Molecular Subtypes and the Evolution of Treatment Decisions in Metastatic Colorectal Cancer

Colorectal cancer (CRC) has clinically relevant molecular heterogeneity at multiple levels: genomics, epigenomics, transcriptomics, and microenvironment features. Genomic events acquired during carcinogenesis remain drivers of cancer progression in the metastatic setting. For example, KRAS and NRAS mutations define a population refractory to epidermal growth factor receptor monoclonal antibodies, BRAF^V600E mutations associate with poor outcomes under standard therapies and response to targeted inhibitors in combinations, and HER2 amplifications confer unique sensitivity to double HER2 blockade. Multiple rare gene alterations driving resistance to epidermal growth factor receptor monoclonal antibodies have been described, with substantial overlap in primary and acquired mechanisms, in line with a clonal selection process. In this context, sequential analysis of circulating tumor DNA has the potential to guide drug development in a treatment-refractory setting. Rare kinase fusion events and complex alterations in genes involved in DNA damage repair have been described, with emerging evidence for targetability. On the other hand, transcriptomic subtypes and pathway activation signatures have also shown prognostic and potential predictive value in metastatic CRC. These markers reflect stromal and immune microenvironment interactions with cancer cells. For example, the microsatellite instable or POLE ultramutant CRC population is particularly sensitive to immune checkpoint inhibitors, whereas tumors with a mesenchymal phenotype are characterized by activation of immunosuppressive molecules that mandate stratified development of novel immunotherapy combinations. Here, we review the expanding landscape of targetable oncogenic alterations and signatures in metastatic CRC and discuss the clinical implementation of novel molecular diagnostic tests.