Stomach Adenocarcinoma (STAD)

Overview

Stomach adenocarcinoma (STAD) is a malignant epithelial tumor of the gastric mucosa. On OncoTree it is a child of esophagogastric adenocarcinoma (EGC), alongside ESCA and GEJ. TCGA molecular subtypes include EBV-positive, MSI, genomically stable (GS), and chromosomal instability (CIN). Signet ring cell/diffuse-type histology is prevalent in early-onset gastric cancer.

Cohorts in the corpus

  • Part of the combined 1,123-patient EGC cohort (219 early-onset age <50, 904 average-onset age >=50) at MSK, 2005–2018. Gastric primary site was more common in early-onset patients (64% vs. 44%, P<0.0001). MSK-IMPACT profiling in 902 patients; data deposited as egc_msk_2023. PMID:37699004
  • Part of the 37-patient phase II trial cohort of HER2-positive metastatic esophageal/GEJ/gastric adenocarcinoma. Dataset: egc_trap_ccr_msk_2023. PMID:37406106
  • NCI-N87 (HER2+, STAD cell line): preclinical ADC radiosensitization model — a single 0.25 nmol T-DM1 dose + 2.5 Gy × 3 fractions increased tumor doubling time from 9 to 113 days in xenograft. PMID:27698471

Recurrent alterations

  • CDH1 — mutations enriched in early-onset gastric cancer (12% vs. 6%, P=0.004, Q=0.03); consistent with signet ring cell/diffuse-type enrichment. PMID:37699004
  • ERBB2 — amplification; HER2 overexpression is the primary therapeutic target; associated with improved survival (HR=0.65, P=0.01). PMID:37699004 PMID:37406106
  • CDKN2A — enriched in average-onset EGC (22% vs. 11%, P<0.001, Q=0.011); associated with worse survival (HR=1.55, P<0.001). PMID:37699004
  • KRAS — oncogenic alterations; identified as a resistance mechanism to HER2-directed therapy. PMID:37406106
  • See also EGC for shared EGC alterations.
  • ERBB2 (HER2) surface overexpression in NCI-N87 STAD cells: T-DM1 IC50 <1 nM; >100-fold more sensitive than HER2− controls. PMID:27698471
  • SMARCA4 inactivating mutations occur in 5–8% of stomach adenocarcinoma (TCGA data) PMID:24658004
  • Narrative review of familial non-hereditary gastric cancer (FNHGC) in STAD: ~10% of GC shows familial clustering with only 1–3% explained by known high-penetrance syndromes; FIGC tumors enriched for MSI (~38%), somatic TP53, BRCA2, ATM, and FHIT alterations; H. pylori eradication reduced GC incidence by 55% in family-history carriers PMID:24816255
  • TCGA multi-platform profiling of 295 primary gastric adenocarcinomas defines four molecular subtypes: EBV-positive (9%, PIK3CA mutations 80%, 9p24.1 JAK2/CD274/PDCD1LG2 amplification), MSI (22%, MLH1 hypermethylation), GS (20%, RHOA mutations 15%, CLDN18-ARHGAP fusions, CDH1 mutations 37%), and CIN (50%, TP53 71%, RTK amplifications); 76% of CIN tumors bear actionable focal amplifications of ERBB2, EGFR, KRAS, MET, or VEGFA PMID:25079317
  • WES of 78 primary gastric adenocarcinomas (294-patient pooled cohort) identified HiC (high-clonality) and LoC (low-clonality) subtypes; HiC tumors enriched for subclonal TP53, older onset, and significantly shorter survival (adjusted HR 4.69, P=0.0043); NRG1 or ERBB4 mutations in 11.6% and BRCA2 mutations in 5.8% of cases PMID:25583476.
  • TCGA integrated profiling added 77 new gastric adenocarcinomas (total 388) for comparison with esophageal carcinoma: chromosomally-unstable (CIN) gastric adenocarcinoma is molecularly indistinguishable from oesophageal adenocarcinoma; methylation gradient along the gastroesophageal axis shows proximal-to-distal hypermethylated-to-hypomethylated transition; MGMT/CHFR silencing enriched in proximal hypermethylated cluster PMID:28052061
  • In the MSK-IMPACT pan-cancer cohort, TP53 was significantly enriched in gastric cancer vs TCGA; MSI gastric tumors showed responses to immune checkpoint blockade; STAD was included among 62 principal tumor types profiled in msk_impact_2017. PMID:28481359
  • Stomach adenocarcinoma was among the cancer subtypes in the MSK EGC cohort (n=295, stage IV, MSK-IMPACT); the GS molecular subtype (34%) was enriched for diffuse histology (32% vs 9% in CIN, P=3e-5) and CDH1 mutations; TP53 mutation rate in the MSK metastatic cohort (73%) was higher than in TCGA (62%, q=0.11), consistent with metastatic enrichment PMID:29122777
  • Pan-cancer fusion study (9,624 TCGA samples) included STAD; ERBB2 fusions were detected in gastric tumors; WNK-family fusions also present in STAD PMID:29617662
  • Pan-cancer aneuploidy study placed STAD in the gastrointestinal arm-level cluster (alongside COAD, READ, PAAD); STAD is an exception to the positive aneuploidy–mutation-rate correlation, driven by MSI/POLE cases PMID:29622463

Subtypes

  • Signet ring cell/diffuse-type histology: 3-fold more common in early-onset STAD (31% vs. 9%, P<0.0001); associated with genomically stable TCGA subtype (31% vs. 18% in early-onset). PMID:37699004
  • Early-onset STAD associated with lower TMB (3.3 vs. 4.9 mut/Mb, P<0.001), lower fraction genome altered, and higher peritoneal metastasis rate (40.3% vs. 23.8%, P<0.001). PMID:37699004
  • MSI-high less frequent in early-onset (2% vs. 7%, P=0.003). PMID:37699004

Therapeutic landscape

  • Pembrolizumab + trastuzumab + CAPOX in HER2-positive metastatic gastric/GEJ/esophageal cancer: median PFS 13 months, OS 27 months, ORR 89% (n=37). PMID:37406106
  • Uniform HER2 IHC 3+ predicts longer PFS (15 vs. 8.5 months, P=0.004); HER2 IHC heterogeneity and ERBB2 amplification status are key biomarkers. PMID:37406106
  • 35% of early-onset patients were initially treated for an alternative diagnosis, highlighting need for earlier gastric cancer recognition. PMID:37699004
  • ado-trastuzumab emtansine (T-DM1) + IR produced superior long-term tumor control in HER2+ NCI-N87 STAD xenografts vs. trastuzumab or IR alone (tumor doubling time 9 → 113 days); HER2− tumor controls showed no T-DM1 benefit. Authors propose T-DM1 + chemoradiotherapy clinical evaluation for HER2+ locally advanced gastric cancer. PMID:27698471

Sources

  • PMID:37406106 — Determinants of Survival with Combined HER2 and PD-1 Blockade in Metastatic Esophagogastric Cancer (Clinical Cancer Research, 2023)
  • PMID:37699004 — Clinical and molecular characteristics of early-onset vs average-onset esophagogastric cancer (JNCI, 2024)
  • PMID:27698471

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