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<p>Immune checkpoint inhibitors (ICIs) have transformed outcomes in microsatellite instability-high (MSI-H) deficient mismatch repair (dMMR) cancers. The influence of germline MMR gene variants on ICI remains unclear. In this single-center study, 93 patients with Lynch syndrome-associated MSI-H/dMMR digestive cancers received ICI monotherapy or combination therapy. Germline MMR variants were classified, and progression-free survival (PFS) was evaluated by gene and variant type. Most patients carried <i>MLH1</i> or <i>MSH2</i> variants. At 24 months, estimated PFS was 81.5% for <i>MLH1</i>, 67.2% for <i>MSH2/EPCAM</i>, and 78.6% for <i>MSH6</i>, with no PFS events in <i>MLH1</i> promoter methylation or <i>PMS2</i> subgroups. No statistically significant differences in PFS were observed between gene groups. Performance status ≥ 2 was the only factor associated with poorer PFS. Neither MMR gene type nor variant class significantly influenced ICI efficacy in Lynch syndrome-related MSI-H/dMMR digestive cancers, supporting the use of ICIs regardless of germline MMR genotype.</p>

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Impact of germline MMR gene variants on immune checkpoint inhibitors response in patients with MSI-H/dMMR digestive cancers: a retrospective cohort analysis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月18日

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  • Antoine Dardenne,
  • Camille Loisel,
  • Anna Pellat,
  • Alexandre Perrier,
  • Julie Metras,
  • Thomas Samaille,
  • Yann Parc,
  • Julie Leclerc,
  • Romain Cohen,
  • Thierry André

摘要

Immune checkpoint inhibitors (ICIs) have transformed outcomes in microsatellite instability-high (MSI-H) deficient mismatch repair (dMMR) cancers. The influence of germline MMR gene variants on ICI remains unclear. In this single-center study, 93 patients with Lynch syndrome-associated MSI-H/dMMR digestive cancers received ICI monotherapy or combination therapy. Germline MMR variants were classified, and progression-free survival (PFS) was evaluated by gene and variant type. Most patients carried MLH1 or MSH2 variants. At 24 months, estimated PFS was 81.5% for MLH1, 67.2% for MSH2/EPCAM, and 78.6% for MSH6, with no PFS events in MLH1 promoter methylation or PMS2 subgroups. No statistically significant differences in PFS were observed between gene groups. Performance status ≥ 2 was the only factor associated with poorer PFS. Neither MMR gene type nor variant class significantly influenced ICI efficacy in Lynch syndrome-related MSI-H/dMMR digestive cancers, supporting the use of ICIs regardless of germline MMR genotype.