Optimizing Surveillance in Barrett’s Esophagus: From Chemoprevention and Biomarkers to Cost-effectiveness and Survival

__Abstract__ Barrett slokdarm is een premaligne aandoening waarbij patiënten een verhoogd risico hebben op het ontwikkelen van een adenocarcinoom van de slokdarm. Aan patiënten met een Barrett slokdarm wordt daarom surveillance geadviseerd. Het doel van dit proefschrift was te onderzoeken of toepassing van chemopreventie en biomarkers surveillance van patiënten met een Barrett slokdarm kan verbeteren. Daarnaast evalueerden we het effect van surveillance op kosteneffectiviteit en overleving. Zuurremming met proton pomp remmers speelt een belangrijke rol in de behandeling van patiënten met een Barrett slokdarm. In dit proefschrift laten we zien dat gebruik van proton pomp remmers het risico op het ontwikkelen van een adenocarcinoom met 75% verlaagd. Daarnaast laten we zien dat chemopreventie met NSAIDs en statines leidt tot een 50% verlaagd risico. Toepassing van biomarkers kan ook bijdragen aan de identificatie van hoog risico patiënten. In dit proefschrift laten we zien dat overexpressie van p53 is geassocieerd met een 5 keer verhoogd risico op het ontwikkelen van een adenocarcinoom en verlies van p53 expressie met een 14 keer verhoogd risico. Afwijkende p53 expressie blijkt een krachtiger voorspeller te zijn dan histologie. Daarnaast laten we zien dat expressie van Alpha-Methylacyl-CoA Racemase (AMACR) is geassocieerd met een 2 keer verhoogd r

Value of cyclin A immunohistochemistry for cancer risk stratification in Barrett esophagus surveillance A multicenter case-control study

The value of endoscopic Barrett esophagus (BE) surveillance based on histological diagnosis of low-grade dysplasia (LGD) remains debated given the lack of adequate risk stratification. The aim of this study was to evaluate the predictive value of cyclin A expression and to combine these results with our previously reported immunohistochemical p53, AMACR, and SOX2 data, to identify a panel of biomarkers predicting neoplastic progression in BE. We conducted a case–control study within a prospective cohort of 720 BE patients. BE patients who progressed to high-grade dysplasia (HGD, n=37) or esophageal adenocarcinoma (EAC, n=13), defined as neoplastic progression, were classified as cases and patients without neoplastic progression were classified as controls (n=575). Cyclin A expression was determined by immunohistochemistry in all 625 patients; these results were combined with the histological diagnosis and our previous p53, AMACR, and SOX2 data in loglinear regression models. Differences in discriminatory ability were quantified as changes in area under the ROC curve (AUC) for predicting neoplastic progression. Cyclin A surface positivity significantly increased throughout the metaplasia–dysplasia–carcinoma sequences and was seen in 10% (107/1050) of biopsy series without dysplasia, 33% (109/335) in LGD, and 69% (34/50) in HGD/EAC. Positive cyclin A expression was associated with an increased risk of neoplastic progression (adjusted relative risk (RRa) 2.4; 95% CI: 1.7–3.4). Increases in AUC were substantial for P53 (+0.05), smaller for SOX2 (+0.014), minor for cyclin A (+0.003), and none for AMARC (0.00). Cyclin A immunopositivity was associated with an increased progression risk in BE patients. However, compared to p53 and SOX2, the incremental value of cyclin A was limited. The use of biomarkers has the potential to significantly improve risk stratification in BE

Cyclooxygenase inhibitors use is associated with reduced risk of esophageal adenocarcinoma in patients with Barrett's esophagus: A meta-analysis

Background: Esophageal adenocarcinoma (EAC) has high mortality and is increasing in incidence. Barrett's esophagus (BE) increases the risk for EAC. Studies have reported inconsistent findings on the association between use of cyclooxygenase (COX) inhibitors and the risk of neoplastic progression in BE patients. Therefore, we performed a meta-analysis to investigate this association. Methods: A meta-analysis was undertaken among a total of 9 observational studies using fixed- and random-effects models, comprising 5446 participants; 605 had EAC or high-grade dysplasia (HGD). Results: Overall, COX inhibitors use was associated with a reduced risk of EAC/HGD among BE patients (relative risk (RR)=0.64, 95% confidence interval (CI)=0.53-0.77). Aspirin use also reduced the risk of EAC/HGD (RR=0.63, 95% CI=0.43-0.94), as well as non-aspirin COX inhibitors (RR=0.50, 95% CI=0.32-0.78). The chemopreventive effect seemed to be independent of duration response. Conclusions: Cyclooxygenase inhibitors use is associated with a reduced risk of developing EAC in patients with BE. Both low-dose aspirin and non-aspirin COX inhibitors are associated with a reduced risk of neoplasia. More well-designed randomised controlled trials are needed to increase our understanding of the chemopreventive effect of COX inhibitors

Aberrant P53 protein expression is associated with an increased risk of neoplastic progression in patients with Barrett's oesophagus

Objective: The value of surveillance for patients with Barrett's oesophagus (BO) is under discussion given the overall low incidence of neoplastic progression and lack of discriminative tests for risk stratification. Histological diagnosis of low-grade dysplasia (LGD) is the only accepted predictor for progression to date, but has a low predictive value. The aim of this study was therefore to evaluate the value of P53 immunohistochemistry for predicting neoplastic progression in patients with BO. Design: We conducted a case-control study within a prospective cohort of 720 patients with BO. Patients who developed high-grade dysplasia (HGD) or oesophageal adenocarcinoma (OAC) were classified as cases and patients without neoplastic progression were classified as controls. P53 protein expression was determined by immunohistochemistry in more than 12 000 biopsies from 635 patients and was scored independently by two expert pathologists who were blinded to long-term outcome. Results: During follow-up, 49 (8%) patients developed HGD or OAC. P53 overexpression was associated with an increased risk of neoplastic progression in patients with BO after adjusting for age, gender, Barrett length and oesophagitis (adjusted relative risks (RRa) 5.6; 95% CI 3.1 to 10.3), but the risk was even higher with loss o

Predictors for Neoplastic Progression in Patients With Barrett's Esophagus: A Prospective Cohort Study

OBJECTIVES: Patients with Barrett's esophagus (BE) have an increased risk of developing esophageal adenocarcinoma (EAC). As the absolute risk remains low, there is a need for predictors of neoplastic progression to tailor more individualized surveillance programs. The aim of this study was to identify such predictors of progression to high-grade dysplasia (HGD) and EAC in patients with BE after 4 years of surveillance and to develop a prediction model based on these factors. METHODS: We included 713 patients with BE (>= 2 cm) with no dysplasia (ND) or low-grade dysplasia (LGD) in a multicenter, prospective cohort study. Data on age, gender, body mass index (BMI), reflux symptoms, tobacco and alcohol use, medication use, upper gastrointestinal (GI) endoscopy findings, and histology were prospectively collected. As part of this study, patients with ND underwent surveillance every 2 years, whereas those with LGD were followed on a yearly basis. Log linear regression analysis was performed to identify risk factors associated with the development of HGD or EAC during surveillance. RESULTS: After 4 years of follow-up, 26/713 (3.4%) patients developed HGD or EAC, with the remaining 687 patients remaining stable with ND or LGD. Multivariable analysis showed that a known duration of BE of >= 10 years (risk ratio (RR) 3.2; 95% confidence interval (CI) 1.3-7.8), length of BE (RR 1.11 per cm increase in length; 95% CI 1.01-1.2), esophagitis (RR 3.5; 95% CI 1.3-9.5), and LGD (RR 9.7; 95% CI 4.4-21.5) were significant predictors of progression to HGD or EAC. In a prediction model, we found that the annual risk of developing HGD or EAC in BE varied between 0.3% and up to 40%. Patients with ND and no other risk factors had the lowest risk of developing HGD or EAC (= 10 years, longer length of BE, and presence of esophagitis. One or combinations of these risk factors are able to identify patients with a low or high risk of neoplastic progression and could therefore be used to individualize surveillance intervals in BE