Introduction: Metastatic colorectal cancer (mCRC) remains a leading cause of cancer mortality worldwide, with limited long-term survival despite therapeutic advances. The increasing understanding of its molecular heterogeneity has paved the way for precision medicine approaches aiming to optimize treatment efficacy and reduce unnecessary toxicity.
Areas covered: This review provides an in-depth analysis of the current and emerging molecular targets in mCRC, including RAS, BRAF, HER2, and microsatellite instability. We discuss the clinical relevance of tumor sidedness, hyperselection panels, EGFR ligand expression, and rare alterations such as NTRK, RET, and ALK fusions. The review also explores the evolving role of KRAS G12C inhibitors, HER2-targeted therapies, and the application of liquid biopsy - particularly circulating tumor DNA (ctDNA) - in treatment monitoring, rechallenge strategies, and resistance detection. Literature was selected through a comprehensive review of recent clinical trials, consensus guidelines, and translational studies.
Expert opinion: Personalized treatment is now an attainable goal in mCRC. While promising, broader implementation of molecular-driven strategies requires overcoming challenges such as resistance mechanisms, assay standardization, and equitable access. The integration of innovative agents with real-time molecular monitoring holds the key to a more dynamic and effective management of mCRC.
Keywords: BRAF V600E; HER2-targeted therapy; KRAS G12C inhibitors; MSI-H/dMMR; NGS; immunotherapy; liquid biopsy; metastatic colorectal cancer.