The treatment of gastroesophageal cancer has evolved alongside a shift in histology from squamous cell carcinoma to adenocarcinoma. For resectable adenocarcinoma, perioperative chemotherapy plus immunotherapy has become the standard, supported by the MATTERHORN trial, and experts now say radiation is no longer used for these patients. In contrast, squamous cell carcinoma still follows the CROSS trial's neoadjuvant chemoradiation approach, with adjuvant nivolumab for high-risk residual disease.
The rise of adenocarcinoma has also accelerated biomarker-driven care. HER2-positive disease now has multiple options, including trastuzumab with chemotherapy, the addition of pembrolizumab, trastuzumab deruxtecan in the second line, and the recently approved zanidatamab plus tislelizumab regimen. For HER2-negative tumors, the Claudin 18.2 inhibitor zolbetuximab has shown survival benefits and received FDA approval. The latest NCCN guidelines recommend testing all resectable esophageal cancer patients for HER2, Claudin 18.2, PD-L1, and mismatch repair deficiency.
Despite these advances, the article stresses that precision guidance is still missing. Many potential targets—such as VEGF, EGFR, HER3, and various adhesion molecules—are under investigation but have not been validated in phase III trials. Experts call for more research to identify which biomarkers truly guide treatment decisions, noting that next-generation sequencing may be useful mainly for patients considering clinical trials. The source presents broad agreement on current standards but also highlights the ongoing gap between available therapies and the biomarkers needed to personalize them.