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

Area of Science:

• Gastrointestinal Oncology
• Cancer Biomarkers
• Immunotherapy

Background:

• Gastroesophageal adenocarcinomas (GEAs) are a leading cause of cancer mortality worldwide.
• Biomarker-directed therapies, including for HER2 and Claudin18.2, have improved outcomes in specific GEA subgroups.
• Immune checkpoint inhibitors (ICIs) show promise in GEA, but validated biomarkers beyond PD-L1 are needed.

Purpose of the Study:

• To highlight the significance of mismatch repair deficiency and/or high microsatellite instability (dMMR/MSI-H) as a biomarker in GEA.
• To review the clinical implications of dMMR/MSI-H status across different stages of GEA.
• To advocate for universal MMR/MSI testing at diagnosis for all GEA patients.

Main Methods:

• Review of existing literature and clinical data on dMMR/MSI-H prevalence in GEA.
• Analysis of treatment outcomes for dMMR/MSI-H GEA patients receiving ICIs and chemotherapy.
• Evaluation of evidence for perioperative and adjuvant treatment strategies in dMMR/MSI-H GEA.

Main Results:

• dMMR/MSI-H is found in 8-22% of nonmetastatic and 3-5% of metastatic GEA.
• dMMR/MSI-H tumors generally have a better prognosis and respond well to ICIs, even in the frontline setting.
• Non-metastatic dMMR/MSI-H GEA patients may not benefit from perioperative or adjuvant chemotherapy, with chemotherapy-free ICI regimens showing promise.

Conclusions:

• MMR/MSI testing should be standard at diagnosis for all GEA patients to identify the dMMR/MSI-H subgroup.
• This subgroup demonstrates significant benefit from ICIs, supporting their use across therapy lines, including frontline.
• Chemotherapy may be omitted in the perioperative and adjuvant settings for nonmetastatic dMMR/MSI-H GEA, warranting further investigation.