Abstract 7908: Distinct molecular and clinical aggressiveness in very early-onset colorectal cancer: Survival and genomic divergence between patients aged 30-39 vs 40-49 years

Abstract 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. Citation Format: Andrea Pretta, Gaia Rebecchi, Giulia Maddalena, Federica Marmorino, Pina Ziranu, Federica Manoni, Maria Caterina De Grandis, Martina Carullo, Clelia Donisi, Giovanni Randon, Eleonora Perissinotto, Ada Taravella, Vincenzo Nasca, Federica Buggin, Paolo Ciracì, Francesca Bergamo, Chiara Cremolini, Sara Lonardi, Mario Scartozzi, Filippo Pietrantonio. Distinct molecular and clinical aggressiveness in very early-onset colorectal cancer: Survival and genomic divergence between patients aged 30-39 vs 40-49 years abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7908.