Ascites and resistance to immune checkpoint inhibition in dMMR/MSI-H metastatic colorectal and gastric cancers
Fucà, Giovanni (Fondazione IRCCS Istituto Nazionale dei Tumori)
Cohen, Romain (Hôpital Saint-Antoine)
Lonardi, Sara (Istituto Oncologico Veneto IOV-IRCSS)
Shitara, Kohei (National Cancer Center Hospital East)
Elez, Elena (Vall d'Hebron Institut d'Oncologia)
Fakih, Marwan (City of Hope Comprehensive Cancer Center)
Chao, Joseph (City of Hope Comprehensive Cancer Center)
Klempner, Samuel J. (Harvard Medical School)
Emmett, Matthew (Harvard Medical School)
Jayachandran, Priya (University of Southern California)
Bergamo, Francesca (Istituto Oncologico Veneto IOV-IRCSS)
García, Marc Díez (Vall d'Hebron Institut d'Oncologia)
Mazzoli, Giacomo (Fondazione IRCCS Istituto Nazionale dei Tumori)
Provenzano, Leonardo (Fondazione IRCCS Istituto Nazionale dei Tumori)
Colle, Raphael (Hôpital Saint-Antoine)
Svrcek, Magali (Hôpital Saint-Antoine, AP-HP, and INSERM, Unité Mixte de Recherche Scientifique 938, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer)
Ambrosini, Margherita (Fondazione IRCCS Istituto Nazionale dei Tumori)
Randon, Giovanni (Fondazione IRCCS Istituto Nazionale dei Tumori)
Shah, Aakash Tushar (Baylor College of Medicine)
Salati, Massimiliano (University Hospital of Modena)
Fenocchio, Elisabetta (Candiolo Cancer Institute FPO-IRCCS)
Salvatore, Lisa (Fondazione Policlinico Universitario Agostino Gemelli IRCCS)
Chida, Keigo (National Cancer Center Hospital East)
Kawazoe, Akihito (National Cancer Center Hospital East)
Conca, Veronica (University of Pisa)
Curigliano, Giuseppe (University of Milan)
Corti, Francesca (Fondazione IRCCS Istituto Nazionale dei Tumori)
Cremolini, Chiara (University of Pisa)
Overman, Michael (University of Texas MD Anderson Cancer Center)
André, Thierry (Hôpital Saint-Antoine)
Pietrantonio, Filippo (Fondazione IRCCS Istituto Nazionale dei Tumori)
Universitat Autònoma de Barcelona

Date:	2022
Abstract:	Despite unprecedented benefit from immune checkpoint inhibitors (ICIs) in patients with mismatch repair deficient (dMMR)/microsatellite instability high (MSI-H) advanced gastrointestinal cancers, a relevant proportion of patients shows primary resistance or short-term disease control. Since malignant effusions represent an immune-suppressed niche, we investigated whether peritoneal involvement with or without ascites is a poor prognostic factor in patients with dMMR/MSI-H metastatic colorectal cancer (mCRC) and gastric cancer (mGC) receiving ICIs. We conducted a global multicohort study at Tertiary Cancer Centers and collected clinic-pathological data from a cohort of patients with dMMR/MSI-H mCRC treated with anti-PD-(L)1 ±anti-CTLA-4 agents at 12 institutions (developing set). A cohort of patients with dMMR/MSI-high mGC treated with anti-PD-1 agents±chemotherapy at five institutions was used as validating dataset. The mCRC cohort included 502 patients. After a median follow-up of 31. 2 months, patients without peritoneal metastases and those with peritoneal metastases and no ascites had similar outcomes (adjusted HR (aHR) 1. 15, 95% CI 0. 85 to 1. 56 for progression-free survival (PFS); aHR 0. 96, 95% CI 0. 65 to 1. 42 for overall survival (OS)), whereas inferior outcomes were observed in patients with peritoneal metastases and ascites (aHR 2. 90, 95% CI 1. 70 to 4. 94; aHR 3. 33, 95% CI 1. 88 to 5. 91) compared with patients without peritoneal involvement. The mGC cohort included 59 patients. After a median follow-up of 17. 4 months, inferior PFS and OS were reported in patients with peritoneal metastases and ascites (aHR 3. 83, 95% CI 1. 68 to 8. 72; aHR 3. 44, 95% CI 1. 39 to 8. 53, respectively), but not in patients with only peritoneal metastases (aHR 1. 87, 95% CI 0. 64 to 5. 46; aHR 2. 15, 95% CI 0. 64 to 7. 27) when compared with patients without peritoneal involvement. Patients with dMMR/MSI-H gastrointestinal cancers with peritoneal metastases and ascites should be considered as a peculiar subgroup with highly unfavorable outcomes to current ICI-based therapies. Novel strategies to target the immune-suppressive niche in malignant effusions should be investigated, as well as next-generation ICIs or intraperitoneal approaches.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Immunotherapy ; Gastrointestinal neoplasms ; Translational medical research ; Tumor biomarkers
Published in:	Journal for immunotherapy of cancer, Vol. 10 (february 2022) , ISSN 2051-1426

DOI: 10.1136/jitc-2021-004001
PMID: 35110358

13 p, 1.6 MB

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