Incidence Of Esophageal Adenocarcinoma Research Articles

There has been a rise in the incidence of esophageal adenocarcinoma (EAC) over the past five decades in the United States, and it remains a highly lethal malignancy due to frequent late-stage diagnosis. Barrett’s esophagus (BE), a well-established precursor to EAC, presents a critical window for early intervention through screening, surveillance, and endoscopic eradication therapy. Despite gastrointestinal society guideline recommendations for screening, the majority of patients with BE or early EAC remain undiagnosed until symptoms of late-stage cancer emerge. This review outlines current challenges and evolving strategies in the United States in BE detection and management, including risk stratification models, non-endoscopic screening tools, high-quality endoscopic techniques, tissue-based biomarkers, and artificial intelligence-enhanced imaging. We highlight best practices for surveillance, emphasizing the importance of thorough inspection of high-risk anatomic zones and the integration of advanced imaging. Endoscopic eradication therapy, including endoscopic mucosal resection and ablation, achieves high rates of complete eradication when performed with meticulous technique, especially with comprehensive treatment of the gastroesophageal junction and gastric cardia. Long-term surveillance remains essential due to the risk of recurrence. As new technologies continue to emerge, integrating precision tools into routine practice will be key to improving outcomes and reducing EAC mortality.

The incidence of esophageal adenocarcinoma (EAC) has been steadily rising in China, emphasizing the need for effective strategies in primary prevention and early detection. Emerging evidence suggests that tongue coating microbiota may play a significant role in gastrointestinal diseases. However, the alterations in tongue coating microbiota and associated metabolic pathways in Chinese EAC patients remain poorly understood. This case-control study analyzed tongue coating microbiota samples from 28 EAC patients and 28 age- and sex-matched control subjects. Microbiota composition and predicted metabolic functions were assessed using PICRUSt2. Alpha diversity was measured using the Shannon and Chao1 indices, and microbial taxa were compared between groups using the Wilcoxon signed-rank test. The Shannon index was significantly higher in the EAC group (P = .033), suggesting greater microbial diversity, while no significant difference was found in the Chao1 index (P = .50). The EAC group exhibited significant enrichment of Porphyromonas and Tannerella, while Rothia was significantly reduced. Predicted metabolic pathways, including pyrimidine metabolism, amino acid metabolism, and carbon metabolism, showed notable differences between the groups. This exploratory study highlights distinct alterations in tongue coating microbiota and metabolic functions in EAC patients, offering potential insights for the development of noninvasive diagnostic approaches for EAC.

S999 Divergent Trends in Esophageal Adenocarcinoma and Squamous Cell Carcinoma Incidence in the United States, 2000-2022

The incidence of esophageal adenocarcinoma (EAC), an aggressive cancer, is rising in Western countries, and incidence is higher in men. To better understand the roles of DNA copy number evolution, tumor heterogeneity, and tumor microenvironment in EAC and its origins, we evaluated EAC, Barrett's Esophagus (BE), and normal adjacent tissue using our previously developed ultra-sensitive, single-nucleus DNA copy number analysis (12,186 nuclei, 20 specimens) and single-nucleus RNA-sequencing (snRNA-seq; 87,027 nuclei, 32 specimens). Loss of Y (LOY) chromosome was rare in BE but markedly enriched in EAC. In genome unstable cells, complete LOY chromosome often coincided with X-chromosome duplication. We did not detect X-chromosome inactivation via XIST expression in cells with LOY, suggesting increased expression of X-chromosome genes and potential effects on tumor immune evasion. When considering patients' clinical features, we identified distinct differences in tumor microenvironment by sex, age, and obesity status, particularly massively reduced immune cell composition in obese patients. Finally, our cell line models recapitulate LOY, and we identify the first candidate anti-LOY agent. Our findings highlight how LOY affects tumor subpopulations and shapes the tumor microenvironment during EAC progression.

Background:The incidence of esophageal adenocarcinoma (EA) has significantly increased in developed Western countries. Despite medical advancements, the prognosis remains poor, with a 5-year survival rate of less than 20%. By 2024, the global incidence is expected to reach 141,300 new cases annually, underscoring the urgent need to elucidate the mechanisms underlying EA pathogenesis to develop effective preventive and therapeutic strategies.Methods:To identify differentially expressed genes (DEGs) linked to EA, microarray datasets sourced from the Gene Expression Omnibus (GEO) database were scrutinized, incorporating 4 datasets that met the defined criteria. Using expression quantitative trait loci and Mendelian randomization (MR) analyses, the contribution of genetic factors to EA development was evaluated. Functional pathways were explored using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis, which revealed enrichment in lipid metabolism. Consequently, Bayesian-weighted MR analysis was performed on 179 plasma lipid subgroups.Results:We identified 492 DEGs, 211 of which were downregulated and 281 were upregulated. The MR analysis identified 178 genes with significant causal effects on EA. Four co-expressed genes were ultimately determined: FZD2, KRT23, and CES1 were significantly upregulated in EA and positively associated with its occurrence, whereas ALDOC (aldolase, fructose-bisphosphate C) was inversely associated with EA risk. Elevated levels of sphingomyelins, sterol esters, diacylglycerols, and triacylglycerols were linked to a reduced risk of EA, whereas high levels of phosphatidylethanolamine correlated with a heightened risk.Conclusions:Integration of DEGs, expression quantitative trait loci, and lipidomics data provides robust insights into the molecular mechanisms of EA. These findings provide a promising foundation for the development of novel targeted therapies.

Barrett esophagus (BE) is the only known histological precursor to esophageal adenocarcinoma (EAC). The incidence of EAC has risen significantly over the past 4 decades in the United States and other Western countries, and the prognosis of EAC remains poor, with over half of individuals diagnosed at a late stage. Despite this, fewer than 1 in 5 eligible individuals undergo endoscopic screening for BE. Current screening practices rely on upper endoscopy, limiting widespread adoption and missing a significant portion of at-risk individuals. Recent technological advancements in minimally invasive screening modalities have the potential to expand screening efforts, improve detection rates, and reduce healthcare resource utilization. This review discusses the conceptual underpinnings and hurdles to successful screening for EAC and BE, evaluates newer technologies for screening, including nonendoscopic cell collection devices, blood-based biomarkers, transnasal endoscopy, and exhaled volatile organic compounds, and examines emerging methods for enhancing detection of dysplasia and intestinal metaplasia, including artificial intelligence and wide area transepithelial sampling. The value of screening in light of a recent randomized trial of surveillance from the United Kingdom, as well as a landmark study on nonendoscopic risk stratification for dysplasia in BE, are considered. While direct evidence linking screening to reduced EAC mortality is lacking, trials highlight promising outcomes in early detection of precancerous and cancerous lesions. Future directions, challenges, and recommendations for optimizing BE screening are discussed.

Background and purposeEsophageal cancer (EC) histological subtypes have contrasting incidence trends according to previous studies. In high-income countries, the incidence of esophageal squamous cell carcinoma (SCC) has decreased, while the incidence of esophageal adenocarcinoma (AC) has increased. This descriptive registry-based study evaluates incidence trends by EC subtype in Finland during 2000–2021.Material and methodsData on all EC cases by histological subtype, sex and 10-year age group diagnosed over the period 2000–2021 was obtained from the Finnish Cancer Registry. In total, 6,482 cases (2,604 AC, 2,979 SCC) were observed. Time trends by histology, sex and age group were evaluated with Poisson regression and joinpoint regression.ResultsEC incidence in men increased by an annual percentage change (APC) of 1.3 (95% confidence intervals [CI] 0.8–1.8) while no significant increase was observed in women with APC of -0.1, 95% CI -0.8–0.6). Incidence of AC in men increased with APC of 3.5 (95% CI 2.7–4.2) and by 2.0 (95% CI 0.4–3.6) in women. No consistent trends were observed in SCC incidence although in joinpoint regression, from 2000 to 2006 SCC incidence decreased in men by APC of -6.5 (95% CI -20.3 to -1.1). From 2006 to 2021, rates plateaued with APC of 0.9 (95% CI -0.4 to 7.2). No other joinpoints were identified.InterpretationEC incidence increased in Finland during 2000–2021 due to an increase in AC. Incidence of AC increased more than threefold in men, with a lesser increase in women. SCC incidence declined until 2006 and plateaued thereafter.

Neoplasia Detection Rate and Risk of Post-endoscopy Esophageal Adenocarcinoma and Neoplasia in a Population-based Cohort Study.

Esophageal adenocarcinoma (EAC) has increased substantially to become the most common type of esophageal cancer in the United States, surpassing esophageal squamous cell carcinoma (ESCC). Whether the increasing incidence of EAC is linked to trends in esophageal cancer mortality is unclear. We analyzed esophageal cancer data from the Surveillance, Epidemiology, and End Results-12 cancer registry program, using Joinpoint regression for trend analysis and a decomposition method to attribute changes to population growth, population aging, and epidemiological changes. Age–period–cohort models were employed to estimate incidence and mortality through 2044. Between 1992 and 2019, 39,700 individuals were diagnosed with esophageal cancer, and 35,259 deaths were recorded from 1993 to 2019. The overall incidence of esophageal cancer declined [average annual percent change (AAPC), − 0.7%], but the incidence of EAC increased by an AAPC of 1.6% per year (P < 0.001) from 1992 to 2019. The overall mortality rates decreased by an annual percentage change of 1.0% [95% confidence intervals − 1.2% to − 0.7%] from 1998 to 2019, primarily related to decline in ESCC in 1996–2019. The mortality of EAC increased by an AAPC of 2.2% per year (P < 0.001) over the study period and increased for all demographic characteristic groups. Population aging and growth largely explain the increase in esophageal cancer over the last 3 decades. Future projections (2019–2044) suggest a 31% increase in incidence and deaths, with EAC rates continuing to rise (AAPC, 0.25; 95% CI 0.23–0.28). The number of esophageal cancer cases and deaths have significantly increased and projections indicate that this trend will continue. Effective measures must be taken to address the burden of esophageal cancer.

Gastroesophageal reflux disease (GERD) is associated with inflammatory and neoplastic changes in the esophageal epithelium. Despite widespread PPI use, esophageal adenocarcinoma (EAC) incidence continues to rise, implicating non-acidic reflux components such as pepsin in disease progression. We performed transcriptomic profiling to assess pepsin-induced changes and the protective effect of amprenavir in vitro. Het-1A (normal) and BAR-T (Barrett’s) cells (n = 3) were treated at pH 7.0 with pepsin and/or 10 μM amprenavir for 1 h. RNA-seq identified DEGs (FDR ≤ 0.05, |log₂FC| ≥ 0.375), and Ingenuity Pathway Analysis revealed enriched pathways. Pepsin exposure altered mitochondrial function, oxidative phosphorylation, epithelial integrity, signaling, and inflammatory pathways in both cell lines. Amprenavir attenuated these transcriptomic perturbations, preserving mitochondrial and stress-response pathways. Notably, BAR-T cells exhibited heightened activation of wound-healing and epithelial repair pathways, whereas Het-1A cells showed greater mitochondrial and systemic stress pathway alterations. Pepsin drives transcriptomic dysregulation in esophageal epithelial cells under non-acidic conditions, and amprenavir shows potential to counteract peptic injury. Further studies are needed to validate these findings and explore amprenavir’s therapeutic utility in GERD management and EAC prevention.

Background: Esophageal adenocarcinoma (EAC) diagnosis involves invasive and expensive endoscopy with biopsy, but rising EAC incidence has not been reduced by increased surveillance. This study aimed to develop and clinically validate a novel glycoprotein biomarker blood test for EAC, named PromarkerEso. Methods: Serum glycoprotein relative concentrations were measured using a lectin-based magnetic bead array pulldown method, with multiple reaction monitoring mass spectrometry in 259 samples across three independent cohorts. A panel of glycoproteins: alpha-1-antitrypsin, alpha-1-antichymotrypsin, complement C9 and plasma kallikrein, were combined with clinical factors (age, sex and BMI) in an algorithm to categorize the samples by the risk of EAC. Results: PromarkerEso demonstrated a strong discrimination of EAC from the controls (area under the curve (AUC) of 0.91 in the development cohort and 0.82 and 0.98 in the validation cohorts). The test exhibited a high sensitivity for EAC (98% in the development cohort, and 99.9% and 91% in the validation cohorts) and a high specificity (88% in the development cohort, and 86% and 99% in the validation cohorts). PromarkerEso identified individuals with and without EAC (96% and 95% positive and negative predictive values). Conclusions: This less invasive approach for EAC detection with the novel combination of these glycoprotein biomarkers and clinical factors coalesces in a potential step toward improved diagnosis.

e16098 Background: Esophageal adenocarcinoma (EAC) is a rapidly growing cancer in the United States. Although often associated with older populations, there is interest in understanding incidence trends across all age groups, particularly younger individuals (&lt; 49 years). This study evaluates both the incidence of EAC and stage distribution across age groups to inform targeted screening and prevention strategies. Methods: This retrospective cohort study utilized data from the National Cancer Database (NCDB) from 2012 to 2021. Annual incidence rates were analyzed across three age groups (&lt; 49, 50–69, and 70–90 years) and visualized with linear trend lines. Stage distribution at diagnosis (Stages 0–IV) was also compared among these age groups to identify differences in disease presentation. Results: Incidence trends revealed significant differences among age groups. Linear regression analysis showed a slight decline in incidence for the &lt; 49 age group (slope = -0.0016) over the 10-year period, with rates remaining low and stable. In contrast, the 50–69 and 70–90 age groups demonstrated similar upward trends (slope = 0.0527) reflecting a moderate and consistent increase in incidence over time. The 50–69 age group had the highest overall incidence rates, increasing from approximately 2.0 to 2.5 per 100,000 between 2012 and 2021. Stage distribution analysis revealed that younger patients (&lt; 49 years) were more likely to present with advanced-stage disease, with 47.08% diagnosed at Stage IV compared to 38.99% in the 50–69 group and 34.26% in the 70–90 group. Early-stage diagnoses (Stages 0/I) were most common in the 70–90 age group (20.05%) and least common in the &lt; 49 group (13.42%). Conclusions: The incidence of EAC is increasing in middle-aged (50–69) and older (70–90) populations, while younger individuals (&lt; 49) maintain stable but low rates of disease. However, the younger group is disproportionately diagnosed at advanced stages, highlighting a need for greater awareness and potential early detection efforts in high-risk young individuals. Meanwhile, middle-aged and older populations should remain the primary focus of prevention and screening programs to address the rising burden of EAC in these age groups.

Stable Trends in Incidence of Young-onset Esophageal Adenocarcinoma: A 20-year Analysis From the United States Cancer Statistics Database.

Current screening methods for Barrett esophagus (BE), the precursor to esophageal adenocarcinoma (EAC), are inadequate with less than one-third of screen-eligible patients currently undergoing screening. In addition to low screening rates, key issues include overemphasis on gastroesophageal reflux disease symptoms and lack of provider awareness, owing in part to heterogeneous guidelines. To address these challenges, several new approaches are being explored: swallowable cell collection devices, exhaled volatile organic compounds analysis, blood-based molecular biomarkers, microbiome analysis, and alternative visualization methods such as transnasal and capsule endos-copy. Proposed strategies to improve BE screening integrate enhanced risk stratification tools using machine learning and electronic health record data, noninvasive screening for low-risk patients, traditional endoscopy for high-risk patients, primary care education, and public health initiatives to increase awareness. This article highlights the latest developments in BE detection, including noninvasive screening methods and strategies to improve risk stratification, that have the potential to reduce EAC incidence and mortality.

Barrett's esophagus is a premalignant precursor lesion of esophageal adenocarcinoma that affects approximately 1% of the population worldwide. Esophageal adenocarcinoma has a high mortality rate with a five-year survival of 15% to 20%. Early detection of Barrett's esophagus and dysplasia via endoscopy is crucial for preventing its progression to esophageal adenocarcinoma. New imaging techniques, such as image-enhanced endoscopy, have simplified the identification of Barrett's esophagus, dysplasia, and esophageal adenocarcinoma. Narrow-band imaging, blue-light imaging, and i-Scan are the prominent image-enhanced endoscopic techniques used to detect neoplasia. In Barrett's screening and surveillance, key aspects such as the screening population, tools, and intervals need to be clearly defined and standardized for future guidelines to improve the detection of precursor lesions and reduce the incidence of esophageal adenocarcinoma. Making image-enhanced endoscopy less subjective and enhancing the quality measures during endoscopy are crucial steps. Examples of quality measures include cleaning the esophagus before endoscopy and allowing sufficient time for inspection. Artificial intelligence systems can aid the early identification of lesions and reduce subjectivity.

ABSTRACTAimThe incidence of certain cancers in those under 50 years old (early‐onset cancers) has been rising in many countries. This increase is generally unexplained and has significant implications for health policies and treatment. We wish to understand if this trend is occurring in Aotearoa New Zealand and whether it is across the spectrum of adenocarcinomas or site (cancer location)‐specific. Differences in patterns between sites would suggest different possible etiologies for any increase in incidence and hence differences in how this trend might be managed.MethodThe change in incidence of esophageal, gastric, colorectal, pancreatic, breast, lung, uterine, ovarian, and prostate adenocarcinomas from 2000 to 2020 in Aotearoa New Zealand was analyzed. Data was extracted from the New Zealand Cancer Registry. All new cases of relevant adenocarcinomas were analyzed to calculate the crude incidence, incidence rate ratios (IRRs), and age‐standardized incidence. Trends were estimated by age and ethnicity, focusing on early‐onset adenocarcinomas.ResultsThere was evidence for increases in early‐onset colorectal (IRR 1.23, p < 0.01), breast (IRR 1.08, p < 0.01), uterine (IRR 1.73, p < 0.01), and prostate adenocarcinomas (IRR 1.14, p < 0.05). In Māori, there was evidence for significant increases in colorectal (IRR 1.42, p < 0.01), uterine (IRR 1.98, p < 0.01), and lung adenocarcinomas (IRR 1.23, p < 0.05).ConclusionFrom 2000 to 2020, there were increases in multiple early‐onset adenocarcinomas. This is site‐specific, namely colorectal, breast, uterine, and prostate. Ongoing research is needed to investigate possible causes and develop strategies to address the increase in site‐specific early‐onset adenocarcinoma incidence.

Barrett's esophagus is the precursor to esophageal adenocarcinoma. Esophageal adenocarcinoma detected from endoscopic surveillance programs accounts for <10% of all cases, suggesting majority of patients with Barrett's esophagus are likely unaccounted for. Previous observational studies have estimated the observed prevalence of Barrett's esophagus to be approximately 1%, but others suggest may be an underestimate. The aim of this study was twofold: (i) calculate lifetime risk of esophageal adenocarcinoma and (ii) estimate overall and age-specific prevalence of Barrett's esophagus. A tree cohort model was created for progression to esophageal adenocarcinoma from birth to death (100years) for USA and Australian population. Lifetime risk of esophageal cancer and adenocarcinoma were necessary for calculating Barrett's esophagus prevalence. The model incorporated age- and sex-specific incidence data from national cancer registries: the Australian Institute of Health and Welfare and the Surveillance, Epidemiology, and End Results database for the USA. The model was calibrated using an optimization algorithm, which matched progression rates from Barrett's esophagus to esophageal adenocarcinoma with known national cancer data. A Monte Carlo simulation, with 10,000 iterations, was conducted to derive error margins. Estimates of age-specific and overall prevalence of Barrett's esophagus in the population were generated through a similar process. Results: The lifetime risk of esophageal cancer and adenocarcinoma in USA non-Hispanic White population was 0.56% and 0.36%, respectively, while it was somewhat higher at 0.81% and 0.61% (range 0.57%-0.65%) in the Australian population. Estimated overall prevalence of Barrett's esophagus was ~3% (±0.3%) and ~ 5.4% (±0.6%) in USA White and Australian populations (male and female). Prevalence for age brackets was estimated at 0.06% (±0.02%), 1.6% (±0.7%), 3.2% (±1.3%), 8% (±3%), and 12% (±4%) for USA, and 0.05% (±0.02%), 0.9% (±0.5%), 2.8% (±1.2%), 7% (±3%), and 12% (±4%) for Australian population for ages 0-29, 30-44, 45-59, 60-74, and 75+, respectively. Observed estimates of Barrett's esophagus prevalence are likely lower than projected overall prevalence. This study also presents age-specific prevalence estimates of Barrett's esophagus, which are key in developing screening programs for esophageal adenocarcinoma.

Abstract The incidence of esophageal adenocarcinoma (EAC) has rising rapidly during the past four decades in the US and Western countries, becoming the dominant type of esophageal cancer and a significant clinical challenge. However, the prognosis of EAC patients is still poor with 5-year overall survival rate about 20%. There is an urgent need to identify novel therapeutic targets associated with EAC biology. NEK2 is a serine/threonine protein kinase of NEK (NIMA related kinase) family which has 11 members, NEK1-NEK11. NEK2 is frequently overexpressed in human cancers, associated with tumor progression and drug resistance. We detected the overexpression of NEK2 in both mRNA and protein levels in EAC cell lines and primary EAC tissues using qRT-PCR, western blotting, immunohistochemistry. Functionally, we demonstrated that overexpression of NEK2 in EAC cells promoted tumor cell growth. Targeting NEK2 using specific siRNAs and a recent NEK2 specific inhibitor NBI-961 in EAC cells significantly inhibited EAC tumor growth in vitro and in vivo in a xenograft mouse model. RNA-seq analyses indicate that NEK2 inhibition using NBI-961 impaired important signaling pathways such as EMT, IL6-JAK -STAT3, mTOR1 and DNA repair, and enhanced interferon alpha response pathway in EAC cells. Our data suggests that targeting frequently overexpressed NEK2 in EAC is a promising approach. Citation Format: Lei Chen, Heng Lu, Farah Ballout, Wael El-Rifai, Oliver Gene McDonald, Dunfa Peng. Targeting overexpressed NEK2 kinase in esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6968.

Abstract Background: The incidence of esophageal adenocarcinoma (EAC) is rapidly increasing in Western countries. Most EACs originate from Barrett’s esophagus (BE), a precancerous lesion initiated by chronic reflux of gastrointestinal contents, especially acidic bile salts (ABS). Several chemotherapeutics induce high reactive oxygen species (ROS) levels to eliminate tumor growth. Ferroptosis is a recently identified cell death mode triggered by ROS and subsequent lipid peroxidation. However, cancer cells develop adaptive abilities to recalibrate redox balance via hijacking the antioxidant systems, resulting in drug resistance. PRDX2 protein is a member of the peroxiredoxin family of antioxidant enzymes. We hypothesized that PRDX2 may be a critical mediator in redox-associated chemoresistance under reflux conditions. Methods: We analyzed RNA sequencing data and public databases to unveil the aberrant overexpression and potential chemoresistance function of PRDX2 in EAC. To simulate both acute and chronic clinical conditions of gastroesophageal reflux disease (GERD) in vitro, we employed transient and repeated ABS exposure (rABS). EAC cells and 3D organotypic culture (OTC) served as platforms to explore the anti-ferroptosis function and regulatory mechanisms of PRDX2. Our initial findings were validated in patient-derived xenografts (PDX), and human EAC tissue microarrays (TMA). Results: Aberrant expression of PRDX2 was detected in both human EAC tissues and cell lines exhibiting resistance to oxaliplatin treatment. Knockdown of PRDX2 impaired the recovery of EAC cells from ABS-induced ROS-dependent lipid peroxidation. Moreover, silencing PRDX2 sensitized the chemo-resistant EAC cells to oxaliplatin. Chromatin immunoprecipitation (ChIP) assay identified that NF-kB activated PRDX2 transcription by directly binding to its promoter region. We also found that APE1-redox-mediated NF-kB activation is crucial for ABS-induced PRDX2. We further discovered that PRDX2 contributes to chemoresistance by upregulating GPX4 and suppressing ferroptosis. Furthermore, immunofluorescent staining in the 3D model (OTC) and immunohistochemistry staining in human TMA confirmed co-overexpression of APE1 and PRDX2. In addition, APX2009, an APE1-redox-specific inhibitor, significantly sensitized EAC cells to oxaliplatin by inhibiting PRDX2 expression and inducing ferroptosis. Notably, we observed synergistic effects of the combination of Oxaliplatin and APX2009 in the xenografts derived from a chemo-resistant EAC cell line. Conclusion: Our findings revealed a novel link between reflux-induced redox unbalance and ferroptosis-related chemoresistance in EAC via APE1/redox/NF-kB/PRDX2/GPX4 axis. Targeting PRDX2 by APE1-redox-specific inhibitors is a potential novel strategy for drug combination in refractory EAC. Citation Format: Lei Chen, Heng Lu, Farah Ballout, Dunfa Peng, Zheng Chen, Jianwen Que, Oliver G. McDonald, Alexander Zaika, Wael El-Rifai. Chronic gastroesophageal reflux promotes chemoresistance in esophageal adenocarcinoma through APE1-redox-dependent PRDX2 activation and ferroptosis inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 542.

Abstract Background: The incidence of esophageal adenocarcinoma (EAC) is rapidly rising in the United States and Western countries. Unfortunately, EAC has one of the lowest survival rates due to limited treatment options. Identifying disease drivers through functional studies is crucial for improving treatment options. This study aimed to explore the role of APE1 in regulating SMAD3 and promoting EAC progression. Methods and Results: Analysis of publicly available datasets revealed that APE1 and SMAD3 are upregulated and positively correlated in EAC compared to normal samples. Immunofluorescence staining of esophageal cancer progression tissue arrays confirmed significantly higher levels of APE1 and SMAD3 in EAC than in normal tissues. Western blot analysis showed that silencing APE1 reduced SMAD3 nuclear expression, which was also confirmed by immunofluorescence staining showing a loss of nuclear SMAD3 accumulation following APE1 knockdown. Immunoprecipitation and proximity ligation assays indicated a direct interaction between APE1 and SMAD3 in the nucleus. Further analysis revealed that APE1 binds to the C-terminal MH2 domain of SMAD3, protecting it from ubiquitin-mediated proteasomal degradation by preventing its interaction with the RING finger protein, ROC1. Notably, inhibiting APE1’s redox or endonuclease activity with pharmacological inhibitors or mutants disrupted APE1-SMAD3 binding, suggesting a conformational regulation. Interestingly, knocking down APE1 reduced angiogenesis in tube formation assays and 3D co-cultures; however, this effect was reversed by overexpressing SMAD3, suggesting that APE1 regulates angiogenesis through SMAD3. Conclusion: The findings establish the role of APE1 in regulating SMAD3 in EAC and suggest a potential therapeutic approach for treating EAC patients. Citation Format: Farah Ballout, Heng Lu, Nadeem Bhat, Lei Chen, Dunfa Peng, Zheng Chen, Alexander Zaika, Oliver McDonald, Wael El Rifai. APE1 mediates angiogenesis by stabilizing SMAD3 and blocking its ubiquitin induced degradation in esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3847.