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

Background: Early-onset colorectal cancer (EO-CRC) is rising worldwide and exhibits clinical heterogeneity. Patients under 40 may constitute a biologically distinct subgroup within EO-CRC. We investigated whether “very early-onset” colorectal cancer (VEO-CRC, ages 30-39) exhibits specific clinical and genomic features compared with patients aged 40-49, and whether these differences lead to variations in survival at the point of metastatic diagnosis. Methods: We analysed metastatic EO-CRC patients from a multi-institutional database, divided into two predefined age groups: 30-39 years (n=65) and 40-49 years (n=199). 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® CDx / Heme; over 300 cancer-related genes). Key molecular alterations (KRAS, NRAS, BRAF, APC, PTEN, POLE) were compared using odds ratios (ORs), with prespecified one-sided tests for directionality. Baseline clinicopathologic characteristics were assessed with χ² or Fisher's exact tests. Results: Median OS was notably shorter in patients aged 30-39 years than in those aged 40-49 years (30.0 vs 38.0 months; log-rank p = 0.0269; HR = 0.67, 95% CI 0.48-0.96). A distinct genomic profile appeared in VEO-CRC, characterised by higher KRAS mutation rates (55.4% vs 42.0%; OR=1.71; 95% CI 0.98-3.01; one-sided p=0.041) and lower APC alterations (69.2% vs 82.0%; OR=0.49; 95% CI 0.26-0.94; 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 ECOG distribution was similar (χ² p=0.099), but ECOG 0 was more common in VEO-CRC (89.1% vs 76.8%; p=0.0468). Peritoneal metastases occurred significantly more frequently in patients aged 30-39 (32.3% vs 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 EO-CRC, with shorter survival, greater KRAS enrichment, fewer APC alterations, and increased peritoneal involvement, despite similar performance status. These findings support the emerging idea of an “ultra-young,” genomically driven CRC subtype, with implications for disease biology, risk assessment, and treatment development.