antiangiogenic, and immunomodulatory effects, which prevent cancer development and growth . This effect has also been shown in EC cell lines . Some recent observational studies have shown that statins may be associated with a lower risk of EC, particularly in patients with BE whereas others have shown no beneficial effect . Studies of human-derived EAC cell lines suggest that statins may offer exciting potential as chemopreventive agents in EAC, especially in BE .
It was shown that statins inhibit proliferation and induce apoptosis in EAC cells via inhibition of Ras farnesylation and inhibition of the ERK and Akt signaling pathways; thus, they may have some potential as chemopreventative agents in EAC, however, human studies are lacking .
In a recent retrospective observational study , Nguyen et al. examined data from 344 patients diagnosed with BE (mean age: 61 years, 90% Caucasian, 94% male) investigating the association between prescriptions for PPI, NSAIDs/aspirin or statins and the risk of developing esophageal dysplasia or adenocarcinoma during follow-up (from 1982 to 2005). After BE diagnosis, 25.3% were prescribed statins for a mean duration of 2.8 years. They found that while PPI treatment reduces the risk of neoplasms and NSAIDs/aspirin appear to reduce cancer risk in patients with BE, statin use was not significantly associated with lowering the risk of neoplasia in patients with BE.
However, in a recent systematic review with meta-analysis of existing randomized controlled trials and observational studies which investigated the association between statins and risk of development of EAC or progression of dysplasia in patients with BE , it was revealed that use of statins was associated with a statistically significant 43% reduction in development of EAC and/or HGD (unadjusted OR, 0.57; 95% CI, 0.44–0.75). This effect remained after adjustment for potential confounders, including use of NSAIDs/aspirin and length and dysplasia status of BE (adjusted OR, 0.59; 95% CI, 0.45–0.78). Authors found that the number needed to treat with statins to prevent one case of EAC per year in patients with BE was a dismal 389.
However, in a more recent population-based nested case–control study within a BE cohort from two primary care settings (located in the United Kingdom and Netherlands), authors aimed to estimate the risk of EAC among patients with BE exposed to NSAIDs, statins, and PPIs. In this study, drug use was assessed from BE diagnosis until study matching date. Controls were matched on age, sex, year of BO diagnosis and database. Authors found that statins did not significantly reduce the risk of HGD and EAC among patients with BE (OR for statin use >3 years, 0.5; 95% CI, 0.1–1.7). Although not statistically significant, authors found that there was a dose–duration–response seen for statins, with lower OR for longer duration of use compared with nonuse of statins. Higher doses of statins showed lower estimates for EAC and HGD. In a more recent study reported by Agrawal et al. in patients with BE and EAC during 20-year period, statin use was found to be protective against EAC in patients with BE ( p =0.001) .
Finally, in patients with multiple risk factors for EAC, statins may have a chemoprotective effect on dysplasia progression and development of EAC. However, there are no animal models that effectively mimic human disease in terms of risk factors, molecular pathogenesis, and response to interventions . Therefore, chemopreventive potential of statins in phase I/II trials is warranted.
14.3.5
Metformin
As outlined earlier, obesity is associated with neoplasia through several mechanisms, most likely via insulin-mediated cell pathways that affect cell proliferation. Metformin, a commonly used antidiabetic drug shown to be protective agent against different types of cancers, has been proposed to protect against obesity-associated cancers by decreasing serum insulin. However, there are few studies and limited data whether metformin is effective on chemoprevention of BE and EAC.
In a study which investigated patients with BE and EAC between 1992 and 2012, metformin use was neither associated with an increased nor a decreased risk of esophageal cancer . In another study that assessed the effect of metformin on phosphorylated S6 kinase (pS6K1), which is a biomarker of insulin pathway activation, 74 patients with BE (mean age 59 years, 58 men) were randomly assigned to two groups and given metformin daily ( n =38) or placebo ( n =36) for 12 weeks. Biopsy specimens were collected at baseline and at week 12 by upper endoscopy. The primary end point was percent changes in median levels of pS6K1 between subjects given metformin versus placebo. While it was found that metformin was associated with a significant reduction in serum levels of insulin as well as in homeostatic model assessments of insulin resistance (HOMA-IR), the percent changes in median level of pS6K1 did not differ significantly between two groups.
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