Esophagogastric Junction Adenocarcinoma Patients Research Articles

A Nomogram Based on Nutrition-Related Indicators and Computed Tomography Imaging Features for Predicting Preoperative Lymph Node Metastasis in Curatively Resected Esophagogastric Junction Adenocarcinoma.

Preoperative noninvasive tools to predict pretreatment lymph node metastasis (PLNM) status accurately for esophagogastric junction adenocarcinoma (EJA) are few. Thus, the authors aimed to construct a nomogram for predicting PLNM in curatively resected EJA. This study enrolled 638 EJA patients who received curative surgery resection and divided them randomly (7:3) into training and validation groups. For nomogram construction, 26 candidate parameters involving 21 preoperative clinical laboratory blood nutrition-related indicators, computed tomography (CT)-reported tumor size, CT-reported PLNM, gender, age, and body mass index were screened. In the training group, Lasso regression included nine nutrition-related blood indicators in the PLNM-prediction nomogram. The PLNM prediction nomogram yielded an area under the receiver operating characteristic (ROC) curve of 0.741 (95 % confidence interval [CI], 0.697-0.781), which was better than that of the CT-reported PLNM (0.635; 95% CI 0.588-0.680; p < 0.0001). Application of the nomogram in the validation cohort still gave good discrimination (0.725 [95% CI 0.658-0.785] vs 0.634 [95% CI 0.563-0.700]; p = 0.0042). Good calibration and a net benefit were observed in both groups. This study presented a nomogram incorporating preoperative nutrition-related blood indicators and CT imaging features that might be used as a convenient tool to facilitate the preoperative individualized prediction of PLNM for patients with curatively resected EJA.

Safety and short-term efficacy of neoadjuvant FLOT therapy in patients with resectable esophageal squamous cell carcinoma.

373 Background: Docetaxel and cisplatin, 5-FU (DCF) is a standard neoadjuvant treatment for resectable esophageal squamous cell carcinoma (ESCC) based on the results of the JCOG1109 study. However, DCF therapy showed that 18.6% of patients achieved pathological complete response but 16.3% had febrile neutropenia (FN) and needed hydration. In Western countries, 5-FU plus leucovorin, oxaliplatin, docetaxel (FLOT) is a standard perioperative treatment for resectable gastric and esophagogastric junction adenocarcinoma patients. FLOT therapy showed that 2% of patients had FN and did not need hydration. However, safety and efficacy of neoadjuvant FLOT (NeoFLOT) in locally advanced ESCC patients was unclear. Methods: The subjects for this study were patients with resectable ESCC diagnosed as cT1N1-3M0, cT2-3N0-3M0, and cT1-3N0-3M1 (UICC-TNM 8th) and received NeoFLOT therapy between Feb 2021 to July 2022 at our hospital. NeoFLOT therapy (oxaliplatin: 85 mg/m2, leucovorin: 200 mg/m2, 5-FU: 2600 mg/m2, docetaxel: 50 mg/m2, every 2 weeks) was administered for 4 courses. We evaluated adverse events (CTCAE ver. 5.0) and histopathological response. Results: We identified 16 eligible patients and 12 of all patients (75%) underwent surgery. 4 patients (25%) resulted in progressive disease (1 patient underwent chemoradiotherapy and 3 patients underwent surgery). R0 resection rate was 75% and complete pathologic response in primary tumor was seen in 2 patients (17%). The most common adverse events were hematologic toxicity, with grade 3 or 4 leukopenia in 6 patients (38%), neutropenia in 9 patients (56%). The common non-hematological toxicity, with all grades deceased appetite in 7 patients (44%) and malaise in 8 patients (50%), peripheral neuropathy in (44%). Furthermore, the incidence of FN was 6%. In patients with grade 2 or higher renal failure, no one (0%) had worsened renal function. Conclusions: NeoFLOT therapy showed well-tolerated and comparable efficacy with DCF therapy.

A novel nomogram based on clinical blood indicators for prognosis prediction in curatively resected esophagogastric junction adenocarcinoma patients.

Background: The incidence of esophagogastric junction adenocarcinoma (EJA) patients was increasing but their prognoses were poor. Blood-based predictive biomarkers were associated with prognosis. This study was to build a nomogram based on preoperative clinical laboratory blood biomarkers for predicting prognosis in curatively resected EJA. Methods: Curatively resected EJA patients, recruited between 2003 and 2017 in the Cancer Hospital of Shantou University Medical College, were divided chronologically into the training (n=465) and validation groups (n=289). Fifty markers, involving sociodemographic characteristics and preoperative clinical laboratory blood indicators, were screened for nomogram construction. Independent predictive factors were selected using Cox regression analysis and then were combined to build a nomogram to predict overall survival (OS). Results: Composed of 12 factors, including age, body mass index, platelets, aspartate aminotransferase-to-alanine transaminase ratio, alkaline phosphatase, albumin, uric acid, IgA, IgG, complement C3, complement factor B and systemic immune-inflammation index, we constructed a novel nomogram for OS prediction. In the training group, when combined with TNM system, it acquired a C-index of 0.71, better than using TNM system only (C-index: 0.62, p < 0.001). When applied in the validation group, the combined C-index was 0.70, also better than using TNM system (C-index: 0.62, p < 0.001). Calibration curves exhibited that the nomogram-predicted probabilities of 5-year OS were both in consistency with the actual 5-year OS in both groups. Kaplan-Meier analysis exhibited that patients with higher nomogram scores contained poorer 5-year OS than those with lower scores (p < 0.0001). Conclusions: In conclusion, the novel nomogram built based on preoperative blood indicators might be the potential prognosis prediction model of curatively resected EJA.

309 ASSOCIATION BETWEEN CERVICAL ANASTOMOSIS METHODS AND ANASTOMOSIS STRICTURE AFTER ESOPHAGECTOMY FOR CANCER

Abstract Esophagectomy with three-field lymph node dissection is the most important part of advanced esophageal cancer therapy, especially for squamous cell carcinoma (SCC) patients. After esophagectomy, cervical anastomosis with gastric tube is required. However, some patients suffer anastomotic stenosis and require endoscopic balloon dilations. In this study, we investigated the relationship between cervical anastomosis methods and anastomosis stricture after esophagectomy for cancer patients. Methods Patients with esophageal cancer undergoing radical esophagectomy with cervical anastomosis were identified from the prospectively maintained database at our institution. From 2013 to 2019, 28 patients received esophagectomy with cervical lymph node dissection in our institution. Association between anastomotic methods, linear stapler vs circular stapler, and other factors (patient characteristics, surgical complications including anastomotic stenosis, and length of postoperative stay) were analyzed. Results Their average age was 63.3 years. Males and SCC cases predominated. Thirteen patients (46%) received cervical anastomosis with the circular stapler (Group C), and 11 patients (39%) received treatment with the linear stapler (Group L). None of the following variables were significant different between the two methods: preoperative chemotherapy (53.8% in group C vs. 45.5% in group L; p = 0.58), length of hospital stay (25.8 vs. 20.7 days; p = 0.15), pulmonary complications (16.7% vs. 0.0%; p = 0.36), and anastomotic leakage (33.3% vs. 9.1%; p = 0.24). However, the rate of anastomotic stenosis without malignancies was significantly higher in group C patients (66.7% vs. 0%, p &amp;lt; 0.01). Conclusion Cervical anastomosis with the linear stapler may be safer and associated with a lower stenosis rate than with the circular stapler. In future, cervical anastomosis with linear stapler after mediastinoscopic esophagectomy would be better for not only esophageal SCC patients but also esophagogastric junction adenocarcinoma patients with pulmonary complications.

The Early Diagnostic Value of Serum Interleukin-8 in Esophagogastric Junction Adenocarcinoma.

Background:Esophagogastric junction adenocarcinoma (EJA) is one of the most common malignant tumors of digestive tract with high mortality worldwide. Given a lack of early diagnosis biomarkers, the prognosis of EJA is poor. Non-invasive biomarkers for early-stage EJA are urgently required.Objective:We aimed at evaluating the early diagnostic value of serum interleukin-8 (IL-8) level in EJA patients.Methods:The IL-8 mRNA expression data were analyzed based on the stomach cardia adenocarcinoma samples of The Cancer Genome Atlas (TCGA) database. Enzyme-linked immunosorbent assay (ELISA) was used to measure the concentration of serum IL-8 in 95 EJA patients and 95 normal controls enrolled from 2 different cancer hospitals. The diagnostic accuracy of serum IL-8 was evaluated by applying Mann-Whitney U test and receiver operating characteristic (ROC) curve.Results:The mRNA expression levels and serum levels of IL-8 in EJA group were significantly higher than those in the normal group (all P < 0.001). The areas under the ROC curve (AUC) were 0.661 (95% CI, 0.583-0.740) and 0.745 (95% CI, 0.606-0.885), with the sensitivities of 43.2% (95% CI, 33.2%-53.7%) and 66.7% (95% CI, 46.0%-82.8%) and the specificities of 87.4% (95% CI, 78.6%-93.1%) in EJA group and early-EJA group, respectively, when the optimal cutoff value was 109.086 pg/mL. The clinical data analysis showed there were significant correlations between patient genders, depth of invasion, lymph node metastasis, TNM stage and the serum level of IL-8 (all P < 0.05).Conclusions:Serum IL-8 represents a potential diagnostic biomarker to identify early-stage EJA.

Analysis of survival and prognosis of Siewert Ⅱ/Ⅲ esophagogastric junction adenocarcinoma patients with non-operative acute upper gastrointestinal hemorrhage

Objective: To analyze the clinical characteristics and risk factors of non-operative acute upper gastrointestinal hemorrhage in patients with adenocarcinoma of the esophagogastric junction. Methods: The clinical diagnosis and treatment data of patients with adenocarcinoma of esophagogastric junction with non-operative acute upper gastrointestinal hemorrhage admitted to Cancer Hospital of Chinese Academy of Medical Sciences from 2004 to 2018 were collected retrospectively, and the survival of patients was followed up by telephone. SPSS software was used for database establishment and analysis. Cox proportional-hazards model was applied to analyse the survival and related risk factors. Results: A total of 70 patients were included in this study, with a median age of 65 (20-81 years). The ratio of male to female is 2.18∶1. There were 36 cases of Siewert type Ⅱ (51.4%) and 34 cases of Siewert type Ⅲ (48.6%). The lymph node metastasis rates of Siewert Ⅱ and Siewert Ⅲ were 75.0% and 94.1%, respectively (P=0.028). The median overall survival time (OS) of all 70 patients was 11.6 months. The median OS of Siewert Ⅱ and Siewert Ⅲ were 20.0 months and 8.5 months, respectively, and the 1-year survival rates were 42% and 9%, respectively (P=0.027). The median OS of M0 and M1 patients were 19.1 and 7.7 months, respectively, and the 1-year survival rates were 40% and 4%, respectively (P=0.049). The median OS of the treatment of operation+chemotherapy, chemotherapy or best supportive care after hemorrhage were 60.0, 22.2, and 7.9 months, respectively, and the 1-year survival rates were 89%, 45%, and 2%, respectively (all P<0.05). Multivariate analysis showed that Siewert Ⅲ (HR=1.965, 95%CI: 1.078-3.583), M1 stage (HR=1.787, 95%CI: 1.002-3.187) and operation+chemotherapy treatment after hemorrhage (HR=0.132, 95%CI:0.032-0.552) were independent prognostic factors for patients of esophagogastric junction adenocarcinoma with non-operative acute upper gastrointestinal hemorrhage. Conclusions: The survival of patients of esophageal gastric junction adenocarcinoma with non-operative acute upper gastrointestinal hemorrhage is poor, especially for patients of Siewert Ⅲ and the late stage. Active operation and chemotherapy after bleeding may positively affect the survival of these patients.

Association of Long Noncoding RNAs Polymorphisms with the Risk of Esophagogastric Junction Adenocarcinoma: A Three-Center Study of 1063 Cases and 1677 Controls.

Increasing evidence suggested that long noncoding RNAs (lncRNAs) variants may be involved in the progression of various cancers. However, the association of the lncRNAs polymorphisms with the risk for esophagogastric junction adenocarcinoma (EGJA) is still unknown. In this case-control study, we selected two cancer-related lncRNAs polymorphisms (rs944289 C > T and rs7990916 C>T), and recruited a total of 1063 EGJA patients and 1677 noncancer controls to determine whether the lncRNAs rs944289 C > T and rs7990916 C > T polymorphisms could influence EGJA susceptibility and lymph node status. And SNPscan™ genotyping assay was applied to test the genotypes of the mentioned two variants. We found no statistically significant differences in the distribution of lncRNAs rs944289 C > T and rs7990916 C > T polymorphisms between EGJA patients and healthy controls. Similar negative findings were also revealed in the correlation of those polymorphisms with different lymph node status. However, after adjustment by multiple environmental factors, including gender, age, drinking, and smoking consumption, the stratified analyses showed that the lncRNAs rs944289 C > T variant was significantly related with the risk of EGJA in <60 years populations [CT vs. CC: adjusted odds ratio (OR) = 0.75, 95% confidence interval (CI) = 0.58-0.98, p = 0.032] and ever smoking populations (CT/CC vs. TT: adjusted OR = 1.65, 95% CI = 1.11-2.46, p = 0.013). In short, this population-based study highlights that lncRNAs rs944289 C > T polymorphism may be associated with genetic susceptibility to EGJA in the <60 years and ever smoking populations.

LINE-1 hypo-methylation as a distinct phenotype in non-EBV/non-MSI-H esophagogastric junction adenocarcinoma.

411 Background: Most esophagogastric junction (EGJ) adenocarcinoma exhibits chromosomal instability (CIN) type with wide range of CpG site methylation. However, it is still uncertain if epigenetic alteration is clinically useful. LINE-1 methylation level is representative of genome-wide methylation status. The aim of this is to examine clinicopathological and molecular characteristics of LINE-1 methylation, and its prognostic role, in non-EBV/non-MSI-H EGJ adenocarcinoma. Methods: After removing EBV-associated or MSI-H tumors, which are the distinct molecular subtype with hyper methylation, a total 335 case of chemo-naïve non-EBV/non-MSI-H EGJ adenocarcinoma from four academic institutions in Japan, were eligible. LINE-1 methylation was examined by Pyrosequencing. Results: LINE-1 methylation level was successfully sequenced in 319 cases (92.5%). LINE-1 methylation level was associate with tumor differentiation. Intestinal type was frequently observed in the lowest quartile Q1 cases (P = 0.0006). Of note, TP53 mutation rate was significantly frequent in Q1-2 cases (P &lt; 0.0001). Ki-67 index was also higher in Q1-2 cases. Tumor PD-L1 expression, or CD8+ cell infiltration was not associated with LINE-1 methylation level. In survival analysis, the patients with the lowest LINE-1 methylation level (Q1), experienced the worst outcome in disease-specific survival, relapse-free survival, and overall survival rates. Conclusions: Tumor with LINE-1 hypomethylation harbors significantly higher TP53 mutation and higher Ki-67 index, resulting in worse outcome in EGJ adenocarcinoma patients.

Circulating Levels of L1-cell Adhesion Molecule as a Serum Biomarker for Early Detection of Gastric Cancer and Esophagogastric Junction Adenocarcinoma.

Background: Low serum L1 cell adhesion molecule (L1CAM) has been found in several malignant tumors. Here, we aimed to evaluate the diagnostic potential for serum L1CAM in patients with gastric cancers (GC) and esophagogastric junction adenocarcinoma (EJA).Methods: Enzyme-linked immunosorbent assay (ELISA) was carried out to detect L1CAM level in sera of 148 GC patients, 59 EJA patients and 148 healthy controls. Receiver operating characteristics (ROC) was employed to evaluate diagnostic accuracy.Results: The concentrations of serum L1CAM were significantly lower in GC and EJA than those in healthy controls (P<0.001). Detection of L1CAM provided a sensitivity of 83.1%, a specificity of 62.2%, and an area under the curve (AUC) of 0.769 (95% CI: 0.715-0.823) in diagnosing GC, and a sensitivity of 66.1%, a specificity of 62.2%, and an AUC of 0.672 (95% CI: 0.590-0.755) in diagnosing EJA. Similar results were observed in the diagnosis of early-stage GC (0.681 (95%CI: 0.596-0.766)) and early-stage EJA (0.674 (95%CI: 0.528-0.820)). Analysis of clinical data showed that the levels of L1CAM were significantly associated with lymph node metastasis in GC (P<0.05).Conclusions: Our study showed that serum L1CAM might be a diagnostic biomarker for GC and EJA.

Serum Insulin-Like Growth Factor Binding Protein 7 as a Potential Biomarker in the Diagnosis and Prognosis of Esophagogastric Junction Adenocarcinoma.

Background/AimsEsophagogastric junction adenocarcinoma (EJA) is a malignant tumor associated with high morbidity and has attracted increasing attention due to a rising incidence and low survival rate. Pathological biopsy is the gold standard for diagnosis, but noninvasive and effective tests are lacking, resulting in diagnoses at advanced stages. This study explored the diagnostic value of insulin-like growth factor binding protein 7 (IGFBP7) in EJA.MethodsA total of 120 EJA patients and 88 normal controls were recruited, and their serum levels of IGFBP7 were measured by enzyme-linked immunosorbent assay. Receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic value, and Pearson chi-square analysis was used to evaluate the correlation between IGFBP7 and clinical parameters. Kaplan-Meier survival analysis was carried out to assess the effect of IGFBP7 on overall survival (OS).ResultsThe levels of IGFBP7 were higher in both early- and late-stage EJA patients than in normal controls (p<0.001). The area under the ROC curve for EJA patients was 0.794 (95% confidence interval [CI], 0.733 to 0.854), with a cutoff value of 2.716 ng/mL, a sensitivity of 63.3% (95% CI, 54.0% to 71.8%) and a specificity of 90.9% (95% CI, 82.4% to 95.7%). For the diagnosis of early-stage EJA, the same cutoff value and specificity were obtained, but the sensitivity of IGFBP7 was 54.3% (95% CI, 36.9% to 70.8%). Patients with low IGFBP7 protein expression had lower OS than those with high expression (p=0.034). The multivariate analysis showed that IGFBP7 is an independent prognostic factor for EJA (p=0.011).ConclusionsSerum IGFBP7 acts as a potential diagnostic and prognostic marker for EJA.

Serum tumor-associated glycoprotein 72, a helpful predictor of lymph nodes invasion in esophagogastric junction adenocarcinoma

Disruption of cell-cell junction and adhesion to vessels are crucial steps in tumor metastasis. Tumor-associated glycoprotein 72 (TAG-72) is a crucial membrane mucin in gastroesophageal mucosa for microenvironment contact with cells. Thus, the TAG-72 value may be an indicator of the malignant involvement of lymph nodes in esophagogastric junction adenocarcinoma (EGAC) patients. Of the 183 patients suspected as gastroesophageal neoplasms, 129 were subsequently diagnosed as EGAC, and 54 were subsequently diagnosed as benign gastroesophageal diseases by imageological or/and histological examination. After we obtained preoperative serum TAG-72 values, the relationship between serum TAG-72 and lymphatic metastasis status, extent of invaded lymph nodes and clinical stage was tested using Spearman correlation analysis and χ2 tests. Compared with those in patients who suffered either benign gastroesophageal diseases or preinvasive carcinoma, the median serum TAG-72 values were statistically higher in EGAC patients with positive lymph nodes (Kruskal-Wallis test; P < 0.001). Serum TAG-72 values were significantly correlated with Lymph Node Ratio (LNR) (Spearman correlation; P < 0.001). Using corresponding ROC (95% CI = 0.621–0.783, P < 0.0001), serum TAG-72 values with an optimal cut-off (2.2 kU/mL) showed a sensitivity of 0.632 and a specificity of 0.690 for predicting malignant lymph node involvement in EGAC. These results suggest that the serum TAG-72 value is a clinically helpful predictor of lymph nodes invasion in resectable EGAC.

Combined detection of serum autoantibodies as diagnostic biomarkers in esophagogastric junction adenocarcinoma

BackgroundWe previously found that autoantibodies against a panel of six tumor-associated antigens (p53, NY-ESO-1, MMP-7, Hsp70, PRDX6 and Bmi-1) may aid in early detection of esophageal squamous cell carcinoma. Here we aimed to evaluate the diagnostic value of this autoantibody panel in esophagogastric junction adenocarcinoma (EJA) patients.MethodsSerum autoantibody levels were measured by enzyme-linked immunosorbent assay in a training cohort and a validation cohort. We used receiver-operating characteristics (ROC) to calculate diagnostic accuracy.ResultsWe recruited 169 normal controls and 122 EJA patients to the training cohort, and 80 normal controls and 70 EJA patients to the validation cohort. Detection of the autoantibody panel demonstrated an area under the curve (AUC) of 0.818, sensitivity 59.0% and specificity 90.5% in training cohort, and AUC 0.815, sensitivity 61.4% and specificity 90.0% in validation cohort in the diagnosis of EJA. Measurement of the autoantibody panel could distinguish early stage EJA patients from normal controls (AUC 0.786 and 0.786, sensitivity 50.0% and 56.0%, and specificity 90.5% and 90.0%, for training and validation cohorts, respectively). Moreover, a restricted panel consisting of autoantibodies against p53, NY-ESO-1 and Bmi-1 exhibited similar diagnostic performance for EJA (AUC 0.814 and 0.823, sensitivity 53.5% and 60.0%, and specificity 90.5% and 93.7%, for training and validation cohorts, respectively) and early stage EJA (AUC 0.744 and 0.773, sensitivity 55.6% and 52.0%, and specificity 90.5% and 93.7%, for training and validation cohorts, respectively).ConclusionsAutoantibodies against an optimized TAA panel as serum biomarkers appear to help identify the present of early stage EJA.

Short-term postoperative complications and prognostic factors in patients with adenocarcinoma of the esophagogastric junction.

BackgroundThe study was conducted to investigate the short‐term complications and prognostic factors in patients with esophagogastric junction adenocarcinoma (EGJA).MethodsThis retrospective study included 110 EGJA patients who underwent surgery from January 2010 to November 2012 at The First Affiliated Hospital of BengBu Medical College. The overall survival and short‐term complications were analyzed according to the patients’ clinical characteristics.ResultsThe incidence of postoperative cardiopulmonary complications was significantly higher in patients with preoperative cardiopulmonary disease or elderly patients (P < 0.05). Four cases of upper margin cancer residue were detected using the abdominal approach and three using the thoracic approach, which indicated that the cancer residue margin was related to surgical approach. The overall five‐year survival rate was 34.3% and statistically differed according to pathological stage and en block resection (P all < 0.05). Cox regression analysis showed that lymph node metastasis (P < 0.05) and the extent of tumor invasion (P < 0.05) were independent prognostic factors.ConclusionElderly patients with preoperative cardiopulmonary disease had an increased risk of developing postoperative cardiopulmonary complications. Lymph node status and depth of tumor invasion were independent factors related to patient prognosis.

MiRNA-146a rs2910164 C>G polymorphism increased the risk of esophagogastric junction adenocarcinoma: a case-control study involving 2,740 participants.

PurposeThe miRNA-146a rs2910164 C>G polymorphism may contribute to the development of cancer. However, the association between this polymorphism and the risk of esophagogastric junction adenocarcinoma (EGJA) remains unclear. In the present study, we carried out a case–control study to explore the potential relationship between miRNA-146a rs2910164 C>G polymorphism and EGJA risk.Patients and methodsIn total, 1,063 EGJA patients and 1,677 cancer-free controls were enrolled. The SNPscan™ genotyping assay, a patented technology, was used to test the genotyping of miRNA-146a rs2910164 C>G polymorphism.ResultsWe found that miRNA-146a rs2910164 C>G polymorphism was associated with a risk of developing EGJA (additive model: adjusted odds ratio (OR), 1.27; 95% CI, 1.07–1.51; P=0.006; homozygote model: adjusted OR, 1.31; 95% CI, 1.03–1.65; P=0.027 and dominant model: adjusted OR, 1.36; 95% CI, 1.15–1.60; P<0.001). After adjustment for the Bonferroni correction, these associations were also found in additive and dominant genetic models. In the subgroup analyses, after adjustment by sex, age, alcohol consumption, and smoking status, results of multiple logistic regression analysis indicated that miRNA-146a rs2910164 C>G polymorphism increased the risk of EGJA in males, females, <64 years old, ≥64 years old, never smoking, and never drinking subgroups.ConclusionThe current study highlights that the miRNA-146a rs2910164 C>G polymorphism increased the risk of EGJA in eastern Chinese Han population.

Programmed death-1 polymorphisms is associated with risk of esophagogastric junction adenocarcinoma in the Chinese Han population: A case-control study involving 2,740 subjects.

Single nucleotide polymorphisms (SNPs) in Programmed cell death 1 (PD-1) gene may contribute to the development of cancer. In this study, we selected PD-1 rs10204525 T>C, rs2227982 A>G, rs36084323 T>C and rs7421861 A>G polymorphisms and designed a hospital-based case-control study to determine the potential relationship between these functional SNPs in PD-1 gene and esophagogastric junction adenocarcinoma (EGJA) risk. A total of 1,063 EGJA patients and 1,677 controls were enrolled from Eastern Chinese Han population. SNPscanTMgenotyping assay was used to analyze the genotyping of PD-1 polymorphisms. We found that PD-1 rs7421861 A>G polymorphism was associated with the development of EGJA. However, PD-1 rs2227982 A>G polymorphism was a protective factor for EGJA. In addition, PD-1 rs36084323 CC homozygote genotype might be associated with a borderline decreased risk of EGJA. In a subgroup analysis, a decreased risk of EGJA in never drinking and never smoking groups was identified. Haplotype comparison analysis suggested that PD-1 Trs10204525Grs2227982C36084323Ars7421861 haplotype significantly decreased the risk of EGJA. However, Trs10204525Grs2227982C36084323Grs7421861 haplotype in PD-1 gene may confer risk to EGJA. In conclusion, our study highlights rs2227982 A>G, rs36084323 T>C and rs7421861 A>G polymorphisms and haplotypes in PD-1 gene, especially within the intron region, are significantly associated with the risk of EGJA. Further case-control studies with larger sample size and detailed gene-environmental data to replicate these findings in different populations are needed to validate our conclusion.

Abstract 579: TAK1-regulated expression of BIRC3 is responsible for chemoradiotherapy (CRT) resistance in esophagogastric junction (EGJ) adenocarcinoma

Abstract Introduction: Preoperative CRT followed by surgery is the most common approach for patients with resectable esophageal and EGJ cancers. Based on the histology, patients with adenocarcinoma consistently demonstrated significantly lower rate of pathological complete response if compared with patients with squamous cell carcinoma, thus the need for accurate biomarkers to select the patients with esophageal and EGJ adenocarcinoma most likely to benefit from preoperative CRT has become even more critical. We recently demonstrated that the MAP3K TGF-βeta-activated kinase-1 (TAK1) is responsible for the resistance to the proapoptotic effect of chemotherapeutic agents by increasing the transcription of the member of the inhibitor of apoptosis proteins family BIRC3 in preclinical models of pancreatic cancer. Here, we hypothesized that the TAK1-regulated expression of BIRC3 might be responsible for the resistance to CRT in EGJ adenocarcinoma. Materials and methods: TAK1 kinase activity was targeted in FLO-1 and KYAE-1 esophageal cells by using (5Z)-7oxozeaenol. To test the effect of reducing BIRC3 expression on the resistance to CRT, FLO-1 and KYAE-1 cells were treated with increasing doses of cisplatin, 5-fluorouracil, paclitaxel, or radiotherapy in combination with (5Z)-7oxozeaenol. Drug interactions were studied for synergism according to Chou and Talalay method. Apoptotic induction was studied by western blot analysis of PARP and caspase 3 cleavages as well as by AnnexinV staining. BIRC3 expression was measured in 33 pretreatment biopsies from patients with EGJ adenocarcinoma and 34 from patients with esophageal squamous cell carcinoma receiving neoadjuvant CRT by Real-Time PCR. Tumor response was evaluated by Tumour regression grade (TRG) and by Size-based Pathological Response (SPR) scores. Correlation between BIRC3 expression and treatment response was analysed by ROC curve analysis. Results: In vitro, (5Z)-7oxozeaenol significantly reduced BIRC3 expression in FLO-1 and KYAE-1 esophageal cells. Exposure to sublethal equitoxic doses of chemotherapeutic agents plus (5Z)-7oxozeaenol pretreatment resulted in a strong synergistic anti-proliferative effect. Baseline expression of BIRC3 was significantly higher in patients with EGJ adenocarcinoma if compared with the more sensitive squamous-cell carcinoma subtype. Moreover, patients with EGJ adenocarcinoma expressing higher pretreatment levels of BIRC3 had a significantly poorer treatment response than did those with lower expression, indicating that BIRC3 expression significantly correlates with response to preoperative CRT (AUC-ROC = 0.777 and 0.807 for SPR and TRG, respectively). Conclusions: TAK1-regulated expression of BIRC3 might be a valid biomarker to predict resistance to CRT in EGJ adenocarcinoma patients. Citation Format: Geny Piro, Simone Giacopuzzi, Maria Bencivenga, Carmine Carbone, Giuseppe Verlato, Melissa Frizziero, Maria Mihaela Mina, Marco Zanotto, Valeria Merz, Giovanni De Manzoni, Giampaolo Tortora, Davide Melisi. TAK1-regulated expression of BIRC3 is responsible for chemoradiotherapy (CRT) resistance in esophagogastric junction (EGJ) adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 579. doi:10.1158/1538-7445.AM2015-579

Abstract 4696: Identification of driver mutations and gene amplifications in resected asophageal adenocarcinoma: Impact on clinical care

Abstract BACKGROUND: Adenocarcinoma of the distal esophagus and esophagogastric junction (EGJ) have received much attention because of increasing frequency and poor outcome despite multimodality therapy. Driver mutations and gene amplifications in resected esophageal adenocarcinoma are not widely investigated. Opportunity exists to discover actionable mutations in resected esophageal adenocarcinoma. METHODS: We analyzed driver mutations harbored in coding regions of 25 selected genes (∼95 point mutations) using a multiplex PCR-based assay. EGFR, HER2, MET, and PI3K amplifications were tested using fluorescent in situ hybridization in patients who underwent esophagectomy for distal esophagus and EGJ adenocarcinoma from 2009 to 2013. Disease free survival (DFS) and overall survival (OS) were compared between patients with TP53, KRAS, PI3K, BRAF, APC mutant and wild-type tumors using Kaplan-Meier methods and Cox regression models. The impact of HER2 expression and outcomes were also analyzed. RESULTS: Of 54 distal esophagus and EGJ adenocarcinoma patients, 5 different driver mutations were observed in 39 patients, including TP53 (11/39, 28.2%), KRAS (6/39,15.4%), PI3K (2/11,5.1%), BRAF(1/39, 2.6%) and APC (2/39,5.1%). Double driver mutations (3/39, 7.9%) were shared in 3 patients with TP53 and KRAS (1/39, 2.6%), TP53 and PI3K (1/39, 2.6%), KRAS and PI3K (1/39, 2.6%), respectively. Amplifications in HER2 (10/45, 22.2%), MET (1/34, 2.9%) and EGFR (2/17, 11.8%) were observed where directed therapy was altered in 5 patients (1 patient received induction herceptin and 4 patients received adjuvant herceptin). In the targeted patients with HER2 amplification who received herceptin, mean progression-free survival was 18.8 (range 7-41 months) vs. 8.9 (1-28 months) [p=0.089] and OS was 35.7 (range 26-46 months) vs. 24.2 (range 20-29 months) [p=0.053], compared to herceptin naive patients. We did not identify any significant difference in DFS and OS (inclusive of all stages) between TP53, KRAS or any mutation compared to wild type patients. DISCUSSION: Oncogenic driver mutations are under-investigated in resected distal esophageal and EGJ adenocarcinoma. Different therapeutic opportunities may become available if routine tumor genotyping is employed in the treatment of esophageal adenocarcinoma. We recommend the routine use of driver mutation and gene amplification analysis for esophageal cancer. Citation Format: Haiyu Zhou, Luis Tapias Vargas, Justin Elliot, Douglas J. Mathisen, Michael Lanuti. Identification of driver mutations and gene amplifications in resected asophageal adenocarcinoma: Impact on clinical care. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4696. doi:10.1158/1538-7445.AM2014-4696

Adenocarcinoma of the esophagogastric junction: relationship between clinicopathological data and p53, cyclin D1 and Bcl-2 immunoexpressions

Esophagogastric junction adenocarcinoma has an aggressive behavior, and TNM (UICC) staging is not always accurate enough to categorize patient's outcome. To evaluated p53, cyclin D1 and Bcl-2 immunoexpressions in esophagogastric junction adenocarcinoma patients, without Barrett's esophagus, and to compared to clinicopathological characteristics and survival rate. Tissue sections from 75 esophagogastric junction adenocarcinomas resected from 1991 to 2003 were analyzed by immunohistochemistry for p53, cyclin D1 and Bcl-2 using streptavidin-biotin-peroxidase method. The mean follow-up time was 60 months SD = 61.5 (varying from 4 to 273 months). Fifty (66.7%) of the tumors were intestinal type and 25 (33.3%) were diffuse. Vascular, lymph node and perineural infiltration were verified in 16%, 80% and 68% of the patients, respectively. The patients were distributed according to the TNM staging in IA in 4 (5.3%), IB in 10 (13.3%), II in 15 (20%), IIA in 15 (20%), IIIB in 15 (20%) and IV in 16 (21.3%). Immunohistochemical analysis was positive for p53, cyclin D1 and bcl-2 in 68%, 18.7% and 100%, respectively. There was no association between immunoexpression and vascular and/or perineural invasions, clinicopathological characteristics and patients' survival rate. In this selected population, there was no association between the immunomarkers, p53, cyclin D1 and bcl-2 and clinicopathological data and/or overall survival.