Adenocarcinoma of the Gastroesophageal Junction (GEJ)

Overview

Adenocarcinoma of the gastroesophageal junction (GEJ) arises at the junction of the esophagus and stomach. On OncoTree it is a child of esophagogastric adenocarcinoma (EGC), alongside ESCA and STAD. GEJ adenocarcinoma shares molecular features with both esophageal and gastric adenocarcinomas, particularly the chromosomal instability (CIN) subtype.

Cohorts in the corpus

  • Part of the combined 1,123-patient EGC cohort (219 early-onset, 904 average-onset) at MSK, 2005–2018. MSK-IMPACT somatic 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, gastroesophageal junction, or gastric adenocarcinoma. Dataset: egc_trap_ccr_msk_2023. PMID:37406106

Recurrent alterations

  • CCNE1 — amplification enriched in early-onset EGC (16% vs. 7%), driven by chromosomal instability in the esophageal/GEJ subgroup. PMID:37699004
  • ERBB2 — amplification; HER2 overexpression is a key therapeutic target. PMID:37406106
  • CDKN2A — enriched in average-onset EGC; associated with worse survival (HR=1.55, P<0.001). PMID:37699004
  • See also EGC for shared alterations across the esophagogastric spectrum.
  • WES of 149 treatment-naïve EAC tumors including gastroesophageal junction adenocarcinomas identified 26 significantly mutated genes and a distinctive EAC/GEJ-specific A>C transversion signature; 23% harbored mutations in genes with approved/preclinical inhibitors, rising to 48% when amplifications included PMID:23525077
  • TCGA profiling included 36 GEJ adenocarcinomas of indeterminate origin showing continuous molecular spectrum from oesophageal adenocarcinoma to CIN gastric cancer with no discrete boundary; CIN proportion increases proximally along the gastroesophageal axis PMID:28052061
  • Gastroesophageal junction tumors were included in the 295-patient MSK-IMPACT EGC cohort; CIN subtype dominated (63%) across EGC including GEJ; ERBB2 amplification (25% of CIN tumors) was the most frequent actionable alteration and predicted trastuzumab PFS dose-dependently by NGS PMID:29122777

Subtypes

  • GEJ adenocarcinomas enriched in early-onset cohort compared to ESCA (higher GEJ proportion in early-onset setting). CIN subtype most common for GEJ. PMID:37699004

Therapeutic landscape

  • Pembrolizumab + trastuzumab + CAPOX achieved median PFS 13 months, OS 27 months, ORR 89% in HER2-positive metastatic GEJ/esophageal/gastric cancer (n=37). PMID:37406106
  • Uniform HER2 IHC 3+ expression predicts longer PFS (15 vs. 8.5 months, P=0.004). PMID:37406106

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:23525077 — Dulak et al. Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity. Nat Genet 2013.

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