{
  "abstract": "Background Tumors with mismatch repair deficiency (MMRd) classically display concomitant loss of MLH1/PMS2 or MSH2/MSH6 on immunohistochemistry (IHC) with microsatellite instability-high (MSI-High) status on molecular testing. Nevertheless, a different phenotype can occur in up to 15% of MMRd tumors (unusual phenotype). Data on the efficacy of immunotherapy in this population remain scarce.Methods We conducted a retrospective study within the IMMUNODIG MSI cohort including patients with advanced gastrointestinal MMRd tumors treated with immune checkpoint blockade in the real-world setting. We selected patients with both IHC and MSI assays data available. Unusual MMRd tumors were classified into four distinct groups: (1) isolated loss of PMS2 or MSH6 with MSI-H (isolated/MSI-H), (2) complex loss of MMR proteins with MSI-H (complex/MSI-H), (3) loss of one or more MMR proteins without MSI-H (MMRd-IHC/microsatellite stability (MSS) or MSI-low (MSI-L)), and (4) four MMR proteins retained with MSI-H (retained IHC/MSI-H).Results Out of 759 patients in the IMMUNODIG-MSI cohort, 571 patients met inclusion criteria. Of these, 90 (15.8%) had an unusual phenotype (47 isolated/MSI-H, 19 complex/MSI-H, 16 MMRd-IHC/MSS or MSI-L and 8 retained IHC/MSI-H). Compared with classical phenotypes, patients with a tumor harboring an unusual phenotype had a younger age at treatment (p=0.005), increased RAS mutation (p=0.005), reduced BRAF p.V600E mutation rates (p<0.001), a higher proportion of Lynch syndrome (p<0.001) and a higher prevalence of non-colorectal cancers (p=0.021). After a median follow-up of 28.1 months (mo), there was a significant difference in progression-free survival, with median values of not reached, 66.4 mo, 37.2 mo, 18.3 mo and 5.5 mo for complex/MSI-H, isolated/MSI-H, classical, retained IHC/MSI-H and MMRd-IHC/MSS or MSI-L subgroups, respectively (p<0.001). Notably, objective response rates were 59.1%, 58.7%, and 63.2% for complex/MSI-H, isolated/MSI-H and classical contrasting with 50% and 25% for retained IHC/MSI-H and MMRd-IHC/MSS or MSI-L, with no complete response observed in the latter two.Conclusion Our findings underscore the need for dual testing and advocate for the presence of both MMRd-IHC and MSI-H for optimal immunotherapy response. Of note, complex MMR aberrations and isolated PMS2/MSH6 losses with MSI-H may represent promising candidates for enhanced immunotherapy efficacy.",
  "authors": [
    {
      "affiliations": [
        "Digestive Medical Oncology Department, Hôpital de Rangueil, Centre Hospitalier Universitaire de Toulouse, Toulouse, France"
      ],
      "name": "Emily Alouani"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Gastrointestinal Oncology, CARPEM comprehensive cancer center, Georges-Pompidou European Hospital, AP-HP, Paris, France"
      ],
      "name": "Julien Taieb"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology Department, Poitiers University Hospital, Poitiers, France"
      ],
      "name": "David Tougeron"
    },
    {
      "affiliations": [
        "Digestive Medical Oncology Department, Hôpital de Rangueil, Centre Hospitalier Universitaire de Toulouse, Toulouse, France"
      ],
      "name": "Guillaume Roces"
    },
    {
      "affiliations": [
        "Drug Development Department (DITEP), Gustave Roussy, Villejuif, France"
      ],
      "name": "Antoine Hollebecque"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Lille University Hospital, Lille, France"
      ],
      "name": "Pauline Parent"
    },
    {
      "affiliations": [
        "Department of Medicine, Bergonie Institute, Bordeaux, France"
      ],
      "name": "Simon Pernot"
    },
    {
      "affiliations": [
        "Division of Oncology and of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA"
      ],
      "name": "Frank A Sinicrope"
    },
    {
      "affiliations": [
        "Department of Hepato-Gastroenterology and Digestive Oncology, Amiens University Hospital, Amiens, France"
      ],
      "name": "Vincent Hautefeuille"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, European Oncology Institute of Strasbourg, Strasbourg, France"
      ],
      "name": "Meher Ben-Abdelghani"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Rouen University Hospital, Rouen, France"
      ],
      "name": "Marie Dutherage"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Saint-Antoine hospital, APHP, Sorbonne University, Paris, France"
      ],
      "name": "Romain Cohen"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Gastrointestinal Oncology, CARPEM comprehensive cancer center, Georges-Pompidou European Hospital, AP-HP, Paris, France"
      ],
      "name": "Emilie Hafliger"
    },
    {
      "affiliations": [
        "Department of Gastrointestinal Oncology, Université libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (HUB), Institut Jules Bordet Brussels, Bruxelles, Belgium"
      ],
      "name": "Francesco Sclafani"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Nancy University Hospital Center, Nancy, France"
      ],
      "name": "Marie Muller"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Rennes University Hospital, Rennes, France"
      ],
      "name": "Géraldine Perkins"
    },
    {
      "affiliations": [
        "Medical Oncology Department, La Rochelle Hospital, La Rochelle, France"
      ],
      "name": "Thérèse Masson"
    },
    {
      "affiliations": [
        "Gastroenterology Department, Saint Louis Hospital, APHP, Paris, France"
      ],
      "name": "Thomas Aparicio"
    },
    {
      "affiliations": [
        "Medical Oncology Department, Centre Léon Bérard, Lyon, France"
      ],
      "name": "Clélia Coutzac"
    },
    {
      "affiliations": [
        "Institut de Recherche en Cancérologie de Montpellier, Montpellier, France"
      ],
      "name": "Thibault Mazard"
    },
    {
      "affiliations": [
        "Department of Hepato-Gastroenterology and Digestive Oncology, University Hospital Centre of Bordeaux, Bordeaux, France"
      ],
      "name": "Marie Decraecker"
    },
    {
      "affiliations": [
        "Digestive Medical Oncology Department, Hôpital de Rangueil, Centre Hospitalier Universitaire de Toulouse, Toulouse, France"
      ],
      "name": "Marion Jaffrelot"
    },
    {
      "affiliations": [
        "Digestive Medical Oncology Department, Hôpital de Rangueil, Centre Hospitalier Universitaire de Toulouse, Toulouse, France"
      ],
      "name": "Rosine Guimbaud"
    },
    {
      "affiliations": [
        "Department of Pathology, Centre hospitalier Universitaire de Toulouse, Toulouse, France"
      ],
      "name": "Janick Selves"
    }
  ],
  "title": "Efficacy of immunotherapy in gastrointestinal (GI) tumors with mismatch repair deficient (MMRd) unusual phenotype: an AGEO real-world study",
  "uid": "5e0541d1-9b13-5185-885d-557c68ad702e"
}