Clinical and Molecular Evolution During Panitumumab-Containing Therapy in EGFR-Amplified Esophagogastric Adenocarcinoma

Esophagogastric adenocarcinoma (EGA) is an aggressive malignancy with limited targeted treatment options. EGFR amplification defines a molecular subset associated with response to EGFR-directed therapy, although mechanisms of resistance remain poorly characterized. We present a 66-year-old man with EGFR-amplified metastatic EGA who achieved a metabolic response on positron emission tomography-CT (PET/CT) during panitumumab-containing therapy, accompanied by loss of detectable EGFR amplification on serial plasma circulating tumor DNA (ctDNA). At progression, repeat tissue biopsy demonstrated HER2 IHC 2+/SISH-positive disease not identified at baseline, and next-generation sequencing identified ERBB2 and KRAS amplifications. These findings suggest ERBB2-mediated bypass signaling as a potential mechanism of resistance to EGFR inhibition, with concurrent KRAS amplification as a possible contributor. It also demonstrates the utility of longitudinal tissue and plasma profiling to capture tumor evolution, identify potential resistance mechanisms, and inform adaptive treatment strategies.