Advanced Esophageal Adenocarcinoma Research Articles

Prognostic, Diagnostic and Predictive Biomarkers in the Barrett's Oesophagus-Adenocarcinoma Disease Sequence.

Simple SummaryOesophageal adenocarcinoma (OAC) is a type of cancer of the oesophagus (food pipe) which is associated with poor patient outcomes. Barrett’s oesophagus (BO) is a precancerous condition of the oesophagus associated with chronic heartburn. Currently, surveillance programs exist which monitor patients with BO to prevent it from developing into OAC. However, these surveillance programs are expensive and unpleasant for patients. Prognostic biomarkers are signs which could be measured to determine the chance of someone with BO developing OAC, allowing more targeted surveillance. Similarly, diagnostic biomarkers are indicators which could be measured to see if someone has OAC. Developing new diagnostic biomarkers could allow wider population testing. Only a small proportion of patients with OAC respond to treatment before surgery. Predictive biomarkers could be measured to predict whether someone would respond to the treatments, allowing more individualized therapy. This review focuses on potential biomarkers which could improve patient outcomes in BO/OAC.Oesophageal adenocarcinoma (OAC) incidence has increased dramatically in the developed world, yet outcomes remain poor. Extensive endoscopic surveillance programs among patients with Barrett’s oesophagus (BO), the precursor lesion to OAC, have aimed to both prevent the development of OAC via radiofrequency ablation (RFA) and allow earlier detection of disease. However, given the low annual progression rate and the costs of endoscopy/RFA, improvement is needed. Prognostic biomarkers to stratify BO patients based on their likelihood to progress would enable a more targeted approach to surveillance and RFA of high-risk precursor lesions, improving the cost–risk–benefit ratio. Similarly, diagnostic biomarkers for OAC could enable earlier diagnosis of disease by allowing broader population screening. Current standard treatment for locally advanced OAC includes neoadjuvant chemotherapy (+/− radiotherapy) despite only a minority of patients benefiting from neoadjuvant treatment. Accordingly, biomarkers predictive of response to neoadjuvant therapy could improve patient outcomes by reducing time to surgery and unnecessary toxicity for the patients who would have received no benefit from the therapy. In this mini-review, we will discuss the emerging biomarkers which promise to dramatically improve patient outcomes along the BO-OAC disease sequence.

Sex Differences in Neoplastic Progression in Barrett's Esophagus: A Multicenter Prospective Cohort Study.

Simple SummaryBarrett’s esophagus (BE) is the only known precursor lesion of esophageal adenocarcinoma (EAC). Endoscopic surveillance plays an important role in the timely detection of neoplastic progression. However, the cost-effectiveness of current surveillance strategies is debatable. Previous studies have shown that male Barrett’s patients have lower neoplastic progression risk than females. However, these studies do not provide a more practical translation of these sex disparities into different surveillance intervals. The current multicenter prospective cohort study aimed to evaluate sex differences in 868 BE patients; not only with respect to neoplastic progression risk, but also concerning the difference in time to detection of high-grade dysplasia (HGD)/EAC: time to neoplastic progression was estimated to be almost twice as low in males than in females. In contrast, the stage of neoplasia appeared to be higher in females. Our results can guide future discussions for sex-specific guidelines, supporting the implementation of neoplastic risk stratification per individual patient in BE surveillance.Recommendations in Barrett’s esophagus (BE) guidelines are mainly based on male patients. We aimed to evaluate sex differences in BE patients in (1) probability of and (2) time to neoplastic progression, and (3) differences in the stage distribution of neoplasia. We conducted a multicenter prospective cohort study including 868 BE patients. Cox regression modeling and accelerated failure time modeling were used to estimate the sex differences. Neoplastic progression was defined as high-grade dysplasia (HGD) and/or esophageal adenocarcinoma (EAC). Among the 639 (74%) males and 229 females that were included (median follow-up 7.1 years), 61 (7.0%) developed HGD/EAC. Neoplastic progression risk was estimated to be twice as high among males (HR 2.26, 95% CI 1.11–4.62) than females. The risk of HGD was found to be higher in males (HR 3.76, 95% CI 1.33–10.6). Time to HGD/EAC (AR 0.52, 95% CI 0.29–0.95) and HGD (AR 0.40, 95% CI 0.19–0.86) was shorter in males. Females had proportionally more EAC than HGD and tended to have higher stages of neoplasia at diagnosis. In conclusion, both the risk of and time to neoplastic progression were higher in males. However, females were proportionally more often diagnosed with (advanced) EAC. We should strive for improved neoplastic risk stratification per individual BE patient, incorporating sex disparities into new prediction models.

Development and validation of a molecular tool to predict pathologic complete response in esophageal adenocarcinoma.

Pathologic complete response (pCR) to neoadjuvant chemoradiation for locally advanced esophageal adenocarcinoma (EAC) confers significantly improved survival. The ability to infer pCR may spare esophagectomy in some patients. Currently, there are no validated biomarkers of pCR. This study sought to evaluate whether a distinct signature of DNA copy number alterations (CNA) can be predictive of pCR in EAC. Pretreatment biopsies from 38 patients with locally advanced EAC (19 with pCR and 19 with pathologic partial/poor response) were assessed for CNA using OncoScan assay. A novel technique was employed where within every cytogenetic band, the quantity of bases gained by each sample was computed as the sum of gained genomic segment lengths weighted by the surplus copy number of each segment. A threefold cross-validation was used to assess association with pCR or pathologic partial/poor response. Forty patients with locally advanced EAC from The Cancer Genome Atlas (TCGA) constituted an independent validation cohort. Gains in the chromosomal loci 14q11 and 17p11 were preferentially associated with pCR. Average area under the receiver operating characteristic curve (AUC) for predicting pCR was 0.80 among the threefold cross-validation test sets. Using 0.3 megabases as the cutoff that optimizes trade-off between sensitivity (63%) and specificity (89%) in the discovery cohort, similar prediction performance for clinical and radiographic response was demonstrated in the validation cohort from TCGA (sensitivity 61%, specificity 82%). Copy number gains in the 14q11 and 17p11 loci may be useful for prediction of pCR, and, potentially, personalization of esophagectomy in EAC.

Abstract 1066: BMS-754807, a small-molecule inhibitor of insulin-like growth factor-1 receptor/insulin receptor is cytotoxic to esophageal adenocarcinoma cells and enhances nab-paclitaxel response in experimental esophageal adenocarcinoma

Abstract Introduction: Esophageal adenocarcinoma (EAC) is one of the fastest growing cancers in the Western world and the overall 5-year survival rate of EAC is below 20 percent. Epidemiological studies have linked obesity with EAC. Insulin-like growth factor (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 have 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. In this study, we evaluated the potential of targeting IGF signaling and improvement in nab-paclitaxel response by the addition of BMS-754807 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, cell apoptosis, cell migration and cell cycle analyses of EAC cell lines detected respectively by WST-1 assay, Western blotting, would healing scratch assay and propidium iodide flow cytometry. We then explored the antitumor efficacy of BMS-754807 and nab-paclitaxel monotherapy and in combination in murine subcutaneous xenograft and peritoneal metastatic survival models of human EAC. Results: BMS-754807 dose-dependently inhibited in-vitro cell proliferation of EAC cell lines having phosphorylation of IGF-1R/IR protein. The co-administration of BMS-754807 and nab-paclitaxel effectively enhanced cell growth inhibition, cleavage of caspase-3 and PARP, in-vitro wound healing inhibition and cell cycle arrest at sub G0/G1 phase. BMS-754807 in combination with nab-paclitaxel treatment resulted in significantly higher antitumor efficacy by increasing intratumoral apoptosis and survival benefit compared with BMS-754807 or nab-paclitaxel treatment alone. 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). There was a significant increase in median animal survival after BMS-754807 plus nab-paclitaxel treatment (85 days) compared to control (47 days, p=0.0034), BMS-754807 monotherapy (57 days, p=0.0021) or nab-paclitaxel (68 days, p=0.0339) monotherapy. Conclusion: 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, Nicholas Cwidak, Chloe Johnson, Saisantosh Ponna, Niranjan Awasthi, Urs von Holzen. BMS-754807, a small-molecule inhibitor of insulin-like growth factor-1 receptor/insulin receptor is cytotoxic to esophageal adenocarcinoma cells and enhances nab-paclitaxel response in experimental esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1066.

P-30 First-line (1L) treatment patterns in advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma (GC/GEJC/EAC): Data from the Spanish AGAMENON-SEOM registry

Data on treatment patterns and outcomes in patients with advanced gastroesophageal adenocarcinoma in daily clinical practice are scarce. Using real-world data from the Spanish AGAMENON-SEOM registry, this retrospective study assessed patient characteristics, treatment patterns, and outcomes for 1L advanced GC/GEJC/EAC. Adult patients diagnosed with locally advanced unresectable or metastatic GC/GEJC/EAC between 2008 and 2021 were identified from 34 centers. This analysis only included patients who received ≥1 cycle of 1L polychemotherapy. Primary endpoints included description of demographic and clinical characteristics at initial diagnosis (equivalent to 1L therapy initiation), 1L treatment patterns, progression-free survival (PFS) and overall survival (OS) from 1L therapy initiation. Secondary endpoints included subgroup analyses in patients with human epidermal growth factor receptor 2 (HER2)-negative status and in patients who met the eligibility criteria of the CheckMate 649 study (Janjigian YY et al, Lancet 2021;398:27-40) and were treated with FOLFOX or XELOX (hereafter, CheckMate 649-matched subgroup). The proportion of patients who received second-line (2L) or third-line (3L) therapy and the reasons for not receiving subsequent therapy were explored. Overall, patients initiating 1L treatment (n=3,110) had a median (range) age of 65 (20–89) years, were mostly male (71.0%), had an ECOG performance status (PS) of 1 (61.7%) or 0 (23.7%), and had normal (>35 g/dL) basal albumin levels (64.8%). The most prevalent comorbidities were diabetes (15.3%) and chronic cardiopathy (11.6%). The most common primary tumor location was the stomach (77.7%) versus GEJ (13.4%) or esophagus (8.7%). 5.6% of patients had unresectable locally advanced disease and 94.4% of patients had metastatic disease, primarily synchronous (77.6%); the number of metastastic sites was unknown in 13 (synchronous) and 4 (metachronous) patients. The most frequent metastatic locations were lymph nodes (46.4%) or peritoneum (43.7%). In the HER2-evaluable population (n=2,650), 73.3% of patients had HER2-negative tumors. Clinical characteristics of patients in the HER2-negative (n=2,385; includes 460 patients with unknown HER2 status) and CheckMate 649-matched (n=383) subgroups were generally similar to those of the overall population. The most common 1L treatments for HER2-negative tumors were FOLFOX6 (20%) and XELOX (19%). In the overall population, 1,588 patients received 2L therapy and 218 patients received 3L therapy. The primary reason for patients not receiving 2L or 3L therapy was poor ECOG PS (68.0% and 79.8%, respectively). At a median follow-up of 57.0 months in the overall population (n=3,037), the median (95% confidence interval [CI]) PFS and OS were 6.0 (5.8–6.2) and 10.8 (10.4–11.2) months, respectively. Median OS was 10.1 (95% CI 9.7–10.5) months in the HER2-negative subgroup (n=2,346). At a median follow-up of 32 months in the CheckMate 649-matched subgroup, median (95% CI) PFS and OS were 6.4 (5.7–7.2) and 11.7 (10.6–12.8) months, respectively. In this real-world observational study of the Spanish AGAMENON-SEOM registry, PFS and OS outcomes for 1L treatment of advanced GC/GEJC/EAC were comparable to those of historical studies. With an estimated median OS of < 1 year from 1L therapy initiation, better treatment options for patients with advanced GC/GEJC/EAC remain an unmet need and deserve further investigation.

EA2183: A phase III study of consolidative radiotherapy in patients with oligometastatic HER2-negative esophageal and gastric adenocarcinoma.

TPS4162 Background: Advanced esophageal and gastric adenocarcinomas (EGA) have poor prognosis. Doublet chemotherapy with fluoropyrimidine and platinum agents in combination with nivolumab for PD-L1 positive tumors is now the standard first-line approach, but overall survival (OS) remains &lt; 1.5 years. A subset of EGA patients have limited burden of metastatic disease. There is accumulating evidence that patients with oligometastatic states across disease types may benefit from locoregional ablative therapies during the course of their treatment. EA2183 is the first prospective study to evaluate the potential benefits of consolidative radiotherapy (XRT) in oligometastatic EGA. Methods: This is a prospective, randomized phase 3 study evaluating the role of consolidative XRT in oligometastatic EGA. Patients with ≤3 metastases at the time of diagnosis of advanced disease are eligible for enrollment. After completion of 4 months of systemic therapy, patients whose disease has not progressed are randomized to consolidation with XRT to all sites of disease followed by continuation of systemic therapy or continuation of systemic therapy alone. Patients are able to enroll in the study at the time of diagnosis of advanced disease or after completion of induction therapy. Systemic therapy is left to the discretion of the treating physician and can include FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine, oxaliplatin) in combination with nivolumab. Unless there are contraindications to immunotherapy or a history of prior treatment with immune checkpoint inhibitors, nivolumab use is mandatory if tumor has PD-L1 combined positive score (CPS) ≥5. The goal of radiation is to consolidate gains made by chemotherapy by delivering the highest dose that maintains the greatest tumor control probability that is also safe to deliver given the anatomic and normal tissue constraints. Specific radiation dose and fractionation are recommended in the protocol but is left to the discretion of the treating radiation oncologist to choose the course that is most suitable. Radiation must be administered over a maximum of 15 treatment days to minimize systemic therapy treatment breaks. Primary endpoint is OS from the time of randomization. Secondary endpoints include progression free survival from the time of randomization and safety and tolerability of consolidative XRT. We hypothesize that consolidative XRT will prolong OS from 10 to 15.6 months (an increase in median OS of 55.6%). The study is planning to enroll 314 patients with the goal of randomizing 204 patients in a 2:1 fashion. Stratification factors include number of metastatic sites, choice of immunotherapy with relation to PD-L1 CPS, as well as time of registration to the protocol (before or after systemic therapy initiation). Enrollment to the study is ongoing. Clinical trial information: NCT04248452.

PD1 inhibition effect on immunization with MRNA vaccines against SARS-CoV-2.

e14594 Background: We provide care for the rural, low-income, and underserved population of Oroville. The community has a vaccination rate of 50% and booster rate of over 20% in the 3rd year of the ongoing global SARS-CoV-2 pandemic in 2022. During this period, a subset of our cancer patients benefited from the use of immune checkpoint inhibitors. Methods: This is a cross-sectional observational study of the effectiveness of a mRNA-based vaccine in medical care workers compared to patients with systemic malignancies treated with immunomodulation of PD-1 and CTLA-4 inhibitors. The study was approved by the hospital IRB. We evaluated the total anti-Spike protein antibody titer using a commercial semi-quantitative assay, Labcorp Test #164090. All subjects received 3 doses of the mRNA vaccine. We excluded anyone who was administered therapeutic monoclonal antibodies (mAb) or had a recent infection within 120 days. Results: Subjects with systemic malignancies were significantly older, p = 0.0001 by t-test: median age: 76, range: 64-82, compared to health care workers: median age: 52, range: 21-75. Accrual had to be prematurely stopped upon the arrival of Omicron wave in the community. Out of the seven subjects treated with immunomodulation, six received nivolumab, including two in combination with ipilimumab. One subject received pembrolizumab. Six of the subjects had metastatic disease: one was treated adjuvantly for locally advanced esophageal adenocarcinoma. The rest had NSCLC and one case of urothelioma. We divided the groups to those who had the highest titer of antibody versus everybody else and found a similar distribution in both groups using the Chi2 test. The vast majority of the healthcare workers, 24/27 or 89%, had above the upper limit antibody titer. Patients with systemic malignancy, 5/7 or 71%, had above the upper limit antibody titer p = N.S. Conclusions: Three doses of the mRNA vaccine provided high titers irrespective of frailty or age. We hypothesize that immunomodulation could favorably affect vaccination response.

ChemoTherapy aNd chemoradioTherapy for adenocarcinoma of the OESophagus and esophagogastric junction with oligometastases: Protocol of the TNT-OES-1 trial

BackgroundFLOT and CROSS are effective neoadjuvant regimens for esophageal cancer patients. Chemotherapy (FLOT) is aimed to have merely a systemic effect whereas neoadjuvant chemoradiotherapy (CROSS) achieves good locoregional response with clinically complete response (cCR) rates up to 33% [1]. The aim of the present study is to assess safety and feasibility of dual therapy (FLOT-CROSS) in patients with oligometastases. MethodsThis phase-II single-center, single-arm, intervention study includes patients with oligometastatic adenocarcinoma of the esophagus or esophagogastric junction. Patients will be treated with four biweekly cycles of FLOT, consisting of intravenous fluorouracil (2600 mg/m2), leucovorin (200 mg/m2), oxaliplatin (85 mg/m2) and docetaxel (50 mg/m2). Response evaluation by CT-scan will be performed 4–6 weeks after completion of FLOT. In case of regression or stable disease according to RECIST criteria (v.1.1), patients will receive additional CROSS, consisting of five weekly cycles of intravenous carboplatin (AUC 2) and paclitaxel (50 mg/m2), with concurrent 41.4 Gy radiotherapy, in 23 daily fractions of 1.8 Gy [2]. Response evaluation by endoscopy with biopsies, endoscopic ultrasonography and CT-scan will be performed 4–6 weeks after completion of CROSS. Primary endpoint is tolerability of FLOT-CROSS, defined as the proportion of patients who complete the full regimen. Secondary endpoints include disease control rate, objective response rate, overall survival and progression-free survival. In total, 20 patients will be included. DiscussionIf patients are able to complete and tolerate FLOT-CROSS, this regimen should be tested in a phase-III trial and as neoadjuvant treatment in patients with locally advanced non-metastatic esophageal or junctional adenocarcinoma.

Dose-escalated neoadjuvant chemoradiotherapy for locally advanced oesophageal or oesophagogastric junctional adenocarcinoma.

BackgroundNeoadjuvant chemoradiotherapy with CROSS-protocol is the standard of care for locally advanced esophageal cancer. The purpose of this study was to demonstrate an improvement in complete pathological response (ypCR) after a dose-escalation neoadjuvant protocol compared to standard treatment. Secondary endpoints were disease-free survival (DFS) and acute gastrointestinal toxicity.Material and methodsWe prospectively evaluated patients with locally advanced esophageal adenocarcinoma who received neoadjuvant chemoradiotherapy. The radiation dose was 41.4 Gy in 23 fractions or 50.4 Gy in 28 fractions with weekly administration of six intravenous cycles of carboplatin AUC 2 mg/mL and intravenous paclitaxel 50 mg/m2 followed by surgery.ResultsBetween December 2015 and July 2020, 21 patients were treated according to the reported radiation schedules. Median age was 61 years (57–67). 20 (95.2%) tumors were located at the esophagogastric junction and 1 (4.8%) in the middle esophagus. Five (23.8%) were stage II and 16 (76.2%) stage III. Twelve (57.1%) patients received 41.4 Gy (standard group) and 9 (42.9%) received 50.4 Gy (intensification group), with 5 (41.67%) and 5 (55.6%) presenting ypCR in the standard and intensification group, respectively (p = 0.67). After a median follow-up of 17 months (8–30), DFS in the standard group was 17.78 months [95% (CI, confidence interval): 12.9–22.6] and 45.5 months (95% CI: 24.4–66.05) in the intensification group (p = 0.299). Grade III acute gastrointestinal toxicity was 16% and 33.33%, respectively (p = 0.552). Postoperative toxicity events ≥ Grade III were 5 (41.7%) and 4 (44.4%), respectively (p = 0.623).ConclusionsIn our study we found a trend towards a higher complete pathological response-rate and disease-free survival in the intensification group compared to the standard group, with no differences in gastrointestinal toxicity. Well-designed randomized and controlled trials are needed to obtain conclusive data.

The Role of the TP53 Pathway in Predicting Response to Neoadjuvant Therapy in Esophageal Adenocarcinoma.

In patients with locally advanced esophageal adenocarcinoma, response to neoadjuvant therapy strongly predicts survival, but robust molecular predictors of response have been lacking. We therefore sought to discover meaningful predictors of response in these patients. We retrospectively identified all patients with adenocarcinoma of the lower esophagus or gastroesophageal junction who (i) were treated with multimodality therapy with curative intent at our institution from 2014 through 2020 and (ii) underwent prospective sequencing by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets. Clinicopathologic and genomic data were analyzed to identify potential genomic features, somatic alterations, and oncogenic pathways associated with treatment response. In total, 237 patients were included. MDM2 amplification was independently associated with poor response to neoadjuvant therapy [OR, 0.10 (95% confidence interval, 0.01-0.55); P = 0.032], when accounting for significant clinicopathologic variables, including clinical stage, tumor grade, and chemotherapy regimen. Moreover, TP53 pathway alterations, grouped according to inferred severity of TP53 dysfunction, were significantly associated with response to neoadjuvant therapy (P = 0.004, q = 0.07). Patients with MDM2 amplifications or truncating biallelic TP53 mutations had similar outcomes in terms of poor responses to neoadjuvant therapy and, consequently, shorter progression-free survival, compared with patients with TP53 pathway wild-type tumors. Thus, worsening TP53 dysfunction was directly correlated with worse outcomes. MDM2 amplification and TP53 status are associated with response to therapy in patients with esophageal adenocarcinoma. Given the dearth of actionable targets in esophageal adenocarcinoma, MDM2 inhibition, in combination with cytotoxic chemotherapy, may represent an important therapeutic strategy to overcome treatment resistance and improve outcomes in these patients.

International Tumor Budding Consensus Conference criteria determine the prognosis of oesophageal adenocarcinoma with poor response to neoadjuvant treatment

BackgroundNeoadjuvant therapy regimens followed by surgery represent the current standard treatment of locally advanced oesophageal adenocarcinomas. Tumour regression determines prognosis, but more than half of patients do have more than 10% residual tumour after neoadjuvant therapy. In these cases, classical histopathological parameters for the determination of prognosis are of limited value. Therefore, we investigated whether tumour budding could be an additional prognostic factor for tumours with poor response to neoadjuvant therapy. MethodsTumour budding was assessed according to a standardized consensus quantification method as proposed by the International Tumor Budding Consensus Conference (ITBCC) in H&E-stained whole tissue slides of 278 formalin-fixed paraffin-embedded (FFPE) resected oesophageal adenocarcinomas with a poor response (> 10% vital residual tumour) to neoadjuvant therapy. ResultsWe could demonstrate a strong positive correlation (p < 0.05) between the budding group, ypN stage and UICC tumour stage. Further, high numbers of tumour buds were a significant and independent negative prognostic marker for OS in all studied patients (HR = 1.039 (95% CI 1.012–1.066), p = 0.004). ITBCC budding groups were an independent prognostic parameter. ConclusionsTumour budding assessed in accordance with the ITBCC criteria may aid in the prognostic stratification of locally advanced oesophageal adenocarcinoma with poor response to neoadjuvant treatment.

(Neo)Adjuvant Treatment of Locally Advanced Esophageal and Gastroesophageal Adenocarcinoma: Special Focus on Sex Differences.

Simple SummaryMultimodal therapy is standard in locally advanced esophageal and gastroesophageal adenocarcinoma. Although substantial differences in incidence and outcome between women and men have been observed, no clear sex-specific treatment guide has been developed. In this summary, we described known sex differences focusing on locally advanced esophageal and gastroesophageal adenocarcinoma.Adenocarcinoma of the esophagus and gastroesophageal junction is a common disease. This disease is significantly more prevalent in men, although the main underlying risk factor has an equal sex distribution. In locally advanced disease, multimodal therapy has been developed as the standard in the western world. Neoadjuvant chemoradiotherapy or perioperative chemotherapy using the FLOT regimen was established as the standard. Most recently, adjuvant immunotherapy after neoadjuvant chemoradiotherapy and surgery has been introduced into the multimodal therapy. Substantial sex-specific differences in outcome in multimodal therapy have been described in retrospective subgroup analysis. Further studies are warranted to dissect the sex-specific differences in these treatment regimens.

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.

P-OGC57 Predicting survival and response to therapy using diagnostic biopsies: A machine learning approach to facilitate treatment decisions for oesophageal adenocarcinoma

Abstract Background Standard of care for locally advanced oesophageal adenocarcinoma is neoadjuvant chemotherapy or chemoradiotherapy followed by surgery. Only a minority of patients (&amp;lt;25%) derive significant survival benefit from neoadjuvant treatment and there are no reliable means of establishing prior to treatment in whom this benefit will occur. Moreover, accurate prediction of survival prior to treatment is also not possible. The availability of machine learning techniques provides the potential to use complex data sources to answer these problems. In this study, we assessed the utility of high-resolution digital microscopy of pre-treatment biopsies in predicting both response to neoadjuvant therapy and overall survival. Methods A total of 157 cases were included in the study. Pre-treatment clinical information, including neoadjuvant treatment, was obtained, along with diagnostic biopsies. Diagnostic biopsies were converted into high-resolution whole slide-images and features extracted using the pre-trained convolutional neural network Xception. Single representative images were converted into patches from which predictive models were trained. Elastic net regression classifiers were derived and validated with bootstrapping and 1000 resampled datasets. The response to treatment was considered according to Mandard tumour regression grade (TRG). Model performance was quantified using the C-index (for TRG) and time-dependent AUC (tAUC, fo Overall survival) along with calibration plots. Results Median survival was 78.9months (95%CI 35.9 months – not reached). Survival at 5-years was 52.1%. Neoadjuvant treatment was received by 123 patients (78.3%), with a significant response seen in 45 cases (36.6%). A response was more likely in those patients who received chemoradiotherapy than chemotherapy (53.3% vs 23.1% p &amp;lt; 0.001) and in older patients (median age 69.4 vs 66.0 years, p = 0.038), with other characteristics similar. A predictive model for response to neoadjuvant treatment derived from image features and clinical data achieved good discrimination (C-index 0.767, 95%CI 0.701-0.833) and calibration. Accuracy of prediction of overall survival was more modest (tAUC 0.640, 95%CI 0.518-0.762). Conclusions Using a small dataset, utility of a feature extraction pipeline in prediction of patient level outcomes has been demonstrated. This was more marked in prediction of response to neoadjuvant treatment than overall survival, which may reflect the importance of pre-treatment clinical data in determining the former outcome. Further study to refine the methodology and confirmation in larger datasets are required before expansion to clinical settings.

Low Programmed Death-Ligand 1-Expressing Subgroup Outcomes of First-Line Immune Checkpoint Inhibitors in Gastric or Esophageal Adenocarcinoma.

The US Food and Drug Administration has granted regulatory approval for the use of nivolumab-an immune checkpoint inhibitor (ICI)-in the first-line treatment of advanced gastric or esophageal adenocarcinoma (GEAC), regardless of programmed death-ligand 1 (PD-L1) expression. However, the efficacy of ICIs in low PD-L1-expressing tumors remains unclear. This study aims to reconstruct unreported Kaplan-Meier (KM) plots of PD-L1 combined positive score (CPS) subgroups of randomized phase III trials comparing the addition of ICIs with conventional chemotherapy in the first-line treatment of GEAC. A graphical reconstructive algorithm was adopted to estimate time-to-event outcomes from reported overall survival and progression-free survival (OS and PFS) KM plots describing overall or subgroup cohorts. Using reconstructed time-to-event outcomes, KMSubtraction conducts bipartite matching of patients from the reported subgroup among the overall cohort. By excluding matched patients, KM plots and survival analyses of the unreported subgroups were retrieved. CheckMate-649, KEYNOTE-062, and KEYNOTE-590 were included. Two PD-L1 subgroups were identified with data unreported in the primary manuscripts: PD-L1 CPS 1-4 from CheckMate-649 and PD-L1 CPS 1-9 from KEYNOTE-062. No significant differences in OS and PFS were demonstrated in ICI-chemotherapy combinations when compared with chemotherapy among CheckMate-649 PD-L1 CPS 1-4 (OS: hazard ratio [HR] = 0.950, 95% CI, 0.747 to 1.209, P = .678; PFS: HR = 0.958, 95% CI, 0.743 to 1.236, P = .743) and KEYNOTE-062 PD-L1 CPS 1-9 subgroups. In the KEYNOTE-062 PD-L1 CPS 1-9 subgroup, patients treated with pembrolizumab had an increased hazard of tumor progression (HR = 2.092, 95% CI, 1.661 to 2.635, P < .001). Using KMSubtraction, data of PD-L1 subgroups previously unreported by primary manuscripts of pivotal clinical trials were retrieved. These data suggest the lack of benefit in the addition of ICI to chemotherapy in low PD-L1-expressing GEAC tumors.

Application of Physiologically Based Pharmacokinetic Modeling to Evaluate the Drug-Drug and Drug-Disease Interactions of Apatinib.

Aim: Apatinib is an orally administered vascular epidermal growth factor receptor (VEGFR)-tyrosine kinase inhibitors approved for the treatment of advanced gastric adenocarcinoma or gastric esophageal junction adenocarcinoma. Apatinib is predominantly metabolized by CYP3A4/5, followed by CYP2D6. The present study aimed to evaluate the potential drug–drug interaction (DDI) and drug–disease interaction (DDZI) risks of apatinib in Chinese volunteers. Methods: Modeling and simulation were conducted using Simcyp Simulator. The input parameters required for modeling were obtained from literature research or experiments. Then, the developed physiologically based pharmacokinetic (PBPK) models were applied to evaluate single-dose DDI potential in Chinese healthy volunteers with weak and moderate CYP3A inhibitors, strong CYP2D6 inhibitors, as well as CYP3A4 inducers. The DDZI potential was also predicted in patients with hepatic or renal impairment. Results: The developed PBPK models accurately assessed apatinib pharmacokinetics following single-dose administration in Chinese healthy volunteers and cancer patients. The DDI simulation showed 2–4-fold changes in apatinib exposures by moderate CYP3A4 inhibitors and CYP3A4 inducers. A moderate increase of apatinib exposure (1.25–2-fold) was found with strong CYP2D6 inhibitor. In the DDZI simulation with hepatic impairment, the AUC of apatinib was significantly increased by 2.25-fold and 3.04-fold for Child–Pugh B and Child–Pugh C, respectively, with slightly decreased Cmax by 1.54 and 1.67-fold, respectively. Conclusion: The PBPK models developed in the present study would be highly beneficial to quantitatively predict the pharmacokinetic changes of apatinib under different circumstances, which might be difficult to evaluate clinically, so as to avoid some risks in advance.

Clinical Predictors of Locally Advanced Pathology in Esophageal Adenocarcinoma.

BackgroundIn patients with resectable esophageal adenocarcinoma (EAC), the decision for neoadjuvant treatment depends on clinical staging with endoscopic ultrasound (EUS) and positron-emission tomography (PET) scan. Patients with locally advanced EAC pathology misclassified as early EAC by clinical staging are missing the opportunity to receive neoadjuvant therapy. We aim to identify predictors of locally advanced pathology in EAC to determine more accurately those who benefit from neoadjuvant therapy. MethodsRetrospective study of patients who underwent upfront endoscopic or surgical resection for EAC without neoadjuvant therapy from January 2011 to December 2017 was performed. Clinical characteristics, EUS, PET scan and histologic findings were analyzed. Multivariable analysis of predictors of locally advanced stage was performed and a risk prediction score was developed.ResultsA total of 97 patients were included; 68 patients were staged as early EAC (pT1 or pT2 and pN0) and 29 patients were staged as locally advanced EAC (pT1 or pT2 with pN1 and pT3 or pT4 irrespective of N status). In a predictive model of EAC, patients presenting with dysphagia, tumor size >2 cm, exophytic mass appearance on endoscopy and absence of hiatal hernia were more likely to be have locally advanced pathology with a probability of 70% (C-statistic 0.766).ConclusionsA risk prediction model based on the presence of dysphagia, tumor size >2 cm, exophytic mass appearance and absence of hiatal hernia can be used to identify locally advanced pathology in EAC patients.

Surgery in Locally Advanced Esophageal Adenocarcinoma for Patients of Advanced Age or Significant Comorbidities

<h3>Purpose/Objective(s)</h3> The addition of surgery to chemoradiation (CRT) for esophageal adenocarcinoma has shown improved overall survival (OS) in many retrospective studies but has not demonstrated improved OS in randomized trials. Patients with comorbidities or advanced age are more likely to be given definitive CRT without surgery. Using the National Cancer Database (NCDB), we aim to identify if there is medical equipoise between trimodality therapy (TMT) with neoadjuvant CRT compared to definitive CRT for patients with locally advanced esophageal adenocarcinoma with advanced age or with significant comorbidities. <h3>Materials/Methods</h3> The NCDB was queried for patients with stage II-III esophageal adenocarcinoma who received either definitive CRT, or neoadjuvant CRT followed by surgery. Patients under 18 years old, with T4 disease, or who received under 4140 cGy were excluded. Bivariate analysis was used to assess the association between patient characteristics and treatment groups (TMT or definitive CRT). Log-rank tests and Cox proportional hazards models were performed to assess for differences in survival. <i>P</i>-value significance was set to < 0.05. <h3>Results</h3> A total of 14,945 patients met the inclusion criteria. Median age in the TMT and definitive CRT groups was 63 years vs 70 years, while Charlson/Deyo comorbidity condition (CDCC) score was ≥3 in 1.6% vs 2.8%, respectively. TMT was associated with improved survival in patients < 50, 50-60, 61-70, 71-80, and 81-90 years old (<i>P</i> < 0.05 for all). In patients 81-90 years old, 2-year OS was 39.7% vs 27.9% (<i>P</i> = 0.0065). TMT was also associated with significantly improved survival in patients with a CDCC score of 0, 1, 2 and ≥3 (<i>P</i> < 0.05 for all). In patients with a CDCC score ≥3, 2-year OS was 53.3 vs 29.7% (<i>P</i> = 0.0002). Nearly all sub-groups of sex, facility type, income, insurance, primary site, histology, T stage, N stage, and group stage also had significantly improved OS with TMT. Only patients with primary tumors in the upper third of the esophagus (<i>P</i> = 0.3633) or with a T stage of 1B (<i>P</i> = 0.0694) did not have a significant OS benefit with TMT. <h3>Conclusion</h3> No single analyzed characteristic was associated with a lack of OS benefit from TMT compared to definitive CRT, including age > 80 years old and CDCC score ≥3. This suggests that TMT should be offered to patients who can tolerate it, and that caution and clinical judgment should be used when considering the omission of surgery in locally advanced esophageal adenocarcinoma.

Novel Predictive and Prognostic Gene Signatures for Chemoradiotherapy in Locally Advanced Esophageal Adenocarcinoma

Esophageal adenocarcinoma is the sixth leading cause of cancer-related deaths in the United States. For locally advanced patients, neoadjuvant chemoradiotherapy followed by surgery is the standard of care. Risk stratification relies heavily on clinicopathologic features, particularly pathologic response, which is inadequate. This highlights the need for the development of biomarkers that can help improve outcomes. Herein, we have developed 2 distinct biomarker signatures to either predict response to neoadjuvant therapy or stratify patients into risk categories for survival.We assembled a cohort of 34 patients with locally advanced esophageal adenocarcinoma, with the majority (21) receiving concurrent chemoradiotherapy with carboplatin/paclitaxel. A capture based targeted sequencing was performed in paired biopsy specimens obtained at baseline, 3- and 6-weeks post-treatment. Differentially mutated gene analysis between responders and non-responders of treatment was performed to determine predictors of response. A univariate Cox proportional hazard regression was used to examine associations between gene mutation status and overall survival. A risk score was then calculated for each patient using a linear combination of univariate coefficient and mutation status of gene.15 patients (71%) receiving the CROSS regimen were classified as responders. Among responders to chemotherapy, the most frequently mutated genes were MKI67, SYNE1, PCLO, MSH3, RECQL4, NOTCH2, ILR7, CIITA, LRRK2 and EML4. Tumor mutation count was significantly reduced for these genes in post-treatment samples (P = 5.89E-03). We have identified a 3 gene signature based on mutations in EPHA5, BCL6, and ERBB2 that robustly predicts response to carboplatin/paclitaxel based neoadjuvant therapy. For this model, sensitivity is 84.6% and specificity is 100%. In the overall cohort, a 9 gene signature using APC, MAP3K6, ETS1, CSF3R, PDGFRB, GATA2, ARID1A, and FGF6, was also created that significantly stratifies patients into risk categories, prognosticating for improved relapse-free (P = 0.005) and overall survival (P = 3.325E-06). Sensitivity for this model is 73.33% and specificity is 94.74%.We have identified a 3-gene signature (EPHA5, BCL6 and ERBB2) that is predictive of response to neoadjuvant therapy and a separate 9 gene classifier which prognosticates for survival outcomes. These provide significant potential for personalized management of locally advanced esophageal cancer.

Complete response after neoadjuvant therapy for esophageal cancer : Implications for surgery

Arelevant number of patients with locally advanced esophageal squamous cell carcinoma and adenocarcinoma show a locoregional complete response of the tumor in the resected material after neoadjuvant therapy with modern chemotherapy and chemoradiation protocols. Due to ahigh rate of perioperative morbidity and decreased long-term quality of life following esophagectomy, the current treatment algorithm with neoadjuvant therapy and post-neoadjuvant esophagectomy on principle is critically questioned. An individualized treatment algorithm with extended clinical evaluation of post-neoadjuvant remission status and esophagectomy as needed is discussed. Patients with complete remission after neoadjuvant therapy are identified in an extended restaging protocol. Cases of clinical complete remission are treated with an active surveillance concept with esophagectomy as needed, i.e. surgery only when a local tumor recurrence is detected. Retrospective cohort studies have suggested that the active surveillance concept with esophagectomy as needed does not lead to a deterioration of overall survival rates in the patient collective. European prospective randomized, controlled, noninferiority studies with an oncological endpoint are currently evaluating the possibilities of organ-preserving concepts for clinical complete remission of esophageal cancer.