Esophageal Adenocarcinoma Patients Research Articles

Predictors for Lymph Node Metastasis and Survival of Patients with T1b Esophageal Adenocarcinoma Treated with Surgery and Endoscopic Therapy: An Analysis of Surveillance, Epidemiology, and End Results Database

Limited data exists regarding the long-term outcomes of endoscopic therapy (ET) with or without chemoradiation therapy (CRT) for T1b esophageal adenocarcinoma (EAC). Our aim was to identify the risk factors for lymph node metastasis (LNM) in T1b EAC and assess how the chosen treatment modality affects overall survival (OS) and cancer-specific survival (CSS). We analyzed histologically confirmed T1b EAC patients diagnosed between 2004 and 2018 using Surveillance Epidemiology and End Results database. Focusing on T1bN0M0 staging, we divided the patients into two groups: ET (n=174) and surgery (n=769), and calculated OS and CSS rates. Out of 1418 patients with T1b EAC, 228 cases (16.1%) exhibited LNM at diagnosis. Notable risk factors for LNM included poorly differentiated tumor and lesion size ≥20 mm. For T1bN0M0 cases, ET was commonly performed from 2009 to 2018 (OR 4.3), especially for patients aged ≥ 65 years (OR 3.1) with tumor size <20mm (OR 2.3). During 50 months median follow-up, age ≥ 65 years (HR 1.9), ET (HR 1.5), and CRT (HR 1.4) were associated with poorer OS. Factors linked to decreased CSS were age ≥ 65 years (sub hazard ratio (SHR) 1.6), poorly differentiated tumors (SHR 1.5), and CRT (SHR 1.5). In T1b EAC, tumor size ≥20mm and poor differentiation are notable risk factors for LNM. ET showed comparable CSS outcomes to surgery for carefully selected T1bN0M0 lesions. CRT did not provide additional survival benefit for these lesions; however, large scale studies are required to validate this finding.

Analysing the Combined Effects of Radiotherapy and Chemokine Receptor 5 Antagonism: Complementary Approaches to Promote T Cell Function and Migration in Oesophageal Adenocarcinoma.

The presence of an immunosuppressive tumour microenvironment in oesophageal adenocarcinoma (OAC) is a major contributor to poor responses. Novel treatment strategies are required to supplement current regimens and improve patient survival. This study examined the immunomodulatory effects that radiation therapy and chemokine receptor antagonism impose on T cell phenotypes in OAC with a primary goal of identifying potential therapeutic targets to combine with radiation to improve anti-tumour responses. Compared with healthy controls, anti-tumour T cell function was impaired in OAC patients, demonstrated by lower IFN-γ production by CD4+ T helper cells and lower CD8+ T cell cytotoxic potential. Such diminished T cell effector functions were enhanced following treatment with clinically relevant doses of irradiation. Interestingly, CCR5+ T cells were significantly more abundant in OAC patient blood compared with healthy controls, and CCR5 surface expression by T cells was further enhanced by clinically relevant doses of irradiation. Moreover, irradiation enhanced T cell migration towards OAC patient-derived tumour-conditioned media (TCM). In vitro treatment with the CCR5 antagonist Maraviroc enhanced IFN-γ production by CD4+ T cells and increased the migration of irradiated CD8+ T cells towards irradiated TCM, suggesting its synergistic therapeutic potential in combination with irradiation. Overall, this study highlights the immunostimulatory properties of radiation in promoting anti-tumour T cell responses in OAC and increasing T cell migration towards chemotactic cues in the tumour. Importantly, the CCR5 antagonist Maraviroc holds promise to be repurposed in combination with radiotherapy to promote anti-tumour T cell responses in OAC.

Clinicopathological and therapeutic comparisons of esophageal cancer between China and the USA: a multicenter hospital-based study

BackgroundEsophageal cancer (EC) remains a global health challenge due to its poor prognosis. China and the United States of America (USA) represent two distinct epicenters of EC burden. Understanding the EC disparities in these two countries is vital for tailoring prevention strategies, optimizing treatment, and enhancing outcomes in both countries. Yet, there lacks a comprehensive comparison of EC characteristics between the two countries. MethodsIn this multicenter, retrospective hospital-based study, we enrolled primary EC patients who received their initial treatment at one of 23 hospitals in China during 2016–2017. Using electronic medical records and cancer registration records, information on demographics, lifestyle, and clinicopathological characteristics (including tumor site, pathology, stage, metastases, differentiation, and treatment) were collected. Additionally, we compared these data with the clinicopathological information of invasive EC patients diagnosed in 2016–2017 from the Surveillance, Epidemiology, and End Results (SEER) database in the USA. ResultsA total of 6,658 EC patients in China and 8,555 EC patients in the USA were included finally. 85.5% (n = 5,694) of EC were esophageal squamous cell carcinoma (ESCC) in China, while esophageal adenocarcinoma (EAC) was prominent in the USA (58.9%, n = 5,041). Among EC patients with known staging, the proportion of early stage was higher in China compared to the USA (48.3% vs. 30.5%). Among ESCC patients, early-stage cases were higher in China than in the USA (49.8% vs. 31.8%), while among EAC patients, late-stage cases were higher in China than in the USA (77.3% vs. 68.5%) (all P < 0.001). In China, EC mainly occurred in the middle third (60.2%) of the esophagus, whereas in the USA, it was more common in the lower third (59.9%) of the organ. Compared with EC patients with known metastatic status in the USA, China had fewer cases of lymph node metastases (51.4% vs. 57.7%) and distant metastases (7.9% vs. 33.8%). Regarding treatment, China had more surgical therapy (53.7% vs. 22.6%), less radiotherapy (35.6% vs. 53.3%), and less chemotherapy (46.7% vs. 59.7%) compared to the USA. ConclusionsThis study reveals notable disparities in EC between China and the USA, encompassing epidemiological, clinicopathological, and treatment dimensions. These findings provide insight for tailored strategies addressing regional variations in clinicopathological and therapeutic characteristics.

Adjuvant treatment patterns for pT3N0M0 esophageal cancer undergoing surgery.

To assess adjuvant treatment patterns on survival in patients with pT3N0M0 esophageal cancer who underwent esophagectomy without neoadjuvant chemoradiotherapy. Stage pT3N0M0 esophageal cancer patients were assessed between 2000 and 2020 from the Surveillance, Epidemiology, and End Results databases. Kaplan-Meier analysis was used to compare overall survival (OS) among various treatment patterns. We identified 445 patients: 252 (56.6%) received surgery alone, 85 (19.1%) received surgery+chemoradiotherapy, 80 (18.0%) underwent surgery+chemotherapy, and 28 (6.3%) received surgery+ radiotherapy. For squamous cell carcinoma, surgery+chemoradiotherapy ([hazard ratio] HR = 1.04, 95% confidence interval (CI): 0.65-1.66; P= 0.873), surgery+chemotherapy (HR = 0.72, 95% CI: 0.42-1.22; P = 0.221), and surgery+radiotherapy (HR = 1.33, 95% CI: 0.74-2.39; P = 0.341) had similar OS compared to surgery alone. For adenocarcinoma, surgery+chemoradiotherapy (HR = 0.51, 95% CI: 0.36-0.74; P < 0.001) and surgery+chemotherapy (HR = 0.61, 95% CI: 0.42-0.87; P = 0.006) had better OS compared to surgery alone. However, surgery+radiotherapy had a comparable OS (HR = 0.81, 95% CI: 0.44-1.49; P = 0.495).Adjuvant treatments did not improve survival in stage pT3N0M0 esophageal squamous cell carcinoma patients. In contrast, adjuvant chemoradiotherapy and chemotherapy were recommended for esophageal adenocarcinoma patients.

Abstract 3268: A novel signaling axis of APE1-redox-sensitive SOX9 activation underlying reflux-condition-associated chemoresistance in esophageal adenocarcinoma

Abstract Chronic gastroesophageal reflux disease (GERD), characterized by the reflux of acidic bile salts (ABS) into the esophagus, stands as the primary risk factor for esophageal adenocarcinoma (EAC). EAC, known for its aggressive nature and limited response to therapy, exhibits a disheartening 5-year survival rate of less than 20%. Overcoming drug resistance remains a pressing challenge in achieving optimal therapeutic outcomes for EAC patients. Previous studies from our team have unveiled that exposure to ABS leads to the overexpression of Apurinic/apyrimidinic endonuclease (APE1), which orchestrates various oncogenic pathways in EAC cells. In this study, we delve into the influence of ABS in driving APE1-redox-mediated activation of the SOX9 pathway, thus contributing to the chemoresistance observed in EAC. To identify the enrichment of the SOX9 pathway and the heightened downstream target genes in EAC, we analyzed RNA sequencing data and public databases. Cell models, patient tissue arrays, pL2-IL1β transgenic mice, and de-identified xenografts derived from EAC patients (PDXs) were employed to investigate the signaling axis of APE1-redox-SOX9 in oxaliplatin resistance of EAC. Our analysis of public databases unveiled a significant enrichment of the SOX9 pathway in EAC patients. RNA sequencing data from EAC cells exposed to ABS, with or without APE1-knockdown, suggested APE1's involvement in the GERD-activated SOX9 signaling pathway. Immunohistochemistry staining of human patient tissue arrays, along with immunofluorescent staining of L2-IL1ß transgenic mice, confirmed the co-overexpression of APE1, SOX9, and ALDH1A1 in EAC. Furthermore, APE1 silencing led to the downregulation of SOX9 and exhibited synergistic effects with oxaliplatin in chemo-resistant EAC cells. Mechanistically, we uncovered that APE1's redox function is crucial for AKT-GSK3ß-mediated SOX9 stability. Treatment with the APE1-redox-specific inhibitor, APX2009, sensitized patient-derived xenograft (PDX) tumors to oxaliplatin by repressing SOX9-regulated chemoresistance genes. This study sheds light on a novel signaling axis involving APE1-redox-AKT-GSK3ß-SOX9 in Barrett’s carcinogenesis. The pharmacological inhibition of APE1-redox function presents itself as a promising therapeutic approach to target the previously intractable SOX9 signals, potentially overcoming chemoresistance in EAC. Citation Format: Heng Lu, Lei Chen, Farah Ballout, Dunfa Peng, Zheng Chen, Jianwen Que, Steven Chen, Oliver Gene McDonald, Alexander Zaika, Wael El-Rifai. A novel signaling axis of APE1-redox-sensitive SOX9 activation underlying reflux-condition-associated chemoresistance in esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3268.

Abstract 555: Role of TRIM31 in the pathogenesis of esophageal adenocarcinoma

Abstract Background: Esophageal adenocarcinoma (EAC) is one the deadliest cancers in United States (US) and the only major cancer in the US with increasing incidence. Gastroesophageal reflux disease (GERD) can cause Barrett’s esophagus (BE), a columnar metaplasia of the esophagus strongly associated with the development of EAC. GERD leading to BE is a common pre-occurrence in EAC patients, but the mechanism remains obscure. To explore the mechanism and its components, we compared gene expression in BE and EAC cells with normal esophageal cells and found high expression of tripartite motif-containing protein 31 (TRIM31) in BE and EAC compared to normal esophagus (NE) by transcriptomic profiling of RNA extracted from human esophageal tissues. E3 ubiquitin ligase TRIM 31 is a new member of TRIM family and it has been reported to have oncogenic potentials in some cancers. However, its role in EAC pathogenesis is yet to be understood. Methods: RNA sequencing and transcriptomic profiling were performed on human NE, BE, and EAC epithelial tissue samples. TRIM31 expression in NE cell line (Het-1A) and EAC cell lines (OE19, Flo-1, OE33, SK-GT-2, and OACM5.1C) were identified by Western blot analysis. The Het-1A cell line, after exposure to acidic pH and bile acids, was assessed for variable TRIM31 expression. Cell morphology and viability analyses of NE and EAC cell lines after exposure to acidic pH and bile acids either alone or in combinations were observed by microscopy and WST-1 assay respectively. Results: Transcriptomic analysis showed that BE and EAC are similar in their differential gene expression with upregulation of the TRIM31 compared to that in NE. Concordant with their columnar phenotype, BE and EAC groups displayed a multitude of differentially expressed genes relative to NE samples; however, less differentially expressed genes were found comparing BE and EAC groups. Western blot demonstrated frequent overexpression of TRIM31 in EAC cell lines with very low expression of TRIM31 in NE epithelial cell line. When NE epithelial cell line Het-1A was exposed to acidic pH as well as bile acids in acidic pH, we saw a change in cell morphology that may correlate with the metaplasia of these cells to more resilient forms, as seen in human BE and EAC. Interestingly, bile acids in acidic pH increased TRIM31 expression in NE cell line Het-1A. Bile acids had a greater effect on decreasing cell viability at high concentrations and that effect is enhanced when bile acids were added in acidic pH. WST-1 cell viability assay revealed that EAC cells were more resistant to bile acids as well as bile acids in acidic pH induced decreased in cell viability compared to that in NE cell line Het-1A. The sustained cell viability of EAC cell lines under these harsh conditions correlates with the upregulation of TRIM31. Conclusions: Thus, TRIM31 may be an important oncogenic factor in GERD-induced EAC development and may be an innovative therapeutic target and marker for EAC. Citation Format: Md Sazzad Hassan, Jesse Mast, Annie Ritter, Saisantosh Ponna, Niranjan Awasthi, Urs von Holzen. Role of TRIM31 in the pathogenesis of esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 555.

Abstract 3269: APE1/NF-κB/PRDX2 activated by reflux conditions mediates chemoresistance in esophageal adenocarcinoma by suppressing ferroptosis

Abstract Background: Esophageal adenocarcinoma (EAC) stands out as one of the most lethal malignancies, characterized by a discouragingly low 5-year survival rate of less than 20%. Accumulating lines of evidence indicate that ferroptosis, a novel type of cell death, can regulate drug resistance. Peroxiredoxin 2 (PRDX2), an antioxidant enzyme, plays an antioxidant protective role in the cells under stress by regulating redox homeostasis. We aimed to elucidate the role of PRDX2 in regulating reactive oxygen species (ROS), ferroptosis, and chemoresistance in EAC. Methods: In this investigation, we analyzed RNA sequencing data and public databases to uncover the aberrant overexpression and potential chemoresistance function of PRDX2 in EAC. We employed transient acidic bile salts exposure (ABS) and repeated ABS exposure (rABS) to mimic gastroesophageal reflux disease, the main risk factor for EAC, in in vitro cell models. EAC cells and 3D organotypic culture (OTC) served as platforms to delve into the anti-ferroptosis function and regulatory mechanisms of PRDX2. The findings were validated using patient-derived xenografts (PDX) and human EAC tissue microarrays (TMA). Results: Elevated PRDX2 level was observed in both EAC patients and cell lines exhibiting poor responsiveness to chemotherapy. Intrinsic overexpression of PRDX2 emerged as a crucial factor in the recovery from ABS-exposure-induced lipid peroxidation. Silencing PRDX2 heightened the sensitivity of EAC cells to Oxaliplatin by inhibiting ferroptosis in a GPX4-dependent manner. Mechanistically, we found ABS activate the APE1/redox/NF-kB signal axis, leading to the upregulation of PRDX2 transcription. The co-overexpression of APE1 and PRDX2 was identified through both immunofluorescent staining in cells/OTC and immunohistochemistry staining in TMA. Moreover, the APE1-redox-specific inhibitor, APX2009, significantly sensitized EAC cells to Oxaliplatin by repressing PRDX2 and inducing ferroptosis. Remarkably, the combination therapy of Oxaliplatin and APX2009 achieved a synergistic effect in EAC-PDX tumors. Conclusion: The study unveils a novel signaling axis, APE1/NF-kB/PRDX2, linking disease-associated ROS unbalance and ferroptosis-related chemoresistance. Targeting PRDX2 signaling by APE1-redox-specific inhibition provides a potential novel strategy for combined chemotherapies in refractory EAC. Citation Format: Lei Chen, Heng Lu, Farah Ballout, Dunfa Peng, Zheng Chen, Jianwen Que, Steven Chen, Oliver McDonald, Alexander Zaika, Wael El-Rifai. APE1/NF-κB/PRDX2 activated by reflux conditions mediates chemoresistance in esophageal adenocarcinoma by suppressing ferroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3269.

Abstract 550: Identification of isoform switching events linked with esophageal adenocarcinoma patient survival informs novel prognostic and therapeutic targets

Abstract Esophageal adenocarcinoma (EAC) represents a growing health problem characterized by rising incidence and poor prognosis. Although it is a cancer with a high mutational burden, it lacks highly prevalent oncogenic drivers that can be therapeutically targeted. Recently, our group characterized isoform switching events, defined by the changing of dominant gene isoforms between conditions, associated with EAC progression and identified 75 switching events comparing Barrett’s low-grade dysplasia (BE.LGD) and Barrett’s high-grade dysplasia (BE.HGD) patient samples. Herein, we further investigated whether isoform-switching events may offer prognostic or therapeutic value in EAC. Isoform switching analysis was performed using RNA-seq data derived from patient samples between BE.LGD and BE.HGD combined with EAC (BE.HGD + EAC) alone or in combination with TP53 mutations. Patients were further stratified into tertiles based on isoform expression level followed by survival analysis. Thirty isoforms were significantly (P≤0.05) linked with all-cause mortality, comparing BE.LGD with BE.HGD + EAC, whereas 20 isoforms were identified when TP53 mutation status was included. In terms of cancer-specific mortality, 10 isoforms were significantly linked with survival comparing BE.LGD with BE.HGD+EAC. With the inclusion of TP53 mutation, 16 isoforms were also significantly linked with cancer-specific mortality. Isoform-specific genetic knockdown experiments were designed targeting the top isoforms identified in the analysis, including TTLL12 and HM13 isoforms. Knockdown of TTLL12 and HM13 isoforms led to significant inhibition of cell viability and migration in two EAC cell lines (OE19 and OE33). Chemotherapeutic agents (Paclitaxel + Carboplatin) further decreased cell viability with synergistic effects observed in both siRNA-treated cell lines suggesting a role for specific isoform switches in therapeutic sensitization. Protein-interaction prediction using STRING and immunoblot analysis suggest different mechanisms leading to the inhibition of cell viability and migration. TTLL12 is linked with the activation of chaperon-medicated autophagy (LAMP2A and HSC70) and protein translation, whereas HM13 is linked with unfolded protein response (IRE1α, PERK, and ATF6) and may be linked with immunotherapy outcome. An antigen-dependent cell-mediated cytotoxicity assay is currently underway to investigate whether the knockdown of HM13 isoforms can sensitize EAC cells to PD-1/PD-L1 immunotherapy agents. Future direction includes using FDA-approved agents to target the two major pathways identified above. In conclusion, isoform switching may provide fresh insight for the identification of prognostic markers and inform new potential therapeutic targets for EAC treatment or prevention. Citation Format: Yun Zhang, Rachel Israel, Bryce Vandenburg, Shari Barnett, Jean-Jack Riethoven, Jennifer L. Clarke, Michelle P. Lee, Kiran Lagisetty, Jules Lin, Rishindra Reddy, Andrew Chang, Laura A. Kresty. Identification of isoform switching events linked with esophageal adenocarcinoma patient survival informs novel prognostic and therapeutic targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 550.

Abstract 757: Integrating microbiome analysis and multi-modal data to identify high-risk population for esophageal adenocarcinoma

Abstract INTRODUCTION: Esophageal Adenocarcinoma (EAC) represents a pressing public health concern with a rising incidence and a staggering 5-year survival rate of less than 20%, emphasizing the critical need for early detection. Barrett's Esophagus (BE) serves as a well-established precursor to EAC, presenting an opportunity for proactive screening. The salivary microbiome provides a novel opportunity to identify a high-risk population with early-stage esophageal diseases. Here, we assessed whether the oral microbiome, in combination with lifestyle and clinical data, is associated with esophageal disease progression. METHODS: The study included n=23 esophageal adenocarcinoma patients, n=51 with Barrett's Esophagus, and n=32 healthy controls. Saliva samples were collected along with comprehensive lifestyle, dietary intake, and clinical data. Shotgun Metagenomics Sequencing was employed to investigate the microbiome composition of participants. Comprehensive microbiome analyses were performed to evaluate taxonomic profiles, including microbial abundance, microbiome diversity, and functional/metabolic insights. A multi-modal data integration strategy was used to incorporate data from the Diet Health Questionnaire (DHQ) and lifestyle and health records, aiming to utilize these multimodal features to predict esophageal disease formation and progression. RESULTS: A significant difference was observed in the salivary microbiome beta diversity between healthy controls and esophagus disease groups (p= 0.03). Clustering by microbiome taxonomic composition using the Dirichlet Multinomial Mixtures (DMM) framework indicates that some microbial signatures are associated with esophageal diseases (p=0.03). Healthy Eating Index Scores, total score (p=0.01); vegetables (p=0.003); greens, and beans score (p=0.009) were significantly different between study groups. Microbial pathways associated with diet, microbial taxa linked to lifestyle and medications, and supervised classification results reveal group characteristics and diversity variations based on key covariates such as B12 and sugar uptakes. CONCLUSION: The study presents an innovative analytic approach to identify high-risk populations for esophageal diseases by integrating microbiome analysis and multi-modal data, providing insights into early detection and prevention. The potential of this research lies in its ability to revolutionize screening strategies, offering a non-invasive and cost-effective means to identify individuals at risk of EAC at earlier, more treatable stages. Citation Format: Duygu Altinok Dindar, Madeline Krieger, Amy Palma, John Cheney, Fouad Otaki, Jessica Yu, Stephanie Wood, Thomas J. Sharpton, James McGann, Lisa Karstens, Gurkan G. Yardimci, Zhenzhen Zhang. Integrating microbiome analysis and multi-modal data to identify high-risk population for esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 757.

A four-gene signature predicts overall survival of patients with esophageal adenocarcinoma.

Esophageal adenocarcinoma (EAC) is an aggressive cancer with poor prognosis. Thus, this study aimed to identify a prognostic molecular signature to predict the overall survival (OS) of patients with EAC. The mRNA microarray data sets GSE13898 and GSE26886 were downloaded from the Gene Expression Omnibus (GEO) database. RNA sequencing profile and clinical data of EAC patients were downloaded from The Cancer Genome Atlas (TCGA) database. Differentially expressed genes (DEGs) between EAC tissues and adjacent non-cancerous tissues were obtained using R software. DEGs associated with prognosis of OS were assessed by univariate Cox analysis, and a prognostic signature was built using stepwise multivariate Cox analysis. Time-dependent receiver operating characteristic (ROC) analysis and stratification analysis were conducted to evaluate its predictive performance. Functional enrichment analysis was performed for genes co-expressed with the signature to explore its biological functions in EAC. A total of 336 genes were identified to be differentially expressed between EAC tissues and adjacent non-cancerous tissues. After univariate and multivariate Cox regression analysis, four genes (ALAD, ABLIM3, IL17RB and IFI6) were screened out to construct a prognostic signature. According to this signature, patients could be assigned into high-risk and low-risk group with significantly different OS (P=4.92e-05<0.0001). Multivariate Cox regression analysis suggested that the four-gene signature served as an independent factor in OS prediction. In the time-dependent ROC analysis, the areas under the curves (AUCs) were 0.804, 0.792 and 0.695 for 1-, 3- and 5-year survival prediction, respectively, suggesting a good performance. Functional enrichment analysis showed that the signature was mainly clustered in cell proliferation related biological processes or pathways. The four-gene signature identified in the current study may be a potential prognostic factor for predicting OS of EAC patients.

Clinicopathological, metastatic and prognostic features of stage IV esophageal adenocarcinoma versus squamous cell carcinoma: a SEER database analysis.

It is important to note that although the current treatment for advanced esophageal cancer (EC) has made great technological advances, patients' 5-year survival rates do not appear to be encouraging. Therefore, understanding the clinicopathological features and metastasis patterns of the patients with stage IV EC, combined with the prognosis of these patients, can aid in choosing the optimal treatment plan. It is well known that esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are the two most common pathological types. The aim of this study is to examine and compare the clinicopathological features and metastatic modes of stage IV ESCC and EAC, as well as their prognosis and survival. Based on the Surveillance, Epidemiology, and End Results (SEER) database, we assessed the characteristics of ESCCs and EACs associated with prognosis using the Kaplan-Meier survival analysis, and the Cox regression model. Furthermore, the clinical data of 217 patients with stage IV ESCC and EAC in the Department of Gastroenterology of the Second Affiliated Hospital of Nantong University between 2014 and 2016 were reviewed. A total of 3,707 cases treated between 2010 and 2016 were included. The incidence of EAC in the United States is much higher than that of ESCC. Common metastasis patterns were lungs only, liver only, bones only, and lung & liver. The multivariate Cox analysis showed that treatment mode and metastasis patterns were independent risk factors affecting the overall survival (OS) time of patients (stage IV ESCC & EAC). EAC patients with only lung metastases may have a longer survival if chose treatment options that included surgery. In the external cohort, a total of 217 cases were included. The prevalence of ESCC is much higher than that of EAC, and the common metastasis patterns are liver only, lung only, and liver & lung. The multivariate Cox analysis showed that treatment mode was independent risk factor affecting the OS time of patients (stage IV ESCC & EAC). EAC patients treated with surgery combined with chemoradiotherapy may have a better prognosis. In general, the prognosis of patients with stage IV ESCC and EAC are poor. However, surgery was found to significantly improve the OS time of patients with stage IV EAC in this study.

Chemotherapy and chemoradiotherapy for adenocarcinoma of the esophagus and junction with oligometastases: Results of the TNT-OES-1 trial.

328 Background: Chemotherapy (FLOT) and chemoradiotherapy (CROSS) are effective as neoadjuvant regimens for esophageal and junction cancer. Total Neoadjuvant Therapy (TNT) aims to increase efficacy by combining chemotherapy with chemoradiotherapy. Although TNT is increasingly used in rectal cancer, there are no data on combining FLOT and CROSS in esophageal cancer. This study aimed to evaluate the feasibility and safety of the FLOT-CROSS combination in esophageal and junction adenocarcinoma patients with oligometastatic disease. Methods: This phase-II study included patients with oligometastatic (a maximum of four lesions in up to two organs, excluding lymph nodes) esophageal adenocarcinoma. Patients were treated with four biweekly cycles of FLOT. Response was evaluated by CT-scan 4-6 weeks after completion of FLOT. If patients showed regression or stable disease (SD) based on RECIST criteria (v1.1), they received CROSS. Four to six weeks after completion of CROSS, response was assessed by CT-scan, endoscopy with biopsies and endoscopic ultrasonography. The multidisciplinary tumor board discussed whether patients could proceed to four additional cycles of FLOT or local therapy of metastases and/or esophagectomy. Primary endpoint was tolerability of FLOT-CROSS, defined as the proportion completing the full regimens. Secondary endpoints included disease control rate (DCR), objective response rate, toxicity and the proportion proceeding to local therapy of metastases and/or esophagectomy. Results: Twenty patients were included, the majority was male (85%) with a median age of 62.5 years (interquartile range 58-66) Most patients (80%) had a single metastatic lesion. 14 of 20 patients (70%) successfully completed the FLOT regimen, four are still in therapy and two patients died. Eleven of 14 patients completed FLOT-CROSS and three patients showed disease progression following FLOT. Toxicity mainly consisted of grade 1-2 leukopenia/neutropenia during FLOT, leading to treatment delay in seven patients. One patient had malaise grade 2. No grade 3-4 toxicities or treatment delays/discontinuations occurred during CROSS. Following FLOT-CROSS, seven patients underwent four additional cycles of FLOT. Six patients underwent esophagectomy and two of those also underwent local treatment of metastases. A pathologically complete response was seen in two of these six patients (33%). Three of seven patients had a clinically complete response and opted for active surveillance after shared decision making. Three months after completion of FLOT-CROSS, the DCR was 82%. Conclusions: This study showed that sequencing FLOT-CROSS in patients with oligometastatic esophageal adenocarcinoma is feasible and comes with manageable toxicity. We saw promising efficacy, with 82% having disease control three months after FLOT-CROSS. Survival data are expected mid-2024. Clinical trial information: NL9269 .

TRIM31: A Protein With an Oncogenic Role in Esophageal Adenocarcinoma

Background: Esophageal adenocarcinoma (EAC) is a major cancer in the United States with increasing incidence. It is an aggressive cancer involving columnar-type cells different from the normal esophageal (NE) squamous cells. This metaplasia often involves an intermediary morphology called Barrett’s esophagus (BE), which occurs from repeated acid exposure of the esophagus from gastroesophageal reflux disease (GERD). GERD leading to BE is a common pre-occurrence in EAC patients, but the mechanism remains obscure. To explore the mechanism and its components, we compared gene expression in BE and EAC cells with normal cells and discovered the overexpression of TRIM31 in the pathogenic cells. Although previous studies have shown oncogenic potential of TRIM31 in some cancers, its role in EAC is yet to be understood.&#x0D; Methods: RNA sequencing and transcriptomic profiling were performed on human NE, BE, and EAC epithelial tissue samples. TRIM31 expression in NE cell line (Het-1A) and EAC cell lines (OE19, Flo-1, OE33, SK-GT-2, and OACM5.1C) were identified by Western blot. The Het-1A cell line, after exposure to acidic pH and bile acid, was assessed for variable TRIM31 expression. Cell viability analysis of NE and EAC cell lines after exposure to acidic pH and bile acids was observed by WST-1 assay.&#x0D; Results: RNA sequencing, transcriptomic profiling, and western blot revealed overexpression of TRIM31 in BE and EAC epithelium. Exposure of Het-1A cells to bile acids in acidic pH changed the cell morphology with enhanced expression of TRIM31. WST-1 revealed that EAC cells were more resistant to acidic pH and bile acid exposure.&#x0D; Conclusions and potential impact: Our data suggests that increased TRIM31 expression correlates with esophageal epithelium resistance when exposed to bile acids and acidic pH. Consequently, TRIM31 may be a key player in the metaplasia of GERD-induced EAC development and may be an innovative therapeutic target and marker for EAC.

Using saliva epigenetic data to develop and validate a multivariable predictor of esophageal cancer status.

Background: Salivary epigenetic biomarkers may detect esophageal cancer. Methods: A total of 256 saliva samples from esophageal adenocarcinoma patients and matched volunteers were analyzed with Illumina EPIC methylation arrays. Three datasets were created, using 64% for discovery, 16% for testing and 20% for validation. Modules of gene-based methylation probes were created using weighted gene coexpression network analysis. Module significance to disease and gene importance to module were determined and a random forest classifier generated using best-scoring gene-related epigenetic probes. A cost-sensitive wrapper algorithm maximized cancer diagnosis. Results: Using age, sex and seven probes, esophageal adenocarcinoma was detected with area under the curve of 0.72 in discovery, 0.73 in testing and 0.75 in validation datasets. Cancer sensitivity was 88% with specificity of 31%. Conclusion: We have demonstrated a potentially clinically viable classifier of esophageal cancer based on saliva methylation.

The Expression Patterns and Implications of MALAT1, MANCR, PSMA3-AS1 and miR-101 in Esophageal Adenocarcinoma.

Esophageal adenocarcinoma (EAC) is a malignant tumor with poorly understood molecular mechanisms. This study endeavors to elucidate how the long non-coding RNAs (lncRNAs) MALAT1, MANCR and PSMA3-AS1, as well as the microRNA miR-101, exhibit specific expression patterns in the pathogenesis and prognosis of EAC. A total of 50 EAC tissue samples (tumors and lymph nodes) and a control group comprising 26 healthy individuals were recruited. The samples underwent quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analyses. The relative expression levels of MALAT1, MANCR, PSMA3-AS1, and miR-101 were ascertained and correlated with various clinicopathological parameters including TNM staging, tumor characteristics (size and grade of the tumor) lymphatic invasion, disease-free (DFS) and overall survival (OS) of EAC patients. Quantitative analyses revealed that MALAT1 and MANCR were significantly upregulated in EAC tumors and positive lymph nodes when compared to control tissues (p < 0.05). Such dysregulations correlated positively with advanced lymphatic metastases and a higher N stage. DFS in the subgroup of patients with negative lymph nodes was higher in the setting of low-MANCR-expression patients compared to patients with high MANCR expression (p = 0.02). Conversely, miR-101 displayed a significant downregulation in EAC tumors and positive lymph nodes (p < 0.05), and correlated negatively with advanced tumor stage, lymphatic invasion and the grade of the tumor (p = 0.006). Also, patients with low miR-101 expression showed a tendency towards inferior overall survival. PSMA3-AS1 did not demonstrate statistically significant alterations (p > 0.05). This study reveals MALAT1, MANCR, and miR-101 as putative molecular markers for prognostic evaluation in EAC and suggests their involvement in EAC progression.

Cranberry Proanthocyanidins Mitigate Reflux-Induced Transporter Dysregulation in an Esophageal Adenocarcinoma Model.

We recently reported that cranberry proanthocyanidins (C-PACs) inhibit esophageal adenocarcinoma (EAC) by 83% through reversing reflux-induced bacterial, inflammatory and immune-implicated proteins and genes as well as reducing esophageal bile acids, which drive EAC progression. This study investigated whether C-PACs' mitigation of bile reflux-induced transporter dysregulation mechanistically contributes to EAC prevention. RNA was isolated from water-, C-PAC- and reflux-exposed rat esophagi with and without C-PAC treatment. Differential gene expression was determined by means of RNA sequencing and RT-PCR, followed by protein assessments. The literature, coupled with the publicly available Gene Expression Omnibus dataset GSE26886, was used to assess transporter expression levels in normal and EAC patient biopsies for translational relevance. Significant changes in ATP-binding cassette (ABC) transporters implicated in therapeutic resistance in humans (i.e., Abcb1, Abcb4, Abcc1, Abcc3, Abcc4, Abcc6 and Abcc10) and the transport of drugs, xenobiotics, lipids, and bile were altered in the reflux model with C-PACs' mitigating changes. Additionally, C-PACs restored reflux-induced changes in solute carrier (SLC), aquaporin, proton and cation transporters (i.e., Slc2a1, Slc7a11, Slc9a1, Slco2a1 and Atp6v0c). This research supports the suggestion that transporters merit investigation not only for their roles in metabolism and therapeutic resistance, but as targets for cancer prevention and targeting preventive agents in combination with chemotherapeutics.

Abstract C157: Targeting PIK3CA and CDKN2A alterations in Esophageal Adenocarcinoma with Alpelisib and Palbociclib

Abstract Our study investigates the efficacy of targeted therapies for Esophageal Adenocarcinoma (EAC) tumors harboring an activating PIK3CA mutation and inactivating CDKN2A mutation. We tested the small molecule inhibitors alpelisib, which targets the Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit (PIK3CA), and palbociclib, which targets Cyclin D kinase 4/6 (CDK4/6), in EAC in vitro organoid and in vivo mouse models. EAC and Gastric cancer (GC) organoid models were treated with single agent alpelisib or palbociclib on a log scale to determine their IC50 values. An EAC organoid harboring activating PIK3CA E545K and inactivating CDKN2A D74A mutations demonstrated more significant growth inhibition when treated with each agent alone versus standard of care chemotherapy. Subsequent experiments involved combination treatment of our EAC-mutant organoid with alpelisib and palbociclib as well as a representative GC organoid and EAC organoids lacking these specific mutations as controls. We confirmed PIK3CA downstream target engagement after alpelisib treatment by qPCR, western blot analysis and immunofluorescence analysis. Once in vitro efficacy was confirmed, EAC-mutant organoids were transplanted into mice by either subcutaneous or orthotopic injections and treated with chemotherapy, alpelisib and palbociclib alone or in combination. Our data demonstrate that a PIK3CA/CDKN2A mutated patient-derived EAC organoid is sensitive to alpelisib and palbociclib in a dose dependent manner, and analysis of PIK3CA downstream targets by western and qPCR was consistent with growth inhibition of treated organoids. These findings offer support for the use of alpelisib and palbociclib in the treatment of EAC patients with PIK3CA/CDKN2A mutations. Citation Format: Naryan Rustgi, Thomas Ryan, Jin Cho, Ryan Moy, Sam Yoon, Sandra Ryeom, Changhwan Yoon. Targeting PIK3CA and CDKN2A alterations in Esophageal Adenocarcinoma with Alpelisib and Palbociclib [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C157.

Predicting outcomes in esophageal adenocarcinoma following neoadjuvant chemoradiation: Interactions between tumor response and survival

ObjectivesThe prognostic value of tumor regression scores (TRS) in patients with esophageal adenocarcinoma (EAC) who underwent neoadjuvant chemoradiation remains unclear. We sought to investigate the prognostic value of pathologic and metabolic treatment response among EAC patients undergoing neoadjuvant chemoradiation. MethodsPatients who underwent esophagectomy for EAC after neoadjuvant CROSS protocol between 2016 and 2020 were evaluated. TRS was grouped according to the modified Ryan score; metabolic response, according to the PERCIST criteria. Variables from endoscopic ultrasound, endoscopic biopsies, and positron emission tomography (primary and regional lymph node standardized uptake values [SUVs]) were collected. ResultsThe study population comprised 277 patients. A TRS of 0 (complete response) was identified in 66 patients (23.8%). Seventy-eight patients (28.1%) had TRS 1 (partial response), 97 (35%) had TRS 2 (poor response), and 36 (13%) had TRS 3 (no response). On survival analysis for overall survival (OS), patients with TRS 0 had longer survival compared to those with TRS 1, 2, or 3 (P = .010, P < .001, and P = .005, respectively). On multivariable logistic regression, the presence of signet ring cell features on endoscopic biopsy (odds ratio [OR], 7.54; P = .012) and greater SUV uptake at regional lymph nodes (OR, 1.42; P = .007) were significantly associated with residual tumor at pathology (TRS 1, 2, or 3). On multivariate Cox regression for predictors of OS, higher SUVmax at the most metabolically active nodal station (hazard ratio [HR], 1.08; P = .005) was independently associated with decreased OS, whereas pathologic complete response (HR, 0.61; P = .021) was independently associated with higher OS. ConclusionsPatients with pathologic complete response had prolonged OS, whereas no difference in survival was detected among other TRS categories. At initial staging, the presence of signet ring cells and greater SUV uptake at regional lymph nodes predicted residual disease at pathology and shorter OS, suggesting the need for new treatment strategies for these patients.

Developing sarcopenia during neoadjuvant therapy is associated with worse survival in esophageal adenocarcinoma patients

BackgroundSarcopenia in cancer patients has been associated with mixed postoperative outcomes. The aim of this study was to evaluate whether the development of sarcopenia during the neoadjuvant period is predictive of postoperative mortality in esophageal adenocarcinoma patients. MethodsWe queried a prospective database to retrieve the sarcopenic status of patients with esophageal adenocarcinoma who underwent cross-sectional imaging of the third lumbar vertebra at diagnosis and within 2 months of undergoing an esophagogastrectomy between 2014 and 2022. ResultsOf the 71 patients included in the study, 36 (50.7%) presented with sarcopenia at diagnosis. Of the 35 non-sarcopenic patients, 14 (40%) developed sarcopenia during the neo-adjuvant period. Patients who were not sarcopenic at diagnosis but developed sarcopenia preoperatively had significantly worse overall survival than patients sarcopenic at diagnosis and not sarcopenic preoperatively and patients experiencing no change in sarcopenic status (median 18 vs 47 vs 31 months; P = .02). Diagnostic and preoperative sarcopenic status alone were not significantly associated with overall survival (P = .48 and P = .56, respectively). Although 37 (52.1%) patients died, the cause of death was often not cancer-related (54.1%) and included acute respiratory failure, pneumonia, and cardiac arrest. No significant survival difference was observed when stratified by >10% weight loss (P = .9) or large loss in body mass index (P = .8). ConclusionDeveloping sarcopenia during the neo-adjuvant period may be associated with worse overall survival in patients requiring esophagogastrectomy.

Risk of second cancer in esophageal squamous cell carcinoma and adenocarcinoma survivors: a population-based analysis in SEER dataset.

Previous studies have reported increased risk of second cancer in both esophageal squamous cell cancer (ESCC) and esophageal adenocarcinoma (EAC) survivors. This study aimed to examine the risk and influential factors of second cancer in ESCC and EAC patients. This population-based cohort study included 7,297 ESCC patients and 11,812 EAC patients who were in 1992-2019 from the Surveillance, Epidemiology, and End Results (SEER) program in the United States. These patients were followed up until diagnosis of second cancer, death, or end of the study (December 31, 2019). We calculated standard incidence ratio (SIR) and 95% confidence interval (CI) of second cancer and performed competing-risk regression to estimate the subdistribution hazard ratios (sHR) comparing categories of patients' characteristics. After a total of 49,509.38 person-years of follow-up, 431 (5.9%) ESCC patients and 636 (5.9%) EAC patients developed a second cancer. An overall increased risk of second cancer was observed in both ESCC patients (SIR: 1.66, 95% CI: 1.51-1.83) and EAC patients (SIR: 1.11, 95% CI: 1.02-1.20). ESCC patients were at increased risk of second malignancy in oral cavity and pharynx (SIR: 12.57, 95% CI: 9.87-15.79), stomach (SIR: 3.03, 95% CI: 1.77-4.85), nose and larynx (SIR: 4.79, 95% CI: 2.47-8.37), and lung and bronchus (SIR: 2.44, 95% CI: 1.96-2.99), but decreased risk of prostate cancer (SIR: 0.73, 95% CI: 0.52-0.99). EAC patients had increased risk of second malignancies in stomach (SIR: 4.41, 95% CI: 3.23-5.89), lung and bronchus (SIR: 1.26, 95% CI: 1.02-1.54), and kidney (SIR: 1.57, 95% CI: 1.05-2.25). The risk of second cancer was higher in female ESCC patients than in males (sHR: 1.34, 95% CI: 1.11-1.63) and decreased with more advanced tumor stage in both ESCC patients (sHR: 0.62, 95% CI: 0.50-0.76 for regional stage; sHR: 0.27, 95% CI: 0.20-0.36 for distant stage) and EAC patients (sHR: 0.47, 95% CI: 0.40-0.56 for regional stage; sHR: 0.10, 95% CI: 0.07-0.13 for distant stage). Both ESCC and EAC patients are at considerable risk of certain types of second cancer.