Distinct molecular and clinical aggressiveness in very early-onset metastatic colorectal cancer: survival and genomic divergence between patients aged 30-39 versus 40-49 years

Early-onset colorectal cancer (EOCRC) is increasing worldwide and exhibits clinical heterogeneity. Patients younger than 40 years may constitute a biologically distinct subgroup within EOCRC. A total of 264 patients were included (aged 30-39: n = 65; aged 40-49: n = 199). Median OS was shorter in patients aged 30-39 years than in those aged 40-49 years. A distinct genomic profile appeared in patients with VEOCRC, characterized by higher KRAS mutation rates and fewer APC alterations. NRAS, BRAF, PTEN, and POLE alterations were directionally consistent with a more aggressive biology, although event counts were limited. Peritoneal metastases occurred significantly more frequently in patients aged 30-39. No differences were observed regarding liver, lung, or nodal involvement. Patients aged 30-39 years constitute a biologically distinct subgroup within EOCRC, with shorter survival, KRAS mutation enrichment, fewer APC alterations, and increased peritoneal involvement. These findings support the emerging idea of an 'ultra-young', genomically driven CRC subtype, with implications for disease biology, risk assessment, and treatment development.