The oncologist · 2026
Mucinous histology and resistance to immune checkpoint blockade in patients with microsatellite instability-high metastatic colorectal cancer.
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Nasca Vincenzo, Ambrosini Margherita, Taieb Julien, Cohen Romain, Lonardi Sara, Boursi Ben, Margalit Ofer, Salvatore Lisa, Ros Javier, Sabella Giovanna, Rossi Chiara, Tougeron David, Guimbaud Rosine, Gallois Claire, Elez Maria Elena, Bergamo Francesca, Cremolini Chiara, Overman Michael J, André Thierry, Randon Giovanni, Pietrantonio Filippo
Аннотация
BACKGROUND: Mucinous phenotype has been associated with an immune-cold microenvironment in dMMR/MSI-H CRC. Here, we investigated the impact of mucinous histology on resistance to ICIs in patients with dMMR/MSI-H mCRC.
PATIENTS AND METHODS: We collected data on patients with dMMR/MSI-H mCRC receiving anti-PD-1 alone or with anti-CTLA-4 agents in any line from a multinational dataset. Mucinous histology was defined locally as ≥50% mucinous component. The occurrence of progression or death of disease within or after 6 months from ICIs initiation were considered innate (IR) and acquired resistance (AR). Progression-free survival (PFS)-1 and overall survival (OS)-1 were calculated using the 6-month landmark from the start of ICIs in patients without IR.
RESULTS: Among 929 patients, 316 (34%) had mucinous tumors and had inferior PFS and OS. At a median follow-up of 44.7 months, the 6-month PFS rate was similar in patients with mucinous and non-mucinous tumors (71.5% and 73.0%) and a subsequent divergence of the PFS and OS curves was observed beyond this timepoint. In patients without IR, mucinous histology was independently associated with shorter PFS-1 (multivariable model HR 2.10, 95%CI 1.56-2.82; p < 0.001), while OS-1 was non-significantly shorter (HR 1.36, 95%CI 0.91-2.02, p = 0.130). Dual anti-CTLA4/PD-1 blockade was associated with longer PFS and OS regardless of mucinous histotype, but the worst outcomes were observed in patients with mucinous histology receiving single-agent anti-PD-1 (3-year PFS and OS: 39.7% and 56.1%).
CONCLUSION: Mucinous histology is associated with ICIs resistance, particularly AR, in dMMR/MSI-H mCRC. These findings may be useful to guide the management of this disease in practice.
PATIENTS AND METHODS: We collected data on patients with dMMR/MSI-H mCRC receiving anti-PD-1 alone or with anti-CTLA-4 agents in any line from a multinational dataset. Mucinous histology was defined locally as ≥50% mucinous component. The occurrence of progression or death of disease within or after 6 months from ICIs initiation were considered innate (IR) and acquired resistance (AR). Progression-free survival (PFS)-1 and overall survival (OS)-1 were calculated using the 6-month landmark from the start of ICIs in patients without IR.
RESULTS: Among 929 patients, 316 (34%) had mucinous tumors and had inferior PFS and OS. At a median follow-up of 44.7 months, the 6-month PFS rate was similar in patients with mucinous and non-mucinous tumors (71.5% and 73.0%) and a subsequent divergence of the PFS and OS curves was observed beyond this timepoint. In patients without IR, mucinous histology was independently associated with shorter PFS-1 (multivariable model HR 2.10, 95%CI 1.56-2.82; p < 0.001), while OS-1 was non-significantly shorter (HR 1.36, 95%CI 0.91-2.02, p = 0.130). Dual anti-CTLA4/PD-1 blockade was associated with longer PFS and OS regardless of mucinous histotype, but the worst outcomes were observed in patients with mucinous histology receiving single-agent anti-PD-1 (3-year PFS and OS: 39.7% and 56.1%).
CONCLUSION: Mucinous histology is associated with ICIs resistance, particularly AR, in dMMR/MSI-H mCRC. These findings may be useful to guide the management of this disease in practice.