{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:15:12Z","timestamp":1790878512929,"version":"4.1.0"},"reference-count":33,"publisher":"BMJ","issue":"10","license":[{"start":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T00:00:00Z","timestamp":1761782400000},"content-version":"unspecified","delay-in-days":29,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,9,14]]},"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>RAS<\/jats:italic>\n                      mutation (p=0.005), reduced\n                      <jats:italic>BRAF p.V600E<\/jats:italic>\n                      mutation rates (p&lt;0.001), a higher proportion of Lynch syndrome (p&lt;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&lt;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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2024-011436","type":"journal-article","created":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T08:55:11Z","timestamp":1761814511000},"page":"e011436","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["Efficacy of immunotherapy in gastrointestinal (GI) tumors with mismatch repair deficient (MMRd) unusual phenotype: an AGEO real-world study"],"prefix":"10.1136","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2303-118X","authenticated-orcid":false,"given":"Emily","family":"Alouani","sequence":"first","affiliation":[{"name":"Digestive Medical Oncology Department, H\u00f4pital de Rangueil, Centre Hospitalier Universitaire de Toulouse, Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9955-4753","authenticated-orcid":false,"given":"Julien","family":"Taieb","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Gastrointestinal Oncology, CARPEM comprehensive cancer center, Georges-Pompidou European Hospital, AP-HP, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8065-9635","authenticated-orcid":false,"given":"David","family":"Tougeron","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Department, Poitiers University Hospital, Poitiers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillaume","family":"Roces","sequence":"additional","affiliation":[{"name":"Digestive Medical Oncology Department, H\u00f4pital de Rangueil, Centre Hospitalier Universitaire de Toulouse, Toulouse, 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Hautefeuille","sequence":"additional","affiliation":[{"name":"Department of Hepato-Gastroenterology and Digestive Oncology, Amiens University Hospital, Amiens, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meher","family":"Ben-Abdelghani","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, European Oncology Institute of Strasbourg, Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Dutherage","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Rouen University Hospital, Rouen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9602-5162","authenticated-orcid":false,"given":"Romain","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Saint-Antoine hospital, APHP, Sorbonne University, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilie","family":"Hafliger","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Gastrointestinal Oncology, CARPEM comprehensive cancer center, Georges-Pompidou European Hospital, AP-HP, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Sclafani","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Oncology, Universit\u00e9 libre de Bruxelles (ULB), H\u00f4pital Universitaire de Bruxelles (HUB), Institut Jules Bordet Brussels, Bruxelles, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Muller","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nancy University Hospital Center, Nancy, 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