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Gastric Cancer (C16.0)

Gastric cancer, or stomach cancer, is a malignant disease arising from the lining of the stomach, most commonly from the gastric mucosal epithelium. The vast majority of cases are classified as gastric adenocarcinoma, although less common subtypes such as gastrointestinal stromal tumors (GISTs), lymphomas, and neuroendocrine tumors can also occur. Gastric cancer remains a major global health burden, particularly in East Asia, Eastern Europe, and parts of South America, despite declining incidence in some regions. Risk factors include chronic Helicobacter pylori infection infection, chronic gastritis, smoking, high-salt diets, obesity, genetic predisposition, and certain hereditary cancer syndromes. The disease often develops gradually through a multistep progression involving chronic inflammation, atrophic gastritis, intestinal metaplasia, dysplasia, and eventual malignant transformation. Symptoms may initially be nonspecific and include epigastric discomfort, early satiety, nausea, weight loss, anemia, or gastrointestinal bleeding, leading many patients to present with advanced disease. Molecularly, gastric cancer is highly heterogeneous and may involve abnormalities in pathways such as HER2, VEGF, MET, FGFR2, PD-L1, microsatellite instability (MSI), and claudin 18.2 expression, which increasingly guide targeted and immunotherapeutic treatment strategies. Diagnosis is established primarily through upper endoscopy with biopsy, while treatment depends on stage and may include surgical resection, chemotherapy, radiation therapy, targeted therapy, immunotherapy, or combinations thereof.

Causes

The etiology of gastric cancer is multifactorial and involves a complex interaction between chronic inflammation, environmental exposures, infectious agents, and genetic susceptibility. The most important risk factor worldwide is chronic infection with Helicobacter pylori infection, which induces persistent gastritis and promotes a progressive sequence of mucosal injury, atrophic gastritis, intestinal metaplasia, dysplasia, and ultimately malignant transformation. Additional environmental contributors include smoking, heavy alcohol use, diets high in smoked or salted foods, nitrosamine exposure, and obesity. Certain hereditary syndromes, such as hereditary diffuse gastric cancer associated with CDH1 mutations, Lynch syndrome, and familial adenomatous polyposis, also increase risk. Chronic gastric inflammation from autoimmune gastritis or Epstein–Barr virus infection may further contribute to carcinogenesis. Over time, these factors drive accumulation of genetic and epigenetic alterations affecting oncogenic signaling pathways, cell adhesion, DNA repair, and immune regulation, ultimately leading to uncontrolled proliferation and invasive gastric malignancy.

Pathophysiology

The pathophysiology of gastric cancer involves a progressive sequence of chronic inflammation, mucosal injury, genetic alteration, and malignant transformation within the gastric epithelium. In many cases, persistent Helicobacter pylori infection induces chronic gastritis that damages the gastric mucosa and promotes a stepwise process known as the Correa cascade: chronic active gastritis progressing to atrophic gastritis, intestinal metaplasia, dysplasia, and ultimately adenocarcinoma. Ongoing inflammatory signaling generates oxidative stress, DNA damage, and epigenetic changes that disrupt normal cellular regulation. Molecular abnormalities commonly involve pathways controlling cell proliferation, apoptosis, angiogenesis, immune evasion, and cellular adhesion, including HER2 amplification, TP53 mutations, MET and FGFR2 activation, microsatellite instability, and loss of E-cadherin function in diffuse-type disease. As malignant cells proliferate, they invade through the gastric wall, stimulate angiogenesis, and may disseminate through lymphatic, hematogenous, or peritoneal spread. The biologic behavior of gastric cancer varies considerably depending on histologic subtype, molecular profile, and tumor microenvironment, contributing to its heterogeneous clinical presentation and treatment response.

Clinical features

The clinical features of gastric cancer are often nonspecific in the early stages, which contributes to delayed diagnosis and advanced presentation in many patients. Common initial symptoms include epigastric discomfort or pain, early satiety, bloating, nausea, anorexia, and unintentional weight loss. As the disease progresses, patients may develop dysphagia, persistent vomiting, gastrointestinal bleeding, iron deficiency anemia, fatigue, or melena due to mucosal ulceration and chronic blood loss. Advanced gastric cancer can produce palpable abdominal masses, ascites, jaundice, or metastatic manifestations such as supraclavicular lymphadenopathy (Virchow node), periumbilical nodules (Sister Mary Joseph nodule), or ovarian metastases (Krukenberg tumors). Diffuse-type gastric cancer may infiltrate the stomach wall extensively, producing a rigid “linitis plastica” appearance associated with impaired gastric distensibility and severe early satiety. Because symptoms frequently overlap with benign gastrointestinal disorders, clinical suspicion is particularly important in patients with risk factors or persistent upper gastrointestinal complaints.

Diagnosis

The diagnosis of gastric cancer is established primarily through upper gastrointestinal endoscopy with tissue biopsy, which allows direct visualization of suspicious gastric lesions and histopathologic confirmation of malignancy. During endoscopy, multiple biopsies are typically obtained to improve diagnostic accuracy and permit molecular testing for biomarkers such as HER2, PD-L1, microsatellite instability (MSI), mismatch repair deficiency, and claudin 18.2 expression, which may guide targeted or immunotherapeutic treatment. Imaging studies including contrast-enhanced CT scanning, endoscopic ultrasound, and PET/CT are used for staging and assessment of local invasion, lymph node involvement, and distant metastases. Laboratory findings may reveal iron deficiency anemia, occult gastrointestinal bleeding, or evidence of hepatic involvement in advanced disease. In some patients, diagnostic laparoscopy is performed to detect occult peritoneal spread not visible on imaging. Accurate staging is essential because treatment strategies differ substantially between localized, locally advanced, and metastatic gastric cancer.

Mechanism of action videos

Biological pathways

  • PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
  • p53 signaling pathway
  • TGF-beta signaling pathway
  • Gastric cancer
  • Epithelial cell signaling in Helicobacter pylori infection
  • Negative regulation of the PI3K/AKT network
  • Cell cycle
  • Adherens junction
  • Diseases of signal transduction by growth factor receptors and second messengers
  • Constitutive Signaling by Aberrant PI3K in Cancer
  • PI3K/AKT Signaling in Cancer
  • Signaling by ERBB2 KD Mutants
  • Signaling by ERBB2 in Cancer
  • Signaling by Receptor Tyrosine Kinases
  • Signaling by FGFR in disease
  • RAF/MAP kinase cascade
  • PIP3 activates AKT signaling
  • MAPK1/MAPK3 signaling
  • Signaling by ERBB2
  • ERBB2 Regulates Cell Motility
  • SHC1 events in ERBB2 signaling
  • Intracellular signaling by second messengers
  • MAPK family signaling cascades
  • Signaling by PTK6
  • ERBB2 Activates PTK6 Signaling
  • IRS-mediated signalling
  • IRS-related events triggered by IGF1R
  • Insulin receptor signalling cascade
  • IGF1R signaling cascade
  • Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)
  • Signal Transduction
  • Downregulation of ERBB2 signaling
  • Downstream signaling of activated FGFR2
  • Signaling by Insulin receptor
  • Signaling by FGFR
  • Transcriptional Regulation by VENTX
  • Regulation of Homotypic Cell-Cell Adhesion
  • SHC-mediated cascade:FGFR2
  • PI3K Cascade
  • FRS-mediated FGFR2 signaling

Clinical trials

  • A Phase III, Open-Label, Multicenter, Randomized, Parallel-Group Study to Evaluate the Efficacy and Safety of LM-108 in Combination With Toripalimab Versus Paclitaxel Injection as Second-Line Therapy for CCR8-Positive Locally Advanced or Metastatic Gastric Cancer/Gastroesophageal Junction Adenocarcinoma
  • Safety and Efficacy of Brodalumab in the Treatment of Immune-Related Adverse Events: A Pilot Study
  • Randomized Phase II/III Trial of 2nd Line Nivolumab + Paclitaxel + Ramucirumab Versus Paclitaxel + Ramucirumab in Patients With PD-L1 CPS >/= 1 Advanced Gastric and Esophageal Adenocarcinoma (PARAMUNE)
  • An Open-Label, Multi-Drug, Multi-Centre, Phase II Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Immunogenicity of Novel Combinations in Participants With Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma
  • ROSETTA Gastric-204: A Blinded, Randomized, Phase 2/3 Study of Pumitamig in Combination With Chemotherapy Versus Nivolumab in Combination With Chemotherapy in Participants With Previously Untreated Advanced or Metastatic Gastric, Gastroesophageal Junction, or Esophageal Adenocarcinoma
  • A Phase II Multicenter Trial of ESK981 in Patients With Select Solid Tumors
  • A Phase 1 Study Investigating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Antitumor Activity of BGB-B2033, Alone or in Combination With Tislelizumab With or Without Bevacizumab, in Participants With Selected Advanced or Metastatic Solid Tumors
  • A Dose Escalation and Dose Optimization Phase 1a/1b Study to Evaluate Safety, Tolerability and Dosimetry of Radioligand Therapy With LY4337713 in Adults With FAP-Positive Solid Tumors (FiREBOLT)
  • A Phase I/IIa First-in-Human Study of [212Pb]VMT-α-NET Targeted Alpha-Particle Therapy for Advanced SSTR2 Positive Tumors
  • A Randomized, Multicenter, Open-Label, Phase 2 Study of Givastomig (TJ033721) in Combination With Nivolumab and Chemotherapy Versus Nivolumab and Chemotherapy in Participants With Previously Untreated CLDN18.2 Positive and PD-1L Positive Locally Advanced or Metastatic Gastric, Esophageal, or Gastroesophageal Junction Adenocarcinoma
  • Conversion Surgery for Gastric Cancer With Peritoneal Metastases (CONVERGENCE)
  • DART: Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors
  • A Phase 3, Multicenter, 2-Arm Randomized, Open-Label Study of Trastuzumab Deruxtecan in Subjects With HER2-Positive Metastatic and/or Unresectable Gastric or Gastro-Esophageal Junction (GEJ) Adenocarcinoma Subjects Who Have Progressed on or After a Trastuzumab-Containing Regimen (DESTINY-Gastric04)
  • Phase 2 Study of Rogaratinib (BAY 1163877) in the Treatment of Patients With Sarcoma Harboring Alterations in Fibroblast Growth Factor Receptor (FGFR) 1-4 and SDH-Deficient Gastrointestinal Stromal Tumor (GIST)
  • A Randomized Phase II Study of Perioperative Atezolizumab +/- Chemotherapy in Resectable MSI-H/dMMR Gastric and Gastroesophageal Junction (GEJ) Cancer
  • Phase 1/1B Study of DS-8201a in Combination With ATR Inhibition (AZD6738) in Advanced Solid Tumors With HER2 Expression (DASH Trial)
  • Phase 1 Study of Trastuzumab Deruxtecan (DS-8201a) in Combination With Azenosertib (ZN-c3) in HER2-Expressing/Amplified Gastric/Gastroesophageal Junction Cancer and Other Solid Tumors
  • A Pharmacodynamics-Driven Trial of Talazoparib, an Oral PARP Inhibitor, in Patients With Advanced Solid Tumors and Aberrations in Genes Involved in DNA Damage Response
  • A Randomized, Double-blind, Multicenter Phase III Trial of Adebrelimab (SHR-1316) Plus S-1 and Oxaliplatin (SOX) Versus Placebo Plus S-1 and Oxaliplatin in the Perioperative Treatment of Resectable Gastric or Gastroesophageal Junction Cancer
  • A Global First-in-Human Study in NSCLC, HNSCC, and Solid Tumors With Azirkitug as a Single Agent and in Combination(s) With Budigalimab, Bevacizumab, or Telisotuzumab Adizutecan
  • A Phase II Study of the Non-Covalent BTK Inhibitor Nemtabrutinib in Combination With the CD20 Monoclonal Antibody Rituximab in Patients With Marginal Zone Lymphoma
  • Molecular Analysis for Therapy Choice (MATCH)
  • A Phase 1b/2 Multicenter, Open-label, Dose-escalation and Dose-expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Immunogenicity, and Antitumor Activity of Trastuzumab Deruxtecan (T-DXd) Monotherapy and Combinations in Adult Participants With HER2-expressing Gastric Cancer (DESTINY-Gastric-03)
  • A Phase 1a/1b, Open-label, Multicenter Trial Investigating the Safety, Tolerability, and Preliminary Anti-neoplastic Activity of S095029 (Anti-NKG2A) as Monotherapy and in Combination With Sym021 (Anti-PD-1) in Patients With Advanced Solid Tumor Malignancies Followed by an Expansion Part With Triplet Combinations of S095029 and Sym021 and an Anti-HER2 mAb or Anti-EGFR mAbs (Futuximab/Modotuximab) in Patients With Metastatic Gastric or Colorectal Cancers
  • A Randomized, Phase Ⅲ Study of Rilvegostomig in Combination With Fluoropyrimidine and Trastuzumab Deruxtecan Versus Trastuzumab, Chemotherapy, and Pembrolizumab for the First Line Treatment of HER2-positive Gastric Cancer (ARTEMIDE-Gastric01)
  • A Modular Phase I, Open-Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-tumour Activity of Ceralasertib in Combination With Cytotoxic Chemotherapy and/or DNA Damage Repair/Novel Anti-cancer Agents in Patients With Advanced Solid Malignancies.
  • A Multi-center, Open-label, Phase II Clinical Trial to Evaluate the Efficacy, Safety and Tolerability of Savolitinib in Treating Gastric Cancer and Esophagogastric Junction Adenocarcinoma Patients With MET Gene Amplifications
  • A Phase 1/2 Study of CBX-12 in Subjects With Advanced or Metastatic Refractory Solid Tumors
  • Efficacy and Safety of Beta-Blockers Combined With Neoadjuvant Immunotherapy for Locally Advanced Gastric Cancer: an Open-lable, Single-arm Study
  • GI-05: The Impact of Olanzapine Among Patients Receiving Neoadjuvant Chemotherapy for Gastric Cancer
  • A Phase 1 Study of Sigvotatug Vedotin in Advanced Solid Tumors
  • A Phase 1a/1b Study of BG-68501, a Selective CDK2 Inhibitor, in Participants With Advanced Solid Tumors
  • A Phase I-II, First-in-Human Study of SKB264 in Patients With Locally Advanced Unresectable /Metastatic Solid Tumors Who Are Refractory to Available Standard Therapies
  • An Open-Label, Single-Arm, Phase 2 Study to Evaluate the Efficacy and Safety of Tislelizumab Plus Chemotherapy in a First-Line Setting for Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Adenocarcinoma and Esophageal Squamous Cell Carcinoma in US Racial and Ethnic Minority Patients
  • A Phase 1 Study of IM-1617 in Participants With Advanced Malignancies
  • A Phase II, Multicenter, Open-label Study to Evaluate the Efficacy and Safety of Trastuzumab Deruxtecan (T-DXd, DS-8201a) as Monotherapy or in Combination With Anti-cancer Agents for the Treatment of Patients With Selected HER2-expressing Tumors (DESTINY PanTumor03)
  • A Phase Ia/Ib, Open Label, Multicenter, Dose-escalation Study to Evaluate the Safety, Pharmacokinetics, and Activity of Enzelkitug as a Single Agent and in Combination With Checkpoint Inhibitor in Patients With Locally Advanced or Metastatic Solid Tumors
  • A Cancer Research UK Phase I/II Trial to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-tumour Activity of UCB4594 Alone and in Combination With Anti-cancer Treatments in Participants With Advanced Malignancies
  • Perioperative Treatment in Resectable Gastric Cancer With Spartalizumab (PDR001) in Combination With Fluorouracil, Leucovorin, Oxaliplatin, and Docetaxel (FLOT): A Phase II Study (GASPAR)
  • Pilot Study of [68Ga]Ga-ABY-025 Imaging in Patients Undergoing Treatment With HER2-targeted Therapy

Therapeutic area: Oncology

Gastric Cancer (C16.0)