Ascites and resistance to immune checkpoint inhibition in dMMR/MSI-H metastatic colorectal and gastric cancers. Issue 2 (2nd February 2022)

• Record Type: Journal Article
• Authors: Fucà, Giovanni; Cohen, Romain; Lonardi, Sara; Shitara, Kohei; Elez, Maria Elena; Fakih, Marwan; Chao, Joseph; Klempner, Samuel J; Emmett, Matthew; Jayachandran, Priya; Bergamo, Francesca; García, Marc Díez; Mazzoli, Giacomo; Provenzano, Leonardo; Colle, Raphael; Svrcek, Magali; Ambrosini, Margherita; Randon, Giovanni; Shah, Aakash Tushar; Salati, Massimiliano; Fenocchio, Elisabetta; Salvatore, Lisa; Chida, Keigo; Kawazoe, Akihito; Conca, Veronica; Curigliano, Giuseppe; Corti, Francesca; Cremolini, Chiara; Overman, Michael; Andre, Thierry; Pietrantonio, Filippo;
• Is Part Of: Journal for immunotherapy of cancer. Volume 10:Issue 2(2022)
• Publication Date: 2022-02-02
• Subjects: immunotherapy -- gastrointestinal neoplasms -- translational medical research -- tumor biomarkers; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2021-004001
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : Background: 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. Methods: 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. Results: 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. Conclusions: 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.