Esophagogastric Adenocarcinoma (EGC)

Overview

Esophagogastric adenocarcinoma (EGC) encompasses adenocarcinomas of the esophagus (ESCA), gastroesophageal junction (GEJ), and stomach (STAD). It is the parent concept on OncoTree for these three histologic sub-sites. EGC is among the most common gastrointestinal cancers worldwide and carries a poor prognosis in metastatic disease.

Cohorts in the corpus

  • 37 patients with HER2-positive metastatic EGC in a phase II trial of pembrolizumab + trastuzumab + chemotherapy (NCT02954536), plus 226 patients in the MSK retrospective cohort. Dataset: egc_trap_ccr_msk_2023. PMID:37406106
  • 1,123 patients (219 early-onset age <50, 904 average-onset age >=50) with EGC treated at MSK 2005–2018, somatic profiling via MSK-IMPACT in 902 patients. Data deposited as egc_msk_2023 in cBioPortal. PMID:37699004

Recurrent alterations

  • ERBB2 — amplification present in 88% of IHC 3+ vs. 36% of IHC 2+/heterogeneous tumors; associated with improved survival in multivariable analysis (HR=0.65, P=0.01); loss of HER2 expression was a major resistance mechanism (48% of progressing patients). PMID:37406106 PMID:37699004
  • TP53 — nearly all HER2-expressing EGC patients harbor TP53 mutations; highly correlated with ERBB2 amplification status. PMID:37406106
  • KRAS — oncogenic alterations associated with inferior PFS; identified as a resistance mechanism in escape lesions. PMID:37406106
  • MYC — alterations associated with inferior PFS on multivariable analysis. PMID:37406106
  • CDKN2A / CDKN2B — alterations associated with inferior PFS; enriched in average-onset disease (22% vs. 11%, P<0.001). PMID:37406106 PMID:37699004
  • CCNE1 — amplification enriched in early-onset EGC (16% vs. 7%, P=0.001); driven by chromosomal instability esophageal/GEJ subgroup. PMID:37699004
  • CDH1 — mutations enriched in early-onset EGC (12% vs. 6%, P=0.004); consistent with signet ring cell/diffuse-type enrichment. PMID:37699004
  • PIK3CA — present in >10% of patients; identified as a resistance mechanism. PMID:37406106
  • MET — co-amplification detected in ctDNA at progression; MET IHC expression confirmed in escape lesions. PMID:37406106
  • FGFR3-TACC3 — subclonal fusion identified at single-cell level by serial ctDNA; expanded on-treatment, implicating it as a resistance driver. PMID:37406106
  • Esophagogastric carcinoma / esophageal gastric adenocarcinoma was included in the MSK-IMPACT pan-cancer cohort (msk_impact_2017) spanning 62 principal tumor types; MSI gastric/esophageal tumors were among those showing responses to immune checkpoint blockade in the pan-cancer MSI analysis. PMID:28481359
  • Janjigian et al. prospectively profiled 295 stage-IV esophagogastric adenocarcinoma patients with MSK-IMPACT (341/410/468-gene panels); 53% had at least one actionable alteration; MSI-H tumors (3%) were chemotherapy-refractory but immunotherapy-sensitive; NGS-based ERBB2 amplification level predicted trastuzumab benefit better than IHC/FISH; HRD/LST did not predict platinum response PMID:29122777

Subtypes

  • Early-onset EGC (age <50): higher proportion of women (39% vs. 28%, P=0.002), gastric primary site (64% vs. 44%), signet ring cell/diffuse-type histology (31% vs. 9%), genomically stable TCGA subtype (31% vs. 18%), lower TMB (3.3 vs. 4.9 mut/Mb); CCNE1 and CDH1 enrichment. PMID:37699004
  • Average-onset EGC (age >=50): higher MSI-H frequency (7% vs. 2%), CDKN2A enrichment. PMID:37699004
  • Overall survival from metastasis did not differ between groups (median 22.7 vs. 22.1 months, P=0.78). PMID:37699004

Therapeutic landscape

  • Phase II trial of pembrolizumab + trastuzumab + CAPOX: median PFS 13 months, median OS 27 months, ORR 89% in 37 HER2-positive EGC patients. PMID:37406106
  • Uniform HER2 IHC 3+ expression, plasma ERBB2 amplification, and intense 89Zr-trastuzumab PET avidity predict durable benefit from pembrolizumab + trastuzumab + chemotherapy. PMID:37406106
  • Early ctDNA clearance (by 9 weeks) predicts longer PFS (HR 0.18; 95% CI 0.06–0.53; P=0.001). PMID:37406106
  • CCNE1 amplification in early-onset tumors is a potential target for CDK2 inhibitors. PMID:37699004
  • 35% of early-onset patients were initially treated for an alternative diagnosis, highlighting the need for increased clinician awareness. PMID:37699004

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:28481359

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