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

Background: 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. We investigated whether ‘very early-onset’ metastatic colorectal cancer (VEOCRC, ages 30-39) exhibits specific clinical and genomic features compared with EOCRC in patients aged 40-49 and whether these differences lead to variations in survival from the time of metastatic diagnosis. Materials and methods: We analysed the data of metastatic EOCRC patients in a multi-institutional database, divided into two predefined age groups: 30-39 years and 40-49 years. Overall survival (OS) from metastatic diagnosis was estimated using Kaplan–Meier methods, and hazard ratios (HRs) were calculated with Cox regression. Comprehensive genomic profiling was carried out using the Foundation Medicine next-generation sequencing platform (FoundationOne®). Key molecular alterations were compared using odds ratios (ORs). Baseline clinicopathologic characteristics were assessed using χ2 or two-sided Fisher's exact tests. Results: 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 (30.0 versus 38.0 months; log-rank P = 0.0269; HR 0.67). A distinct genomic profile appeared in patients with VEOCRC, characterised by higher KRAS mutation rates (55.4% versus 42.0%; OR 1.71; one-sided P = 0.041) and fewer APC alterations (69.2% versus 82.0%; one-sided P = 0.024). NRAS, BRAF, PTEN, and POLE alterations were directionally consistent with a more aggressive biology, although event counts were limited. Clinically, overall Eastern Cooperative Oncology Group performance status (ECOG PS) distribution was similar (χ2 P = 0.099), but ECOG PS 0 was more common in VEOCRC (89.1% versus 76.8%; P = 0.0468). Peritoneal metastases occurred significantly more frequently in patients aged 30-39 (32.3% versus 19.6%; P = 0.041). No differences were observed regarding liver, lung, or nodal involvement. Conclusions: 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.