Late-stage Gastric Cancer Research Articles

Abstract 7466: Exploring tertiary lymphoid structures and immune cell interactions in gastric cancer prognosis

Abstract Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates found in chronically inflamed, infected, and tumor tissues. Prior research indicates that the presence of TLS and tumor-infiltrating lymphocytes (TILs) correlates with a more favorable prognosis in several cancers. Our study investigates the role of TLSs and TILs in gastric cancer, the 4th leading cause of cancer-related death worldwide. We analyzed tumor samples from 107 late-stage gastric cancer patients from mainland China, with a 5-year follow-up period. We performed H&E and multiplex immunofluorescence staining to assess the tumor area and infiltrating immune cells, and we evaluated potential relationships between TILs, clinicopathological features, and patient prognosis. Immunohistological analysis showed that CD4 T cells may have a more significant impact on patient prognosis than CD8 T cells. Notably, the presence of PDL1 and CD4 co-expressing cells was associated with better disease outcomes. We observed PDL1 expressing cells surrounding the tumor margin in a subset of cases, a distribution pattern that could lead to delayed recurrence or complete remission in gastric cancer. In the context of cancer-related TLS, we found that CD20 and CD86 co-expression in the center of the structures may indicate a higher maturation level. Additionally, the ratio and spatial distribution of CD86 and CD163 macrophages appear to play a crucial role in prognosis. We extracted the expression levels of markers from representative samples to examine the spatial relationships between cancer cells and each immune cell type. We then visualized these cellular interactions in the tumor microenvironment using topographic plots. This study broadens our understanding of tumor and immune cell interactions in gastric cancer, with the potential to inform future directions in immunotherapy treatments. Citation Format: Zheng Zeng, Yee Man Au-Yeung, Jiandong Huang. Exploring tertiary lymphoid structures and immune cell interactions in gastric cancer prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7466.

Updates on immunotherapy of gastrointestinal cancers and practical challenges

Gastrointestinal (GI) cancers are the most common tumors of the digestive system, and their high morbidity and cancer-related mortality dramatically threaten the health of the population. With the researching progress of immunotherapy, its use in the treatment of GI cancers in the perioperative and advanced stages is becoming more and more important. Currently, immunotherapy has become the standard first-line treatment for MSI-H late-stage colorectal cancer, while in the first-line treatment of late-stage gastric cancer, immunotherapy combined with chemotherapy and HER2-targeted drugs (in HER2-positive patients) has also achieved significant efficacy and long-term survival benefits. Advances in immunotherapy in the neoadjuvant and adjuvant treatment and in the second- and later-line treatment of late-stage GI cancers have demonstrated its promising therapeutic potential. However, there is still an urgent need for future studies to explore more immunotherapy combination strategies for patients with GI cancers, especially with MSS colorectal cancers.

From mitochondria to tumor suppression: ACAT1's crucial role in gastric cancer.

Acetyl CoA acetyltransferase 1 (ACAT1), a mitochondrial enzyme, is mainly involved in the formation and decomposition of ketones, isoleucine, and fatty acids. Previous clinical studies showed that mutations in the ACAT1 gene lead to ketoacidosis, Notably the role of ACAT1 in human cancer' pathogenesis varies depending on cancer type, and its specific role in gastric cancer remains largely unknown. In the current study, we found that the expression of ACAT1 in primary late-stage gastric cancer tumor tissues was significantly lower than in early-stage tumors. This observation was further confirmed in high-grade gastric cancer cell line MKN45. The expression of CD44 and OCT4 was decreased, while CD24 expression was increased by overexpressing ACAT1 in MKN45 gastric cancer cells. Moreover, the ability of gastric cancer cells to form colonies on soft agar was also reduced by ACAT1 overexpression. Likewise, overexpression of ACAT1 inhibited epithelial mesenchymal transition (EMT) in gastric cancer cells evidenced by increased expression of the epithelial marker E-Cadherin, decreased expression of mesenchymal marker vimentin, and decreased expression levels of SNAI 1/3. In addition, ACAT1 overexpression inhibited cell migration and invasion, improved the response to 5-Fluorouracil (5-FU) and etoposide. In contrast, inhibition of ACAT1 activity promoted the proliferation of gastric cancer cells. The xenotransplantation results in nude mice showed that overexpression of ACAT1 in gastric cancer cells inhibited tumor growth in vivo. In addition, the low expression of ACAT1 in gastric cancer was further validated by searching public databases and conducting bioinformatic analyses. Mechanistically, bioinformatic analysis found that the inhibitory effect of ACAT1 in gastric cancer may be related to the Adipocytokine Signaling Pathway, Ppar Signaling Pathway, Propanoate Metabolism and P53 Signaling Pathway. Correlation analysis indicated ACAT1 mRNA expression was correlated with immune infiltrates. Collectively, our data show that ACAT1 induces pronounced inhibitory effects on gastric cancer initiation and development, which may impact future strategies to treat this aggressive cancer.

Dynamic Changes of Immune Cells and their Relationship with Prognosis in Late-Stage Gastric Cancer Patients During PD-1 Inhibitor Immunotherapy

Dynamic Changes of Immune Cells and their Relationship with Prognosis in Late-Stage Gastric Cancer Patients During PD-1 Inhibitor Immunotherapy

Gastric Cancer Risk Factors ina Veteran Population.

Risk factors for gastric cancer in the United States are not well understood, especially in populations with a low proportion of immigrants. We conducted a matched case-control study in a Veteran Affairs Medical Center to identify risk factors for gastric cancer. Gastric cancer patients and age- and sex-matched controls were identified in a 1:4 ratio from January 1, 1997 to October 31, 2018. Demographic, medical, endoscopic, and histologic data were extracted. We performed conditional logistic regression to estimate odds ratios and 95% CIs for associations between potential risk factors and gastric cancer. Most gastric cancer cases were diagnosed on initial endoscopy (71.4%). Of these, the most common presenting stage was stage IV (40.8%). Risk factors for gastric cancer included Black and Asian race and never or current (compared to former) drinkers, although Helicobacter pylori eradication and pernicious anemia were associated with decreased risk. The high proportion of late-stage gastric cancer diagnoses highlights the need for improved risk stratification as well as screening and surveillance protocols in the U.S. population. Racial disparities among veterans in an equal-access system necessitate further investigation into the etiology of these disparities.

Radiosensitizing effects of pyrogallol-loaded mesoporous or-ganosilica nanoparticles on gastric cancer by amplified ferroptosis.

Radiotherapy (RT) incorporated multidisciplinary treatment is producing excellent clinical results, but its efficacy in treating late-stage gastric cancer is constrained by radioresistance and RT-related toxicity. Especially, since reactive oxygen species are the pivotal effectual molecules of ionizing radiation, improving ROS production by nanoparticles and other pharmacological modulation to amplify oxidation of polyunsaturated fatty acids and subsequent ferroptotic cell death is shown to enhance cancer cell radioresponse. Herein, we constructed a nanosystem by loading Pyrogallol (PG), a polyphenol compound and ROS generator, into mesoporous organosilica nanoparticles named as MON@pG. The nanoparticles exhibit proper size distribution with amplified ROS production and substantial glutathione depletion under X-ray radiation in gastric cancer cell line. Meanwhile, MON@PG enhanced radiosensitivity of gastric cancer in xenograft tumor model by ROS-mediated accumulation of DNA damage and apoptosis. Furthermore, this augmented oxidative process induced mitochondrial dysfunction and ferroptosis. In summary, MON@PG nanoparticles show the capacity to improve RT potency in gastric cancer by disrupting redox balance and augmenting ferroptosis.

Endoscopic advances in the management of gastric cancer and premalignant gastric conditions.

Gastric cancer is the fifth most common cancer and in 2018, it was the third most common cause of cancer-related deaths worldwide. Endoscopic advances continue to be made for the diagnosis and management of both early gastric cancer and premalignant gastric conditions. In this review, we discuss the epidemiology and risk factors of gastric cancer and emphasize the differences in early vs late-stage gastric cancer outcomes. We then discuss endoscopic advances in the diagnosis of early gastric cancer and premalignant gastric lesions. This includes the implementation of different imaging modalities such as narrow-band imaging, chromoendoscopy, confocal laser endomicroscopy, and other experimental techniques. We also discuss the use of endoscopic ultrasound in the diagnosis and staging of early gastric cancer. We then discuss the endoscopic advances made in the treatment of these conditions, including endoscopic mucosal resection, endoscopic submucosal dissection, and hybrid techniques such as laparoscopic endoscopic cooperative surgery. Finally, we comment on the current suggested recommendations for surveillance of both gastric cancer and its premalignant conditions.

Neoadjuvant Therapy with Immune Checkpoint Inhibitors in Gastric Cancer: A Systematic Review and Meta-Analysis.

Immune checkpoint inhibitors (ICIs) have shown great promise in treating late-stage gastric cancer, but their efficacy in the neoadjuvant setting has not been studied in large cohorts. Here, we explored the efficacy and safety of neoadjuvant ICI-based therapy in locally advanced gastric cancer. We included studies containing patients with locally advanced gastric/gastroesophageal cancer who received ICI-based neoadjuvant therapy. We searched PubMed, Embase, Cochrane library, and abstracts from major international oncology conferences. We performed this meta-analysis using the META package in R.3.6.1. Twenty-one prospective phase I/II studies comprising 687 patients were identified. The pathological complete response (pCR) rate was 0.21 (95% CI 0.18-0.24), major pathological response (MPR) rate was 0.41 (95% CI 0.31-0.52), and R0 resection rate was 0.94 (95% CI 0.92-0.96). The efficacy was highest with ICI plus radiochemotherapy, lowest with ICI alone, and in the middle with ICI and chemotherapy ± anti-angiogenesis. dMMR/MSI-H and PD-L1-high patients benefited more than pMMR/MSS and PD-L1-low patients. Grade 3 or higher toxicity rate was 0.23 (95% CI 0.13-0.38). These results exceeded those in trials of neoadjuvant chemotherapy, where the rate of pCR was 0.08 (95% CI 0.06-0.11), MPR was 0.22 (95% CI 0.19-0.26), R0 section was 0.84 (95% CI 0.80-0.87), and overall grade 3 or higher toxicity was 0.28 (95% CI 0.13-0.47) in 4800 patients across 21 studies. In summary, the integrated results show promising efficacy and safety of ICI-based neoadjuvant therapy for locally advanced gastric cancer and support further investigation in large multicenter randomized trials.

Anti-PD-1 plus anti-angiogenesis combined with chemotherapy in patients with HER2-negative advanced or metastatic gastric cancer: a multi-institutional retrospective study.

Immunotherapy plus chemotherapy have been confirmed to be effective in treating advanced or metastatic gastric cancer (GC). Anti- programmed death-1 (PD-1) plus antiangiogenic agents have shown promising activity and tolerant toxicity in subsequent therapy of late-stage gastric cancer. The aim of this study was to assess the efficacy and safety of anti-PD-1 plus anti-angiogenic agents and chemotherapy in advanced or metastatic GC and to explore the potential biomarkers associated with response. We retrospectively reviewed thirty human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic GC patients who received PD-1 plus anti-angiogenic drugs and chemotherapy. Conversion therapy was defined when the patients could undergo resection post combination therapy. Clinical data were retrieved from medical records. We conducted exploratory biomarker analysis of baseline gene mutations and tumor mutation burden (TMB) using the next-generation sequencing (NGS), PD-L1 by immunohistochemistry (IHC), and the tumor immune microenvironment (TIME) by multiplex immunofluorescence. A total of 30 patients received anti-PD-1plus anti-angiogenic drugs and chemotherapy during the study period. The objective response rate (ORR) was 76.7% [95% confidence interval (CI): 57.7-90.1%] and disease control rate (DCR) was 86.7% (95% CI: 69.3-96.2%). A total of 11 patients (36.7%) achieved conversion therapy and underwent surgery. The R0 resection rate was 90.9%. Of the 11 patients, 9 (81.8%) responded to the treatment, 1 with a pathological complete response (pCR) and 8 with a major pathological response (MPR). No adverse events of grade 3 or higher occurred. Neither PD-L1 expression nor TMB was significantly correlated with treatment response. Analysis of TIME revealed that the fraction of CD8+ T cell in the invasive margin was higher in responders than non-responders before treatment. TAM2 in the tumor center and CD8+ T cell in the invasive margin was significantly increased after combination therapy, which suggested that combination therapy promoted infiltration of CD8+ T cells, thereby exerting an antitumor effect. Immunotherapy plus anti-angiogenic drugs and chemotherapy is a promising treatment strategy for advanced or metastatic GC patients. Tumor infiltration CD8+ T cells may serve as potential predictive biomarker.

Neoadjuvant therapy with immune checkpoint blockade, antiangiogenesis, and chemotherapy for locally advanced gastric cancer

Despite neoadjuvant/conversion chemotherapy, the prognosis of cT4a/bN+ gastric cancer is poor. Immune checkpoint inhibitors (ICIs) and antiangiogenic agents have shown activity in late-stage gastric cancer, but their efficacy in the neoadjuvant/conversion setting is unclear. In this single-armed, phase II, exploratory trial (NCT03878472), we evaluate the efficacy of a combination of ICI (camrelizumab), antiangiogenesis (apatinib), and chemotherapy (S-1 ± oxaliplatin) for neoadjuvant/conversion treatment of cT4a/bN+ gastric cancer. The primary endpoints are pathological responses and their potential biomarkers. Secondary endpoints include safety, objective response, progression-free survival, and overall survival. Complete and major pathological response rates are 15.8% and 26.3%. Pathological responses correlate significantly with microsatellite instability status, PD-L1 expression, and tumor mutational burden. In addition, multi-omics examination reveals several putative biomarkers for pathological responses, including RREB1 and SSPO mutation, immune-related signatures, and a peripheral T cell expansion score. Multi-omics also demonstrates dynamic changes in dominant tumor subclones, immune microenvironments, and T cell receptor repertoires during neoadjuvant immunotherapy. The toxicity and post-surgery complications are limited. These data support further validation of ICI- and antiangiogenesis-based neoadjuvant/conversion therapy in large randomized trials and provide candidate biomarkers.

Heterogeneity and prognosis of single organ metastases in gastric cancer.

While single organ metastases generally present a more optimistic prognosis compared to multiple metastases, the influence of the specific organ site for single organ metastases on prognosis remains undetermined. This retrospective study aimed to investigate the prognostic differences in late-stage gastric cancer with single organ metastasis. Data for patients diagnosed with gastric cancer were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database for survival analysis, covering years spanning from 2010 to 2016. Furthermore, Kaplan-Meier survival curves and Cox regression were utilized to analyze overall survival (OS) and disease-specific survival (DSS). Additionally, given the impact of confounders and bias on the results, prognosis was further analyzed using propensity score matching (PSM) and floating absolute risk methods. A cohort comprising 4,297 patients diagnosed with gastric cancer and exhibiting single organ metastasis was hereby enrolled. Liver metastasis was the most common (71% of the total), while brain metastasis accounted for the least (1.7% of the total). Compared to other metastases, patients with bone metastasis presented the worst OS [hazard ratio (HR), 1.319; 95% confidence interval (CI): 1.207-1.442; P<0.001], and this remained consistent even upon the application of floating absolute risk (HR, 1.10; 95% CI: 1.01-1.20) and PSM methods (HR, 1.187; 95% CI: 1.053-1.339; P=0.005). In addition, subgroup analysis and interaction tests of OS revealed an interaction between age (P=0.02), histological type (P=0.002), and bone metastasis. In patients with single organ metastasis of gastric cancer, the prognosis varies by the metastatic site, with bone metastasis presenting the poorest outcome. Overall, this study forges a foundation for further research on the mechanisms and patterns of different metastatic sites in gastric cancer and informs treatment strategies.

Survival outcomes of hepatectomyin gastric cancer liver metastasis. Systematic review and meta-analysis

Background: Surgical treatment of late-stage gastric cancer has been commonly linked to poor outcomes with stage IV gastric cancer liver metastasis (GCLM) constituting a contraindication in current guidelines. However, the results of recent observational studies are questioning this paradigm. We, therefore, aimed to assess survival outcomes following hepatectomy for GCLM and identify potential predictors of improved survival outcomes.

Transcriptomic characterization and construction of M2 macrophage-related prognostic and immunotherapeutic signature in ovarian metastasis of gastric cancer.

Ovarian metastasis (OM) poses a major threat to the outcome of gastric cancer (GC) patients. Recently, immunotherapy emerged as a novel promising therapeutic strategy to treat late-stage GC, whereas its efficacy is influenced by tumor immune microenvironment (TIME). M2 macrophage, a key subset within TIME, plays dual immunosuppressive and pro-tumorigenic roles in cancer progression and is recognized as a potential therapeutic target. However, molecular mechanisms underlying OM remain elusive and the TIME-related prognostic and immunotherapeutic index for these patients is yet to establish. Differential expressed genes (DEGs) between paired normal mucosa, primary GC and OM of patients from Fudan University Shanghai Cancer Center (FUSCC) cohort (n = 6) were identified by transcriptome sequencing, followed by the functional annotation of enriched hallmark pathways of DEGs between them. CIBERSORT was used to profile the relative expression level of 22 immune cell subsets in normal tissues, primary and metastatic tumors, followed by weighted gene coexpression network analysis (WGCNA) uncovering immune cell-correlated gene sets. The intersected genes between DEGs and M2 macrophage-related genes were processed by least absolute shrinkage and selection operator (LASSO) regression analysis to construct a predictive signature, M2GO, which was further validated by training set and test set of The Cancer Genome Atlas-Stomach Adenocarcinoma (TCGA-STAD), GSE62254 and GSE84437 cohorts. GC patients were divided into M2GO-high and -low subgroup according to the optimal cutoff value of the M2GO score. Furthermore, the clinical, molecular and immune features between M2GO-high and -low subgroups were analyzed. Clinical cohorts of immunotherapy were used to validate the predictive value of M2GO in regard to immunotherapy effectiveness. Transcriptomic sequencing and follow-up analyses of triple-matched normal tissues, primary and ovarian metastatic tumors identified distinctive sets of DEGs and enriched immune-, cancer- and metastasis-related pathways between them. Of note, M2 macrophage, a major immunosuppressive and pro-tumorigenic component within TIME, was significantly up-regulated in OMs. WGCNA and LASSO regression were applied to establish a novel OM- and M2 macrophage-related predictive signature, M2GO, based on M2 macrophage-related prognostic genes including GJA1, MAGED1 and SERPINE1. M2GO served as an independent prognostic factor of GC patients. Comprehensive molecular and immune characterization of M2GO-based subgroups uncovered their distinctive features in terms of enriched functional pathways, tumor mutation burden, key immune checkpoints, major regulators of natural immune cGAS-STING pathway, infiltrated subsets of immune cells and tumor immune exclusion/dysfunction (TIDE) score. Notably, the M2GO score was significantly lower in responsive group than non-responsive group (P < 0.05) in clinical cohort of metastatic GC patients undergoing immunotherapy. Transcriptomic characterization of paired normal mucosae, primary and ovarian metastatic tumors revealed their unique molecular and immune features. Follow-up analyses established a novel OM- and M2 macrophage-related signature, M2GO, which served as a promising prognostic and immunotherapeutic biomarker to distinguish the clinical outcome, molecular and immune features of GC patients and predict their differential responses to immunotherapy.

Neoadjuvant PD-1 blockade plus chemotherapy induces a high pathological complete response rate and anti-tumor immune subsets in clinical stage III gastric cancer

ABSTRACT First-line PD-1 blockade plus chemotherapy significantly improves the survival benefits in late-stage gastric cancer (GC) patients. However, the pathological response rate and effects on the immune microenvironment of neoadjuvant PD-1 blockade plus chemotherapy in patients with cTNM-stage III GC remain to be elucidated. Patients with cTNM-stage III GC who underwent neoadjuvant PD-1 blockade plus chemotherapy and surgery were enrolled. Four in vivo models bearing GC were jointly established to investigate the specific roles of chemotherapy and PD-1 blockade for GC treatment. The tumor immune microenvironment was analyzed by hematoxylin and eosin (H&E) and IHC staining, multicolor flow cytometry and immunofluorescence. A total of 75 patients with cTNM-stage III (cT2-4N1-3M0) gastric cancer who received neoadjuvant PD-1 blockade plus chemotherapy (SOX/XELOX) were included in this study. After treatment, 21 (28.0%) and 57 (76.0%) patients achieved pathological complete response (pCR) and post-therapy pathological downstaging. Subgroup analyses revealed that patients with CPS >1 (32.6% vs 8.3%) and dMMR (35.7% vs 25.4%) subtype had better efficacy. Additionally, the resected specimens showed more anti-tumor immune infiltration indicating a response to neoadjuvant PD-1 blockade plus chemotherapy. Multicolor immunofluorescence and in vivo experiments on mouse models revealed that elevated M1/M2 ratio of macrophages, CD8 + T cells and plasma cells indicated effective response to treatment. Furthermore, neoadjuvant PD-1 blockade plus chemotherapy neither delayed surgery nor increased postoperative complication rate. The analyses indicate neoadjuvant PD-1 blockade plus chemotherapy is a promising therapeutic strategy in patients with cTNM-stage III GC with an encouraging pCR rate.

Construction of ovarian metastasis-related immune signature predicting prognosis of gastric cancer patients.

Ovarian metastasis (OM) results in poor survival of gastric cancer (GC) patients. While immunotherapy has emerged as a promising approach for late-stage GC, validated immune-related prognostic signatures still remain in need. In this study, we constructed an ovarian metastasis- and immune-related prognostic signature (OMIRPS), characterized the molecular and immune features of OMIRPS-categorized subgroups and predicted their potential response to immunotherapy. Three individual cohorts were used to construct and evaluate OMIRPS: RNA-seq of matched primary GC and OM from Fudan University Shanghai Cancer Center (FUSCC) (discovery cohort, n=4), The Cancer Genome Atlas (TCGA) (training cohort, n=544) and GSE84437 (validation cohort, n=433). Differentially expressed genes (DEGs) identified between primary GC and OM and immune-related genes (IRGs) from the ImmPort and InnateDB databases were used to identify immune-related prognostic hub genes, which were further used to construct OMIRPS by using LASSO regression analysis. Prognosis, molecular characteristics, immune features, and differential immunotherapy efficacy between different OMIRPS subgroups were analyzed. Functional analyses of DEGs revealed the significance of immune-related signatures and pathways in the OM. Immune-related prognostic hub genes including TNFRSF18, CARD11, BCL11B, NRP1, BNIP3L, and ATF3 were utilized to construct OMIRPS, which was identified as an independent prognostic factor. Comprehensive analyses unveiled the distinctive molecular and immune characteristics of OMIRPS-high and -low subgroup in regard to enriched pathways, mutation rate, tumor mutation burden, microsatellite instability status, infiltrated immune cell, immune exclusion score, andthe prediction ofimmunotherapy efficacy. Additionally, OMIRPS was associated with Immune Subtypes with borderline significance. RNA-seq of paired primary and ovarian metastatic tumors unveiled the significance of immune-related pathways and tumor immune microenvironment in OM. OMIRPS served as a promising biomarker to predict the prognosis of GC patients and distinguish the molecular features, immune characteristics, and efficacy of immunotherapy between different subgroups.

Cellular immunotherapy in gastric cancer: adoptive cell therapy and dendritic cell-based vaccination.

Gastric cancer (GC) is one of the most frequently diagnosed malignancies. Recent studies have highlighted cellular immunotherapy (CI) as a promising approach for treating this disease. Among the CI-based approaches, adoptive cell therapy and dendritic cell-based vaccination are commonly studied in preclinical and clinical trials. Here we review the current evidence on the potentiality of CI in treating GC, the targets for adoptive cell therapy, ongoing clinical trials, constraints and the future outlook. The results suggest that there is a need to identify novel biomarkers that predict which GC patients will most likely respond to these approaches. Also, CI plus chemotherapy or immune checkpoint inhibitors can improve the survival of patients with late-stage GC. Therefore, this approach can be promising for treating these patients.

Efficacy and toxicity of neoadjuvant immune checkpoint inhibitors in resectable gastric cancer: A meta-analysis and systematic review.

291 Background: Immune checkpoint inhibitors (ICI) have made significant breakthroughs in late-stage gastric cancer. It is an attractive issue whether ICIs also function in the neoadjuvant setting. Methods: A systematic review was performed using combined terms related to “stomach cancer”, “gastric cancer”, “gastroesophageal cancer”, “immune checkpoint inhibitor”, “PD-1”, “PD-L1” and “neoadjuvant” in PubMed and annual meeting of ASCO, ASCO GI, ESMO, and ESMO GI from 2019 to 2021. Complete pathological response (CPR) rates, major pathological response (MPR) rates, R0 resection rates, and side effects were pooled and analyzed. MPR was defined as ≤10% viable tumor cells and included CPR. Study outcomes were pooled using the function METAPHOR in the META package in R.3.6.1. The I2 and P statistics were used to evaluate heterogeneity among studies. Funnel plots were used for publication bias assessment. Results: A total of 13 phase I/II clinical trials, including 332 resectable gastric cancer (T2-4 or N+) patients with neoadjuvant ICI-containing treatments, were collected. The pooled rates of CPR, MPR, and R0 resection were 0.16 (95% credible intervals (CI), 0.12-0.22), 0.36 (95% CI, 0.24-0.51), and 0.97 (95% CI, 0.94-0.99), respectively. As a comparison, outcomes from 25 studies on neoadjuvant chemotherapy were also pooled, with rates of CPR 0.08 (95% CI, 0.06-0.11), MPR 0.22 (95% CI, 0.19-0.26), and R0 resection 0.84 (95% CI, 0.80-0.87). Besides, the overall grade 3 or higher toxicity rates were 0.24 (95% CI 0.03-0.54) vs. 0.28 (95% CI 0.13-0.47) in ICI-based treatment and chemotherapy groups. Stratified by treatment strategies, ICI alone showed the lowest efficacy (CPR 0.07, 95% CI 0.02-0.19 and MPR 0.16, 95% CI 0.03-0.29). Addition of chemotherapy to ICI promoted the CPR (0.15, 95% CI 0.10-0.22) and MPR (0.36, 95% CI 0.22-0.50). Further addition of radiotherapy displayed the highest CPR (0.35, 95% CI 0.21-0.52) and MPR (0.74, 95% CI 0.54-0.93). Only four trials reported the outcomes of dMMR/MSI-H patients, with superior CPR (0.39, 95% CI 0.20-0.62) and MPR (0.82, 95% CI 0.82-1.00), while those of pMMR/MSS patients were 0.05 (95% CI 0.00-0.13) and 0.20 (95% CI 0.20-0.31) respectively, among which 2 trials used ICI only. Conclusions: Neoadjuvant ICI plus chemotherapy/radiotherapy, instead of ICI alone, has better pathological responses and R0 resection rates than chemotherapy. dMMR/MSI-H is a superior biomarker for neoadjuvant ICI therapy for resectable gastric cancer. The value or biomarker of immunotherapy in pMMR/MSS patients remains exploring.[Table: see text]

Fusobacterium nucleatum colonization is associated with decreased survival of helicobacter pylori-positive gastric cancer patients.

BACKGROUNDAn increased amount of Fusobacterium nucleatum (F. nucleatum) is frequently detected in the gastric cancer-associated microbiota of the Taiwanese population. F. nucleatum is known to exert cytotoxic effects and play a role in the progression of colorectal cancer, though the impact of F. nucleatum colonization on gastric cancer cells and patient prognosis has not yet been examined.AIMTo identify F. nucleatum-dependent molecular pathways in gastric cancer cells and to determine the impact of F. nucleatum on survival in gastric cancer.METHODSCoculture of F. nucleatum with a gastric cancer cell line was performed, and changes in gene expression were investigated. Genes with significant changes in expression were identified by RNA sequencing. Pathway analysis was carried out to determine deregulated cellular functions. A cohort of gastric cancer patients undergoing gastrectomy was recruited, and nested polymerase chain reaction was performed to detect the presence of F. nucleatum in resected cancer tissues. Statistical analysis was performed to determine whether F. nucleatum colonization affects patient survival.RESULTSRNA sequencing and subsequent pathway analysis revealed a drastic interferon response induced by a high colonization load. This response peaked within 24 h and subsided after 72 h of incubation. In contrast, deregulation of actin and its regulators was observed during prolonged incubation under a low colonization load, likely altering the mobility of gastric cancer cells. According to the clinical specimen analysis, approximately one-third of the gastric cancer patients were positive for F. nucleatum, and statistical analysis indicated that the risk for colonization increases in late-stage cancer patients. Survival analysis demonstrated that F. nucleatum colonization was associated with poorer outcomes among patients also positive for Helicobacter pylori (H. pylori).CONCLUSION F. nucleatum colonization leads to deregulation of actin dynamics and likely changes cancer cell mobility. Cohort analysis demonstrated that F. nucleatum colonization leads to poorer prognosis in H. pylori-positive patients with late-stage gastric cancer. Hence, combined colonization of F. nucleatum and H. pylori is a predictive biomarker for poorer survival in late-stage gastric cancer patients treated with gastrectomy.

1416P Genomic landscape of late-stage gastric cancer

In this exploratory analysis of the phase II KEYNOTE-059 (NCT02335411) and phase III KEYNOTE-061 (NCT02370498) studies of patients (pts) with previously treated advanced gastric cancer (GC) receiving pembrolizumab, we evaluated the genomic landscape of late-stage GC with a focus on comparing our results with previously reported data from TCGA of early-stage tumors in Caucasian pts. We also evaluated genomic features of advanced GC tumors in Caucasian and Asian pts.

A noninvasive gastric cancer Her2 test using surrogate methylation markers.

e16084 Background: There are 10-20% of gastric cancer (GC) with overexpressed Her2. Her2 status remains an essential biomarker for guiding the trastuzumab (Herceptin) therapy, a monoclonal antibody approved for the first-line treatment of late-stage Her2-positive GC. Although IHC, together with FISH, is comprehensively applied to verify Her2 status on tissue samples, an accurate blood test is highly desirable due to the inaccessibility of tissue samples, especially in very late stage GC patients as well as tumor heterogeneity of tissue biopsy. Detecting copy number aberration of Her2 gene in cell-free DNA (cfDNA) gains a lot of interest for its non-invasive approach. However, the limited signal-to-noise ratio poses a great challenge for the accuracy and robustness of the tests (either targeted sequencing or ddPCR). Here, we report a non-invasive test for Her2 status verification based on novel surrogate DNA methylation markers. Methods: Genome-wide DNA methylation sequencing was performed in 30 Her2-negative (IHC 0/1+) and 44 Her2-positive (IHC 3+) tissue samples to identify Her2-overexpression-specific methylation markers. Then we analyzed the performance of these candidate markers using methylation-specific quantitative PCR (qMSP) in plasma samples collected from 102 GC patients before surgical treatment. A Her2-status diagnostic model was built and further validated in a multi-center, prospective cohort (n = 150). The concordance of Her2 status between GC plasma and matching tissue samples (IHC/FISH) was determined. Results: We first discovered 102 statistically significant methylation markers of Her2 status in tissue. Out of these candidate markers, a 3-marker diagnostic model was built and validated on plasma samples, which could discriminate Her2-positive from Her2-negative GC patients with high sensitivity (86.7%) and specificity (96.8%). The overall plasma-tissue concordance of this liquid biopsy test was 95.3%. Furthermore, the Her2-status test was able to classify Her2 2+ status (IHC) into either Her2-negative or Her2-positive status, which was confirmed by conventional FISH test. Conclusions: Overall, the cfDNA-based test is a novel, accurate and noninvasive approach for determining Her2 status in GC patients. The high concordance with IHC/FISH results of this blood test holds great promise as an auxiliary method for guiding Her2-targeted therapy in GC patients. A clinical trial is undergoing to validate this test in the phase-2 clinical trial of a Her2-targeted drug (for GC) in China.