Critical Evaluation of Treatment Response, Driver Mutations, and Circulating Tumor DNA as Markers of Tumor Biology in Colorectal Liver Metastasis

Background: Improved assessment of tumor biology has contributed to better outcomes in colorectal liver metastasis (CLM). Previously, tumor biology was assessed based on clinical factors such as number and size of metastases, primary tumor characteristics, and extent of extrahepatic disease. Currently, tumor biology assessment includes response to chemotherapy, genetic mutations, and circulating tumor DNA (ctDNA). Methods: A review of the literature in Medline/Pubmed, Embase, and Cochrane Library was conducted using keywords and MeSH terms. Results: Tumor response to chemotherapy can be assessed using pathologic and radiologic criteria. Radiologic morphologic response has been associated with more accurate determination of outcomes compared with size-based criteria. Pathologic tumor response can be assessed by the percentage of cancer cells remaining within each tumor, the ratio of cancer cells to fibrosis, and the thickness of the tumor–normal liver interface. Six driver mutations are consistently associated with outcomes in CLM: RAS/BRAF, TP53, SMAD4, FBXW7, and APC. All are associated with decreased overall survival (OS) and recurrence-free survival (RFS) except for APC, which is associated with better survival. More than 50% of patients have co-mutations, and a three-tier pathway-centric risk score integrating these mutations offers a more comprehensive approach. While mutations should be considered when evaluating for locoregional therapy, it should not influence ablation margins, surgical margins, or parenchymal sparing approach. Preoperative ctDNA is associated with worse survival, but clearance after hepatectomy is associated with improved survival. Postoperative ctDNA status is associated with recurrence and has the potential to guide the choice of adjuvant chemotherapy. Conclusion: Tumor biology enables informed, precise, and personalized decision-making. Integration of response to chemotherapy, driver mutations, and ctDNA into routine practice is critical to improve CLM management.