Consensus Molecular Subtypes (CMS) Classification: a progress towards Subtype-Driven treatments in colorectal cancer

Area of Science:

• Oncology
• Molecular Biology
• Bioinformatics

Background:

• Colorectal cancer (CRC) exhibits significant molecular heterogeneity, impacting clinical outcomes and treatment responses.
• The Consensus Molecular Subtypes (CMS) classification stratifies CRC into four subtypes (CMS1-4) based on gene expression, aiming for improved prognosis and personalized therapy.

Purpose of the Study:

• To review the CMS classification system for colorectal cancer.
• To explore its prognostic and predictive value, identification methods, and clinical adoption barriers.
• To discuss applications in immunotherapy and the impact of intratumoral heterogeneity (ITH).

Main Methods:

• A comprehensive literature review of global studies on CMS classification was conducted.
• Searches included PubMed, Scopus, and Web of Science up to June 2025.
• Methods reviewed encompass gene expression profiling, immunohistochemistry (IHC), and computational image-based CMS (imCMS) classifiers, including deep learning models.

Main Results:

• CRC is classified into CMS1 (MSI-immune, ~15%), CMS2 (canonical, ~40%), CMS3 (metabolic, ~13%), and CMS4 (mesenchymal, ~22%).
• CMS is prognostic across adjuvant and metastatic settings, with CMS2 associated with better survival and CMS4 with poorer outcomes.
• Specific CMS subtypes show differential responses to therapies: CMS1 to immunotherapy, CMS2/3 to bevacizumab, and CMS4 to irinotecan.

Conclusions:

• The CMS classification improves colorectal cancer prognosis and treatment personalization.
• Challenges such as intratumoral heterogeneity (ITH) and technical limitations hinder widespread clinical adoption.
• Emerging solutions including advanced IHC, imCMS, and targeted gene panels are expected to facilitate broader clinical use and enhance patient care.