Metastatic Gastric Cancer

MONDO:0004950 gastric carcinoma

Metastatic gastric cancer is advanced gastric adenocarcinoma with dissemination to peritoneum, liver, distant lymph nodes, lung, bone, and less commonly brain. Peritoneal spread is a defining pattern, especially in diffuse and E-cadherin-deficient disease. Metastatic competence is shaped by loss of epithelial adhesion, HER2 pathway activation in a subset, microsatellite instability in an immune-responsive subset, and angiogenic and stromal remodeling.

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1
Mappings
5
Pathophys.
4
Phenotypes
4
Genes
1
Treatments
7
References
1
Deep Research
🔗

Mappings

MONDO
MONDO:0004950 gastric carcinoma
skos:closeMatch MONDO
Closest MONDO parent term available for metastatic gastric cancer.
⚙

Pathophysiology

5
E-Cadherin Loss and Diffuse Invasion
Reduced E-cadherin expression weakens epithelial adhesion, promotes infiltrative growth, and facilitates lymphatic, perineural, and peritoneal dissemination, particularly in diffuse-type gastric cancer.
epithelial to mesenchymal transition link ↑ INCREASED cell migration link ↑ INCREASED
Show evidence (1 reference)
PMID:41710815 SUPPORT Human Clinical
"Loss of E-cadherin expression in advanced tumor stages, higher nodal metastasis, and perineural invasion elucidate the role of E-cadherin as a useful prognostic immunohistochemical marker in gastrointestinal adenocarcinomas."
This supports a direct relationship between E-cadherin loss and invasive metastatic behavior.
Peritoneal Dissemination
Peritoneal spread in gastric cancer is reinforced by interactions between tumor cells and peritoneal mesothelial cells, helping establish invasive implants, serosal disease, and malignant ascites.
mesothelial cell link
positive regulation of cell migration link ↑ INCREASED
Show evidence (1 reference)
PMID:25088196 SUPPORT Model Organism
"The peritoneal dissemination of gastric cancer was significantly increased by mixing cancer cells and PMCs, and was suppressed by knockdown of Tks5 in PMCs."
Model data supports a direct role for mesothelial cell interactions in establishing peritoneal gastric cancer implants.
HER2 Signaling Subset
A clinically important gastric cancer subset that remains relevant in metastatic disease is driven by HER2 amplification and receptor tyrosine kinase signaling, particularly in intestinal-type tumors.
cell surface receptor protein tyrosine kinase signaling pathway link ↑ INCREASED
Show evidence (1 reference)
PMID:15668283 SUPPORT Human Clinical
"HER-2/neu amplification is common in the intestinal type of gastric carcinoma, and it is associated with a poor outcome."
Human cohort data supports a clinically relevant HER2-amplified gastric cancer subset enriched in intestinal-type disease.
MSI-High Immune-Responsive Subset
MSI-high gastric cancers represent a minority of metastatic cases but have distinct mutational and immune biology with implications for checkpoint inhibitor sensitivity.
mismatch repair link ↓ DECREASED
Show evidence (1 reference)
PMID:37271124 SUPPORT Human Clinical
"Microsatellite instability (MSI) is an important prognostic molecular biomarker for gastric cancer (GC)."
This supports MSI as a biologically and clinically important gastric cancer state.
Angiogenesis and Metastatic Outgrowth
Peritoneal and distant outgrowth is reinforced by angiogenic support and reciprocal signaling with stromal compartments such as omental adipocytes.
angiogenesis link ↑ INCREASED
Show evidence (2 references)
PMID:32439934 SUPPORT In Vitro
"Conditioned media derived from OmAd (OmAd-CM) promoted the proliferation, migration and capacity to induce angiogenesis of GC cells through AKT phosphorylation and VEGFA overexpression, whereas silencing CXCL2 in OmAd cancelled OmAd-induced effects."
Coculture data shows stromal adipocyte signals can promote angiogenesis and migratory behavior in gastric cancer cells.
PMID:32439934 SUPPORT Model Organism
"In an orthotopic tumour model using SCID mice, omentectomy suppressed GC growth and peritoneal dissemination, and reduced serum levels of CXCL2."
Orthotopic mouse data links omental stromal support to metastatic outgrowth and peritoneal dissemination.
●

Phenotypes

4
Digestive 1
Ascites OCCASIONAL Ascites (HP:0001541)
Show evidence (1 reference)
PMID:16860627 SUPPORT Human Clinical
"Forty-five of 293 patients (15%) presented with ascites on preoperative CT."
In this advanced gastric cancer cohort, ascites was present in 15% of patients, directly supporting an OCCASIONAL frequency designation.
Constitutional 2
Abdominal pain FREQUENT Abdominal pain (HP:0002027)
Show evidence (1 reference)
PMID:18343948 PARTIAL Human Clinical
"Symptomatic response rates were 88.2, 76.9, 89.5, and 88.9% for abdominal pain, distention, anorexia and weight loss."
Abdominal pain was one of the tracked symptoms in an advanced/metastatic gastric cancer cohort, supporting it as a clinically relevant phenotype.
Fatigue VERY_FREQUENT Fatigue (HP:0012378)
Show evidence (1 reference)
PMID:29266530 PARTIAL Human Clinical
"The incidence of clinically relevant fatigue among patients with gastric cancer was 91.6%."
Human gastric cancer cohorts show fatigue is highly prevalent, supporting it as a clinically relevant phenotype.
Growth 1
Weight loss FREQUENT Weight loss (HP:0001824)
Show evidence (1 reference)
PMID:18343948 PARTIAL Human Clinical
"Symptomatic response rates were 88.2, 76.9, 89.5, and 88.9% for abdominal pain, distention, anorexia and weight loss."
Weight loss was one of the tracked symptoms in an advanced/metastatic gastric cancer cohort, supporting it as a clinically relevant phenotype.
🧬

Genetic Associations

4
CDH1 (Loss of expression or mutation)
Show evidence (1 reference)
PMID:25079317 SUPPORT Human Clinical
"CDH1 somatic mutations were enriched in the genomically stable subtype (37% of cases)."
TCGA data demonstrates CDH1 somatic mutations are enriched in the genomically stable (diffuse) subtype of gastric cancer.
ERBB2 (HER2) (Amplification)
Show evidence (1 reference)
PMID:25079317 SUPPORT Human Clinical
"Focal amplifications targeted oncogenes such as ERBB2, CCNE1, KRAS, MYC, EGFR, CDK6, GATA4, GATA6 and ZNF217."
TCGA data identifies ERBB2 as a recurrent focal amplification target in gastric cancer.
TP53 (Somatic mutation)
Show evidence (1 reference)
PMID:25079317 SUPPORT Human Clinical
"Among the CIN tumours, we observed TP53 mutations in 71% of tumours."
TCGA data shows TP53 mutations are highly prevalent (71%) in the chromosomal instability subtype of gastric cancer.
ARID1A (Somatic loss of function)
Show evidence (1 reference)
PMID:25079317 SUPPORT Human Clinical
"EBV-positive tumours had frequent ARID1A (55%) and BCOR (23%) mutations and only rare TP53 mutations."
TCGA data shows ARID1A mutations are particularly frequent in EBV-positive gastric cancers.
💊

Treatments

1
Zolbetuximab Plus CAPOX for CLDN18.2-Positive Disease
Action: targeted therapy Ontology label: Targeted Therapy NCIT:C93352
Agent: zolbetuximab ↗ capecitabine ↗ oxaliplatin ↗
Zolbetuximab added to capecitabine and oxaliplatin is a biomarker-selected first-line systemic therapy for CLDN18.2-positive, HER2-negative metastatic gastric or gastroesophageal junction adenocarcinoma.
Show evidence (1 reference)
DOI:10.1038/s41591-023-02465-7 SUPPORT Human Clinical
"Zolbetuximab plus CAPOX represents a potential new first-line therapy for patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or mG/GEJ adenocarcinoma."
The randomized phase 3 GLOW trial supports zolbetuximab plus CAPOX as a first-line treatment for the CLDN18.2-positive metastatic gastric/GEJ adenocarcinoma subset.
🌍

Environmental Factors

3
Helicobacter pylori infection
H. pylori remains a dominant upstream risk factor for many gastric cancers that later metastasize.
Show evidence (1 reference)
PMID:39004993 PARTIAL Other
"Gastric cancer is one of the major causes of cancer-related deaths worldwide, and infection with Helicobacter pylori and EBV, smoking and a salt-heavy diet have been shown to be risk factors for the development of gastric cancer."
This review abstract identifies H. pylori infection as an established upstream risk factor for gastric cancer, which precedes metastatic disease.
Smoking
Smoking contributes to gastric cancer risk and may worsen aggressive disease biology.
Show evidence (1 reference)
PMID:39004993 PARTIAL Other
"Gastric cancer is one of the major causes of cancer-related deaths worldwide, and infection with Helicobacter pylori and EBV, smoking and a salt-heavy diet have been shown to be risk factors for the development of gastric cancer."
This review abstract identifies smoking as an upstream gastric cancer risk factor that contributes to the primary disease from which metastases arise.
High-salt diet
High salt exposure can reinforce gastric mucosal injury and carcinogenesis.
Show evidence (1 reference)
PMID:39004993 PARTIAL Other
"Gastric cancer is one of the major causes of cancer-related deaths worldwide, and infection with Helicobacter pylori and EBV, smoking and a salt-heavy diet have been shown to be risk factors for the development of gastric cancer."
This review abstract identifies salt-heavy diet as an upstream gastric cancer risk factor that contributes to the primary disease from which metastases arise.
{ }

Source YAML

click to show 
name: Metastatic Gastric Cancer
creation_date: '2026-03-28T21:35:00Z'
updated_date: '2026-05-10T10:59:02Z'
description: >-
  Metastatic gastric cancer is advanced gastric adenocarcinoma with dissemination
  to
  peritoneum, liver, distant lymph nodes, lung, bone, and less commonly brain.
  Peritoneal spread is a defining pattern, especially in diffuse and E-cadherin-deficient
  disease. Metastatic competence is shaped by loss of epithelial adhesion, HER2 pathway
  activation in a subset, microsatellite instability in an immune-responsive subset,
  and
  angiogenic and stromal remodeling.
categories:
- Gastrointestinal Cancer
- Metastatic Cancer
- Solid Tumor
parents:
- gastric carcinoma
disease_term:
  preferred_term: metastatic gastric carcinoma
  term:
    id: MONDO:0004950
    label: gastric carcinoma
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0004950
      label: gastric carcinoma
    mapping_predicate: skos:closeMatch
    mapping_source: MONDO
    mapping_justification: Closest MONDO parent term available for metastatic gastric cancer.
prevalence:
- population: Clinical metastatic gastric adenocarcinoma cohort
  percentage: 4
  notes: Reported 5-year survival in a national cM1 gastric adenocarcinoma cohort.
  evidence:
  - reference: PMID:34389165
    reference_title: "Palliative gastrectomy for metastatic gastric adenocarcinoma: A national population-based cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The median survival was 6.1 months, and 5-year survival was 4% in the entire cohort.
    explanation: This provides a survival estimate for metastatic gastric adenocarcinoma.
pathophysiology:
- name: E-Cadherin Loss and Diffuse Invasion
  description: >-
    Reduced E-cadherin expression weakens epithelial adhesion, promotes infiltrative
    growth, and facilitates lymphatic, perineural, and peritoneal dissemination,
    particularly in diffuse-type gastric cancer.
  evidence:
  - reference: PMID:41710815
    reference_title: "E-Cadherin Immunohistochemical Expression in Gastrointestinal Adenocarcinomas and Its Association With Histological and Prognostic Parameters."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Loss of E-cadherin expression in advanced tumor stages, higher nodal metastasis, and perineural invasion elucidate the role of E-cadherin as a useful prognostic immunohistochemical marker in gastrointestinal adenocarcinomas.
    explanation: This supports a direct relationship between E-cadherin loss and invasive metastatic behavior.
  biological_processes:
  - preferred_term: epithelial to mesenchymal transition
    modifier: INCREASED
    term:
      id: GO:0001837
      label: epithelial to mesenchymal transition
  - preferred_term: cell migration
    modifier: INCREASED
    term:
      id: GO:0016477
      label: cell migration
- name: Peritoneal Dissemination
  description: >-
    Peritoneal spread in gastric cancer is reinforced by interactions between tumor
    cells
    and peritoneal mesothelial cells, helping establish invasive implants, serosal
    disease,
    and malignant ascites.
  cell_types:
  - preferred_term: mesothelial cell
    term:
      id: CL:0000077
      label: mesothelial cell
  evidence:
  - reference: PMID:25088196
    reference_title: "Tks5 activation in mesothelial cells creates invasion front of peritoneal carcinomatosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The peritoneal dissemination of gastric cancer was significantly increased by mixing cancer cells and PMCs, and was suppressed by knockdown of Tks5 in PMCs."
    explanation: Model data supports a direct role for mesothelial cell interactions in establishing peritoneal gastric cancer implants.
  biological_processes:
  - preferred_term: positive regulation of cell migration
    modifier: INCREASED
    term:
      id: GO:0030335
      label: positive regulation of cell migration
- name: HER2 Signaling Subset
  description: >-
    A clinically important gastric cancer subset that remains relevant in metastatic
    disease
    is driven by HER2 amplification and receptor tyrosine kinase signaling, particularly
    in intestinal-type tumors.
  evidence:
  - reference: PMID:15668283
    reference_title: "Amplification of HER-2 in gastric carcinoma: association with Topoisomerase IIalpha gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HER-2/neu amplification is common in the intestinal type of gastric carcinoma, and it is associated with a poor outcome."
    explanation: Human cohort data supports a clinically relevant HER2-amplified gastric cancer subset enriched in intestinal-type disease.
  biological_processes:
  - preferred_term: cell surface receptor protein tyrosine kinase signaling pathway
    modifier: INCREASED
    term:
      id: GO:0007169
      label: cell surface receptor protein tyrosine kinase signaling pathway
- name: MSI-High Immune-Responsive Subset
  description: >-
    MSI-high gastric cancers represent a minority of metastatic cases but have distinct
    mutational and immune biology with implications for checkpoint inhibitor sensitivity.
  evidence:
  - reference: PMID:37271124
    reference_title: "Performance of Immunohistochemical and Molecular Methods in Detecting Microsatellite Instability in Gastric Cancer: A Multicenter Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Microsatellite instability (MSI) is an important prognostic molecular biomarker for gastric cancer (GC).
    explanation: This supports MSI as a biologically and clinically important gastric cancer state.
  biological_processes:
  - preferred_term: mismatch repair
    modifier: DECREASED
    term:
      id: GO:0006298
      label: mismatch repair
- name: Angiogenesis and Metastatic Outgrowth
  description: >-
    Peritoneal and distant outgrowth is reinforced by angiogenic support and reciprocal
    signaling with stromal compartments such as omental adipocytes.
  evidence:
  - reference: PMID:32439934
    reference_title: "Omental adipocytes promote peritoneal metastasis of gastric cancer through the CXCL2-VEGFA axis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Conditioned media derived from OmAd (OmAd-CM) promoted the proliferation, migration and capacity to induce angiogenesis of GC cells through AKT phosphorylation and VEGFA overexpression, whereas silencing CXCL2 in OmAd cancelled OmAd-induced effects."
    explanation: Coculture data shows stromal adipocyte signals can promote angiogenesis and migratory behavior in gastric cancer cells.
  - reference: PMID:32439934
    reference_title: "Omental adipocytes promote peritoneal metastasis of gastric cancer through the CXCL2-VEGFA axis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In an orthotopic tumour model using SCID mice, omentectomy suppressed GC growth and peritoneal dissemination, and reduced serum levels of CXCL2."
    explanation: Orthotopic mouse data links omental stromal support to metastatic outgrowth and peritoneal dissemination.
  biological_processes:
  - preferred_term: angiogenesis
    modifier: INCREASED
    term:
      id: GO:0001525
      label: angiogenesis
phenotypes:
- category: Gastrointestinal
  name: Abdominal pain
  frequency: FREQUENT
  description: Abdominal pain is common with locally advanced and metastatic gastric cancer.
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
  evidence:
  - reference: PMID:18343948
    reference_title: "Phase II clinical trial of advanced and metastatic gastric cancer based on continuous infusion of 5-fluorouracil combined with epirubicin and oxaliplatin."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Symptomatic response rates were 88.2, 76.9, 89.5, and 88.9% for abdominal pain, distention, anorexia and weight loss."
    explanation: Abdominal pain was one of the tracked symptoms in an advanced/metastatic gastric cancer cohort, supporting it as a clinically relevant phenotype.
- category: Constitutional
  name: Weight loss
  frequency: FREQUENT
  description: Weight loss reflects tumor burden, poor intake, and catabolism.
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss
  evidence:
  - reference: PMID:18343948
    reference_title: "Phase II clinical trial of advanced and metastatic gastric cancer based on continuous infusion of 5-fluorouracil combined with epirubicin and oxaliplatin."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Symptomatic response rates were 88.2, 76.9, 89.5, and 88.9% for abdominal pain, distention, anorexia and weight loss."
    explanation: Weight loss was one of the tracked symptoms in an advanced/metastatic gastric cancer cohort, supporting it as a clinically relevant phenotype.
- category: Constitutional
  name: Fatigue
  frequency: VERY_FREQUENT
  description: Fatigue is prevalent in gastric cancer and is often worsened by advanced disease burden.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:29266530
    reference_title: "Resilience and positive affect contribute to lower cancer-related fatigue among Chinese patients with gastric cancer."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "The incidence of clinically relevant fatigue among patients with gastric cancer was 91.6%."
    explanation: Human gastric cancer cohorts show fatigue is highly prevalent, supporting it as a clinically relevant phenotype.
- category: Gastrointestinal
  name: Ascites
  frequency: OCCASIONAL
  description: Malignant ascites is a clinically important manifestation of peritoneal dissemination.
  phenotype_term:
    preferred_term: Ascites
    term:
      id: HP:0001541
      label: Ascites
  evidence:
  - reference: PMID:16860627
    reference_title: "Clinical and diagnostic significance of preoperative computed tomography findings of ascites in patients with advanced gastric cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Forty-five of 293 patients (15%) presented with ascites on preoperative CT."
    explanation: In this advanced gastric cancer cohort, ascites was present in 15% of patients, directly supporting an OCCASIONAL frequency designation.
genetic:
- name: CDH1
  association: Loss of expression or mutation
  evidence:
  - reference: PMID:25079317
    reference_title: "Comprehensive molecular characterization of gastric adenocarcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CDH1 somatic mutations were enriched in the genomically stable subtype (37% of cases)."
    explanation: "TCGA data demonstrates CDH1 somatic mutations are enriched in the genomically stable (diffuse) subtype of gastric cancer."
  notes: CDH1 loss weakens cell-cell adhesion and promotes diffuse invasion and peritoneal spread.
- name: ERBB2 (HER2)
  association: Amplification
  evidence:
  - reference: PMID:25079317
    reference_title: "Comprehensive molecular characterization of gastric adenocarcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Focal amplifications targeted oncogenes such as ERBB2, CCNE1, KRAS, MYC, EGFR, CDK6, GATA4, GATA6 and ZNF217."
    explanation: "TCGA data identifies ERBB2 as a recurrent focal amplification target in gastric cancer."
  notes: HER2 amplification defines a targetable metastatic subset with strong RTK signaling.
- name: TP53
  association: Somatic mutation
  evidence:
  - reference: PMID:25079317
    reference_title: "Comprehensive molecular characterization of gastric adenocarcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among the CIN tumours, we observed TP53 mutations in 71% of tumours."
    explanation: "TCGA data shows TP53 mutations are highly prevalent (71%) in the chromosomal instability subtype of gastric cancer."
  notes: TP53 alteration is common in advanced gastric cancer and promotes genomic instability.
- name: ARID1A
  association: Somatic loss of function
  evidence:
  - reference: PMID:25079317
    reference_title: "Comprehensive molecular characterization of gastric adenocarcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EBV-positive tumours had frequent ARID1A (55%) and BCOR (23%) mutations and only rare TP53 mutations."
    explanation: "TCGA data shows ARID1A mutations are particularly frequent in EBV-positive gastric cancers."
  notes: ARID1A loss is recurrent in gastric cancer, most frequently in EBV-positive (55%) and genomically stable subtypes per TCGA. In the EBV-positive context, it co-occurs with immune features including PD-L1 amplification.
environmental:
- name: Helicobacter pylori infection
  notes: H. pylori remains a dominant upstream risk factor for many gastric cancers that later metastasize.
  evidence:
  - reference: PMID:39004993
    reference_title: "[Advances in the application of intragastric flora in the diagnosis and treatment of gastric cancer]."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "Gastric cancer is one of the major causes of cancer-related deaths worldwide, and infection with Helicobacter pylori and EBV, smoking and a salt-heavy diet have been shown to be risk factors for the development of gastric cancer."
    explanation: This review abstract identifies H. pylori infection as an established upstream risk factor for gastric cancer, which precedes metastatic disease.
- name: Smoking
  notes: Smoking contributes to gastric cancer risk and may worsen aggressive disease biology.
  evidence:
  - reference: PMID:39004993
    reference_title: "[Advances in the application of intragastric flora in the diagnosis and treatment of gastric cancer]."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "Gastric cancer is one of the major causes of cancer-related deaths worldwide, and infection with Helicobacter pylori and EBV, smoking and a salt-heavy diet have been shown to be risk factors for the development of gastric cancer."
    explanation: This review abstract identifies smoking as an upstream gastric cancer risk factor that contributes to the primary disease from which metastases arise.
- name: High-salt diet
  notes: High salt exposure can reinforce gastric mucosal injury and carcinogenesis.
  evidence:
  - reference: PMID:39004993
    reference_title: "[Advances in the application of intragastric flora in the diagnosis and treatment of gastric cancer]."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "Gastric cancer is one of the major causes of cancer-related deaths worldwide, and infection with Helicobacter pylori and EBV, smoking and a salt-heavy diet have been shown to be risk factors for the development of gastric cancer."
    explanation: This review abstract identifies salt-heavy diet as an upstream gastric cancer risk factor that contributes to the primary disease from which metastases arise.
notes: >-
  Peritoneal dissemination is a key metastatic route in gastric cancer, particularly
  in
  diffuse and CDH1-disrupted disease. Liver metastasis is also common, while HER2-positive
  and MSI-high subsets define biologically distinct metastatic states.
treatments:
- name: Zolbetuximab Plus CAPOX for CLDN18.2-Positive Disease
  description: Zolbetuximab added to capecitabine and oxaliplatin is a biomarker-selected first-line systemic therapy for CLDN18.2-positive, HER2-negative metastatic gastric or gastroesophageal junction adenocarcinoma.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: zolbetuximab
      term:
        id: NCIT:C85475
        label: Zolbetuximab
    - preferred_term: capecitabine
      term:
        id: CHEBI:31348
        label: capecitabine
    - preferred_term: oxaliplatin
      term:
        id: CHEBI:31941
        label: oxaliplatin
  evidence:
  - reference: DOI:10.1038/s41591-023-02465-7
    reference_title: 'Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Zolbetuximab plus CAPOX represents a potential new first-line therapy for patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or mG/GEJ adenocarcinoma.
    explanation: The randomized phase 3 GLOW trial supports zolbetuximab plus CAPOX as a first-line treatment for the CLDN18.2-positive metastatic gastric/GEJ adenocarcinoma subset.
references:
- reference: DOI:10.1002/ags3.70041
  title: 'Essential Updates 2023/2024: Recent Advances of Multimodal Approach in Patients for Gastric Cancer'
  found_in:
  - Metastatic_Gastric_Cancer-deep-research-falcon.md
  findings:
  - statement: Gastric cancer remains a major global health burden, especially in East Asia.
    supporting_text: Gastric cancer remains a major global health burden, especially in East Asia.
    evidence:
    - reference: DOI:10.1002/ags3.70041
      reference_title: 'Essential Updates 2023/2024: Recent Advances of Multimodal Approach in Patients for Gastric Cancer'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Gastric cancer remains a major global health burden, especially in East Asia.
      explanation: Deep research cited this publication as relevant literature for Metastatic Gastric Cancer.
- reference: DOI:10.1007/s10120-024-01479-5
  title: 'International consensus on the management of metastatic gastric cancer: step by step in the foggy landscape'
  found_in:
  - Metastatic_Gastric_Cancer-deep-research-falcon.md
  findings:
  - statement: Many gastric cancer patients in Western countries are diagnosed as metastatic with a median overall survival of less than twelve months using standard chemotherapy.
    supporting_text: Many gastric cancer patients in Western countries are diagnosed as metastatic with a median overall survival of less than twelve months using standard chemotherapy.
    evidence:
    - reference: DOI:10.1007/s10120-024-01479-5
      reference_title: 'International consensus on the management of metastatic gastric cancer: step by step in the foggy landscape'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Many gastric cancer patients in Western countries are diagnosed as metastatic with a median overall survival of less than twelve months using standard chemotherapy.
      explanation: Deep research cited this publication as relevant literature for Metastatic Gastric Cancer.
- reference: DOI:10.1038/s41591-023-02465-7
  title: 'Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial'
  found_in:
  - Metastatic_Gastric_Cancer-deep-research-falcon.md
  findings:
  - statement: There is an urgent need for first-line treatment options for patients with human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma.
    supporting_text: There is an urgent need for first-line treatment options for patients with human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma.
    evidence:
    - reference: DOI:10.1038/s41591-023-02465-7
      reference_title: 'Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: There is an urgent need for first-line treatment options for patients with human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma.
      explanation: Deep research cited this publication as relevant literature for Metastatic Gastric Cancer.
- reference: DOI:10.1056/nejmoa2503119
  title: Trastuzumab Deruxtecan or Ramucirumab plus Paclitaxel in Gastric Cancer
  found_in:
  - Metastatic_Gastric_Cancer-deep-research-falcon.md
  findings:
  - statement: Trastuzumab Deruxtecan or Ramucirumab plus Paclitaxel in Gastric Cancer
    supporting_text: Trastuzumab Deruxtecan or Ramucirumab plus Paclitaxel in Gastric Cancer
- reference: DOI:10.1186/s12967-024-05512-0
  title: Paired organoids from primary gastric cancer and lymphatic metastasis are useful for personalized medicine
  found_in:
  - Metastatic_Gastric_Cancer-deep-research-falcon.md
  findings:
  - statement: Paired organoids from primary gastric cancer and lymphatic metastasis are useful for personalized medicine
    supporting_text: Paired organoids from primary gastric cancer and lymphatic metastasis are useful for personalized medicine
- reference: DOI:10.20892/j.issn.2095-3941.2024.0159
  title: Global, regional, and national burden of early-onset gastric cancer
  found_in:
  - Metastatic_Gastric_Cancer-deep-research-falcon.md
  findings:
  - statement: The burden of gastric cancer (GC) across different age groups needs updating.
    supporting_text: The burden of gastric cancer (GC) across different age groups needs updating.
    evidence:
    - reference: DOI:10.20892/j.issn.2095-3941.2024.0159
      reference_title: Global, regional, and national burden of early-onset gastric cancer
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The burden of gastric cancer (GC) across different age groups needs updating.
      explanation: Deep research cited this publication as relevant literature for Metastatic Gastric Cancer.
- reference: DOI:10.3390/cancers16233960
  title: Circulating Tumor DNA (ctDNA) Dynamics Predict Early Response to Treatment in Metastasized Gastroesophageal Cancer (mGEC) After 2 Weeks of Systemic Treatment
  found_in:
  - Metastatic_Gastric_Cancer-deep-research-falcon.md
  findings:
  - statement: mGEC is associated with poor overall survival (OS) of approximately 4–10 months.
    supporting_text: mGEC is associated with poor overall survival (OS) of approximately 4–10 months.
    evidence:
    - reference: DOI:10.3390/cancers16233960
      reference_title: Circulating Tumor DNA (ctDNA) Dynamics Predict Early Response to Treatment in Metastasized Gastroesophageal Cancer (mGEC) After 2 Weeks of Systemic Treatment
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: mGEC is associated with poor overall survival (OS) of approximately 4–10 months.
      explanation: Deep research cited this publication as relevant literature for Metastatic Gastric Cancer.
📚

References & Deep Research

References

7
DOI:10.1002/ags3.70041
Essential Updates 2023/2024: Recent Advances of Multimodal Approach in Patients for Gastric Cancer
1 finding
Gastric cancer remains a major global health burden, especially in East Asia.
"Gastric cancer remains a major global health burden, especially in East Asia."
Show evidence (1 reference)
DOI:10.1002/ags3.70041 SUPPORT Human Clinical
"Gastric cancer remains a major global health burden, especially in East Asia."
Deep research cited this publication as relevant literature for Metastatic Gastric Cancer.
DOI:10.1007/s10120-024-01479-5
International consensus on the management of metastatic gastric cancer: step by step in the foggy landscape
1 finding
Many gastric cancer patients in Western countries are diagnosed as metastatic with a median overall survival of less than twelve months using standard chemotherapy.
"Many gastric cancer patients in Western countries are diagnosed as metastatic with a median overall survival of less than twelve months using standard chemotherapy."
Show evidence (1 reference)
DOI:10.1007/s10120-024-01479-5 SUPPORT Other
"Many gastric cancer patients in Western countries are diagnosed as metastatic with a median overall survival of less than twelve months using standard chemotherapy."
Deep research cited this publication as relevant literature for Metastatic Gastric Cancer.
DOI:10.1038/s41591-023-02465-7
Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial
1 finding
There is an urgent need for first-line treatment options for patients with human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma.
"There is an urgent need for first-line treatment options for patients with human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma."
Show evidence (1 reference)
DOI:10.1038/s41591-023-02465-7 SUPPORT Human Clinical
"There is an urgent need for first-line treatment options for patients with human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma."
Deep research cited this publication as relevant literature for Metastatic Gastric Cancer.
DOI:10.1056/nejmoa2503119
Trastuzumab Deruxtecan or Ramucirumab plus Paclitaxel in Gastric Cancer
1 finding
Trastuzumab Deruxtecan or Ramucirumab plus Paclitaxel in Gastric Cancer
"Trastuzumab Deruxtecan or Ramucirumab plus Paclitaxel in Gastric Cancer"
DOI:10.1186/s12967-024-05512-0
Paired organoids from primary gastric cancer and lymphatic metastasis are useful for personalized medicine
1 finding
Paired organoids from primary gastric cancer and lymphatic metastasis are useful for personalized medicine
"Paired organoids from primary gastric cancer and lymphatic metastasis are useful for personalized medicine"
DOI:10.20892/j.issn.2095-3941.2024.0159
Global, regional, and national burden of early-onset gastric cancer
1 finding
The burden of gastric cancer (GC) across different age groups needs updating.
"The burden of gastric cancer (GC) across different age groups needs updating."
Show evidence (1 reference)
DOI:10.20892/j.issn.2095-3941.2024.0159 SUPPORT Human Clinical
"The burden of gastric cancer (GC) across different age groups needs updating."
Deep research cited this publication as relevant literature for Metastatic Gastric Cancer.
DOI:10.3390/cancers16233960
Circulating Tumor DNA (ctDNA) Dynamics Predict Early Response to Treatment in Metastasized Gastroesophageal Cancer (mGEC) After 2 Weeks of Systemic Treatment
1 finding
mGEC is associated with poor overall survival (OS) of approximately 4–10 months.
"mGEC is associated with poor overall survival (OS) of approximately 4–10 months."
Show evidence (1 reference)
DOI:10.3390/cancers16233960 SUPPORT Computational
"mGEC is associated with poor overall survival (OS) of approximately 4–10 months."
Deep research cited this publication as relevant literature for Metastatic Gastric Cancer.

Deep Research

1
Falcon ▸
1. Disease Information
Edison Scientific Literature 28 citations 2026-05-10T00:15:24.683329

1. Disease Information

Definition and overview

Metastatic gastric cancer refers to gastric cancer (predominantly adenocarcinoma) that is unresectable and/or has spread beyond the stomach and regional lymph nodes to distant sites, corresponding clinically to stage IV disease. In the biomarker-selected phase 3 literature for advanced disease, populations are frequently described as “locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma”. (shah2023zolbetuximabpluscapox pages 1-2, shah2023zolbetuximabpluscapox pages 2-3)

A central current concept is that systemic therapy is the backbone of management for metastatic disease, with biomarker testing used to select targeted and immunotherapy options. (shoda2025essentialupdates20232024 pages 4-4)

Synonyms and alternative names

Common terms used in recent trials and consensus documents include: - Advanced gastric cancer, unresectable gastric cancer, stage IV gastric cancer - Metastatic gastric/GEJ adenocarcinoma, advanced G/GEJ adenocarcinoma (shah2023zolbetuximabpluscapox pages 1-2, morgagni2024internationalconsensuson pages 1-2)

Data source type

The information summarized here is derived from aggregated disease-level resources (randomized phase 3 trials, cohort analyses, meta-analyses, and international Delphi consensus statements), not from individual EHRs. (shitara2025trastuzumabderuxtecanor pages 1-6, shah2023zolbetuximabpluscapox pages 1-2, morgagni2024internationalconsensuson pages 1-2)

2. Etiology

Primary causes and causal factors (high-level)

Metastatic gastric cancer arises from primary gastric malignancy and subsequent dissemination (hematogenous, lymphatic, or transcoelomic/peritoneal), shaped by tumor intrinsic biology and tumor microenvironment interactions. A large fraction of global gastric cancer burden is linked to modifiable exposures (e.g., smoking and high-sodium diets) in population-level assessments; however, this run prioritized metastatic-disease trials and GLOBOCAN burden statistics, not detailed causal attribution modeling. (tan2024globalregionaland pages 1-2, tan2024globalregionaland pages 2-3)

Risk factors (captured in retrieved evidence)

Recent overview literature reiterates commonly recognized risk factors for gastric cancer including smoking, alcohol consumption, Helicobacter pylori infection, and Epstein–Barr virus (EBV). (tan2024globalregionaland pages 3-4)

Protective factors

Direct quantitative protective effect estimates were not retrieved in this run’s evidence set (gap).

Gene–environment interactions

A 2024 genetics review highlights that “interactions between genetic and environmental traits” influence gastric cell behavior towards neoplastic transformation and progression, consistent with the multifactorial nature of the disease. (tan2024globalregionaland pages 3-4)

3. Phenotypes (clinical presentation)

Metastatic gastric cancer commonly produces systemic and GI symptoms and signs; the retrieved evidence in this run is largely treatment-trial oriented and does not provide symptom frequency tables (gap). Clinically important phenotype concepts for structured annotation include:

Common symptom/sign phenotype suggestions (HPO)

  • Weight loss (HP:0001824)
  • Abdominal pain (HP:0002027)
  • Nausea (HP:0002018) and vomiting (HP:0002013) — also prominent treatment-related AEs in CLDN18.2 antibody trials (shah2023zolbetuximabpluscapox pages 6-7, shah2023zolbetuximabpluscapox pages 3-4)
  • Anemia (HP:0001903)
  • Early satiety (HP:0031190)
  • Gastrointestinal bleeding (HP:0002239)
  • Ascites (HP:0001541), particularly in peritoneal metastasis contexts (morgagni2024internationalconsensuson pages 17-18)

Quality of life impact

Consensus and trial literature emphasize that advanced/metastatic GI cancers have poor outcomes and symptom burden; specific validated QoL instrument data were not extracted in the retrieved snippets (gap). (morgagni2024internationalconsensuson pages 1-2)

4. Genetic/Molecular Information (clinically actionable biomarkers)

Biomarkers used in real-world metastatic gastric cancer care

Recent gastric cancer treatment updates emphasize that biomarkers such as HER2, PD‑L1, and MSI are integrated into treatment selection. (shoda2025essentialupdates20232024 pages 4-4)

Key biomarker concepts supported by retrieved evidence:

1) CLDN18.2 (Claudin 18 isoform 2) - CLDN18.2 is described as a tight-junction protein with gastric lineage specificity and as a therapeutic target in biomarker-selected metastatic disease. (shah2023zolbetuximabpluscapox pages 1-2) - In the GLOW phase 3 screening experience, 42.9% (729/1701) of tumors met the CLDN18.2 positivity cutoff used for enrollment. (shah2023zolbetuximabpluscapox pages 1-2)

2) HER2 (ERBB2) positivity - HER2 defines a major treatable subset of advanced gastric/GEJ adenocarcinoma; in metastatic treatment updates, HER2-targeted therapy is described as “critical” in the first-line setting. (shoda2025essentialupdates20232024 pages 4-4)

3) MSI‑H/dMMR and immunotherapy sensitivity - MSI subtype is recognized as clinically relevant because it has distinctive molecular features and tends to respond better to immune checkpoint inhibitors in clinical experience and synthesis literature. (morgagni2024internationalconsensuson pages 11-13)

4) PD‑L1 expression (CPS) - PD‑L1 combined positive score (CPS) is used in metastatic treatment algorithms, with certain approvals/benefit enrichment in higher CPS groups discussed in contemporary reviews. (shitara2023…advancedunresectable pages 2-2)

Somatic vs germline considerations

This run retrieved limited primary germline variant evidence specific to metastatic disease. However, gastric cancer genetics reviews note that germline CDH1/CTNNA1 underlie hereditary diffuse gastric cancer, which can progress to advanced disease. (tan2024globalregionaland pages 3-4)

5. Mechanism / Pathophysiology (metastasis-focused)

Conceptual causal chain (metastatic progression)

A clinically important mechanistic distinction in metastatic gastric cancer is between: - “Polymetastatic” high-burden stage IV disease (systemic therapy, palliative intent predominates) vs. - Low-burden “oligometastatic” disease where selected patients may be considered for multimodality approaches including surgery after response to systemic therapy.

The 2024 international consensus explicitly defines oligometastatic gastric cancer as a “dynamic” state characterized by metastases that “either regresses or remains stable in response to systemic treatment” and restricts eligible sites to para-aortic nodes, liver, lung, and peritoneum, excluding bone metastases. (morgagni2024internationalconsensuson pages 1-2)

Mechanistic processes implicated in dissemination and outgrowth that are useful for structured annotation (not exhaustively supported by the current evidence snippets but standard in the field): - EMT / epithelial–mesenchymal plasticity (GO:0001837 epithelial to mesenchymal transition) - Angiogenesis (GO:0001525) - Immune evasion / T‑cell dysfunction (GO:0045087 innate immune response; GO:0002682 regulation of immune system process)

Cell types (CL) for annotation (examples)

  • Gastric epithelial cell / tumor epithelial cell (CL:0000066 epithelial cell)
  • Tumor-associated macrophage / macrophage (CL:0000235)
  • Cancer-associated fibroblast (CAF; approximate mapping: CL:0000057 fibroblast)
  • T cell (CL:0000084)

6. Anatomical Structures Affected

Primary site

  • Stomach (UBERON:0000945)

Metastatic sites (evidence-supported conceptual set)

The oligometastatic consensus explicitly includes metastases to: - Liver (UBERON:0002107) - Lung (UBERON:0002048) - Peritoneum (UBERON:0002358) - Para-aortic lymph nodes / para-aortic nodal stations (e.g., station 16a2/16b1) (UBERON:0002509 lymph node; regional qualifier required) (morgagni2024internationalconsensuson pages 1-2)

7. Temporal Development

Stage IV heterogeneity: oligometastatic vs polymetastatic

The 2024 international consensus provides operational thresholds for oligometastatic disease at diagnosis/after induction systemic therapy: - Para-aortic stations: notably 16a2 or 16b1 - Up to three technically resectable liver metastases - Lung: three unilateral or two bilateral metastases - Peritoneal carcinomatosis: PCI ≤ 6 (morgagni2024internationalconsensuson pages 1-2)

This establishes a temporal concept: labeling as oligometastatic is recommended after assessing response/stability on systemic therapy, supporting treatment sequencing where systemic therapy precedes local consolidative interventions. (morgagni2024internationalconsensuson pages 1-2)

8. Inheritance and Population (epidemiology)

Global burden (GLOBOCAN 2022; published analysis 2024)

A 2024 analysis using GLOBOCAN 2022 reports: - 968,000 new gastric cancer cases worldwide in 2022 - 660,000 deaths worldwide in 2022 - Age-standardized rates: ASIR 9.2 per 100,000 and ASMR 6.1 per 100,000 - Male predominance (males >627,000 cases; males 65% of fatalities) - East Asia accounted for 53.8% of cases and 48.2% of deaths (GLOBOCAN 2022 distribution) (tan2024globalregionaland pages 1-2, tan2024globalregionaland pages 2-3, tan2024globalregionaland pages 3-4)

Publication details: Tan et al., Cancer Biology & Medicine, published online 2024-08-07, DOI/URL https://doi.org/10.20892/j.issn.2095-3941.2024.0159. (tan2024globalregionaland pages 1-2)

9. Diagnostics (metastatic disease workup and biomarker testing)

Biomarker testing in practice

Recent multimodal update reviews highlight the practical integration of biomarker testing—HER2, PD‑L1, MSI, and emerging modalities including ctDNA—into treatment planning. (shoda2025essentialupdates20232024 pages 4-4)

CLDN18.2 testing

The GLOW phase 3 trial operationalizes CLDN18.2 positivity by immunohistochemistry thresholds; in that trial program, CLDN18.2 biomarker selection was feasible at scale (42.9% positive among screened tumors). (shah2023zolbetuximabpluscapox pages 1-2)

ctDNA as an emerging diagnostic/monitoring tool (advanced disease)

A 2024 prospective monitoring study in metastasized gastroesophageal cancer reported that ctDNA dynamics early during therapy (2-week change) were associated with subsequent radiographic response assessment and with overall survival/progression-free survival differences, supporting a role for liquid biopsy in early response monitoring. (morgagni2024internationalconsensuson pages 11-13)

Abstract quote (ctDNA early dynamics): the authors conclude “ctDNA is a promising additional biomarker allowing for early evaluation of response to treatment…” (published 2024-11; DOI/URL https://doi.org/10.3390/cancers16233960). (morgagni2024internationalconsensuson pages 11-13)

10. Outcome / Prognosis

Baseline prognosis on chemotherapy alone

Contemporary background in the zolbetuximab phase 3 development literature states that standard platinum–fluoropyrimidine first-line chemotherapy yields “a median overall survival duration of about 1 year” in advanced/unresectable or metastatic gastric/GEJ adenocarcinoma. (shitara2023…advancedunresectable pages 2-2)

11. Treatment (standard of care and recent developments)

Key concepts: biomarker-driven first- and later-line therapy

Current practice is increasingly biomarker driven, with therapies selected based on HER2, PD‑L1, MSI/dMMR, and now CLDN18.2; this is emphasized in 2023/2024 multimodal update syntheses. (shoda2025essentialupdates20232024 pages 4-4)

2023–2025 landmark advances with quantitative data

A structured summary is provided in the table artifact below.

Item (trial/guideline/consensus) Year (pub date month/year) Population/biomarker Regimen/Intervention Key efficacy results (median OS, PFS, HR, ORR) Key safety notes Registry/URL
GLOW (Nature Medicine) Jul 2023 CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric/GEJ adenocarcinoma; 507 randomized; CLDN18.2 positivity in 729/1,701 screened tumors (42.9%) Zolbetuximab + CAPOX vs placebo + CAPOX, first line Median PFS 8.21 vs 6.80 months (HR 0.687, 95% CI 0.544-0.866; P=0.0007); median OS 14.39 vs 12.16 months (HR 0.771, 95% CI 0.615-0.965; P=0.0118); ORR 42.5% vs 40.3% Grade ≥3 TEAEs 72.8% vs 69.9%; nausea 68.5% vs 50.2%; vomiting 66.1% vs 30.9%; most prominent TEAEs were nausea/vomiting, mainly cycle 1, managed with antiemetics, dose interruption, and infusion-rate adjustment (shah2023zolbetuximabpluscapox pages 1-2, shah2023zolbetuximabpluscapox pages 2-3, shah2023zolbetuximabpluscapox pages 6-7, shah2023zolbetuximabpluscapox pages 7-8, shah2023zolbetuximabpluscapox pages 3-4) NCT03653507; https://doi.org/10.1038/s41591-023-02465-7
DESTINY-Gastric04 (NEJM) Jul 2025 HER2-positive metastatic gastric cancer or GEJ adenocarcinoma confirmed on tumor biopsy after progression on trastuzumab-based therapy; 494 randomized Trastuzumab deruxtecan vs ramucirumab + paclitaxel, second line Median OS 14.7 vs 11.4 months (HR 0.70, 95% CI 0.55-0.90; P=0.0044); median PFS 6.7 vs 5.6 months (HR 0.74; P=0.0074); ORR 44.3% vs 29.1% (P=0.0006) (shitara2025trastuzumabderuxtecanor pages 1-6, shitara2025trastuzumabderuxtecanor media d6d76080) Drug-related AEs any grade 93.0% vs 91.4%; grade ≥3 50.0% vs 54.1%; adjudicated drug-related ILD/pneumonitis 13.9% vs 1.3%; in T-DXd arm ILD/pneumonitis mostly grade 1-2 with one grade 3 and no fatal cases reported in figure/text summary (shitara2025trastuzumabderuxtecanor pages 1-6, shitara2025trastuzumabderuxtecanor media d6d76080) NCT04704934; https://doi.org/10.1056/NEJMoa2503119
GIRCG international consensus on oligometastatic gastric cancer (Gastric Cancer) Apr 2024 Metastatic gastric cancer; oligometastatic subset defined dynamically after response/stability on systemic therapy Delphi-based international consensus for defining oligometastatic disease and surgery selection Not a treatment efficacy trial; consensus definition: eligible oligometastatic sites restricted to para-aortic nodal stations, liver, lung, and peritoneum; excludes bone metastases; criteria include para-aortic stations 16a2 or 16b1, up to 3 technically resectable liver metastases, 3 unilateral or 2 bilateral lung metastases, and peritoneal carcinomatosis with PCI ≤6; positive cytology considered oligometastatic by 55% only if converted negative after chemotherapy; surgery should aim for R0 on all disease volume (morgagni2024internationalconsensuson pages 16-17, morgagni2024internationalconsensuson pages 1-2, morgagni2024internationalconsensuson pages 17-18) Not applicable; consensus addresses selection/strategy rather than adverse events (morgagni2024internationalconsensuson pages 1-2, morgagni2024internationalconsensuson pages 17-18) https://doi.org/10.1007/s10120-024-01479-5

Table: This table summarizes key 2023-2025 landmark metastatic gastric/GEJ adenocarcinoma trials and the 2024 international oligometastatic gastric cancer consensus. It highlights biomarker-selected populations, core efficacy results, major safety issues, and actionable consensus criteria relevant to current practice.

11.1 CLDN18.2 targeting (zolbetuximab)

The phase 3 GLOW trial provides the key quantitative evidence for a CLDN18.2-targeted regimen in first-line HER2-negative advanced disease.

Direct abstract quote (GLOW): “GLOW met the primary endpoint of progression-free survival (median, 8.21 months versus 6.80 months with zolbetuximab versus placebo; hazard ratio (HR) = 0.687… P = 0.0007) and key secondary endpoint of overall survival (median, 14.39 months versus 12.16 months; HR = 0.771… P = 0.0118).” (published 2023-07, DOI/URL https://doi.org/10.1038/s41591-023-02465-7). (shah2023zolbetuximabpluscapox pages 1-2)

A consistent real-world implementation point is the high incidence of early-cycle nausea/vomiting with zolbetuximab-containing regimens, which is repeatedly emphasized in trial reports and supporting synthesis; mitigation is via antiemetics and infusion modifications. (shah2023zolbetuximabpluscapox pages 6-7, shah2023zolbetuximabpluscapox pages 3-4)

MAXO suggestions (treatments): - Antineoplastic drug therapy (MAXO:0000746) - Monoclonal antibody therapy (MAXO:0000748) - Combination chemotherapy (MAXO:0000058)

11.2 HER2 targeting with antibody–drug conjugate (trastuzumab deruxtecan)

DESTINY‑Gastric04 (phase 3) demonstrates improved outcomes for second-line HER2-positive metastatic gastric/GEJ cancer when compared with ramucirumab+paclitaxel.

Direct abstract quote (DESTINY-Gastric04): “overall survival was significantly longer with trastuzumab deruxtecan than with ramucirumab plus paclitaxel (median, 14.7 vs. 11.4 months; hazard ratio for death, 0.70… P = 0.004).” (published 2025-07, DOI/URL https://doi.org/10.1056/NEJMoa2503119). (shitara2025trastuzumabderuxtecanor pages 1-6)

A key toxicity requiring expert monitoring is trastuzumab deruxtecan–associated interstitial lung disease/pneumonitis, reported at 13.9% (T‑DXd) vs 1.3% in the control arm in this phase 3 trial. (shitara2025trastuzumabderuxtecanor pages 1-6, shitara2025trastuzumabderuxtecanor media d6d76080)

MAXO suggestions: - Antibody-drug conjugate therapy (MAXO:0001453) - HER2-targeted therapy (MAXO mapping may depend on local MAXO release; conceptually “targeted therapy”)

11.3 Selected expert opinion: defining candidates for aggressive local therapy

The 2024 international consensus provides a framework for selecting oligometastatic patients for R0-intent resection after systemic therapy response, using explicit thresholds such as PCI ≤ 6 for peritoneal disease and limiting sites (excluding bone). This consensus is intended to reduce practice variability in a “foggy landscape” where strong randomized evidence is limited for surgery in stage IV disease. (morgagni2024internationalconsensuson pages 1-2)

12. Prevention

This run did not retrieve primary prevention intervention trials or guideline statements specific to gastric cancer prevention at population scale (gap).

13. Other Species / Natural Disease

Not addressed by the retrieved evidence set (gap).

14. Model Organisms / Model Systems and Advanced Technologies

Patient-derived organoids and metastasis-paired organoids

A 2024 translational organoid study established paired organoid lines from primary gastric cancer and matched lymph node metastasis and reported that metastasis-derived organoids showed transcriptional enrichment for epithelial–mesenchymal transition and angiogenesis and increased migration/invasion and pro-angiogenesis features. (morgagni2024internationalconsensuson pages 17-18)

Abstract quote (paired organoids): “Compared to [organoids] from primary cancer, upregulated genes of [metastatic lymph node organoids] were enriched in pathways of epithelial-mesenchymal transition and angiogenesis …” (published 2024-08, DOI/URL https://doi.org/10.1186/s12967-024-05512-0). (morgagni2024internationalconsensuson pages 17-18)

Single-cell and spatial methods

Single-cell RNA sequencing and spatial transcriptomics are described as enabling higher-resolution mapping of tumor microenvironment heterogeneity and intercellular interactions relevant to individualized therapy in gastric cancer. (morgagni2024internationalconsensuson pages 8-9)

Key gaps and limitations of this evidence set (for knowledge base completion)

1) Formal disease identifiers (MONDO, MeSH, ICD‑10/ICD‑11) were not extracted from the retrieved texts in this run. 2) Phenotype frequencies (percentages for symptoms, signs, lab abnormalities) were not present in the trial-oriented sources retrieved. 3) Prevention: population-level eradication/screening trials and guideline statements were not retrieved here, although they are critical for prevention sections. 4) Comprehensive molecular variant catalog (somatic alteration frequencies, allele frequencies, ClinVar variant classes) was not assembled in the retrieved evidence.

URLs (primary sources cited)

  • GLOW trial (zolbetuximab + CAPOX): https://doi.org/10.1038/s41591-023-02465-7 (published 2023-07). (shah2023zolbetuximabpluscapox pages 1-2)
  • DESTINY-Gastric04 (trastuzumab deruxtecan): https://doi.org/10.1056/NEJMoa2503119 (published 2025-07). (shitara2025trastuzumabderuxtecanor pages 1-6)
  • GLOBOCAN 2022 burden analysis: https://doi.org/10.20892/j.issn.2095-3941.2024.0159 (published online 2024-08-07). (tan2024globalregionaland pages 1-2)
  • Oligometastatic consensus (GIRCG): https://doi.org/10.1007/s10120-024-01479-5 (published 2024-04). (morgagni2024internationalconsensuson pages 1-2)
  • ctDNA dynamics in metastasized gastroesophageal cancer: https://doi.org/10.3390/cancers16233960 (published 2024-11). (morgagni2024internationalconsensuson pages 11-13)
  • Paired primary/metastasis organoids: https://doi.org/10.1186/s12967-024-05512-0 (published 2024-08). (morgagni2024internationalconsensuson pages 17-18)

References

  1. (shah2023zolbetuximabpluscapox pages 1-2): Manish A. Shah, Kohei Shitara, Jaffer A. Ajani, Yung-Jue Bang, Peter Enzinger, David Ilson, Florian Lordick, Eric Van Cutsem, Javier Gallego Plazas, Jing Huang, Lin Shen, Sang Cheul Oh, Patrapim Sunpaweravong, Hwoei Fen Soo Hoo, Haci Mehmet Turk, Mok Oh, Jung Wook Park, Diarmuid Moran, Pranob Bhattacharya, Ahsan Arozullah, and Rui-Hua Xu. Zolbetuximab plus capox in cldn18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 glow trial. Nature Medicine, 29:2133-2141, Jul 2023. URL: https://doi.org/10.1038/s41591-023-02465-7, doi:10.1038/s41591-023-02465-7. This article has 642 citations and is from a highest quality peer-reviewed journal.

  2. (shah2023zolbetuximabpluscapox pages 2-3): Manish A. Shah, Kohei Shitara, Jaffer A. Ajani, Yung-Jue Bang, Peter Enzinger, David Ilson, Florian Lordick, Eric Van Cutsem, Javier Gallego Plazas, Jing Huang, Lin Shen, Sang Cheul Oh, Patrapim Sunpaweravong, Hwoei Fen Soo Hoo, Haci Mehmet Turk, Mok Oh, Jung Wook Park, Diarmuid Moran, Pranob Bhattacharya, Ahsan Arozullah, and Rui-Hua Xu. Zolbetuximab plus capox in cldn18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 glow trial. Nature Medicine, 29:2133-2141, Jul 2023. URL: https://doi.org/10.1038/s41591-023-02465-7, doi:10.1038/s41591-023-02465-7. This article has 642 citations and is from a highest quality peer-reviewed journal.

  3. (shoda2025essentialupdates20232024 pages 4-4): Katsutoshi Shoda, Yoshihiko Kawaguchi, Suguru Maruyama, and Daisuke Ichikawa. Essential updates 2023/2024: recent advances of multimodal approach in patients for gastric cancer. Annals of Gastroenterological Surgery, May 2025. URL: https://doi.org/10.1002/ags3.70041, doi:10.1002/ags3.70041. This article has 2 citations and is from a peer-reviewed journal.

  4. (morgagni2024internationalconsensuson pages 1-2): Paolo Morgagni, Maria Bencivenga, Fatima Carneiro, Stefano Cascinu, Sarah Derks, Maria Di Bartolomeo, Claire Donohoe, Clarisse Eveno, Suzanne Gisbertz, Peter Grimminger, Ines Gockel, Heike Grabsch, Paulo Kassab, Rupert Langer, Sara Lonardi, Marco Maltoni, Sheraz Markar, Markus Moehler, Daniele Marrelli, Maria Antonietta Mazzei, Davide Melisi, Carlo Milandri, Paul Stefan Moenig, Bianca Mostert, Gianni Mura, Wojciech Polkowski, John Reynolds, Luca Saragoni, Mark I. Van Berge Henegouwen, Richard Van Hillegersberg, Michael Vieth, Giuseppe Verlato, Lorena Torroni, Bas Wijnhoven, Guido Alberto Massimo Tiberio, Han-Kwang Yang, Franco Roviello, and Giovanni de Manzoni. International consensus on the management of metastatic gastric cancer: step by step in the foggy landscape. Gastric Cancer, 27:649-671, Apr 2024. URL: https://doi.org/10.1007/s10120-024-01479-5, doi:10.1007/s10120-024-01479-5. This article has 28 citations and is from a domain leading peer-reviewed journal.

  5. (shitara2025trastuzumabderuxtecanor pages 1-6): Kohei Shitara, Eric Van Cutsem, Mahmut Gümüş, Sara Lonardi, Christelle de la Fouchardière, Clélia Coutzac, Jeroen Dekervel, Daniel Hochhauser, Lin Shen, Wasat Mansoor, Bo Liu, Lorenzo Fornaro, Min-Hee Ryu, Jeeyun Lee, Cátia Faustino, Jean-Philippe Metges, Josep Tabernero, Fábio Franke, Yelena Y. Janjigian, Fabricio Souza, Lori Jukofsky, Yumin Zhao, Takahiro Kamio, Aziz Zaanan, and Filippo Pietrantonio. Trastuzumab deruxtecan or ramucirumab plus paclitaxel in gastric cancer. New England Journal of Medicine, 393:336-348, Jul 2025. URL: https://doi.org/10.1056/nejmoa2503119, doi:10.1056/nejmoa2503119. This article has 88 citations and is from a highest quality peer-reviewed journal.

  6. (tan2024globalregionaland pages 1-2): Nuopei Tan, Hongliang Wu, Maomao Cao, Fan Yang, Xinxin Yan, Siyi He, Mengdi Cao, Shaoli Zhang, Yi Teng, Qianru Li, Jiachen Wang, Changfa Xia, and Wanqing Chen. Global, regional, and national burden of early-onset gastric cancer. Cancer Biology & Medicine, 21:1-12, Aug 2024. URL: https://doi.org/10.20892/j.issn.2095-3941.2024.0159, doi:10.20892/j.issn.2095-3941.2024.0159. This article has 54 citations.

  7. (tan2024globalregionaland pages 2-3): Nuopei Tan, Hongliang Wu, Maomao Cao, Fan Yang, Xinxin Yan, Siyi He, Mengdi Cao, Shaoli Zhang, Yi Teng, Qianru Li, Jiachen Wang, Changfa Xia, and Wanqing Chen. Global, regional, and national burden of early-onset gastric cancer. Cancer Biology & Medicine, 21:1-12, Aug 2024. URL: https://doi.org/10.20892/j.issn.2095-3941.2024.0159, doi:10.20892/j.issn.2095-3941.2024.0159. This article has 54 citations.

  8. (tan2024globalregionaland pages 3-4): Nuopei Tan, Hongliang Wu, Maomao Cao, Fan Yang, Xinxin Yan, Siyi He, Mengdi Cao, Shaoli Zhang, Yi Teng, Qianru Li, Jiachen Wang, Changfa Xia, and Wanqing Chen. Global, regional, and national burden of early-onset gastric cancer. Cancer Biology & Medicine, 21:1-12, Aug 2024. URL: https://doi.org/10.20892/j.issn.2095-3941.2024.0159, doi:10.20892/j.issn.2095-3941.2024.0159. This article has 54 citations.

  9. (shah2023zolbetuximabpluscapox pages 6-7): Manish A. Shah, Kohei Shitara, Jaffer A. Ajani, Yung-Jue Bang, Peter Enzinger, David Ilson, Florian Lordick, Eric Van Cutsem, Javier Gallego Plazas, Jing Huang, Lin Shen, Sang Cheul Oh, Patrapim Sunpaweravong, Hwoei Fen Soo Hoo, Haci Mehmet Turk, Mok Oh, Jung Wook Park, Diarmuid Moran, Pranob Bhattacharya, Ahsan Arozullah, and Rui-Hua Xu. Zolbetuximab plus capox in cldn18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 glow trial. Nature Medicine, 29:2133-2141, Jul 2023. URL: https://doi.org/10.1038/s41591-023-02465-7, doi:10.1038/s41591-023-02465-7. This article has 642 citations and is from a highest quality peer-reviewed journal.

  10. (shah2023zolbetuximabpluscapox pages 3-4): Manish A. Shah, Kohei Shitara, Jaffer A. Ajani, Yung-Jue Bang, Peter Enzinger, David Ilson, Florian Lordick, Eric Van Cutsem, Javier Gallego Plazas, Jing Huang, Lin Shen, Sang Cheul Oh, Patrapim Sunpaweravong, Hwoei Fen Soo Hoo, Haci Mehmet Turk, Mok Oh, Jung Wook Park, Diarmuid Moran, Pranob Bhattacharya, Ahsan Arozullah, and Rui-Hua Xu. Zolbetuximab plus capox in cldn18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 glow trial. Nature Medicine, 29:2133-2141, Jul 2023. URL: https://doi.org/10.1038/s41591-023-02465-7, doi:10.1038/s41591-023-02465-7. This article has 642 citations and is from a highest quality peer-reviewed journal.

  11. (morgagni2024internationalconsensuson pages 17-18): Paolo Morgagni, Maria Bencivenga, Fatima Carneiro, Stefano Cascinu, Sarah Derks, Maria Di Bartolomeo, Claire Donohoe, Clarisse Eveno, Suzanne Gisbertz, Peter Grimminger, Ines Gockel, Heike Grabsch, Paulo Kassab, Rupert Langer, Sara Lonardi, Marco Maltoni, Sheraz Markar, Markus Moehler, Daniele Marrelli, Maria Antonietta Mazzei, Davide Melisi, Carlo Milandri, Paul Stefan Moenig, Bianca Mostert, Gianni Mura, Wojciech Polkowski, John Reynolds, Luca Saragoni, Mark I. Van Berge Henegouwen, Richard Van Hillegersberg, Michael Vieth, Giuseppe Verlato, Lorena Torroni, Bas Wijnhoven, Guido Alberto Massimo Tiberio, Han-Kwang Yang, Franco Roviello, and Giovanni de Manzoni. International consensus on the management of metastatic gastric cancer: step by step in the foggy landscape. Gastric Cancer, 27:649-671, Apr 2024. URL: https://doi.org/10.1007/s10120-024-01479-5, doi:10.1007/s10120-024-01479-5. This article has 28 citations and is from a domain leading peer-reviewed journal.

  12. (morgagni2024internationalconsensuson pages 11-13): Paolo Morgagni, Maria Bencivenga, Fatima Carneiro, Stefano Cascinu, Sarah Derks, Maria Di Bartolomeo, Claire Donohoe, Clarisse Eveno, Suzanne Gisbertz, Peter Grimminger, Ines Gockel, Heike Grabsch, Paulo Kassab, Rupert Langer, Sara Lonardi, Marco Maltoni, Sheraz Markar, Markus Moehler, Daniele Marrelli, Maria Antonietta Mazzei, Davide Melisi, Carlo Milandri, Paul Stefan Moenig, Bianca Mostert, Gianni Mura, Wojciech Polkowski, John Reynolds, Luca Saragoni, Mark I. Van Berge Henegouwen, Richard Van Hillegersberg, Michael Vieth, Giuseppe Verlato, Lorena Torroni, Bas Wijnhoven, Guido Alberto Massimo Tiberio, Han-Kwang Yang, Franco Roviello, and Giovanni de Manzoni. International consensus on the management of metastatic gastric cancer: step by step in the foggy landscape. Gastric Cancer, 27:649-671, Apr 2024. URL: https://doi.org/10.1007/s10120-024-01479-5, doi:10.1007/s10120-024-01479-5. This article has 28 citations and is from a domain leading peer-reviewed journal.

  13. (shitara2023…advancedunresectable pages 2-2): K Shitara, F Lordick, YJ Bang, P Enzinger, and D Ilson. … advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (spotlight): a multicentre, randomised, double-blind, phase 3 trial. Unknown journal, 2023.

  14. (shah2023zolbetuximabpluscapox pages 7-8): Manish A. Shah, Kohei Shitara, Jaffer A. Ajani, Yung-Jue Bang, Peter Enzinger, David Ilson, Florian Lordick, Eric Van Cutsem, Javier Gallego Plazas, Jing Huang, Lin Shen, Sang Cheul Oh, Patrapim Sunpaweravong, Hwoei Fen Soo Hoo, Haci Mehmet Turk, Mok Oh, Jung Wook Park, Diarmuid Moran, Pranob Bhattacharya, Ahsan Arozullah, and Rui-Hua Xu. Zolbetuximab plus capox in cldn18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 glow trial. Nature Medicine, 29:2133-2141, Jul 2023. URL: https://doi.org/10.1038/s41591-023-02465-7, doi:10.1038/s41591-023-02465-7. This article has 642 citations and is from a highest quality peer-reviewed journal.

  15. (shitara2025trastuzumabderuxtecanor media d6d76080): Kohei Shitara, Eric Van Cutsem, Mahmut Gümüş, Sara Lonardi, Christelle de la Fouchardière, Clélia Coutzac, Jeroen Dekervel, Daniel Hochhauser, Lin Shen, Wasat Mansoor, Bo Liu, Lorenzo Fornaro, Min-Hee Ryu, Jeeyun Lee, Cátia Faustino, Jean-Philippe Metges, Josep Tabernero, Fábio Franke, Yelena Y. Janjigian, Fabricio Souza, Lori Jukofsky, Yumin Zhao, Takahiro Kamio, Aziz Zaanan, and Filippo Pietrantonio. Trastuzumab deruxtecan or ramucirumab plus paclitaxel in gastric cancer. New England Journal of Medicine, 393:336-348, Jul 2025. URL: https://doi.org/10.1056/nejmoa2503119, doi:10.1056/nejmoa2503119. This article has 88 citations and is from a highest quality peer-reviewed journal.

  16. (morgagni2024internationalconsensuson pages 16-17): Paolo Morgagni, Maria Bencivenga, Fatima Carneiro, Stefano Cascinu, Sarah Derks, Maria Di Bartolomeo, Claire Donohoe, Clarisse Eveno, Suzanne Gisbertz, Peter Grimminger, Ines Gockel, Heike Grabsch, Paulo Kassab, Rupert Langer, Sara Lonardi, Marco Maltoni, Sheraz Markar, Markus Moehler, Daniele Marrelli, Maria Antonietta Mazzei, Davide Melisi, Carlo Milandri, Paul Stefan Moenig, Bianca Mostert, Gianni Mura, Wojciech Polkowski, John Reynolds, Luca Saragoni, Mark I. Van Berge Henegouwen, Richard Van Hillegersberg, Michael Vieth, Giuseppe Verlato, Lorena Torroni, Bas Wijnhoven, Guido Alberto Massimo Tiberio, Han-Kwang Yang, Franco Roviello, and Giovanni de Manzoni. International consensus on the management of metastatic gastric cancer: step by step in the foggy landscape. Gastric Cancer, 27:649-671, Apr 2024. URL: https://doi.org/10.1007/s10120-024-01479-5, doi:10.1007/s10120-024-01479-5. This article has 28 citations and is from a domain leading peer-reviewed journal.

  17. (morgagni2024internationalconsensuson pages 8-9): Paolo Morgagni, Maria Bencivenga, Fatima Carneiro, Stefano Cascinu, Sarah Derks, Maria Di Bartolomeo, Claire Donohoe, Clarisse Eveno, Suzanne Gisbertz, Peter Grimminger, Ines Gockel, Heike Grabsch, Paulo Kassab, Rupert Langer, Sara Lonardi, Marco Maltoni, Sheraz Markar, Markus Moehler, Daniele Marrelli, Maria Antonietta Mazzei, Davide Melisi, Carlo Milandri, Paul Stefan Moenig, Bianca Mostert, Gianni Mura, Wojciech Polkowski, John Reynolds, Luca Saragoni, Mark I. Van Berge Henegouwen, Richard Van Hillegersberg, Michael Vieth, Giuseppe Verlato, Lorena Torroni, Bas Wijnhoven, Guido Alberto Massimo Tiberio, Han-Kwang Yang, Franco Roviello, and Giovanni de Manzoni. International consensus on the management of metastatic gastric cancer: step by step in the foggy landscape. Gastric Cancer, 27:649-671, Apr 2024. URL: https://doi.org/10.1007/s10120-024-01479-5, doi:10.1007/s10120-024-01479-5. This article has 28 citations and is from a domain leading peer-reviewed journal.