Mucinous histology and resistance to immune checkpoint blockade in patients with microsatellite instability-high metastatic colorectal cancer

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.