Journal Article

Ascites and resistance to immune checkpoint inhibition in dMMR/MSI-H metastatic colorectal and gastric cancers

Klempner, Samuel J, Kawazoe, Akihito, Cremolini, Chiara, Curigliano, Giuseppe, Salati, Massimiliano, Svrcek, Magali, Ambrosini, Margherita, Lonardi, Sara, Chida, Keigo, Corti, Francesca, Cohen, Romain, Andre, Thierry, García, Marc Díez, Shah, Aakash Tushar, Randon, Giovanni, Fenocchio, Elisabetta, Shitara, Kohei, Jayachandran, Priya, Conca, Veronica, Chao, Joseph, Fucà, Giovanni, Provenzano, Leonardo, Elez, Maria Elena, Emmett, Matthew, Pietrantonio, Filippo, Bergamo, Francesca, Fakih, Marwan, Mazzoli, Giacomo, Salvatore, Lisa, Colle, Raphael, Overman, Michael

2022

Overview

BackgroundDespite 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.MethodsWe 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.ResultsThe 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.ConclusionsPatients 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.

• Publisher: BMJ Publishing Group Ltd,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Aged / Ascites / Ascites - etiology / Ascites - pathology / Cancer / Cancer therapies / Chemotherapy / Clinical trials / Colorectal cancer / Colorectal Neoplasms - complications / Colorectal Neoplasms - drug therapy / Colorectal Neoplasms - mortality / Female / Gastric cancer / gastrointestinal neoplasms / Human health and pathology / Humans / Hépatology and Gastroenterology / Immune Checkpoint Inhibitors - adverse effects / Immune Checkpoint Inhibitors - pharmacology / Immunology / Immunotherapy / Immunotherapy Biomarkers / Life Sciences / Male / Metastasis / Microsatellite Instability / Neoplasm Metastasis / Retrospective Studies / Stomach Neoplasms - complications / Stomach Neoplasms - drug therapy / Stomach Neoplasms - mortality / Survival Analysis / translational medical research / tumor biomarkers