Ultra–early-onset metastatic colorectal cancer (<35 years): RAS-driven, APC/TP53-depleted, TMB-low molecular features in a real-world analysis of 2,392 patients.

3542 Background: Early-onset colorectal cancer (CRC, <50 years) is on the rise globally and includes a biologically heterogeneous disease. Patients diagnosed before age 35 represent the extreme of early-onset CRC, yet their clinical and genomic features remain poorly understood. We investigated whether ultra–early-onset metastatic CRC (UEO-CRC, <35 years) exhibits distinct outcomes and a unique molecular profile in a large real-world cohort. Methods: We analyzed a multicenter cohort of 2,392 patients with metastatic CRC; 1,612 had comprehensive genomic profiling (Foundation Medicine) and were included in molecular analyses. Patients were classified as ≤35 years (n=130) or >35 years (n=1482) at metastatic diagnosis. Overall survival (OS) was assessed using Kaplan–Meier estimates and log-rank tests. Gene- and pathway-level differences were evaluated using Fisher’s exact test. A composite UEO-CRC molecular signature was defined based on features significantly enriched or depleted in patients <35 years. Results: UEO-CRC represented 8.1% of metastatic cases. Patients ≤35 years had significantly worse survival than those >35 years (median OS 35.0 vs 46.0 months; p=0.0081). Molecular profiling revealed a distinct oncogenic pattern characterized by: enrichment of RAS mutations (KRAS 48.6% vs 36.4%, p=0.011; NRAS 11.7% vs 4.1%, p=0.0011); marked depletion of APC (21.6% vs 63.4%, p<0.001) and TP53 mutations (33.3% vs 63.8%, p<0.001); suppression of WNT pathway alterations (25.2% vs 66.9%, p<0.001); and genomic stability without hypermutation, including absence of TMB-high tumors (0% vs 7.5%, p=0.00037), lower median TMB (3.1 vs 4.8 mut/Mb, p<0.001), no MSI-H cases, and rare POLE/POLD1 or DDR alterations (4.5% vs 1.2%, p=0.017). Integration of these features identified a reproducible UEO-CRC molecular signature (RAS-mutant, APC/TP53 wild-type, TMB-low), over six-fold more frequent in UEO-CRC than in patients ≥35 years (32% vs 5%; p<0.001). Conclusions: Ultra–early-onset metastatic CRC (<35 years) represents a biologically aggressive and genomically distinct entity. UEO-CRC is defined by a non-canonical, RAS-driven, APC/TP53-independent tumorigenic program occurring without hypermutation, MSI-H, or POLE-driven biology. The lack of TMB-high indicates limited immunogenicity, emphasising the need for age-specific biological stratification and customised therapeutic strategies in this high-risk population.