Cancer/testis antigen expression and co-expression patterns in Gastroesophageal Adenocarcinoma.

Gastroesophageal adenocarcinoma (GEAC) poses a significant challenge due to its poor prognosis and limited treatment options. Recently, Cancer/testis antigens (CTAs) have emerged as potential therapy targets due to their high expression in tumor cells and their immunogenic nature. We aimed to explore the expression and co-expression of CTAs in GEAC. We analyzed 63 GEAC patients initially and validated our findings in 329 patients from The Cancer Genome Atlas (TCGA) database. CTA expression was measured after RNA sequencing, while clinical information, including survival outcomes and treatment details, was collected from an institutional database. Co-expression patterns among CTAs were determined using Pearson correlation analysis. The majority of the study cohort were male (87%), Caucasian (94%), and had stage IV disease (64%). CTAs were highly prevalent, ranging from 58-19%. The MAGE gene family showed the highest expression, consistent across both cohorts. The correlation matrix revealed a distinct cluster of significantly co-expressed genes, including MAGEA3, NY-ESO-1, and others (0.27 ≤ r ≤ 0.73). Survival analysis revealed that individual CTAs were associated with poorer survival outcomes in patients not receiving immunotherapy while showing potential for improved survival in those undergoing immunotherapy, although these findings lacked robust reliability. Our study provides a comprehensive characterization of CTA expression and co-expression in GEAC. The strong correlation among CTAs like MAGE, NY-ESO-1, and GAGE suggests a potential for therapies targeting multiple CTAs simultaneously. Further research, including prospective trials, is warranted to assess the prognostic value of CTAs and their suitability as therapeutic targets.

Microbiota metabolized Bile Acids accelerate Gastroesophageal Adenocarcinoma via FXR inhibition.

Background: The incidence of Barrett esophagus (BE) and Gastroesophageal Adenocarcinoma (GEAC) correlates with obesity and a diet rich in fat. Bile acids (BA) support fat digestion and undergo microbial metabolization in the gut. The farnesoid X receptor (FXR) is an important modulator of the BA homeostasis. The capacity of inhibiting cancer-related processes when activated, make FXR an appealing therapeutic target. In this work, we assess the role of diet on the microbiota-BA axis and evaluate the role of FXR in disease progression. Results: Here we show that high fat diet (HFD) accelerated tumorigenesis in L2-IL1B mice (BE- and GEAC- mouse model) while increasing BA levels and enriching gut microbiota that convert primary to secondary BA. While upregulated in BE, expression of FXR was downregulated in GEAC in mice and humans. In L2-IL1B mice, FXR knockout enhanced the dysplastic phenotype and increased Lgr5 progenitor cell numbers. Treatment of murine organoids and L2-IL1B mice with the FXR agonist obeticholic acid (OCA) deacelerated GEAC progression. Conclusion: We provide a novel concept of GEAC carcinogenesis being accelerated via the diet-microbiome-metabolome axis and FXR inhibition on progenitor cells. Further, FXR activation protected with OCA ameliorated the phenotype in vitro and in vivo, suggesting that FXR agonists have potential as differentiation therapy in GEAC prevention.

Transcription factor EHF interacting with coactivator AJUBA aggravates malignancy and acts as a therapeutic target for gastroesophageal adenocarcinoma.

Transcriptional dysregulation of genes is a hallmark of tumors and can serve as targets for cancer drug development. However, it is extremely challenging to develop small-molecule inhibitors to target abnormally expressed transcription factors (TFs) except for the nuclear receptor family of TFs. Little is known about the interaction between TFs and transcription cofactors in gastroesophageal adenocarcinoma (GEA) or the therapeutic effects of targeting TF and transcription cofactor complexes. In this study, we found that ETS homologous factor (EHF) expression is promoted by a core transcriptional regulatory circuitry (CRC), specifically ELF3-KLF5-GATA6, and interference with its expression suppressed the malignant biological behavior of GEA cells. Importantly, we identified Ajuba LIM protein (AJUBA) as a new coactivator of EHF that cooperatively orchestrates transcriptional network activity in GEA. Furthermore, we identified KRAS signaling as a common pathway downstream of EHF and AJUBA. Applicably, dual targeting of EHF and AJUBA by lipid nanoparticles cooperatively attenuated the malignant biological behaviors of GEA in vitro and in vivo. In conclusion, EHF is upregulated by the CRC and promotes GEA malignancy by interacting with AJUBA through the KRAS pathway. Targeting of both EHF and its coactivator AJUBA through lipid nanoparticles is a novel potential therapeutic strategy.

An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma.

BACKGROUND: An improved understanding of which gastroesophageal adenocarcinoma (GOA) patients respond to both chemotherapy and immune checkpoint inhibitors (ICI) is needed. We investigated the predictive role and underlying biology of a 44-gene DNA damage immune response (DDIR) signature in patients with advanced GOA. MATERIALS AND METHODS: Transcriptional profiling was carried out on pretreatment tissue from 252 GOA patients treated with platinum-based chemotherapy (three dose levels) within the randomized phase III GO2 trial. Cross-validation was carried out in two independent GOA cohorts with transcriptional profiling, immune cell immunohistochemistry and epidermal growth factor receptor (EGFR) fluorescent in situ hybridization (FISH) (n = 430). RESULTS: In the GO2 trial, DDIR-positive tumours had a greater radiological response (51.7% versus 28.5%, P = 0.022) and improved overall survival in a dose-dependent manner (P = 0.028). DDIR positivity was associated with a pretreatment inflamed tumour microenvironment (TME) and increased expression of biomarkers associated with ICI response such as CD274 (programmed death-ligand 1, PD-L1) and a microsatellite instability RNA signature. Consensus pathway analysis identified EGFR as a potential key determinant of the DDIR signature. EGFR amplification was associated with DDIR negativity and an immune cold TME. CONCLUSIONS: Our results indicate the importance of the GOA TME in chemotherapy response, its relationship to DNA damage repair and EGFR as a targetable driver of an immune cold TME. Chemotherapy-sensitive inflamed GOAs could benefit from ICI delivered in combination with standard chemotherapy. Combining EGFR inhibitors and ICIs warrants further investigation in patients with EGFR-amplified tumours.

SMARCA4 Mutations in Gastroesophageal Adenocarcinoma: An Observational Study via a Next-Generation Sequencing Panel.

BACKGROUND: The clinical impact of SMARCA4 mutations (SMARCA4ms) in gastroesophageal adenocarcinoma (GEA) remains underexplored. This study aimed to examine the association of SMARCA4ms with clinical outcomes and co-occurrence with other gene mutations identified through a next-generation sequencing (NGS) panel in GEA patients. METHODS: A total of 256 patients with metastatic or recurrent GEA who underwent NGS panel profiling at the MD Anderson Cancer Center between 2016 and 2022 were included. Comparative analyses were performed to assess clinical outcomes related to SMARCA4ms. The frequency and types of SMARCA4ms and their co-occurrence with other gene mutations were also examined. RESULTS: SMARCA4ms were identified in 19 patients (7.4%). These SMARCA4ms were significantly associated with non-signet ring cell subtype (p = 0.044) and PD-L1 positive expression (p = 0.046). No difference in survival between the SMARCA4m and SMARCA4-normal group was observed (p = 0.84). There were significant associations between SMARCA4ms and FANCA, IGF1R, KRAS, FANCL, and PTEN alterations. Notably, 15 of the 19 SMARCA4m cases involved SNV missense mutations, with frequent co-occurrences noted with TP53, KRAS, ARID1A, and ERBB2 mutations. CONCLUSIONS: These results serve as the first comprehensive examination of the relationship between SMARCA4ms and clinical outcomes in GEA.

Targeting HER2 in Gastroesophageal Adenocarcinoma: Molecular Features and Updates in Clinical Practice.

Gastroesophageal adenocarcinoma (GEA) is one of the principal causes of death related to cancer globally. Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase receptor which is found to be overexpressed or amplified in approximately 20% of GEA cases. In GEA, the identification of HER2-positive status is crucial to activate a specific anti-HER2 targeted therapy. The landmark ToGA trial demonstrated the superiority of adding trastuzumab to platinum-based chemotherapy, becoming the first-line standard of treatment. However, unlike breast cancer, the efficacy of other anti-HER2 drugs, such as lapatinib, pertuzumab, and T-DM1, has failed to improve outcomes in advanced and locally advanced resectable GEA. Recently, the combination of trastuzumab with pembrolizumab, along with chemotherapy, and the development of trastuzumab deruxtecan, with its specific bystander activity, demonstrated improved outcomes, renewing attention in the treatment of this disease. This review will summarise historical and emerging therapies for the treatment of HER2-positive GEA, with a section dedicated to the HER2 molecular pathway and the use of novel blood biomarkers, such as circulating tumour DNA and circulating tumour cells, which may be helpful in the future to guide treatment decisions.

HER2 evaluation for clinical decision making in human solid tumours: pearls and pitfalls.

The significant clinical benefits of human epidermal growth factor receptor 2 (HER2)-targeted therapeutic agents have revolutionized the clinical treatment landscape in a variety of human solid tumours. Accordingly, accurate evaluation of HER2 status in these different tumour types is critical for clinical decision making to select appropriate patients who may benefit from life-saving HER2-targeted therapies. HER2 biomarker scoring criteria is different in different organ systems, and close adherence to the corresponding HER2 biomarker testing guidelines and their updates, if available, is essential for accurate evaluation. In addition, knowing the unusual patterns of HER2 expression is also important to avoid inaccurate evaluation. In this review, we discuss the key considerations when evaluating HER2 status in solid tumours for clinical decision making, including tissue handling and preparation for HER2 biomarker testing, as well as pathologist's readout of HER2 testing results in breast carcinomas, gastroesophageal adenocarcinomas, colorectal adenocarcinomas, gynaecologic carcinomas, and non-small cell lung carcinomas.

Oligometastasis of Gastric Cancer: A Review.

The concept of oligometastasis is not yet fully established in the field of gastric cancer. However, metastatic lesions that are localized, technically resectable at diagnosis, present a certain response to preoperative chemotherapy, and present favorable survival outcomes with local treatments, sometimes in combination with chemotherapy, are recognized as oligometastasis in the field of gastric cancer. Oligometastasis is noted in European Society for Medical Oncology guidelines and Japanese gastric cancer treatment guidelines, and local treatment is mentioned as one of the pivotal treatment options for oligometastasis. Solitary liver metastasis or a small number of liver metastases; retroperitoneal lymph node metastasis, especially localized para-aortic lymph node metastasis; localized peritoneal dissemination; and Krukenberg tumor are representative types of oligometastasis in gastric cancer. The AIO-FLOT3 trial prospectively evaluated the efficacy of multimodal treatments for gastric cancer with oligometastasis, including surgical resection of primary and metastatic lesions combined with chemotherapy, confirming favorable survival outcomes. Two phase 3 studies are ongoing to investigate the efficacy of surgical resection combined with perioperative chemotherapy compared with palliative chemotherapy. Thus far, the evidence suggests that multimodal treatment for oligometastasis of gastric cancer is promising.

Efficacy and safety of chemotherapy in young patients with advanced gastroesophageal adenocarcinoma: data from the Spanish AGAMENON-SEOM registry.

BACKGROUND: Gastroesophageal adenocarcinoma in young adults (GCYA) counts for 10-15% of diagnoses. Previous studies have mainly focused on surgical outcomes in patients with resectable tumors; however, systemic therapy for advanced GCYA remains under-evaluated. This study aims to assess the efficacy-related outcomes and safety of first-line chemotherapy (CT) in younger versus older patients with advanced gastroesophageal adenocarcinoma. METHODS: Patients with advanced gastroesophageal adenocarcinoma from the AGAMENON-SEOM registry treated with first-line polychemotherapy between January 2008 and October 2022 were included. We compared clinicopathological features, therapies received, efficacy-related outcomes, and toxicity between individuals aged < and ≥ 45 years. RESULTS: Out of 3386 patients, 263 (7.8%) were < 45 years. Young patients exhibited a higher proportion of females affected, lower ECOG-PS ≥ 2, fewer comorbidities, and more aggressive disease-related features, such as higher proportion of diffuse subtype, signet-ring cells, plastic linitis, grade 3, peritoneal metastases and metastatic disease at diagnosis. They received more triple-agent combinations and underwent more surgeries in metastatic setting. No significant differences were observed between groups in overall response rate (53.1% vs. 52.3% in < and ≥ 45 years, respectively, p = 0.579), progression-free survival (6.1 vs. 6.83 months, p = 0.158) and overall survival (11.07 vs. 10.81 months, p = 0.82), even after adjusting for potential confounding factors. Grade 3-4 adverse events were comparable in both groups, although toxicity leading to treatment discontinuation was more frequent in older patients. CONCLUSIONS: In the AGAMENON-SEOM registry, younger patients with GCYA exhibited more aggressive clinicopathological features, and despite receiving more aggressive treatments, similar efficacy outcomes and toxicity profiles were achieved compared to their older counterparts. In the AGAMENON-SEOM registry, GEAC in < 45 years showed more aggressive clinicopathological features and, although treated with more intense first-line CT regimens, similar efficacy outcomes and toxicity were achieved compared to older patients.

Management of Microsatellite Instability High (MSI-H) Gastroesophageal Adenocarcinoma.

BACKGROUND: Gastroesophageal cancer is a major cause of cancer-related mortality worldwide. Treatment of both early stage and advanced disease remains highly reliant on cytotoxic chemotherapy. About 4-24% of gastroesophageal cancers are microsatellite instability high (MSI-H). The MSI-H subtype is associated with favorable prognosis, resistance to cytotoxic chemotherapy, and sensitivity to immune checkpoint inhibitors (ICI). Recent studies have demonstrated promising activity of ICIs in the MSI-H subtype, resulting in fundamental changes in the management of MSI-H gastroesophageal adenocarcinoma. PURPOSE: In this review, we discuss the prevalence, characteristics, prognosis, and management of MSI-H gastroesophageal adenocarcinoma, with a focus on recent and ongoing studies that have changed the landscape of treatment for the MSI-H subtype. We also discuss current challenges in the management of resectable and advanced MSI-H gastroesophageal cancer, including the need for more accurate biomarkers of response to ICI therapy.

Concomitant Use of Steroids and Immunotherapy in a Patient With Paraneoplastic Dermatomyositis and Gastroesophageal Adenocarcinoma.

Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of autoimmune pathologies often associated with occult malignancies. Glucocorticoids (GCs) represent the initial therapy to control symptoms and avoid complications. Immune checkpoint inhibitors (ICIs) have shifted the paradigm of cancer treatment. Nivolumab has become the first-line therapy in combination with chemotherapy for untreated, unresectable, non-HER-2-positive advanced gastroesophageal adenocarcinoma. The use of ICIs increases the risk of immune-related adverse events (irAEs), especially in patients with autoimmune diseases, and patients receiving steroids or immunosuppressants might be associated with poorer immunotherapy efficacy. We describe the case of a 49-year-old male who was diagnosed with paraneoplastic dermatomyositis (PDM) and gastroesophageal adenocarcinoma. He was started on prednisone taper, and concomitantly, he was started on chemotherapy with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT), with administration of pegfilgrastim and dexamethasone during each cycle. Additionally, he was started on nivolumab. His course was complicated by worsening episodes of myopathies due to the immunotherapy, requiring adjustments to the prednisone taper. A positron emission tomography (PET) scan and repeat endoscopic ultrasonography with biopsy eight months after therapy initiation showed no major evidence of disease compared to prior. In our case, we exemplified the importance of multidisciplinary management for dosing and tapering of GCs and timing of ICI initiation, and we described the successful response to nivolumab in a patient with autoimmune disease concurrently receiving GCs.

Cost-effectiveness analysis of zolbetuximab plus mFOLFOX6 as the first-line treatment for CLDN18.2-positive, HER2-negative advanced gastric or Gastroesophageal Adenocarcinoma.

Background: The SPOTLIGHT trial demonstrated that zolbetuximab plus mFOLFOX6 (ZOL-FO) as a first-line regimen compared with placebo plus mFOLFOX6 (PLB-FO) conferred clinical benefits to patients with CLDN18.2-positive, HER2-negative advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. However, due to the high cost of zolbetuximab, whether ZOL-FO is cost-effective compared with PLB-FO is unclear. This study aimed to evaluate the cost-effectiveness of ZOL-FO as a first-line treatment option for CLDN18.2-positive, HER2-negative advanced G/GEJ adenocarcinoma from the perspective of the Chinese healthcare system. Methods: Markov models with three different health states were developed to assess the cost-effectiveness of ZOL-FO as a first-line treatment option for CLDN18.2-positive, HER2-negative advanced G/GEJ adenocarcinoma. Clinical efficacy data were obtained from the SPOTLIGHT trial; the drug's cost was calculated at national bid prices, and other costs and utility values were obtained from the published literature. Outcomes included total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). The model's robustness was verified using one-way sensitivity and probabilistic sensitivity analyses. Results: The ZOL-FO group gained 1.64 QALYs at $87,746.35, while the PLB-FO group gained 1.23 QALYs at $11,947.81. The ICER for ZOL-FO versus PLB-FO was $185,353.28 per QALY gained. The parameters exerting an important impact on the model results were the price of zolbetuximab, body surface area, and progression-free survival utility. At a willingness-to-pay threshold of $38,201/QALY, ZOL-FO had a 0% probability of cost-effectiveness compared with PLB-FO. Conclusion: From the perspective of the Chinese healthcare system, ZOL-FO is unlikely to be cost-effective as the first-line treatment option for CLDN18.2-positive, HER2-negative advanced G/GEJ adenocarcinoma.

Induction Fluorouracil-Based Chemotherapy and PET-Adapted Consolidation Chemoradiation with Esophagectomy for High-Risk Gastroesophageal Adenocarcinoma.

Background: Neoadjuvant chemoradiation with esophagectomy is standard management for locally advanced esophageal adenocarcinoma. Induction chemotherapy with a tailored approach to chemoradiation based on metabolic response to therapy on PET was explored as an alternative strategy in the CALGB 80803 trial. We sought to describe real-world institutional experience implementing this approach outside of a clinical trial. Methods: Patients who were treated with induction fluorouracil-leucovorin-oxaliplatin (FOLFOX) or fluorouracil-leucovorin-oxaliplatin-docetaxel (FLOT) with tailored chemoradiation based on PET response and subsequent esophagectomy were identified from a prospectively maintained database. Primary outcomes were pathologic complete response (pCR) and overall survival (OS) following completion of all therapy. Results: There were 35 patients who completed induction chemotherapy, chemoradiation, and esophagectomy. Thirty-three completed restaging PET following induction chemotherapy with metabolic response seen in 76% (n = 25/33). The pCR rate was 31% (n = 11/35) and the ypN0 rate was 71% (n = 25/35). Among the patients who demonstrated metabolic response to induction FOLFOX/FLOT and subsequently continued fluorouracil-based chemoradiation, the pCR rate was 39% (n = 9/23). The rate of pathologically negative lymph nodes in this group was high (n = 19/23, 83%) with 100% R0 resection rate (n = 23/23). With the median follow-up of 43 months, the median OS was not reached for this group and was significantly longer than the OS for the remainder of the cohort (p = 0.027, p = 0.046 adjusted for clinical stage). Conclusions: Induction FOLFOX/FLOT chemotherapy with evaluation of sensitivity via metabolic response and tailored chemoradiation seems to lead to high pCR and ypN0 rates in high-risk patients with adenocarcinoma of the esophagus and GE junction. This approach in clinical practice seems to recapitulate encouraging results in clinical trials.

p53/TP53 Status Assessment in Gastroesophageal Adenocarcinoma.

Chromosomal instability (CIN) is very frequent in gastroesophageal adenocarcinoma (GEA) and it is characterized by TP53 deletions/mutations resulting in p53 nuclear accumulation, as revealed by immunohistochemistry (IHC), which considers the cases with "high" staining levels to be positive. Aiming to improve aberrant TP53 detection, droplet digital PCR (ddPCR) was used to evaluate TP53 deletion in formalin-fixed, paraffin-embedded DNA (FFPE-DNA) and cell-free DNA (cfDNA). To further investigate the mutational TP53 profile, next-generation sequencing (NGS) was performed in a subset of FFPE samples. After combining "low" and "high" IHC staining level groups, the proportion of deletion events was significantly higher compared to the "intermediate" group (72.9% vs. 47.5%, p-value = 0.002). The ddPCR TP53 deletion assay was feasible for cfDNA but only had good agreement (72.7%, Cohen's kappa = 0.48) with the assay performed with FFPE-DNA of the "low-level" group. NGS analysis confirmed that, in the "low-level" group, a high percentage (66.7%) of cases were aberrant, with disruptive mutations that probably led to p53 loss. Data suggested that p53 IHC alone underestimates the CIN phenotype in GEA and that molecular analysis in both solid and liquid biopsies could be integrated with it; in particular, in cases of completely negative staining.

Efficacy and survival of anti-PD-1 antibody in combination with trastuzumab and chemotherapy versus trastuzumab and chemotherapy as first-line treatment of HER2-positive metastasis gastric adenocarcinoma: a retrospective study.

Background: The KEYNOTE-811 study exhibited promising preliminary results for HER2-positive metastasis gastric adenocarcinoma; however, long-term survival benefit remains to be determined. Methods: In this single-center, controlled, retrospective study, patients with histologically confirmed HER2-positive unresectable or metastatic gastric/gastroesophageal adenocarcinoma received either anti-PD-1 antibody combined with trastuzumab and chemotherapy (cohort A) or trastuzumab and chemotherapy treatment (cohort B). The primary end points were progression-free survival (PFS) and overall survival (OS). The secondary end points were objective response rate (ORR), disease control rate (DCR), and duration of response (DoR). Results: A total of 56 patients were eligible to join the study, with 30 patients in cohort A and 26 patients in cohort B. The median PFS (mPFS) was 16.2 months (95% CI, 15.093-17.307) in cohort A versus 14.5 months (95% CI, 9.491-19.509) in cohort B (p = 0.58). The median OS in cohort A was 28.1 months (95% CI, 17.625-38.575) versus 31.6 months (95% CI, 13.757-49.443) in cohort B (p = 0.534). ORRs were 66.7% and 50% in the two groups, respectively. DCRs were 90% and 84.6% in the two groups. Median DoR was not reached in cohort A and it was 16.3 (95% CI, 8.453-24.207) months in cohort B (p = 0.141). The most common irAEs were grade 1 hypothyroidism (33.3%) in cohort A. No treatment-related deaths occurred in this study. Conclusions: This retrospective cohort study provided a preliminary picture on the long-term follow-up of combining anti-PD-1 antibody with trastuzumab and chemotherapy in HER2-positive GC, and a trend with longer DoR and ORR was identified. Further studies with larger sample sizes and more in-depth molecular investigation are needed.

Circulating Tumor DNA as a Predictive Biomarker for Clinical Outcomes With Margetuximab and Pembrolizumab in Pretreated HER2-Positive Gastric/ Gastroesophageal Adenocarcinoma.

PURPOSE: To assess the ability of circulating tumor DNA (ctDNA)-based testing to identify patients with HER2 (encoded by ERBB2)-positive gastric/gastroesophageal adenocarcinoma (GEA) who progressed on or after trastuzumab-containing treatments were treated with combination therapy of anti-HER2 and anti-PD-1 agents. METHODS: ctDNA analysis was performed retrospectively using plasma samples collected at study entry from 86 patients participating in the phase 1/2 CP-MGAH22-05 study (NCT02689284). RESULTS: Objective response rate (ORR) was significantly higher in evaluable ERBB2 amplification-positive vs - negative patients based on ctDNA analysis at study entry (37% vs 6%, respectively; P = .00094). ORR was 23% across all patients who were evaluable for response. ERBB2 amplification was detected at study entry in 57% of patients (all HER2 positive at diagnosis), and detection was higher (88%) when HER2 status was determined by immunohistochemistry fewer than 6 months before study entry. ctDNA was detected in 98% (84/86) of patients tested at study entry. Codetected ERBB2-activating mutations were not associated with response. CONCLUSIONS: Current ERBB2 status may be more effective than archival status at predicting clinical benefit from margetuximab plus pembrolizumab therapy. ctDNA testing for ERBB2 status prior to treatment will spare patients from repeat tissue biopsies, which may be reserved for reflex testing when ctDNA is not detected.

Localized Gastroesophageal Adenocarcinoma in the Elderly: Is Age a Factor Associated with Suboptimal Treatment?

INTRODUCTION: Gastroesophageal adenocarcinoma is relatively common in elderly patients as the incidence increases with age. However, the optimal treatment approach is not well established in this group of patients. The aim of this study is to review our experience for localized gastroesophageal adenocarcinoma in patients aged ≥80 years and to assess association between patient characteristics, clinical factors, and overall survival (OS) in order to optimize the therapeutic approaches for this population. METHODS: Patients ≥80 years old treated for localized gastroesophageal adenocarcinoma were retrospectively analyzed. Survival curves were estimated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards regression models were applied to assess the association between patient characteristics and OS. Factors that were significant in the multivariate model were included in the final reduced model. RESULTS: 127 patients ≥80 years old, were included in this study with median age of 83 years. The median follow-up time was 3.2 years, and median OS was 2.5 years (95% CI: 2.0-3.1 years). Independent prognostic factors for OS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) (p = 0.003), baseline clinical stage (p = 0.01), and surgery (p = 0.001). ECOG PS, tumor location, baseline stage, tumor grade, and surgery were included in the final reduced model. CONCLUSION: Surgical treatment can improve survival in elderly patients. Therapeutic decisions should be based on the patients' general condition rather that age alone.

A practical approach for PD-L1 evaluation in gastroesophageal cancer.

PD-L1 is an established predictive immunohistochemical biomarker of response to immune checkpoint inhibitors. At present, PD-L1 is routinely assessed on biopsy samples of advanced gastroesophageal cancer patients before initiating first-line treatment. However, PD-L1 is still a suboptimal biomarker, due to changing cut-off values and scoring systems, interobserver and interlaboratory variability.This practical illustrated review discusses the range of staining patterns of PD-L1 and the potential pitfalls and challenges that can be encountered when evaluating PD-L1, focusing on gastric and gastroesophageal adenocarcinoma (G/GEA) and esophageal squamous cell carcinoma (ESCC).

Does HER2 status influence in the benefit of ramucirumab and paclitaxel as second line treatment of advanced gastro-esophageal adenocarcinoma? Data from the AGAMENON-SEOM registry.

PURPOSE: This study aimed to compare ramucirumab-paclitaxel versus chemotherapy in second-line (2L) advanced gastroesophageal cancer (aGEC) based on HER2 status and analyze prognostic factors. METHODS: The study includes patients from the AGAMENON-SEOM registry with aGEC and known HER2 status who received 2L between 2016 and 2021. The Kaplan-Meier method was used to calculate progression-free survival (PFS) and overall survival (OS) and multivariable Cox regression analysis was done to adjust for confounding variables. RESULTS: Of the 552 patients who met the selection criteria, 149 (26.9%) had HER2-positive aGEC, 89 were treated with chemotherapy, and 60 with ramucirumab-paclitaxel, and 403 had an HER2-negative aGEC, 259 were treated with chemotherapy, and 144 with ramucirumab-paclitaxel. In the whole sample, 2L PFS was 3.0 months (95% CI 2.8-3.2), 2L OS, 5.7 months (5.2-6.3), and ramucirumab-paclitaxel versus chemotherapy was associated with increased PFS (HR 0.64, 95% CI 0.53-0.78, p < 0.0001) and OS (HR 0.68, 0.55-0.83, p = 0.0002). Median PFS of ramucirumab- paclitaxel versus chemotherapy was 3.5 vs 2.8 months (HR 0.67, 0.54-0.83, p = 0.0004) in HER2-negative, and 4.7 vs 2.7 months (HR 0.57, 0.40-0.82, p = 0.0031) in HER2-positive aGEC, respectively. Median OS for ramucirumab-paclitaxel versus chemotherapy was 6.6 vs 5 months (HR 0.67, 0.53-0.85, p = 0.0007) in HER2-negative, and 7.4 vs 5.6 months (HR 0.70, 0.53-1.04, p = 0.083) in HER2-positive aGEC, respectively. ECOG-PS, tumor burden, Lauren subtype, and neutrophil-lymphocyte ratio were prognostic factors. CONCLUSIONS: In patients with an aGEC from the AGAMENON-SEOM registry, 2L treatment with ramucirumab-paclitaxel was superior to chemotherapy in PFS, OS and response rate, independent of HER2 status.

CT-derived body composition measurements as predictors for neoadjuvant treatment tolerance and survival in gastroesophageal adenocarcinoma.

PURPOSE: Treatment for gastroesophageal adenocarcinomas can result in significant morbidity and mortality. The purpose of this study is to supplement methods for choosing treatment strategy by assessing the relationship between CT-derived body composition, patient, and tumor features, and clinical outcomes in this population. METHODS: Patients with neoadjuvant treatment, biopsy-proven gastroesophageal adenocarcinoma, and initial staging CTs were retrospectively identified from institutional clinic encounters between 2000 and 2019. Details about patient, disease, treatment, and outcomes (including therapy tolerance and survival) were extracted from electronic medical records. A deep learning semantic segmentation algorithm was utilized to measure cross-sectional areas of skeletal muscle (SM), visceral fat (VF), and subcutaneous fat (SF) at the L3 vertebra level on staging CTs. Univariate and multivariate analyses were performed to assess the relationships between predictors and outcomes. RESULTS: 142 patients were evaluated. Median survival was 52 months. Univariate and multivariate analysis showed significant associations between treatment tolerance and SM and VF area, SM to fat and VF to SF ratios, and skeletal muscle index (SMI) (p = 0.004-0.04). Increased survival was associated with increased body mass index (BMI) (p = 0.01) and increased SMI (p = 0.004). A multivariate Cox model consisting of BMI, SMI, age, gender, and stage demonstrated that patients in the high-risk group had significantly lower survival (HR = 1.77, 95% CI = 1.13-2.78, p = 0.008). CONCLUSION: CT-based measures of body composition in patients with gastroesophageal adenocarcinoma may be independent predictors of treatment complications and survival and can supplement methods for assessing functional status during treatment planning.