Actionable Alterations for Molecular Targeted Therapy in Esophageal Cancer: An AACR Project GENIE Review

Objective: Prognosis after curative intent resection for esophageal cancer remains low and only few targeted therapy options exist. We sought to analyze the full scope of potential actionable genomic alterations in esophageal cancer to better understand the potential for molecular targeted adjuvant therapy. Methods: We queried the American Association for Cancer Research (AACR) Project GENIE (v17.0) to identify clinically relevant, actionable genomic alterations in 3,605 patients with esophageal adenocarcinoma, gastroesophageal junction (GEJ) adenocarcinoma, or esophageal squamous cell carcinoma (ESCC). Additional data from The Cancer Genome Atlas (TCGA) were analyzed to assess protein overexpression of EGFR and HER2/ERBB2. Prevalence of targetable alterations was compared across histologic subtypes, and co-occurrence analyses using log-odds ratios with false discovery rate correction were performed on the most frequent alterations to identify potential resistance mechanisms. Results: Potentially small-molecule targetable alterations were identified in 64.3% of esophageal adenocarcinomas and 63.6% of GEJ adenocarcinomas, whereas 55.7% of ESCCs carried at least one actionable alteration. HER2/ERBB2 amplification was most common in adenocarcinomas, while PIK3CA mutations were most common in SCCs with no alteration unique present in a plurality of patients. Co-amplification of HER2 and CDK12 emerged as a potential mechanism of resistance to HER2-directed therapies. In addition, numerous genes implicated in PARP inhibitor or PIK3CA-targeted strategies were frequently altered across all histologies. Conclusions: Over half of patients in this large genomic dataset exhibited at least one actionable alteration, although distinct molecular profiles emerged by histology. These findings underscore the potential of using precision oncology to expand adjuvant therapeutic options.