ERBB2 and esophageal adenocarcinoma: Gastric and esophageal cancers exhibit more heterogeneous mechanisms; activation can occur through direct PIK3CA mutations (especially in EBV-positive gastric cancer and esophageal squamous cell carcinoma) or through the amplification of upstream receptors like HER2 (in certain gastric and esophageal adenocarcinoma subtypes), making HER2 a key therapeutic target [4, 138].