Background: NCCN guidelines state that chemotherapies for esophageal and gastric carcinomas may be used interchangeably. We interrogated biomarkers from a large cohort of gastroesophageal cancer patients to identify similar and different alterations with therapeutic implications for gastric and esophageal cancers. Methods: 666 gastric adenocarcinoma (GA) and 640 esophageal (553 adenocarcinoma, or EA, and 87 others) cases were evaluated by a combination of sequencing (Sanger, NGS), protein expression (IHC) and gene amplification (CISH/FISH). Results: In the complete cohort of 1306 patients, 30 of 45 (66%) genes tested had mutations, with the highest rates seen in TP53 (54%), APC (10%), SMAD4 (5.9%), KRAS (5.9%) and PIK3CA (5.1%). Elevated IHC of TOP2A was seen in 76% of cases, TOPO1 in 51% and SPARC in 25%; decreased IHC of ERCC1 was seen in 65%, RRM1 in 62%, TS in 61% and MGMT in 45%, indicating benefit from epirubicin, irinotecan, nab-paclitaxel, platinums, gemcitabine, 5FU/capecitabine and temozolomide, respectively. In the HER2-positive cases, additional alterations were seen including low TS (50%), ERCC1 (63%), RRM1 (55%) and high TOPO1 (53%), indicating potential benefit from combining trastuzumab with 5FU/capecitabine, cisplatin, gemcitabine and irinotecan, respectively. When comparing EA to GA, select biomarkers showed a differential pattern between cancer types (Table), suggesting potential variability in efficacy of available therapeutic agents. Conclusions: A multiplatform biomarker analysis identified common actionable targets in gastric and esophageal cancer as well as significant biomarker differences in EA and GA. This indicates the potential clinical impact of molecular profiling and highlights the need for separation of the two cancer entities for therapeutics.

*Lack of benefit.