Abstract 5361: Clinical implications of The Cancer Genome Atlas molecular classification system in esophagogastric cancer

Purpose: The Cancer Genome Atlas (TCGA) project defined four distinct molecular subtypes of esophagogastric adenocarcinoma (EGAC): microsatellite instable (MSI), Epstein-Barr virus associated (EBV), genomically stable (GS), and chromosomally instable (CIN). However, an association between molecular subtype and clinical outcome has not been clearly demonstrated. Given few actionable biomarkers, we investigated the clinical relevance of the TCGA classification system. Experimental Design: We identified all patients with EGAC whose tumors underwent prospective next-generation sequencing using the MSK-IMPACT assay from 2014 to 2023. We classified all tumors in accordance with TCGA methodology and correlated molecular subtype with high-quality clinicopathologic data. Results: Among 1,438 included patients, 941 had CIN, 344 had GS, 103 had MSI, and 50 had EBV tumors. CIN was associated with White race, male sex, more-advanced stage, a high frequency of TP53 mutations, cell-cycle and RTK-RAS copy number alterations, and high metastatic potential. GS was associated with a higher proportion of Asians and females, Lauren’s diffuse and signet ring histologies, heterogeneous driver alterations, and poor responses to systemic and radiation therapies. MSI and EBV tumors, by contrast, had lower metastatic potential and significantly better survival than CIN and GS tumors, although MSI tumors were associated with the worst rate of response to chemotherapy. Accounting for clinical stage and tumor grade, molecular classification was independently associated with overall cancer-specific survival (p<0.001) on Cox multivariable analysis. Furthermore, genomic signatures, patient demographics, pathologic responses to neoadjuvant therapy, patterns of recurrence, and metastatic organotropism differed significantly by molecular subtype. Although most distal esophageal and gastroesophageal junction tumors were CIN, up to 25% of these included GS, MSI, or EBV subtypes in contrast to the TCGA. Random-forest machine learning demonstrated that molecular subtype is more influential in predicting response to treatment than tumor location. Conclusions: Molecular classification is independently prognostic and may warrant inclusion in future staging and treatment guidelines. Routine molecular profiling is clinically feasible and may play a role in the management of patients to help guide appropriate treatment selection and clinical trial enrollment in place of tumor location. Citation Format: Henry Walch, Raktim Borpatragohain, Justin Jee, Walid Chatila, Christopher Fong, Steven B. Maron, Geoffrey Ku, David H. Ilson, Yelena Y. Janjigian, Abraham J. Wu, Pari Shah, Daniel G. Coit, Manjit S. Bains, Valerie W. Rusch, Bernard Park, Matthew Bott, Katherine Gray, David R. Jones, Michael F. Berger, Nikolaus Schultz, Vivian E. Strong, Daniela Molena, Smita Sihag. Clinical implications of The Cancer Genome Atlas molecular classification system in esophagogastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5361.