Early-Onset Colorectal Cancer: From Genetic Discovery to Clinical Innovation

The rising incidence of early-onset colorectal cancer (EOCRC) presents a growing challenge to traditional approaches in screening, treatment, and survivorship. EOCRC is increasingly recognized as a biologically distinct entity, driven by complex inter-related biological, genetic, behavioral, and socioenvironmental factors. This chapter reviews the molecular and clinical features that distinguish EOCRC, with attention to emerging precision oncology strategies, including germline testing, tumor genomic profiling, and biomarker-directed therapies. In metastatic disease, recent advances in targeting BRAF V600E, KRAS G12C, HER2 amplification, and microsatellite instability-high (MSI-H)/mismatch repair deficiency tumors have reshaped therapeutic paradigms. Tumor sidedness and metastatic site patterns are now recognized as predictive and prognostic factors. In localized disease, neoadjuvant immunotherapy for MSI-H tumors and nonoperative management are redefining standard care, with special relevance to younger patients seeking fertility preservation or organ-sparing approaches. The chapter also addresses key gaps in EOCRC care, including underutilization of fertility preservation counseling and limited guidance for cancer management during pregnancy. A multidisciplinary, lifecycle-based framework is essential to optimize outcomes and improve quality of life for this unique and growing patient population.