Introduction

Current surveillance for low-risk Barrett's Esophagus (BE) patients is burdensome, cost-ineffective and dependent on subjective histological assessment of dysplasia with high inter-observer variability. This study aims to identify genomic features that can be identified in a clinically translatable targeted sequencing panel, enhancing the stratification of low-risk BE patients and enabling personalized surveillance strategies.

Aims & Methods

BE patients identified as progressors to early esophageal adenocarcinoma or non-progressors from a large community-based cohort, were matched for age, sex and BE segment length. DNA from baseline and prior non-dysplastic biopsies was sequenced using a targeted capture-based panel designed to detect mutations and copy number changes (CNV). Detected mutations, homozygous deletions, and high-level amplifications were filtered for likely pathogenic events. We performed logistic regression, covariate analysis, and penalized mixed-effect models. A joint model for survival and mixed effects was implemented to analyze the data distributed over space and time.

Results

331 baseline samples and 214 temporal samples, accounting for 105 progressors who progressed after a median 4 (IQR 2.4-7.2) years, and 115 non-progressors who had a median progression-free follow-up of 6 (IQR 4.3-7.3) years, were analyzed. TP53 mutations strongly predict risk (p < 0.0001, Hazard Ratio (HR) = 3.84, 95% confidence interval (CI) 2.89-5.67) as does CNV 17p loss (p < 0.0001, HR = 4.41, 95% CI 2.29-8.52). While there is significant overlap between TP53 mutations and 17p loss, patients with both trended to progress faster. Chromosomal arm CNVs (p = 0.0012, HR = 1.32, 95% CI 1.14-1.52), amplifications (p < 0.001, HR = 2.89, 95% CI 1.57-5.31) and mutational burden (p<0.0001, HR = 1.30, 95% CI 1.21-1.40) were also associated with progression risk. A combined model incorporating: —TP53 mutations, 17p loss, and mutational burden—demonstrated a 57% sensitivity and 84% specificity and an AUC of 0.758. This model identified 60 of 105 progressors in non-dysplastic BE patients.

Conclusion

As expected, TP53 was a pivotal risk factor in this spatial and time-dependent cohort, even in the absence of dysplasia. Two hits in TP53 (mutation with 17p loss) suggested a trend toward near term progression, suggesting the possibility of more refined stratification. Prior studies focused on either mutations or CNVs for risk stratification. We show the combination of both, detected in a clinically translatable assay, improves prognostic value, effectively identifying the majority of progressors among non-dysplastic BE patients while maintaining an acceptable false-positive rate. This approach has the potential to dramatically impact risk stratification and surveillance strategies in non-dysplastic BE patients.

Supplementary Infographic ↗

Introduction

Eosinophilic esophagitis (EoE) is type-2 chronic inflammatory disorder usually accompanied by other atopic conditions including rhinitis, conjunctivitis, bronchial asthma, dermatitis, hives or chronic rhinosinusitis with nasal polyps. The influence of these atopies in the response to the EoE therapy has been barely investigated, with opposite results in small cohorts (1,2).

Aims & Methods

We aim to describe atopic concomitances in European EoE patients and to evaluate its influence on effectiveness of first-line therapy, consisting in proton-pump inhibitors (PPIs), swallowed topical corticosteroids (STCs) and food-elimination diets (FEDs).
A cross-sectional analysis of the multicenter EoE CONNECT registry (3) was performed. Demographic and clinical data from patients recruited at 42 hospitals in 4 European countries were extracted on March 25^th, 2025. Concomitant atopies were classified as seasonal or persistent. Clinico-histological response (CHR) was defined as the simultaneous presence of symptomatic remission and a peak eosinophil count <15 eosinophils per high power field after therapy.

Results

Overall, 3,900 patients (75.6% males, mean age 33.3 ±15.1 years) were analyzed (Table). CHR rate after first-line monotherapy with PPIs, STCs or FEDs was 50.4% (n=2,685). PPIs was the only treatment affected by concomitant atopy: presence of asthma and hives significantly reduced CHR rates to PPIs (42.7% vs 49.7%, p=0.005, and 39.3% vs 48%, p=0.044, respectively), and CHR also tended to be lower in presence of conjunctivitis (43.6% vs 48.4, p=0.067) and dermatitis (43.2% vs 48.3%, p=0.081). Seasonal or persistent presentation of atopy did not influence response to treatment. Taking into account age at diagnosis, the effect of concomitant atopy in reducing CHR to PPIs was exclusively observed in adults (≥18 years old) for asthma (43.8% vs 51.3%, p=0.007) and dermatitis (42.6% vs 50.3%, p=0.026), and in children (<18 years old) for hives (17.4% vs 39.9%, p=0.032).
We next analyzed whether the number of concomitant atopies influenced CHR to first-line therapy. While no differences were found among patients who presented only one atopic condition, the presence of 2 or more atopies reduced PPI effectiveness in adults (45.0% vs 50.7%, p=0.032) and to FEDs in children (23.5% vs 59.3%, p=0.020). A reduction in CHR rate after PPI therapy was even greater in adults with 3 or more atopies concomitant to EoE (39.0% vs 50.4%, p=0.001). Effectiveness of first-line STCs were not affected in any of these comparisons.

Conclusion

The coexistence of asthma, dermatitis and hives determined lower response to PPI therapy for EoE. Association of 2 or more atopic condition further decreased effectiveness of PPIs in adults and of FEDs in children.

References

1. Ancellin M, Ricolfi-Waligova L, Clerc-Urmès I, et al. Management of eosinophilic esophagitis in children according to atopic status: a retrospective cohort in northeast of France. Arch Pediatr. 2020;27(3):122-127.
2. Reed WD, Ocampo AA, Xue Z, et al. Eosinophilic esophagitis patients with multiple atopic conditions: clinical characteristics and treatment response to topical steroids. Ann Allergy Asthma Immunol. 2023;131(1): 109-115.e2.
3. Lucendo AJ, Santander C, Savarino E, et al. EoE CONNECT, the European Registry of Clinical, Environmental, and Genetic Determinants in Eosinophilic Esophagitis: rationale, design, and study protocol of a large-scale epidemiological study in Europe. Therap Adv Gastroenterol. 2022;15:17562848221074204.