Mismatch Repair Deficiency in Esophageal Squamous Cell Carcinoma: An Underrecognized Biomarker for Immunotherapy Response

TL;DR

A case shows that mismatch repair deficiency in esophageal squamous cell carcinoma can predict response to immunotherapy, suggesting broader testing may help personalize treatment.

Contribution

Highlights the underrecognized potential of dMMR/MSI-H as a biomarker in ESCC, especially in non-White populations.

Findings

A patient with dMMR ESCC showed significant response to chemoimmunotherapy.

dMMR/MSI-H may be more prevalent in ESCC than previously thought, particularly in non-White populations.

Routine dMMR/MSI-H testing in ESCC could identify candidates for immunotherapy.

Abstract

Mismatch repair deficiency (dMMR) and high microsatellite instability (MSI-H) are known predictors of response to immune checkpoint inhibitors in gastrointestinal malignancies, often seen in adenocarcinomas. Their role in esophageal squamous cell carcinoma (ESCC) is less studied, as these alterations were historically considered rare in this subtype.

We report the case of a 74-year-old man with stage IVB proximal ESCC, presenting with bilateral lung metastases and mediastinal lymphadenopathy. Immunohistochemistry revealed dMMR with loss of PMS2 expression and a PD-L1 Combined Positive Score (CPS) of 1. After palliative radiotherapy for dysphagia, he received chemoimmunotherapy with 5-fluorouracil, cisplatin, and nivolumab. Within two months, he experienced symptom improvement, and imaging after four cycles demonstrated a partial response with marked reduction in pulmonary metastases.

This case highlights the value of testing for dMMR and MSI-H in ESCC, a subtype where these alterations have traditionally been considered uncommon. Growing evidence points to a higher prevalence than expected, especially in non-White populations, suggesting that routine dMMR/MSI-H testing in advanced ESCC could help identify patients who might benefit from immunotherapy and support more personalized, effective treatment strategies.

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