Expression Profiling of HER2 and EGFR in Resected Specimens and Plasma Samples from Patients with Esophageal Adenocarcinoma: A Review

Abstract

HER2 and EGFR are the two receptor tyrosine kinases in esophageal adenocarcinoma for which targeted agents exist, and both are assessed on tissue by convention. The difficulty with tissue in this disease is not the assay but the sampling: alterations are distributed unevenly within a tumour and between primary and metastasis, so one block answers for one place at one time. Objectives: To review what has been reported for HER2 and EGFR measured in resected and biopsied tissue against what is recovered from plasma in
esophageal and gastroesophageal adenocarcinoma, and to set out the prevalence, the concordance between compartments, and the treatment consequences of each result. Material and Methods: Narrative review of randomised trials, trial biomarker analyses and clinically annotated sequencing cohorts indexed in PubMed and the major oncology journals. Studies were eligible if they reported HER2 or EGFR status in tissue or plasma in esophageal, gastroesophageal junction or gastric adenocarcinoma, matched comparison between compartments, or outcomes stratified by receptor status. No new patient data were generated; all values quoted are those published by the original investigators. Results: In the largest screening dataset available, covering 3,807 samples, HER2 positivity was 22.1 per cent overall but 32.2 per cent in gastroesophageal junction and distal esophageal tumours against 21.4 per cent in gastric tumours, and 31.8 per cent in intestinal-type against 6.1 per cent in diffuse-type disease. Staining was heterogeneous in almost half of cases. Where primary tumour, metastasis and plasma were sequenced in the same patients, only 26 per cent of alterations were identified by all three; restricted to alterations detectable in plasma, circulating tumour DNA recovered 74 per cent against 57 per cent from metastatic and 54 per cent from primary tissue. Among patients amplified by either compartment, matched HER2 inhibition was associated with median overall survival of 26.3 against 7.4 months, and matched EGFR inhibition with 21.1 against 14.4 months.
EGFR copy number gain was present in 20 per cent of tumours in a randomised trial population, with amplification in 7.2 per cent.
Conclusion: Neither compartment is complete. Tissue defines the protein-level result on which current approvals rest, but samples one region of a heterogeneous tumour; plasma samples the whole disease but only when shedding is sufficient. The published data support using them together rather than choosing between them, particularly for amplification-defined subgroups where the treatment effect is large. Abbreviations: EAC – Esophageal Adenocarcinoma, GEA – Gastroesophageal Adenocarcinoma, GEJ – Gastroesophageal Junction, HER2 – Human Epidermal Growth Factor Receptor 2, EGFR – Epidermal Growth Factor Receptor, IHC – Immunohistochemistry, FISH – Fluorescence In Situ Hybridization, NGS – Next-Generation Sequencing, ctDNA – Circulating Tumour DNA, CNG – Copy Number Gain, OS – Overall Survival, HR – Hazard Ratio.