Clinical implications of the cancer genome atlas molecular classification system in esophagogastric cancer Journal Article
| Authors: | Walch, H. S.; Borpatragohain, R.; Jee, J.; Chatila, W.; Fong, C.; Maron, S. B.; Ku, G. Y.; Ilson, D. H.; Janjigian, Y. Y.; Wu, A. J.; Shah, P.; Coit, D. G.; Bains, M. S.; Rusch, V. W.; Park, B. J.; Bott, M. J.; Gray, K.; Jones, D. R.; Berger, M.; Schultz, N.; Strong, V. E.; Molena, D.; Sihag, S. |
| Article Title: | Clinical implications of the cancer genome atlas molecular classification system in esophagogastric cancer |
| Abstract: | Purpose: The Cancer Genome Atlas (TCGA) project defined four distinct molecular subtypes of esophagogastric adenocarcinoma: microsatellite instable (MSI), Epstein–Barr virus (EBV)–associated, genomically stable (GS), and chromosomally instable (CIN). However, an association between molecular subtypes and clinical outcomes has not been clearly demonstrated. Given few actionable biomarkers, we investigated the clinical relevance of TCGA classification system. Experimental Design: We identified all patients with esophagogastric adenocarcinoma whose tumors underwent prospective next-generation sequencing using the Memorial Sloan Kettering–IMPACT assay from 2014 to 2023. We classified all tumors in accordance with TCGA methodology and correlated molecular subtypes 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. Accounting for the 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 TCGA. Random forest machine learning demonstrated that the 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 the place of tumor location. ©2025 American Association for Cancer Research. |
| Keywords: | aged; middle aged; genetics; mortality; cancer staging; neoplasm staging; adenocarcinoma; classification; pathology; tumor marker; microsatellite instability; stomach neoplasms; therapy; epstein barr virus; esophagus tumor; esophageal neoplasms; stomach tumor; herpesvirus 4, human; high throughput sequencing; high-throughput nucleotide sequencing; humans; prognosis; human; male; female; biomarkers, tumor |
| Journal Title: | Clinical Cancer Research |
| Volume: | 31 |
| Issue: | 10 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2025-05-15 |
| Start Page: | 1912 |
| End Page: | 1921 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-24-3473 |
| PUBMED: | 40299774 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Smita Sihag -- Source: Scopus |
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