The incidence of gastroesophageal cancers is on the rise, driven by factors such as obesity and gastroesophageal reflux. Despite increased awareness and screening efforts, many cases are diagnosed at an advanced, unresectable stage, making effective systemic treatments critical for improving survival and quality of life.
In a recent review by Antonella Cammarota, Rachel Woodford, and Elizabeth C. Smyth, the role of HER2 as an oncogenic driver in gastroesophageal adenocarcinomas (GEAs) is explored in depth. HER2 is present in 5–30% of GEAs and plays a pivotal role in guiding treatment strategies. While trastuzumab was the first approved anti-HER2 therapy for HER2-positive GEA, recent advancements like the addition of pembrolizumab to trastuzumab-chemotherapy and the introduction of trastuzumab deruxtecan in refractory settings have significantly influenced treatment paradigms. However, patient responses to HER2-targeted therapies remain highly variable.
Emerging data suggest that HER2 expression levels, HER2 heterogeneity, receptor alterations, and co-occurring molecular changes may impact treatment efficacy. Understanding these mechanisms of resistance and response is key to optimizing HER2-targeted therapies and exploring novel combination strategies with other biomarker-driven treatments.
This review highlights both the successes and challenges in HER2-targeting, offering insights into future strategies to improve outcomes for patients with HER2-positive GEA.
