Charlotte J. H. Hafkamp

Colorectal cancer (CRC) develops through evolutionary processes involving genomic alterations, epigenetic regulation, and microenvironmental interactions. While traditionally explained by the stepwise accumulation of driver mutations, contemporary evidence supports a ‘Big Bang’ model in which many early-arising clones expand simultaneously to establish extensive heterogeneity. We reviewed recent studies employing spatially resolved multi-omic sequencing of tumour glands combined with computational modelling. These approaches enable high-resolution reconstruction of clonal architecture, transcriptional states, and chromatin accessibility. Findings show that although early clonal mutations shape tumour expansion, gene expression variability can be independent of genetic ancestry and instead reflects phenotypic plasticity driven by microenvironmental cues. Epigenomic analyses identified recurrent somatic chromatin accessibility alterations in promotors and enhancers of oncogenic pathways, frequently in the absence of DNA mutations, suggesting alternative mechanisms of gene regulation. Immune-focused studies demonstrated that early silencing of antigen-presenting genes and loss of neoantigens facilitate immune escape despite active surveillance. CRC is shaped by an interplay of genome, epigenome, and immune evolution, with non-genetic mechanisms and tumour plasticity emerging as important drivers of progression and therapeutic resistance.

Colorectal cancer (CRC) is a major cause of cancer mortality worldwide, with metastatic disease remaining the main driver of poor prognosis. In recent years, the concept of oligometastatic disease, where patients present with a limited number of metastases, has created an opportunity to use local therapies with curative intent. Stereotactic ablative radiotherapy (SABR) has become increasingly important in this setting, as it allows the delivery of high, ablative doses with excellent local control and generally low toxicity. Notably, randomised data such as SABR-COMET, alongside large prospective series including SABR-5, have demonstrated improvements in survival outcomes in the context of oligometastatic disease across mixed primary tumour types, with CRC patients making up a relatively small proportion in these trials. This has presented SABR as a practical treatment option for patients with oligometastatic CRC, although more CRC-specific phase III trials are needed. Other challenges include the radioresistance of CRC metastases, and treatment outcomes that vary depending on the anatomical site, tumour biology, and prior therapies. Technical issues such as motion management and organ-at-risk constraints also continue to limit dose escalation. Emerging strategies—including MR-guided radiotherapy, proton-based SABR, integration with systemic agents such as immunotherapy, and the use of biomarkers and artificial intelligence to refine patient selection—are beginning to address these limitations. This review summarises the current evidence and emerging advancements to highlight how SABR may evolve as part of an integrated approach to oligometastatic CRC.