Molecular subtypes and the evolution of treatment management in metastatic colorectal cancer

Abstract

Colorectal cancer (CRC) is a heterogeneous disease representing a therapeutic challenge, which is further complicated by the common occurrence of several molecular alterations that confer resistance to standard chemotherapy and targeted agents. Mechanisms of resistance have been identified at multiple levels in the epidermal growth factor receptor (EGFR) pathway, including mutations in KRAS, NRAS, and BRAFV600E, and in the HER2 and MET receptors. These alterations represent oncogenic drivers that may co-exist in the same tumor with other primary and acquired alterations via a clonal selection process. Other molecular alterations include DNA damage repair mechanisms and rare kinase fusions, potentially offering a rationale for new therapeutic strategies. In recent years, genomic analysis has been expanded by a more complex study of epigenomic, transcriptomic, and microenvironment features. The Consensus Molecular Subtype (CMS) classification describes four CRC subtypes with distinct biological characteristics that show prognostic and potential predictive value in the clinical setting. Here, we review the panorama of actionable targets in CRC, and the developments in more recent molecular tests, such as liquid biopsy analysis, which are increasingly offering clinicians a means of ensuring optimal tailored treatments for patients with metastatic CRC according to their evolving molecular profile and treatment history.

Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer

“…The heterogeneity of CRC can be characterized by distinct clinical and pathological features, which lead to diverse prognoses and possibly account, at least in part, for resistance to treatment [ 4 , 5 ]. Currently, with the rapid development and wide application of next generation sequencing (NGS), molecular profiles of many cancers have been revealed, including CRC, which allows us to use these molecular biomarkers as both predictive and prognostic tools to manage patients with CRC [ 6 ].…”

Pan-drug and drug-specific mechanisms of 5-FU, irinotecan (CPT-11), oxaliplatin, and cisplatin identified by comparison of transcriptomic and cytokine responses of colorectal cancer cells

“…Preclinical studies suggest a synergistic effect of these combinations and these findings translate to the clinic, with response rates rising to 40–50% or more when single-agent 5-FU treatment is combined with oxaliplatin or CPT-11 [ 4 ]. Advanced CRC in 2021 is treated according to genetic alterations including the microsatellite stable (MSS) groups with KRAS/NRAS mutations, BRAF mutations, and KRAS/NRAS/BRAF WT, or microsatellite unstable (MSI) [ 5 ]. Classification of patients based on certain genetic alterations has some predictive and prognostic value [ 6 ], however more work needs to be done as far as creating prognostic gene signatures to predict outcomes [ 7 ].…”

CRISPR/Cas13-Based Platforms for a Potential Next-Generation Diagnosis of Colorectal Cancer through Exosomes Micro-RNA Detection: A Review

“…Late CRC diagnoses may be explained by numerous factors playing pivotal roles for diagnosis, including that CRC is comprised of a heterogeneous cancer population, known as consensus molecular subtypes of cancer (CSM1 to 4; further in-depth reading in [ 64 , 65 ]). CSM1 to 4 merges up to 27 CRC subtypes, representing four groups with different gene expression profiles between different regions of the tumor and tumor microenvironment (TME) components [ 66 ]. Moreover, intra-tumor heterogenicity (ITH) also drives to spatial heterogenicity [ 67 ], where CRC fully differentiates into functional cells and immature cancer stem cells inside the same cancer [ 67 , 68 ].…”