Esophageal Adenocarcinoma Patients Research Articles

Fructose-1,6-bisphosphatase 1 (FBP1) is an independent biomarker associated with a favorable prognosis in esophageal adenocarcinoma

IntroductionDespite modern multimodal therapeutic regimens, the prognosis of esophageal adenocarcinoma (EAC) is still poor and there is a lack of biological markers estimating the patients’ prognosis. Fructose-1,6-biphosphatase (FBP1) is a key enzyme in gluconeogenesis and is associated with tumor initiation in several cancers. Therefore, this study aims to characterize its implication for EAC patients.Methods and materialsA total of 571 EAC patients who underwent multimodal treatment between 1999 and 2017 were analyzed for FBP1 expression using immunohistochemistry.Results82.5% of the EACs show FBP1 expression in the tumor albeit with different intensities categorizing specimens accordingly into score 0 (no expression), score 1 (weak expression), score 2 (moderate expression) and score 3 (strong expression) (score 1 = 25.0%, score 2 = 35.9%, score 3 = 21.5%). Intratumoral FBP1 expression was significantly associated with a better prognosis (p = 0.024). This observation was particularly relevant among patients who received primary surgery without neoadjuvant treatment (p = 0.004). In multivariate analysis, elevated FBP1 expression was an independent biomarker associated with a favorable prognosis.DiscussionDespite being associated with a favorable prognosis, the majority of patients with high FBP1 expression also require individualized therapy options to ensure long-term survival. Recently, it has been shown that the presence of the FBP1 protein increases the sensitivity of pancreatic cancer cells to the bromodomain and extraterminal domain (BET) inhibitor JQ1.ConclusionWe described for the first time the prognostic and possibly therapeutic relevance of FBP1 in EAC. The efficiency of the BET inhibitor in EAC should be verified in clinical studies and special attention should be paid to the effects of neoadjuvant therapy on FBP1 expression.

FOXO transcriptional activity is associated with response to chemoradiation in EAC

In this study we aimed to investigate signaling pathways that drive therapy resistance in esophageal adenocarcinoma (EAC). Paraffin-embedded material was analyzed in two patient cohorts: (i) 236 EAC patients with a primary tumor biopsy and corresponding post neoadjuvant chemoradiotherapy (nCRT) resection; (ii) 66 EAC patients with resection and corresponding recurrence. Activity of six key cancer-related signaling pathways was inferred using the Bayesian inference method. When assessing pre- and post-nCRT samples, lower FOXO transcriptional activity was observed in poor nCRT responders compared to good nCRT responders (p = 0.0017). This poor responder profile was preserved in recurrences compared to matched resections (p = 0.0007). PI3K pathway activity, inversely linked with FOXO activity, was higher in CRT poor responder cell lines compared to CRT good responders. Poor CRT responder cell lines could be sensitized to CRT using PI3K inhibitors. To conclude, by using a novel method to measure signaling pathway activity on clinically available material, we identified an association of low FOXO transcriptional activity with poor response to nCRT. Targeting this pathway sensitized cells for nCRT, underlining its feasibility to select appropriate targeted therapies.

128: DECIPHERING THE IMMUNOLOGICAL DETERMINANTS OF RESPONSE TO NEOADJUVANT CHEMO-RADIATION IN ESOPHAGEAL ADENOCARCINOMA

Abstract Background and aim The standard therapy for esophageal adenocarcinoma (EAC) is pre-operative neoadjuvant chemo-radiation (NACR) and surgery. Less that 30% of patients achieve a pathological complete response (pCR) and increased 5-year survival after NACR. Understanding the mechanisms of response to NACR is pivotal to better stratify patients and inform the design of more efficacious therapies. Cancer progression partly depends on defective immune surveillance, and the presence of tumor infiltrating T lymphocytes (TILs) is associated with better prognosis of several malignancies. We hypothesize that NACR induces immunogenic cell death that stimulates immune responses against tumor neoantigens (TNAs), derived from cancer somatic mutations, in the responders. We thus compared responders and non-responders for tumor immune contexture, immune molecular pathways, circulating immune markers and TNAs-specific T cells responses. Methods Pre-NACR tumor biopsies prospectively collected from consecutive EAC patients were subjected to DNA whole exome and RNA sequencing, high dimensional (HD) multiparametric flow cytometry and immune contexture analysis by histology and by proteome digital spatial profiling (n = 53 targets), while their peripheral blood mononuclear cells and plasma collected pre- and post- NACR were analyzed by HD flow cytometry and cytokine multiplexing assay respectively. Results Treatment-naïve EACs of NACR responders showed higher TNA load and enriched immune signatures compared to non-responders. Moreover, pre-treatment EACs of responders demonstrate augmented effector T cell infiltration and reduced Treg cells and M2-like pro-tumoral macrophages. High M2-like macrophages score associated with lower overall survival. Increased frequencies of circulating myeloid suppressor populations were detected both at baseline and after NACR in non-responder patients. These observations were associated with circulating levels of n = 30 cytokines/chemokines and with spatial expression of immune markers in tumor biopsies. Conclusion Collectively, these results support pre-existing immune-mediated mechanisms of anti-tumor response stimulated by NACR in the fraction of responder EAC patients, suggesting possible ways to stratify patients and direct them to more tailored neoadjuvant and/or adjuvant treatments, possibly in combination with personalized immunotherapy approaches.

189: THE EFFECT OF COVID -19 ON THE NEW DIAGNOSIS OF ESOPHAGOGASTRIC CANCER IN THE UK: A SINGLE-CENTRE EXPERIENCE

Abstract Background and aim Covid-19 has had a devastating global impact and resulted in over 4.4 million directly attributed deaths. The UK entered lockdown in March 2020, redistributing its medical workforce and resources. Early estimations suggested at least 4700 extra cancer deaths at 5 years if there was a 3-month delay to surgery. Delays to diagnosis and treatment for esophagogastric (EG) cancers can be particularly detrimental to survival. The aim of this study is to assess the impact of Covid-19 on new cancer referrals to a centralised UK EG cancer centre, including presentation, decision making and treatment. Methods Patients with EG cancer referred to a tertiary, high-volume centre between March 2019 and March 2021 were reviewed. Patients were stratified into Pre-covid (March 2019–March 2020) and Covid (March 2020–2021) cohorts. Number of new referrals, clinical stage, treatment decision, and time to treatment were compared for gastric adenocarcinoma (GA), esophagogastric-junction adenocarcinoma (EGJA), esophageal adenocarcinoma (EA) and esophageal SCC (ESCC). Results There was an 11% reduction in new cancer referrals (485 vs 431). GA, EGJA and EA did not have significant change in treatment intent, although there was a significant increase in the decision for definitive non-surgical treatment of EA (P = 0.046). GA and EA patients had a small, but significant increase in average clinical stage at presentation (P < 0.05). There was no increase in time to treatment for GA, EGJA and EA. A significantly higher proportion of ESCC patients were given curative intent treatment in the Covid-19 cohort (P = 0.0006) however, this was accompanied with an increased time to treatment (35.8 days vs 27.9 days P = 0.0198). Conclusion This high-volume centre has seen a reduction in new cancer referrals since the first UK lockdown. This was associated with a small, but significant, increase in clinical stage of GA and EA at presentation. This may represent an early indication of excess esophagogastric cancer deaths due to the impact of Covid-19. This data also confirms initial results showing that oncological decisions were not compromised, although Covid-19 remains a dynamic challenge.

Investigating the susceptibility of treatment-resistant oesophageal tumours to natural killer cell-mediated responses

The majority of oesophageal adenocarcinoma (OAC) patients do not respond to multimodal treatment regimens and face dismal survival rates. Natural killer (NK) cells are crucial anti-tumour immune cells, and this study investigated the susceptibility of treatment-resistant OAC cells to these potent tumour killers. Natural killer receptor (NKR) ligand expression by OE33CisP (cisplatin-sensitive) and OE33CisR (cisplatin-resistant) cells was investigated. The immunomodulatory effects of OE33CisP and OE33CisR cells on NK cell phenotype and function were assessed. Finally, the impact of chemotherapy regimens on NKR ligand shedding was examined. Our data revealed significantly less surface expression of activating ligands B7-H6, MICA/B, ULBP-3 and activating/inhibitory ligands PVRL-1 and PVRL-4 by OE33CisR cells, compared to OE33CisP cells. Co-culture with OE33CisR cells reduced the frequencies of NKp30+ and NKp46+ NK cells and increased frequencies of TIGIT+, FasL+ and TRAIL+ NK cells. Frequencies of IFN-γ-producing NK cells increased while frequencies of TIM-3+ NK cells decreased after culture with OE33CisP and OE33CisR cells. Frequencies of circulating NKp30+ NK cells were significantly lower in OAC patients with the poorest treatment response and in patients who received FLOT chemotherapy, while B7-H6 shedding by OAC tumour cells was induced by FLOT. Overall, OE33CisR cells express less activating NKR ligands than OE33CisP cells and have differential effects on NKR expression by NK cells. However, neither cell line significantly dampened NK cell cytokine production, death receptor expression or degranulation. In addition, our data indicate that FLOT chemotherapy may promote B7-H6 shedding and immune evasion with detrimental consequences in OAC patients.

Cooperation between chemotherapy and immune checkpoint blockade to enhance anti-tumour T cell immunity in oesophageal adenocarcinoma

Response rates to immune checkpoint blockade (ICB) remain low in oesophageal adenocarcinoma (OAC). Combining ICB with immunostimulatory chemotherapies to boost response rates is an attractive approach for converting ‘cold’ tumours into ‘hot’ tumours. This study profiled immune checkpoint (IC) expression on circulating and tumour-infiltrating T cells in OAC patients and correlated these findings with clinical characteristics. The effect of first-line chemotherapy regimens (FLOT and CROSS) on anti-tumour T cell immunity was assessed to help guide design of ICB and chemotherapy combinations in the first-line setting. The ability of ICB to enhance lymphocyte-mediated cytolysis of OAC cells in the absence and presence of post-FLOT and post-CROSS chemotherapy tumour cell secretome was assessed by a CCK-8 assay. Expression of ICs on T cells positively correlated with higher grade tumours and a subsequent poor response to neoadjuvant treatment. First-line chemotherapy regimens substantially altered IC expression profiles of T cells increasing PD-1, A2aR, KLRG-1, PD-L1, PD-L2 and CD160 and decreasing TIM-3 and LAG-3. In addition, pro-inflammatory T cell cytokine profiles were enhanced by first-line chemotherapy regimens. T cell activation status was significantly altered; both chemotherapy regimens upregulated co-stimulatory markers ICOS and CD69 yet downregulated co-stimulatory marker CD27. However, ICB attenuated chemotherapy-induced downregulation of CD27 on T cells and promoted differentiation of effector memory T cells into a terminally differentiated state. Importantly, dual nivolumab-ipilimumab treatment increased lymphocyte-mediated cytolysis of OAC cells, an effect further enhanced in the presence of post-FLOT tumour cell secretome. These findings justify a rationale to administer ICBs concurrently with first-line chemotherapies.

Genomic Signature for the Prognosis of Survival in Relation to the Tumor Microenvironment in Esophageal Adenocarcinoma

Objective: To establish a new genomic signature for the prognosis of survival in relation to the tumor microenvironment in esophageal adenocarcinoma. Methods: Data from The Cancer Genome Atlas (TCGA) were applied, and the stromal and immune scores of patients with esophageal adenocarcinoma (EAC) were generated through the ESTIMATE algorithm. Differentially expressed genes were obtained, and genes concerning immune prognosis were identified on the basis of these scores. Functional analysis showed that these genes were primarily involved in immunobiological processes. Additionally, CIBERSORT was used to analyze 22 subgroups of tumor-infiltrating immune cells in the tumor microenvironment. Results: The results of the genomic assessment shown on the Kaplan-Meier curve revealed that EAC patients with high-risk scores have the worst survival. The risk score is valid as an independent prognostic factor for the overall survival in EAC patients. The tumor microenvironment was systematically analyzed, and the immune-related prognostic biomarkers of EAC have been proposed. Conclusion: The expression of tumor-infiltrating immune cells and immune-related genes in EAC have been identified. Some previously overlooked genes may be used as additional biomarkers for EAC in the future.

CtDNA as a biomarker of progression in oesophageal adenocarcinoma

BackgroundThe incidence of oesophageal adenocarcinoma (OAC) is rapidly increasing and despite improvements in treatment, the 5-year survival rate remains poor. Prognostic biomarkers that address the genomic heterogeneity in this highly complex disease will aid the development of precision therapeutics and improve patient survival. The aim of this study was to determine whether circulating tumour DNA (ctDNA) has prognostic significance as a biomarker in OAC patients.Patients and methodsWe profiled 209 blood and tumour samples from 57 OAC patients. Using a panel of 77 cancer genes, we sequenced ctDNA in plasma samples (n = 127) which were taken at multiple time points before and after therapy. In parallel, we sequenced matched tumour samples from 39 patients using the same gene panel. To assess whether the ctDNA profile reflected the tumour heterogeneity, we sequenced additional multi-region primary tumour samples in 17 patients. In addition, we analysed whole-genome and whole-exome sequencing data from primary tumours for a subset of 18 patients.ResultsUsing a tumour-agnostic approach, we found that detectable ctDNA variants in post-treatment plasma samples were associated with worse disease-specific survival. To evaluate whether the ctDNA originated from the primary tumour, we carried out a tumour-informed analysis which confirmed post-treatment ctDNA variants were associated with worse survival. To determine whether ctDNA could be used as a clinical follow-up test, we assessed blood samples from multiple time points before and after treatment, in a subset of patients. Results showed that the variant allele frequency of ctDNA variants increased with disease recurrence.ConclusionThis study demonstrates that ctDNA variants can be detected in patients with OAC and this has potential clinical utility as a prognostic biomarker for survival.

Unfolded Protein Response Is Activated by Aurora Kinase A in Esophageal Adenocarcinoma.

Simple SummaryEsophageal cancer is the 6th most common cause of cancer-related deaths in 2018 worldwide, with a 5-year survival rate of around 20%. This study reported that esophageal adenocarcinoma cancer cells take advantage of unfolded protein response to survival. Our data using both in vitro cancer cell models and in vivo mice models discovered, for the first time, that Aurora kinase A hijacks pro-survival unfolded protein response in esophageal adenocarcinoma, promoting the survival of cancer cells under reflux-mediated stress conditions.Unfolded protein response (UPR) protects malignant cells from endoplasmic reticulum stress-induced apoptosis. We report that Aurora kinase A (AURKA) promotes cancer cell survival by activating UPR in esophageal adenocarcinoma (EAC). A strong positive correlation between AURKA and binding immunoglobulin protein (BIP) mRNA expression levels was found in EACs. The in vitro assays indicated that AURKA promoted IRE1α protein phosphorylation, activating prosurvival UPR in FLO-1 and OE33 cells. The use of acidic bile salts to mimic reflux conditions in patients induced high AURKA and IRE1α levels. This induction was abrogated by AURKA knockdown in EAC cells. AURKA and p-IRE1α protein colocalization was observed in neoplastic gastroesophageal lesions of the L2-IL1b mouse model of Barrett’s esophageal neoplasia. The combined treatment using AURKA inhibitor and tunicamycin synergistically induced cancer cell death. The use of alisertib for AURKA inhibition in the EAC xenograft model led to a decrease in IRE1α phosphorylation with a significant reduction in tumor growth. These results indicate that AURKA activates UPR, promoting cancer cell survival during ER stress in EAC. Targeting AURKA can significantly reverse prosurvival UPR signaling mechanisms and decrease cancer cell survival, providing a promising approach for the treatment of EAC patients.

Prognostic signature of esophageal adenocarcinoma based on pyroptosis-related genes

BackgroundThe role of pyroptosis-related genes (PRGs) in esophageal adenocarcinoma (EAC) remains unknown.MethodsIn this study, the first PRGs prognostic signature (PPS) of EAC was constructed based on the results of multivariate stepwise Cox regression analysis. Based on 1,047 samples of EAC and normal esophagus (NE), differentially expressed PRGs were selected for the establishment of the PPS. The discrimination effect of this PPS was detected by receiver operating characteristic curves, and the prognosis value of this PPS was determined through Cox regression analysis and Kaplan-Meier curves. Net benefits of the EAC patients from the nomogram (constructed based on the PPS and some clinical parameters) were assessed via decision curve analysis. The potential molecular mechanism of the PPS in EAC was explored via gene set enrichment analysis. The ability of PPS to distinguish EAC and NE was evaluated based on the results of summary receiver operating characteristic curves.ResultsThe significant prognostic value of PPS can be observed at all of the training cohort, test cohort, and validation cohort, such as its independent risk role in the prognosis of the EAC patients (hazard ratio > 0; 95% CI not including 0). The positive net benefits of the nomogram for the EAC patients can be detected via decision curve analysis, and the potential molecular mechanism of the PPS in EAC is likely related to cell pyroptosis. Last, some of the PRGs (particularly CASP5) included in this PPS specifically support its feasibility for identifying EAC (area under the curves > 0.7).ConclusionsThe construction of this PPS in EAC enhances the present understanding of the relationship between PRGs and EAC, thus representing a novel approach to the clinical identification and management of EAC based on PRGs.

The Use of miRNAs in Predicting Response to Neoadjuvant Therapy in Oesophageal Cancer.

Simple SummaryChemotherapy and chemoradiotherapy are only effective in 25% to 30% of patients with oesophageal cancer. Being able to predict which patients will respond to chemotherapy and chemoradiotherapy before they receive this treatment will prevent patients undergoing unnecessary procedures that may reduce their quality of life and help source alternative treatment options faster. The scope of this review was to understand whether microRNAs, small non-coding RNA molecules that regulate gene expression, can be used as biomarkers to predict a patient’s response to chemotherapy and/or chemoradiotherapy treatment. This review showed that a number of microRNAs may have the potential to predict response to chemotherapy and chemoradiotherapy alongside other pre-treatment features already used. More research is needed to translate the use of microRNAs as biomarkers of response to the clinical setting, as well as understanding the effects different types of treatment have on predictability.Oesophageal cancer (OC) is the ninth most common cancer worldwide. Patients receive neoadjuvant therapy (NAT) as standard of care, but less than 20% of patients with oesophageal adenocarcinoma (OAC) or a third of oesophageal squamous cell carcinoma (OSCC) patients, obtain a clinically meaningful response. Developing a method of determining a patient’s response to NAT before treatment will allow rational treatment decisions to be made, thus improving patient outcome and quality of life. (1) Background: To determine the use and accuracy of microRNAs as biomarkers of response to NAT in patients with OAC or OSCC. (2) Methods: MEDLINE, EMBASE, Web of Science and the Cochrane library were searched to identify studies investigating microRNAs in treatment naïve biopsies to predict response to NAT in OC patients. (3) Results: A panel of 20 microRNAs were identified as predictors of good or poor response to NAT, from 15 studies. Specifically, miR-99b, miR-451 and miR-505 showed the strongest ability to predict response in OAC patients along with miR-193b in OSCC patients. (4) Conclusions: MicroRNAs are valuable biomarkers of response to NAT in OC. Research is needed to understand the effects different types of chemotherapy and chemoradiotherapy have on the predictive value of microRNAs; studies also require greater standardization in how response is defined.

Novel epigenetic network biomarkers for early detection of esophageal cancer

BackgroundEarly detection of esophageal cancer is critical to improve survival. Whilst studies have identified biomarkers, their interpretation and validity is often confounded by cell-type heterogeneity.ResultsHere we applied systems-epigenomic and cell-type deconvolution algorithms to a discovery set encompassing RNA-Seq and DNA methylation data from esophageal adenocarcinoma (EAC) patients and matched normal-adjacent tissue, in order to identify robust biomarkers, free from the confounding effect posed by cell-type heterogeneity. We identify 12 gene-modules that are epigenetically deregulated in EAC, and are able to validate all 12 modules in 4 independent EAC cohorts. We demonstrate that the epigenetic deregulation is present in the epithelial compartment of EAC-tissue. Using single-cell RNA-Seq data we show that one of these modules, a proto-cadherin module centered around CTNND2, is inactivated in Barrett’s Esophagus, a precursor lesion to EAC. By measuring DNA methylation in saliva from EAC cases and controls, we identify a chemokine module centered around CCL20, whose methylation patterns in saliva correlate with EAC status.ConclusionsGiven our observations that a CCL20 chemokine network is overactivated in EAC tissue and saliva from EAC patients, and that in independent studies CCL20 has been found to be overactivated in EAC tissue infected with the bacterium F. nucleatum, a bacterium that normally inhabits the oral cavity, our results highlight the possibility of using DNAm measurements in saliva as a proxy for changes occurring in the esophageal epithelium. Both the CTNND2/CCL20 modules represent novel promising network biomarkers for EAC that merit further investigation.

Understanding Compliance, Practice Patterns, and Barriers Among Gastroenterologists and Primary Care Providers Is Crucial for Developing Strategies to Improve Screening for Barrett’s Esophagus

Understanding Compliance, Practice Patterns, and Barriers Among Gastroenterologists and Primary Care Providers Is Crucial for Developing Strategies to Improve Screening for Barrett’s Esophagus

A novel circulating diagnostic and prognostic metagenomic signature in esophageal adenocarcinoma: Implications for precision oncology.

336 Background: The high incidence of esophageal adenocarcinoma (EAC) remains a major clinical challenge as majority of these cases are diagnosed at advanced stages, with poor survival outcomes. Emerging evidence indicate intriguing associations between unique microbial profiles and cancer pathogenesis. More recent data also indicates the potential clinical significance of specific microbial signatures as diagnostic and prognostic biomarkers. However, to date, no studies have systematically interrogated circulating metagenome profiling in EAC patients, particularly as non-invasive, early detection, surveillance and prognostic classifiers that may improve the current management paradigms. Methods: Metagenome sequencing was performed on 81 serum specimens collected from 51 EAC, 10 high grade dysplasia (HGD), 10 Barretts’s esophagus (BE), and 10 gastro-esophageal reflux disease (GERD) patients, respectively. Sequencing reads were classified using Bracken and MetaPhlAn3 to determine relative abundance between various classes. The Linear Discriminant Analysis effect size (LEfSe) method was performed to identify potential conserved and discrete microbial profiles between groups. Logistic regression and Kaplan-Meier analyses were used to build a model according to clinical and metagenomic classifiers to examine the diagnostic and prognostic potential of the identified metagenomic signature. Results: A significant loss of alpha and beta diversity was identified in serum specimens from EAC patients. We observed a shift in microbial taxa between each group – at the phylum, genus, and species level – with Lactobacillus sakei as the most prominent species in GERD vs. other patient groups. Interestingly, LEfSe analysis identified a complete loss of Lactobacillus ( L.Sakei and L. Curvatus), Collinsella stercoris and Bacteroides stercoris, but conversely a significant increase in Escherichia coli in patients with EAC. Finally, we developed a metagenome panel that discriminated EAC from GERD patients with an AUC value of 0.89 (95% CI, 0.78 – 0.95), and this panel in conjunction with the TNM stage was a robust predictor of overall survival (≥24 months; AUC = 0.84 [95% CI 0.66 – 0.92]) and an accompanying hazard ratio (HR) of 6.23 (95% CI, 2.65 – 14.46, P<0.001). Conclusions: This study describes unique blood-based microbial profiles in patients with GERD, BE, HGD, and EAC, that are further utilized to establish a novel circulating diagnostic and prognostic metagenomic signature in EAC.

Quantitative proteomic profiling of esophageal adenocarcinoma tumors to assess prevalence of approved targets and elucidate novel biomarkers.

343 Background: Esophageal adenocarcinoma (EAC) continues to have extremely poor prognosis despite advances in surgical and oncological regimens. Targeted and immune therapy hold promise to improve outcomes in solid tumors including EAC. At present HER-2 and anti-PD-L1 therapies are approved by the FDA for EAC. Additionally, off-label use of EGFR directed therapy has been reported. The aim of this study is to measure expression of 80+ oncoproteins in EAC using multiplexed mass spectrometry to elucidate expression of currently approved-drug targets and explore promising new targets for drug development. Methods: After Institutional Review Board approval (Mayo Clinic and KUMC), EAC patients whose tumors were resected via esophagectomy before chemotherapy and/or radiation were identified. Normal esophageal mucosa samples with no history of EAC were also retrieved for analysis. Tissue sections were microdissected to exclude stroma from adenocarcinoma cells. Isolated EAC cells were solubilized for mass spectrometry-based quantitation of more than 80 clinically relevant tumor markers. Results: 55 EAC tissues were analyzed. HER2, PD-L1 and EGFR were overexpressed only in 16.3%, 0%, and 0% of patients, respectively. New oncoproteins #2 and #6 were noted to have high (7,634.0 and 27,222.6 attomoles/ug) and consistent (98.1% and 94.5%) overexpression in EAC samples. Expression of HER2, oncoproteins #2 and #6 were significantly higher in EAC compared to normal esophageal mucosa. There was no statistical difference in the expression of PD-L1 and EGFR between EAC and normal samples. Conclusions: Mass spectrometry revealed a very low prevalence of target oncoproteins in EAC for currently used drugs. Our study potentially reveals alternate markers which are near universally present at high levels and should be further explored for targeted treatment.[Table: see text]

Feasibility of multimdodal prehabilitation to enhance preoperative functional capacity of esophageal cancer patients during concurrent neoadjuvant chemotherapies - a pilot interventional study

Background: Surgery coupled with neoadjuvant chemotherapy (NACT) have become standard in the management of advanced esophageal adenocarcinoma (EAC), contributing to improved surgical and survival outcomes. However, NACT can have deleterious effects on patients physiological reserves, functional status and is often poorly tolerated. Multimodal prehabilitation has been shown to improve perioperative health in a variety of oncological surgery patients. However, there is a gap in the literature addressing prehabilitation within EAC patients undergoing NACT.

The Impact of Esophageal Oncological Surgery on Perioperative Immune Function; Implications for Adjuvant Immune Checkpoint Inhibition.

BackgroundImmune checkpoint inhibitors (ICIs) are being investigated for their role as an adjunct in the multimodal treatment of esophageal adenocarcinoma (EAC). The most effective time to incorporate ICIs remains unknown. Our study profiles systemic anti-tumor immunity perioperatively to help inform the optimal timing of ICIs into current standards of care for EAC patients.MethodsSystemic immunity in 11 EAC patients was phenotyped immediately prior to esophagectomy (POD-0) and post-operatively (POD)-1, 3, 7 and week 6. Longitudinal serological profiling was conducted by ELISA. The frequency of circulating lymphocytes, activation status, immune checkpoint expression and damage-associated molecular patterns was assessed by flow cytometry.ResultsThe frequency of naïve T-cells significantly increased in circulation post-esophagectomy from POD-0 to POD-7 (p<0.01) with a significant decrease in effector memory T-cells by POD7 followed by a subsequent increase by week 6 (p<0.05). A significant increase in activated circulating CD27+ T-cells was observed from POD-0 to POD-7 (p<0.05). The percentage of PD-1+ and CTLA-4+ T-cells peaked on POD-1 and was significantly decreased by week 6 (p<0.01). There was a significant increase in soluble PD-1, PD-L2, TIGIT and LAG-3 from POD-3 to week 6 (p<0.01). Increased checkpoint expression correlated with those who developed metastatic disease early in their postoperative course. Th1 cytokines and co-stimulatory factors decreased significantly in the immediate post-operative setting, with a reduction in IFN-γ, IL-12p40, IL-1RA, CD28, CD40L and TNF-α. A simultaneous increase was observed in Th2 cytokines in the immediate post-operative setting, with a significant increase in IL-4, IL-10, IL-16 and MCP-1 before returning to preoperative levels at week 6.ConclusionOur study highlights the prevailing Th2-like immunophenotype post-surgery. Therefore, shifting the balance in favour of a Th1-like phenotype would offer a potent therapeutic approach to promote cancer regression and prevent recurrence in the adjuvant setting and could potentially propagate anti-tumour immune responses perioperatively if administered in the immediate neoadjuvant setting. Consequently, this body of work paves the way for further studies and appropriate trial design is needed to further interrogate and validate the use of ICI in the multimodal treatment of locally advanced disease in the neoadjuvant and adjuvant setting.

Prognostic Values and Underlying Regulatory Network of Cohesin Subunits in Esophageal Carcinoma.

Background: Cohesin is a highly conserved and ubiquitously expressed protein complex. While increasing evidence suggests that cohesin dysregulation is vital in the carcinogenesis of numerous malignancies, little is known about the prognostic values and potential mechanisms of cohesin subunits and direct regulators in esophageal carcinoma (ESCA).Methods: RNA-sequencing data from The Cancer Genome Atlas (TCGA) and Genome Tissue Expression (GTEx) were used. The subunits and regulators of cohesin affecting the prognosis of ESCA were screened by Kaplan-Meier survival analysis; univariate and multivariate Cox regression analyses were performed; and the receiver-operating characteristic (ROC) curve was determined. The ESCA hazard model and nomogram map were constructed by integrating the clinical data. We used functional analysis and protein-protein interaction (PPI) networks to explore underlying pathways. Finally, immunohistochemistry was performed to examine the expression levels of cohesin subunits in tissue microarray (TMA).Results: Transcriptome data from multiple ESCA patient datasets showed cohesin subunits SMC1A, SMC1B, SMC3, STAG1, STAG2, RAD21, and cohesin regulators including ESCO2, NIPBL, MAU2, WAPL, PDS5A and PDS5B were all upregulated in ESCA tissues compared to normal tissues. Survival analysis demonstrated that high STAG2 expression was significantly associated with poorer overall survival (OS) and progression-free survival (PFS) in esophageal adenocarcinoma (EAC). In contrast, high RAD21 expression was significantly correlated with better OS in esophageal squamous cell carcinoma (ESCC). Moreover, STAG2 and RAD21 were identified as independent prognostic factors and predictive biomarkers in EAC and ESCC, respectively. Functional enrichment analysis further revealed that STAG2 and RAD21 were mainly involved in the mitotic nuclear division, DNA repair, angiogenesis, epithelial-mesenchymal transition (EMT), and oncogenic signaling pathways. PPI analysis illustrated that STAG2 and RAD21 could cross-talk through cancer-associated modules and performed the core roles of the whole PPI network. Using TMA, STAG2 protein expression positively correlated with lymph node metastasis and advanced clinical stage of EAC patients, whereas there was a negative correlation between RAD21 protein expression and the malignant clinicopathological parameters in ESCC.Conclusion: These findings suggest that STAG2 and RAD21 can be used as predictive biomarkers for risk assessment and prognostic stratification in ESCA, which provide potential novel insights into molecular targets of ESCA.

Clinical Background and Outcomes Including Changes Over Time of Barrett&apos;s Esophageal Adenocarcinoma Patients Treated with Endoscopic Submucosal Dissection in Kagoshima Prefecture, Japan

Clinical Background and Outcomes Including Changes Over Time of Barrett&apos;s Esophageal Adenocarcinoma Patients Treated with Endoscopic Submucosal Dissection in Kagoshima Prefecture, Japan

P-OGC80 The effect of COVID -19 on new diagnosis oesophagogastric cancer patients in the UK: A single-centre experience

BackgroundCovid-19 has had a devastating global impact and resulted in over 4.4 million directly attributed deaths. The UK entered lockdown in March 2020, redistributing its medical workforce and resources. Early estimations suggested at least 4700 extra cancer deaths at 5 years if there was a 3-month delay to surgery. Delays to diagnosis and treatment for osophagogastric (OG) cancers can be particularly detrimental to survival. The aim of this study is to assess the impact of Covid-19 on new cancer referrals to a centralised UK OG cancer centre, including presentation, decision making and treatment. MethodsPatients with OG cancer referred to a tertiary, high-volume centre between March 2019 and March 2021 were reviewed. Patients were stratified into Pre-covid (March 2019-March 2020) and Covid (March 2020-2021) cohorts. Number of new referrals, clinical stage, treatment decision, and time to treatment were compared for gastric adenocarcinoma (GA), oesophagogastric-junction adenocarcinoma (OGJA), oesophageal adenocarcinoma (OA) and oesophageal SCC (OSCC).ResultsThere was an 11% reduction in new cancer referrals (485 vs 431). GA, OGJA and OA did not have significant change in treatment intent, although there was a significant increase in the decision for definitive non-surgical treatment of OA (P = 0.046). GA and OA patients had a small, but significant increase in mean clinical stage at presentation (P < 0.05). There was no increase in time to treatment for GA, OGJA and OA. A significantly higher proportion of OSCC patients were given curative intent treatment in the Covid-19 cohort (P = 0.0006) however, this was accompanied with an increased time to treatment commencement (35.8 days vs 27.9 days P = 0.0198). ConclusionsThis high-volume centre has seen a reduction in new cancer referrals since the first UK lockdown. This was associated with a small, but significant, increase in clinical stage of GA and OA at presentation. This may represent an early indication of excess oesophagogastric cancer deaths due to the impact of Covid-19. This data also confirms initial results showing that oncological decisions were not compromised, although Covid-19 remains a dynamic challenge.