Esophageal Adenocarcinoma (ESCA)

Overview

Esophageal adenocarcinoma (ESCA) is a subtype of esophagogastric adenocarcinoma (EGC) originating in the esophagus, frequently arising from Barrett’s esophagus. On OncoTree it is a child of EGC, alongside GEJ and STAD.

Cohorts in the corpus

  • Part of the combined 1,123-patient EGC cohort (219 early-onset, 904 average-onset) at MSK, 2005–2018. Esophageal primary site was less common in early-onset (16% vs. 28%, P<0.001). 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
  • OE19 (HER2+, ESCA cell line): preclinical ADC radiosensitization model — a single 0.25 nmol T-DM1 dose + 2.5 Gy × 3 fractions increased tumor doubling time from 7 to 66 days in xenograft. PMID:27698471

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 present; trend toward higher frequency in average-onset tumors. Associated with improved survival in multivariable analysis (HR=0.65, P=0.01). PMID:37699004
  • CDKN2A — enriched in average-onset EGC (22% vs. 11%, P<0.001); associated with worse survival. PMID:37699004
  • See also EGC for shared alterations across the esophagogastric spectrum.
  • ERBB2 (HER2) amplification/overexpression: OE19 ESCA cells are HER2+ with T-DM1 IC50 <1 nM vs. >100 nM in HER2− controls; T-DM1 more potent than paclitaxel, cisplatin, trastuzumab, lapatinib, or erlotinib in OE19. PMID:27698471
  • WES of 149 treatment-naïve EAC tumors (including esophageal adenocarcinomas) identified 26 significantly mutated genes (TP53, CDKN2A, SMAD4, PIK3CA, ELMO1, DOCK2) and a distinctive A>C transversion signature at AA dinucleotides accounting for 29% of all mutations, with 48% of tumors harboring a targetable alteration PMID:23525077
  • Systematic review of 18 studies (1,191 ESCC/EAC cases) found EAC-specific oral microbial enrichment of Actinomyces species across the Barrett’s-to-adenocarcinoma sequence; pooled OR of 9.50 (95% CI 5.89–15.29) derived from ESCC meta-analysis should not be extrapolated to EAC PMID:24670651
  • TCGA multi-platform profiling of 72 oesophageal adenocarcinomas (EACs) plus 90 ESCCs: EAC is molecularly indistinguishable from chromosomally unstable (CIN) gastric cancer; significantly mutated genes in EAC are TP53, CDKN2A, ARID1A, SMAD4, ERBB2; recurrent amplifications include VEGFA, ERBB2, GATA6, CCNE1; EAC-specific ERBB2-JUP fusion transcript identified in 6 ERBB2-amplified cases; CDKN2A inactivated in 76% by mutation/deletion/epigenetic silencing PMID:28052061
  • Esophageal adenocarcinoma (included in ESCA in the MSK-IMPACT pan-cancer cohort) had one of the highest TP53 mutation rates at 89% — second only to HGSOC (98%) across the 62 principal tumor types in msk_impact_2017. PMID:28481359
  • Esophageal carcinoma was among the cancer subtypes in the MSK cohort of 295 stage-IV esophagogastric adenocarcinoma patients profiled with MSK-IMPACT; most-mutated genes across EGC including ESCA were TP53 (73%), ARID1A (15%), CDKN2A (12%) PMID:29122777
  • TCGA ESCA mutational signatures were used as a reference comparison in the first WES landscape of vulvar squamous cell carcinoma, placing vulvar SCC in the context of other SCCs PMID:29422544
  • MC3 pan-cancer mutation-calling project (10,510 TCGA pairs) included ESCA as one of 33 cancer types PMID:29596782
  • Pan-cancer fusion study (9,624 TCGA samples) identified WNK1/WNK2 fusions in ESCA without matching copy-number amplification, suggesting promoter-swap-driven overexpression; ERC1–WNK1 was independently reported in a Chinese ESCC cohort PMID:29617662
  • Pan-cancer aneuploidy study placed non-squamous ESCA in the gastrointestinal arm-level cluster; squamous ESCA (ESCC) was part of the squamous cluster defined by chr_3p loss and chr_3q gain PMID:29622463

Subtypes

  • Early-onset esophageal cancer is less prevalent than gastric in the early-onset setting (16% vs. 64% gastric site). PMID:37699004
  • CCNE1 amplification enrichment in early-onset tumors is driven by the chromosomal instability (CIN) esophageal/GEJ subgroup. PMID:37699004

Therapeutic landscape

  • HER2-directed therapy (trastuzumab) combined with PD-1 blockade (pembrolizumab) and chemotherapy showed median PFS 13 months, OS 27 months, ORR 89% in HER2-positive metastatic esophagogastric cancer including ESCA. PMID:37406106
  • CCNE1 amplification represents a potential therapeutic target (CDK2 inhibitors) in early-onset ESCA. PMID:37699004
  • ado-trastuzumab emtansine (T-DM1) combined with IR produced long-term tumor control in HER2+ OE19 (ESCA) xenografts; T-MMAE was equally efficacious at 1 nmol. Authors propose T-DM1 + chemoradiotherapy as a strategy warranting clinical evaluation in HER2+ locally advanced esophageal 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

  • 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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