Gastroesophageal Adenocarcinomas With Defective Mismatch Repair: Current Knowledge and Clinical Management

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Matthew R. Strickland Division of Hematology-Oncology, Department of Medicine, Massachusetts General Cancer Center, Boston, MA

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Eric M. Lander Division of Hematology/Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN

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Michael K. Gibson Division of Hematology/Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN

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David H. Ilson Memorial Sloan Kettering Cancer Center, New York City, NY

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Jaffer A. Ajani GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX

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Samuel J. Klempner Division of Hematology-Oncology, Department of Medicine, Massachusetts General Cancer Center, Boston, MA

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Esophageal, gastroesophageal junction, and gastric adenocarcinomas, referred to collectively as gastroesophageal adenocarcinomas (GEAs), are a major cause of global cancer-related mortality. Our increasing molecular understanding has led to the addition of biomarker-directed approaches to defined subgroups and has improved survival in selected patients, such as those with HER2 and Claudin18.2 overexpression. Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer, including GEA, but biomarkers beyond PD-L1 expression are lacking. Mismatch repair deficiency and/or high microsatellite instability (dMMR/MSI-H) is observed in 8% to 22% of nonmetastatic GEA, and 3% to 5% of patients with metastatic disease. dMMR/MSI-H tumors are associated with more favorable prognosis and significant benefit from ICIs, although some heterogeneity exists. The activity of ICIs in advanced dMMR/MSI-H cancer is seen across lines of therapy and should be recommended in the frontline setting. In patients with nonmetastatic dMMR/MSI-H cancer, increasing evidence suggests that perioperative and adjuvant chemotherapy may not provide benefit to the dMMR/MSI-H subgroup. The activity of perioperative chemotherapy-free immune checkpoint regimens in patients with nonmetastatic dMMR/MSI-H cancer is highly promising and underscores the need to identify this unique subgroup. We recommend MMR/MSI testing for all patients with GEA at diagnosis, and review the key rationale and clinical management implications for patient with dMMR/MSI-H tumors across disease stages.

Submitted July 8, 2023; final revision received October 19, 2023; accepted for publication October 25, 2023. Published online March 19, 2024.

Disclosures: Dr. Ilson has disclosed serving on an advisory board and as a consultant for AstraZeneca, Bristol Myers Squibb, and Merck & Co., Inc. Dr. Ajani has disclosed participating in research and serving as a principal investigator for Bristol Myers Squibb, and Merck & Co., Inc.; and serving on an advisory board for AstraZeneca, BeiGene, Bristol Myers Squibb, and Merck & Co., Inc. Dr. Klempner has disclosed serving on an advisory board for Amgen, Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Inc., Novartis, and sanofi-aventis; and serving as a consultant for Bristol Myers Squibb, Merck & Co., Inc., and Novartis. The remaining authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.

Correspondence: Samuel J. Klempner, MD, Division of Hematology-Oncology, Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114. Email: sklempner@partners.org
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