Survival In Esophageal Adenocarcinoma Research Articles

Abstract 247: Molecular markers of the vitamin D pathway and esophageal adenocarcinoma survival

Abstract We investigated the potential prognostic association between vitamin D levels (25-Hydroxyvitamin D [25(OH)D]) and vitamin D pathway single nucleotide polymorphisms (SNPs) with overall survival (OS) in esophageal adenocarcinoma (EA) patients. EA patients were recruited from Massachusetts General Hospital near the time of their diagnosis between 1999 and 2016. At the time of recruitment, patients completed a baseline questionnaire and provided blood and serum samples. Serum 25(OH)D levels were measured using radioimmunoassay and adjusted for month of blood draw. Genotypes for 48 tag SNPs from seven candidate genes in the vitamin D pathway (GC, CYP2R1, CYP27A1, CYP27B1, CYP24A1, VDR and RXRA) were determined from whole blood DNA. For survival outcomes, we used log-rank test and a multivariable extended Cox model to estimate adjusted hazard ratio (HR) of death. HR models for each SNP were restricted to patients who identified as White and adjusted for age, sex, smoking status, diagnosis year, and treatment, stratifying baseline hazard by clinical stage and modeling surgical resection as a time-dependent covariate. HR models by quartiles 25(OH)D, additionally adjusted for body mass index (BMI), and timing of blood draw. Our analyses included EA patients with complete information on relevant confounders and predictors of OS. The 25(OH)D analysis included 463 EA patients and 337 deaths, with median follow-up of 23.1 months. The mean 25(OH)D level at diagnosis was 20.7 ng/mL. We found no evidence that OS curves differed across quartiles of vitamin D (log rank p=0.83). In the adjusted extended cox model, we found no difference in OS among the highest quartile and quartiles 2-4 (respectively, HR (95% confidence interval), 0.95 (0.70, 1.31), 1.03 (0.76,1.39), 1.01 (0.73, 1.38), global p=0.97). We did not find evidence of interaction between 25(OH)D and clinical stage (p=0.88) or BMI (p=0.43) on OS, and this relationship did not differ by timing of blood draw. Preliminary SNP analysis included 424 EA patients and 305 deaths, with median follow-up of 24.1 months. Two SNPs in CYP24A1 (SNP, HR (95% confidence interval) per minor allele: rs1570669, 1.23 (1.04-1.45); rs927650, 1.22 (1.04-1.44)), two SNPs in GC (rs4588, 1.25(1.04-1.49); rs7041, 0.84(0.71-0.99)), and one SNP in RXRA (rs7039190, 1.57(1.06, 2.31)) were marginally associated with OS in the multivariable survival model. SNPs were not statistically significant after adjusting p-value for multiple testing. Based on the available evidence from our analyses, markers in the vitamin D pathway at the time of diagnosis are not clinically relevant markers of EA survival. Citation Format: Elizabeth Loehrer, Rebecca Betensky, Ruyang Zhang, Li Su, Edward Giovannucci, David Christiani. Molecular markers of the vitamin D pathway and esophageal adenocarcinoma survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 247.

Abstract 4813: Enhancement of nab-paclitaxel response by inhibition of insulin-like growth factor (IGF) signaling in experimental esophageal adenocarcinoma

Abstract Introduction: Esophageal adenocarcinoma (EAC) is the fastest growing cancer in the western world and the overall 5 year survival rate of EAC is below 20 percent. Most patients with EAC present with locally advanced or widespread metastatic disease, where current treatment is largely ineffective. Therefore, new therapeutic approaches are urgently needed. Epidemiological studies have linked obesity with EAC. IGF signaling is an important mediator in obesity-associated EAC. Paclitaxel (PT) has been used in combination with carboplatin as a standard combination therapy for advanced EAC. PT required emulsification with solvents which has resulted in serious adverse effects in patients. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is an albumin-stabilized, cremophor-free and water soluble nanoparticle formulation of PT. Nab-paclitaxel has recently shown greater efficacy over PT in EAC. Here we evaluated the improvement in nab-paclitaxel response by addition of BMS-754807, a small molecule inhibitor of IGF-1R/IR signaling, in experimental EAC. Methods: We first evaluated the phosphorylation status of IGF-1R/IR protein by western blot in a panel of EAC cell lines. BMS-754807 and nab-paclitaxel, alone or in combination were tested for effects on cell growth detected by WST-1 assay and on cell apoptosis detected by western blot of cleavage of caspase 3 and PARP. We then explored the antitumor efficacy with survival advantage following BMS-754807 and nab-paclitaxel mono and combination therapies in murine subcutaneous xenograft and peritoneal metastatic survival models of human EAC. Results: BMS-754807 dose dependently inhibited in-vitro cell proliferation of OE19 and FLO-1 EAC cell lines having strong tyrosine phosphorylation of IGF-1R/IR protein and interestingly the addition of IC25 dose of BMS-754807 significantly decreased the nab-paclitaxel IC50 in these EAC cells. In addition, co-administration of BMS-754807 and nab-paclitaxel effectively enhanced cleavage of caspase-3 and PARP in these EAC cells. In subcutaneous xenografts using OE19 cells, average net tumor growth after two weeks in different therapy groups was 558.67 mm3 in control, 208.47 mm3 after BMS-754807 (p=0.043), 104.60 mm3 after nab-paclitaxel (p=0.013), and 14.30 mm3 after BMS-754807 plus nab-paclitaxel (p=0.0005). In OE19 EAC survival model there was a significant increase in median animal survival after two weeks BMS-754807 plus nab-paclitaxel treatment (85 days) compared to control (47 days, p=0.0034), to BMS-754807 therapy (57 days, p=0.0021) or to nab-paclitaxel (68 days, p=0.0339) therapy. Conclusion: Thus BMS-754807 with nab-paclitaxel treatment resulted in significantly higher antitumor efficacy and survival benefit. These results support the potential of BMS-754807 in combination with nab-paclitaxel as an effective option for EAC therapy. Citation Format: Md Sazzad Hassan, Fiona Williams, Niranjan Awasthi, Margaret A. Schwarz, Roderich E. Schwarz, Urs von Holzen. Enhancement of nab-paclitaxel response by inhibition of insulin-like growth factor (IGF) signaling in experimental esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4813.

Programmed Death Ligand 1: A Step Toward Immunoscore for Esophageal Cancer

This study sought to evaluate the effect of tumor-infiltrating lymphocyte (TIL) density and programmed death ligand 1 (PD-L1) expression on the prognosis of esophageal cancer. Banked tissue specimens from 53 patients who underwent esophagectomies for malignancy at a single institution over a 6-year period were stained for cluster of differentiation 3 (CD3), CD8, and PD-L1. Tumors were characterized as staining high or low density for CD3 and CD8, as well as positive or negative for PD-L1. TIL density and PD-L1 expression were analyzed in the context of survival, recurrence, and perioperative characteristics. Median follow-up was 823 days, with 92.5% survival and 26.8% recurrence rates. All tumors were adenocarcinomas. Neoadjuvant chemotherapy was given in 56.6% of cases, and neoadjuvant radiotherapy was given in 37.7%. High CD3 density was found in 83%, whereas high CD8 density was found in 56.6%. A total of 18.9% of the tumors stained positive for PD-L1. Survival was significantly shorter in Kaplan-Meier analysis for patients with primary tumors staining positive for PD-L1 (log rank: p= 0.05). Multivariable analysis controlling for neoadjuvant therapy, TIL markers, PD-L1, age, and sex found no significant difference in recurrence or survival. Positive staining for PD-L1 may be a prognostic marker for decreased survival in esophageal adenocarcinoma. Additional TIL cell types should be investigated for creation of an esophageal cancer Immunoscore. PD-L1 has potential as a therapeutic target.

Effects of socioeconomic status on esophageal adenocarcinoma stage at diagnosis, receipt of treatment, and survival: A population-based cohort study.

The incidence of esophageal adenocarcinoma (EAC) is increasing worldwide and has overtaken squamous histology in occurrence. We studied the impact of socioeconomic status (SES) on EAC stage at diagnosis, receipt of treatment, and survival. A population-based retrospective cohort study was conducted using Ontario Cancer Registry-linked administrative health data. Multinomial logistic regression was used to examine the association between SES (income quintile) and stage at EAC diagnosis and EAC treatment. Survival times following EAC diagnosis were estimated using Kaplan-Meier method. Cox proportional-hazards regression analysis was used to examine the association between SES and EAC survival. Between 2003–2012, 2,125 EAC cases were diagnosed. Median survival for the lowest-SES group was 10.9 months compared to 11.6 months for the highest-SES group; the 5-year survival was 9.8% vs. 15.0%. Compared to individuals in the highest-SES group, individuals in the lowest-SES category experienced no significant difference in EAC treatment (91.6% vs. 93.3%, P = 0.314) and deaths (78.9% vs. 75.6%, P = 0.727). After controlling for covariates, no significant associations were found between SES and cancer stage at diagnosis and EAC treatment. Additionally, after controlling for age, gender, urban/rural residence, birth country, health region, aggregated diagnosis groups, cancer stage, treatment, and year of diagnosis, no significant association was found between SES and EAC survival. Moreover, increased mortality risk was observed among those with older age (P = 0.001), advanced-stage of EAC at diagnosis (P < 0.001), and those receiving chemotherapy alone, radiotherapy alone, or surgery plus chemotherapy (P < 0.001). Adjusted proportional-hazards model findings suggest that there is no association between SES and EAC survival. While the unadjusted model suggests reduced survival among individuals in lower income quintiles, this is no longer significant after adjusting for any covariate. Additionally, there is an apparent association between SES and survival when considering only those individuals diagnosed with stage 0-III EAC. These analyses suggest that the observed direct relationship between SES and survival is explained by patient-level factors including receipt of treatment, something that is potentially modifiable.

Abstract 5322: BMI and esophageal adenocarcinoma survival

Abstract Purpose: Though BMI is a known risk factor for esophageal adenocarcinoma (EA), the effect of BMI on EA overall survival remains unclear. Procedures: The source population is the Esophageal Cancer Study, an ongoing case-control and survivorship study of esophageal cancer patients recruited from Massachusets General Hospital and Dana-Farber Cancer Institute. In September of 2004, the study introduced a new patient questionnaire that included questions on weight throughout adulthood. For this study, we restricted our analysis to Caucasian, male patients with histologically confirmed EA who received their initial diagnosis between 9/1/2004 and 12/31/2014, and who were older than age 40 at time of diagnosis (281 patients). Our exposures of interests were BMI categories (&amp;lt;18.5, 18.5-24.99, 25-29.99, &amp;gt;30) and ΔBMI (the average BMI past the age of 40 minus BMI at time of diagnosis), categorized the differences into &amp;lt;0 (people who gained weight, 0-2 (people who lost some weight), &amp;gt;2 (people who lost substantial weight). We used an extended Cox proportional hazards model to obtain hazard ratios (HR) of BMI at diagnosis and ΔBMI, stratifying baseline hazard by cancer stage, having surgery as a time dependent covariate, and adjusting for radiation and chemotherapy treatment, age, sustained inability to eat solid foods after diagnosis, and smoking status. Results: Of the 282 patients that met our eligibility criteria, 211 men with complete information available were included in the analyses, and there were 131 recorded events during follow-up. In this study population, mean age at diagnosis was 63.7 years (SD±9.8), median survival was 2.6 years, mean average BMI after 40 years of age was 29.0 kg/m2(SD±4.5), and mean BMI at diagnosis was 27.4 kg/m2(SD±4.4). Compared to obese subjects at diagnosis, underweight, healthy weight, and overweight at diagnosis respectively had an adjusted hazard ratios of death (HR) of 2.72(95% CI: 0.59-12.45), 1.79 (95%, CI: 1.06-3.02) and 1.08 (95% CI: 0.65-1.74) (BMI category p=0.04), likely demonstrating reverse causation. Adjusting for confounders, the ΔBMI model shows that patients who lost substantial weight by diagnosis had the highest hazard of death, compared to patients who gained weight in late life prior to diagnosis (HR=0.70, 95% CI: 0.45-1.1) and patients who lost some weight (HR=0.55, 95% CI: 0.35-0.9)( ΔBMI category p=0.05). The strong effect of ΔBMI even after adjusting for patients’ inability or lack of desire to eat (anorexia), implicates cachexia as a possible independent mechanism of this association. In addition, age at dx, stage at diagnosis, and surgical resection were significant predictors of overall survival. Conclusion: Substantial change in BMI prior to diagnosis indicates poor overall survival in middle-aged and elderly Caucasian men with esophageal adenocarcinoma. Citation Format: Elizabeth A. Loehrer, David Christiani. BMI and esophageal adenocarcinoma survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5322. doi:10.1158/1538-7445.AM2017-5322

The Impact of a Prior Diagnosis of Barrett's Esophagus on Esophageal Adenocarcinoma Survival.

Endoscopic surveillance of patients with Barrett's Esophagus (BE) is recommended to detect esophageal adenocarcinoma (EAC) and its dysplasia precursors, but survival benefits are unclear. Using Surveillance, Epidemiology, and End Results (SEER) and linked Medicare data, we sought to determine the impact of a prior BE diagnosis on survival in patients with EAC. Our analysis focused on patients over age 65 with primary EAC diagnosed in a SEER region from 2000-2011 and enrolled in Medicare. We identified patients with preexisting BE prior to EAC diagnosis and compared this group to EAC patients without a prior BE diagnosis. A Cox Proportional Hazards model compared survival and included variables such as age, sex, cancer stage, treatment, and medical comorbidities. Among 4,978 SEER-Medicare patients identified with EAC, 577 (12%) had preexisting BE; 4,401 (88%) did not. BE patients had overall lower stage (28.5% stage I vs. 12.8% stage IV) than those without preexisting BE (16.4% stage I vs. 30.6% stage IV). Overall survival was better among patients in the BE group (hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.50-0.61); this benefit persisted in the adjusted model (HR, 0.72; 95%, 0.65-0.80). After adjusting for lead-time bias, the HRs attenuated to the null, with an unadjusted HR of 0.96 (95% CI: 0.86-1.05, P=0.39) and adjusted HR of 0.99 (CI: 0.89-1.10, P=0.92). Survival outcomes in patients with a BE diagnosis prior to EAC were statistically better in both the unadjusted and adjusted Cox proportional hazards model. However, this benefit appears to be predominantly lead-time and length-time bias.

Early adulthood body mass index, cumulative smoking, and esophageal adenocarcinoma survival

BackgroundSmoking and obesity are esophageal adenocarcinoma (EAC) risk factors. However, the same risk factors may also affect biological aggressiveness and cancer outcomes. Our study evaluated the combined effects of early-adulthood obesity and cumulative smoking on the EAC survival. Patients and methodsIn two EAC cohorts, Toronto (TO; N=235) and Boston (BO; N=329), associations between early adulthood body mass index (EA-BMI), BMI at 1year prior to diagnosis (BMI-1), and smoking with overall survival (OS) were assessed using Cox proportional hazard models, adjusted for relevant covariates. ResultsBoth cohorts were predominantly Caucasian (89%), male (88%), ever-smokers (73%) with locally advanced/metastatic EAC (78%), and good ECOG performance status (90%); median packyears was 34; median EA-BMI, 24; median BMI-1, 25. No relationships with survival were found with BMI-1. For smoking and EA-BMI, TO, BO, and combined TO-BO analyses showed similar associations: smoking conferred worse OS in the combined TO-BO cohort, with adjusted hazard ratios (aHR) of 1.22 (95%CI: 1.15–1.43;p<0.0001) for each 20 pack-year increase. Likewise, EA-BMI ≥25 was associated with worse OS (EA-BMI of 25−<30, aHR=1.84,95%CI: 1.37–2.48; and EA-BMI>30, aHR=2.78, 95%CI: 1.94–3.99). Risk of death was also increased in remotely underweight patients with EA-BMI<18.5 (aHR=2.03,95%CI: 1.27–3.24), when compared to normal-EA-BMI (18≤EA-BMI<25). ConclusionsTwo key modifiable behaviors, elevated BMI in early adulthood and heavy cumulative smoking history are independently associated with increased mortality risk in two North American cohorts of EAC patients.

Validation of microRNA pathway polymorphisms in esophageal adenocarcinoma survival.

Polymorphisms in miRNA and miRNA pathway genes have been previously associated with cancer risk and outcome, but have not been studied in esophageal adenocarcinoma outcomes. Here, we evaluate candidate miRNA pathway polymorphisms in esophageal adenocarcinoma prognosis and attempt to validate them in an independent cohort of esophageal adenocarcinoma patients. Among 231 esophageal adenocarcinoma patients of all stages/treatment plans, 38 candidate genetic polymorphisms (17 biogenesis, 9 miRNA targets, 5 pri‐miRNA, 7 pre‐miRNA) were genotyped and analyzed. Cox proportional hazard models adjusted for sociodemographic and clinicopathological covariates helped assess the association of genetic polymorphisms with overall survival (OS) and progression‐free survival (PFS). Significantly associated polymorphisms were then evaluated in an independent cohort of 137 esophageal adenocarcinoma patients. Among the 231 discovery cohort patients, 86% were male, median diagnosis age was 64 years, 34% were metastatic at diagnosis, and median OS and PFS were 20 and 12 months, respectively. GEMIN3 rs197412 (aHR = 1.37, 95%CI: [1.04–1.80]; P = 0.02), hsa‐mir‐124‐1 rs531564 (aHR = 0.60, 95% CI: [0.53–0.90]; P = 0.05), and KIAA0423 rs1053667 (aHR = 0.51, 95% CI: [0.28–0.96]; P = 0.04) were found associated with OS. Furthermore, GEMIN3 rs197412 (aHR = 1.33, 95% CI: [1.03–1.74]; P = 0.03) and KRT81 rs3660 (aHR = 1.29, 95% CI: [1.01–1.64]; P = 0.04) were found associated with PFS. Although none of these polymorphisms were significant in the second cohort, hsa‐mir‐124‐1 rs531564 and KIAA0423 rs1053667 had trends in the same direction; when both cohorts were combined together, GEMIN3 rs197412, hsa‐mir‐124‐1 rs531564, and KIAA0423 rs1053667 remained significantly associated with OS. We demonstrate the association of multiple miRNA pathway polymorphisms with esophageal adenocarcinoma prognosis in a discovery cohort of patients, which did not validate in a separate cohort but had consistent associations in the pooled cohort. Larger studies are required to confirm/validate the prognostic value of these polymorphisms in esophageal adenocarcinoma.

Tumour infiltrating lymphocytes correlate with improved survival in patients with oesophageal adenocarcinoma.

Background Oesophageal adenocarcinoma (OAC) is increasingly common in the west, and survival remains poor at 10–15 % at 5 years. Immune responses are increasingly implicated as a determining factor of tumour progression. The ability of lymphocytes to recognise tumour antigens provides a mechanism for a host immune attack against cancer providing a potential treatment strategy.Materials and MethodsTumour infiltrating lymphocytes (TILs: CD3+, CD4+, CD8+ and FOXp3+) were assessed by immunohistochemistry using tissue microarrays in a contemporary and homogeneous cohort of OAC patients (n = 128) undergoing curative treatment.Results Multivariate analysis identified three independent prognostic factors for improved cancer-specific survival (CSS): increased CD8+ TILs (p = 0.003), completeness of resection (p < 0.0001) and lower pathological N stage (p < 0.0001). Independent prognostic factors for favourable disease-free survival included surgery-only treatment (p = 0.015), completeness of resection (p = 0.001), increased CD8+ TILs (p < 0.0001) and reduced pathological N stage (p < 0.0001). Higher levels of TILs in the pathological specimen were associated with significant pathological response to neoadjuvant chemotherapy (NAC). On multivariate analysis increased levels of CD4+ (p = 0.017) and CD8+ TILs (p = 0.005) were associated with significant local tumour regression and lymph node downstaging, respectively.DiscussionOur results establish an association of TILs and survival in OAC, as seen in other solid tumours, and identify particular TIL subsets that are present at higher levels in patients who responded to NAC compared to non-responders. These findings highlight potential therapeutic strategies in EAC based on utilising the host immunological response and highlight the immune responses biomarker potential.Electronic supplementary materialThe online version of this article (doi:10.1007/s00262-016-1826-5) contains supplementary material, which is available to authorized users.

MicroRNA Expression Signatures During Malignant Progression From Barrett's Esophagus.

The rapid increase and poor survival of esophageal adenocarcinoma (EAC) have led to significant efforts to promote early detection. Given that the premalignant lesion of Barrett's esophagus (BE) is the major known risk factor for EAC, multiple investigators have studied biomarker signatures that can predict malignant progression of BE to EAC. MicroRNAs, a novel class of gene regulators, are small non-coding RNAs and have been associated with carcinogenesis. MicroRNAs are ideal biomarkers because of their remarkable stability in fixed tissues, a common method for collection of clinical specimens, and in blood either within exosomes or as microRNA-protein complexes. Multiple studies show potential of microRNAs as tissue and blood biomarkers for diagnosis and prognosis of EAC but the results need confirmation in prospective studies. Although head-to-head comparisons are lacking, microRNA panels require less genes than messenger RNA panels for diagnosis of EAC in BE. MicroRNA diagnostic panels will need to be compared for accuracy against global measures of genome instability that were recently shown to be good predictors of progression but require sophisticated analytic techniques. Early studies on blood microRNA panels are promising but have found microRNA markers to be inconsistent among studies. MicroRNA expression in blood is different between various microRNA sub-compartments such as exosomes and microRNA-protein complexes and could affect blood microRNA measurements. Further standardization is needed to yield consistent results. We have summarized the current understanding of the tissue and blood microRNA signatures that may predict the development and progression of EAC.

Androgen Receptor and Androgen-Responsive Gene FKBP5 Are Independent Prognostic Indicators for Esophageal Adenocarcinoma.

Esophageal adenocarcinoma is a male-dominant disease, but the role of androgens is unclear. To examine the expression and clinical correlates of the androgen receptor (AR) and the androgen-responsive gene FK506-binding protein 5 (FKBP5) in esophageal adenocarcinoma. Expression of AR and FKBP5 was determined by immunohistochemistry. The effect of the AR ligand 5α-dihydrotestosterone (DHT) on the expression of a panel of androgen-responsive genes was measured in AR-positive and AR-negative esophageal adenocarcinoma cell lines. Correlations in expression between androgen-responsive genes were analyzed in an independent cohort of esophageal adenocarcinoma tissues. There was AR staining in 75 of 77 cases (97 %), and FKBP5 staining in 49 (64 %), all of which had nuclear AR. Nuclear AR with FKBP5 expression was associated with decreased median survival (451 vs. 2800 days) and was an independent prognostic indicator (HR 2.894, 95 % CI 1.396–6.002, p = 0.0043) in multivariable Cox proportional hazards models. DHT induced a significant increase in expression of the androgen-responsive genes FKBP5, HMOX1, FBXO32, VEGFA, WNT5A, and KLK3 only in AR-positive cells in vitro. Significant correlations in expression were observed between these androgen-responsive genes in an independent cohort of esophageal adenocarcinoma tissues. Nuclear AR and expression of FKBP5 is associated with decreased survival in esophageal adenocarcinoma.

LC3B globular structures correlate with survival in esophageal adenocarcinoma.

BackgroundEsophageal adenocarcinoma has the fastest growing incidence of any solid tumor in the Western world. Prognosis remains poor with overall five-year survival rates under 25 %. Only a limited number of patients benefit from chemotherapy and there are no biomarkers that can predict outcome. Previous studies have indicated that induction of autophagy can influence various aspects of tumor cell biology, including chemosensitivity. The objective of this study was to assess whether expression of the autophagy marker (LC3B) correlated with patient outcome.MethodsEsophageal adenocarcinoma tumor tissue from two independent sites, was examined retrospectively. Tumors from 104 neoadjuvant naïve patients and 48 patients post neoadjuvant therapy were assembled into tissue microarrays prior to immunohistochemical analysis. Kaplan-Meier survival curves and log-rank tests were used to assess impact of LC3B expression on survival. Cox regression was used to examine association with clinical risk factors.ResultsA distinct globular pattern of LC3B expression was found to be predictive of outcome in both patient groups, irrespective of treatment (p < 0.001). Multivariate analysis found that this was a strong independent predictor of poor prognosis (p < 0.001).ConclusionsThis distinctive staining pattern of LC3B represents a novel prognostic marker for resectable esophageal adenocarcinoma.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1574-5) contains supplementary material, which is available to authorized users.

The correlation between high body mass index and survival in patients with esophageal cancer after curative esophagectomy: evidence from retrospective studies.

To investigate the predictive value of high body mass index (H-BMI) on the survival of patients with esophageal cancer (EC) after curative esophagectomy. Studies were systematically identified to investigate the relationship between overweight and obese (H-BMI) and clinical outcomes in EC patients treated with curative esophagectomy. Measured clinical outcomes were disease-free survival (DFS) and overall survival (OS). The pooled hazard ratio (HR) with 95% confidence interval (CI) was estimated. Subgroup analyses were performed according to tumour type and body mass index (BMI). Fourteen studies with 4823 cases were included in the final pooled quantitative analysis. In EC patients overall, H-BMI was associated with improved DFS (HR, 0.83; 95% CI: 0.75-0.90) and OS (HR, 0.79; 95 % CI: 0.73-0.85), as compared with normal BMI. The results were consistent with those who were overweight. Among patients with esophageal adenocarcinoma (EAC), a better prognosis, as reflected by OS, was observed with H-BMI (HR, 0.81; 95% CI: 0.73-0.89). The same results were also observed in EAC patients who were obese and overweight. In contrast, among patients with esophageal squamous cell carcinoma (ESCC), H-BMI was associated with a worse prognosis, as reflected by DFS (HR, 2.26; 95% CI: 1.29-3.24). H-BMI has distinctly different impacts on the postoperative survival of EAC and ESCC patients. H-BMI is a potential predictor for better prognosis in EC patients overall, and particularly in EAC patients, treated with curative esophagectomy. However, in ESCC patients, H-BMI is a potential predictor for a worse prognosis of postoperative survival.

Value of CT–PET after neoadjuvant chemoradiation in the prediction of histological tumour regression, nodal status and survival in oesophageal adenocarcinoma

The role of CT-PET after neoadjuvant chemoradiation (nCRT) for prediction of pathological response and oncological outcome in oesophageal and junctional adenocarcinoma (OAC) is unclear. The relationship between complete metabolic response (cMR), pathological complete response (pCR) and nodal status has not been clarified. Patients with locally advanced OAC selected to receive nCRT and surgery with curative intent, on the basis of staging that included CT-PET positivity, were included. Repeat scanning (PET2) with an identical protocol was performed 2-4 weeks after completion of nCRT (cisplatin and 5-fluorouracil plus 44 Gy radiation). Changes in [(18) F]fluorodeoxyglucose uptake, considered as either a maximum standardized uptake value (SUVmax) or a relative reduction (%ΔSUVmax), and PET-predicted nodal status following nCRT were compared with histopathological response, histological node positivity and survival. One hundred consecutive patients with PET-positive OAC were studied. Following nCRT, PET2 identified M1 disease in 2·0 per cent of patients. There were no significant associations between PET2 SUVmax or %ΔSUVmax with respect to primary tumour stage (ypT) (P = 0.216 and P = 0·975 respectively), tumour regression grade (P = 0·109 and P = 0·232), pCR (P = 0·633 and P = 0·870) or complete resection (R0) (P = 0·440 and P = 0·235). The sensitivity of PET2 for ypN was 10 per cent. %ΔSUVmax was not associated with disease-free or overall survival (P = 0·162 and P = 0·154 respectively). Of 46 patients with a cMR on PET2, 37 (80 per cent) had histological evidence of residual tumour in the resected specimen, and cMR was not associated with overall survival benefit (P = 0·478). CT-PET following nCRT for OAC has poor prognostic and discriminatory value for clinical application.

GATA6 expression in Barrett's oesophagus and oesophageal adenocarcinoma

BackgroundBarrett's oesophagus can progress towards oesophageal adenocarcinoma through a metaplasia–dysplasia–carcinoma sequence, but the underlying mechanisms are poorly understood. The transcription factor GATA6 is known to be involved in columnar differentiation and proliferation, and GATA6 gene amplification was recently linked with poor survival in oesophageal adenocarcinoma. AimTo study the expression of GATA6 during Barrett's oesophagus development and malignant transformation. To determine the prognostic value of GATA6 in oesophageal adenocarcinoma. MethodsTwo retrospective cohorts were derived from the pathological archive of the University Medical Center Groningen. The first cohort contained 130 tissue samples of normal squamous epithelium, metaplasia, dysplasia and oesophageal adenocarcinoma. The second cohort consisted of a tissue microarray containing tissue from 92 oesophageal adenocarcinoma patients. Immunohistochemistry was used to examine GATA6 protein expression and to correlate GATA6 expression in oesophageal adenocarcinoma with overall and disease-free survival. ResultsThe percentage of GATA6-positive cells was low in squamous epithelium (10%) but increased progressively in Barrett's oesophagus (30%, P<0.001) and high-grade dysplasia (82%, P=0.005). GATA6 expression was not associated with overall or disease-free survival in oesophageal adenocarcinoma patients (P=0.599 and P=0.700 respectively). ConclusionGATA6 expression is progressively increased during Barrett's oesophagus development and its malignant transformation. However, no prognostic value of GATA6 expression could be found in oesophageal adenocarcinoma.

Clinicopathological and prognostic significance of epidermal growth factor receptor overexpression in patients with esophageal adenocarcinoma: a meta-analysis.

The prognostic significance of epidermal growth factor receptor (EGFR) overexpression in patients with esophageal adenocarcinoma (EAC) remains controversial. Eligible studies that investigated the association between survival in EAC and the expression status of EGFR were identified by an electronic search of PubMed, EMBASE, and ISI Web of Science. A meta-analysis was performed to clarify the impact of EGFR overexpression on clinicopathological parameters or overall survival (OS) in EAC. A total of seven studies including 1028 patients were subjected to the final analysis. The overall results suggested that overexpression of EGFR was significantly correlated with not only the depth of invasion, lymph node status, and tumors stage of EAC, with a pooled odds ratio of 2.99 (95% confidence interval [CI]: 1.07-8.35; Z = 2.09; P = 0.037), 3.05 (95% CI: 1.77-5.27; Z = 4.00; P < 0.001), and 5.37 (95% CI: 2.49-11.57; Z = 4.29; P < 0.001), respectively, but also the poorer OS with a pooled hazard ratio of 2.20 (95% CI: 1.47-3.31; Z = 3.79; P < 0.001). Overexpression of EGFR correlates with not only the clinicopathological features, but also the worse OS, and it might be useful as a predictive biomarker in clinical practice, yet the clinicopathological and prognostic role of EGFR in EAC still needs further confirmation by well-designed prospective studies.

Early adulthood body mass index, cumulative smoking, and esophageal adenocarcinoma survival.

10 Background: Little is known about the individual and combined effect of early-adulthood obesity and cumulative smoking on the survival of esophageal adenocarcinoma (EAC) patients. Methods: We analyzed two independent cohorts of EAC patients: 235 patients from Toronto, Canada (TO, 2006-2011) and 329 patients from Boston, USA (BO,1999-2004). Associations between early adulthood body mass index (EA-BMI) and smoking with overall survival (OS) were assessed using Cox proportional hazard models, adjusted for stage, treatment, and other relevant covariates. Results: Median age (range) for TO dataset was 64(29-88)yrs; for BO dataset, 64(21-91)yrs. Males comprised 86% of TO and 89% of BO datasets. 90% of TO and 98% of BO patients were Caucasians. The Median (range) for packyears was 34 (0.2-118; TO) and 34 (0.2-212; BO). The Median (range) for EA-BMI was 24(15-44; TO) and 24(15-47; BO). Median BMI 1 yr prior to diagnosis was 25(16-43; TO) and 25(20-49; BO). 92% of TO and 88% of BO patients had ECOG 0 or 1. Disease stage distribution (early/locally-advanced/metastatic) was 11%/64%/25% (TO) and 30%/52%/18% (BO). For TO, the aHR for smoking was 1.03 (95%CI: 1.02-1.04; p=8E-08) per packyear, while for BO, smoking also independently conferred worse OS, with aHR of 1.007 (95%CI: 1.002-1.01; p=0.003) for each packyear increase. The aHRs for being underweight (EA-BMI&lt;18.5), overweight (EA-BMI 25-30), and obese (EA-BMI&gt;30) in early adulthood were 2.19 (95%CI: 1.0-4.6), 1.89 (95%CI:1.2-3.0), and 2.49 (95%CI:1.5-4.2), respectively for the TO dataset (global p=0.003 for EA-BMI). In BO, the corresponding values were 1.30 (95%CI: 0.8-2.2), 1.45 (95%CI: 1.0-2.5), and 2.39 (95%CI:1.5-3.8), respectively (global p=0.002). In contrast, BMI at one year prior to diagnosis had no association with OS in either study. Conclusions: Elevated BMI in early adulthood and heavy cumulative smoking history are independently associated with increased mortality risk in two North American EAC populations. These survival differences may reflect comorbidity differences, biological differences or both, and offer insight into how key modifiable behaviors in prevention can also affect cancer prognoses. AS, LC, DCC and GL contributed equally.

Autocrine Extra-Pancreatic Trypsin 3 Secretion Promotes Cell Proliferation and Survival in Esophageal Adenocarcinoma

Trypsin or Tumor associated trypsin (TAT) activation of Protease-activated receptor 2 (PAR-2) promotes tumor cell proliferation in gastrointestinal cancers. The role of the trypsin/PAR-2 network in esophageal adenocarcinoma (EA) development has not yet been investigated. The aim of this study is to investigate the role of trypsin/PAR-2 activation in EA tumorogenesis and therapy. We found that esophageal adenocarcinoma cells (EACs) and Barrett’s Metaplasia (BART) expressed high levels of type 3 extra-pancreatic trypsinogen (PRSS3), a novel type of TAT. Activity of secreted trypsin was detected in cultured media from EA OE19 and OE33 cultures but not from BART culture. Surface PAR-2 expression in BART and EACs was confirmed by both flow cytometry and immunofluorescence. Trypsin induced cell proliferation (∼ 2 fold; P<0.01) in all tested cell lines at a concentration of 10 nM. Inhibition of PAR-2 activity in EACs via the PAR-2 antagonist ENMD (500 µM), anti-PAR2 antibody SAM-11 (2 µg/ml), or siRNA PAR-2 knockdown, reduced cell proliferation and increased apoptosis by up to 4 fold (P<0.01). Trypsin stimulation led to phosphorylation of ERK1/2, suggesting involvement of MAPK pathway in PAR-2 signal transduction. Inhibition of PAR-2 activation or siRNA PAR-2 knockdown in EACs prior to treatment with 5 FU reduced cell viability of EACs by an additional 30% (P<0.01) compared to chemotherapy alone. Our data suggest that extra-pancreatic trypsinogen 3 is produced by EACs and activates PAR-2 in an autocrine manner. PAR-2 activation increases cancer cell proliferation, and promotes cancer cell survival. Targeting the trypsin activated PAR-2 pathway in conjunction with current chemotherapeutic agents may be a viable therapeutic strategy in EA.

Association of MDM2 T309G and p53 Arg72Pro polymorphisms and gastroesophageal reflux disease with survival in esophageal adenocarcinoma

Although gastroesophageal reflux disease (GERD) is a risk factor for esophageal adenocarcinoma (EAC), some patients develop EAC in the absence of GERD. A putative mechanism of reflux-induced tumorigenesis involves disruptions in the p53 pathway. We assessed the interaction of GERD and p53 pathway polymorphisms on EAC prognosis. In a prospective cohort of 358 EAC patients, clinical data (including GERD history and survival) were collected. Germline DNA was genotyped for MDM2 T309G and p53 Arg72Pro. Cox proportional hazards models were used to determine adjusted hazard ratios (AHR) for associations between genotype, GERD, and genotype-GERD interactions with survival. Compared with other genotypes, MDM2 G/G (median overall survival 21 vs 30 months; P < 0.001) and p53 Pro/Pro (12 vs 30 months; P = 0.004) were associated with shorter survival. When analyzed by GERD, MDM2 G/G was associated with shorter survival in patients without GERD (AHR 3.4, 95% CI 2.0-6.0), but not in patients with GERD (AHR 1.1 [0.7-1.8]); the MDM2-GERD interaction was significant (P = 0.003). A similar trend was seen for p53 Pro/Pro (AHRs 2.5 without GERD vs 1.4 with GERD). Combined analysis of at-risk variants (MDM2 G or p53 Pro), revealed each additional at-risk variant was associated with shorter survival in patients without GERD (AHR 1.6) but not with GERD (AHR 1.0). MDM2 G/G and the combination of MDM2 G and p53 Pro were negative prognostic factors for EAC patients without GERD but not for those with GERD. There may be biological differences between GERD positive and GERD negative EAC.

Over-expression of phosphorylated mammalian target of rapamycin is associated with poor survival in oesophageal adenocarcinoma: a tissue microarray study

BackgroundProtein kinase mammalian target of rapamycin (mTOR) is an important downstream effector of the phosphatidylinositol 3-kinase (PI3K)/Akt signalling pathway. In several tumour types, phosphorylated mTOR (p-mTOR) over-expression is an independent...