Targetable genomic alterations in early-onset colorectal cancer and their therapeutic implications: Real-world data.

Abstract

e15542 Background: Colorectal cancer (CRC) diagnosed before the age of 50, referred to early-onset colorectal cancer (EOCRC), is increasing in incidence worldwide. The majority of cases are sporadic, with hereditary cancer syndromes accounting for only a small proportion. The clinical behavior and molecular characteristics of EOCRC remain incompletely characterized. This study aimed to compare the clinical and genomic features of EOCRC and late-onset colorectal cancer (LOCRC). Methods: Patients with CRC were identified from the GENIE Biopharma Collaborative (BPC) CRC v2.0 public dataset and the GENIE Cohort v18.0 public dataset, and were stratified into EOCRC and LOCRC groups based on age at the time of sequencing. Clinical and molecular characteristics were systematically analyzed. The prevalence of potentially targetable genomic alterations with FDA-approved or investigational therapies was evaluated using OncoKB, and levels of clinical actionability were assigned according to the OncoKB Therapeutic Level of Evidence (Version 2). Results: Among 21,853 patients with CRC, comprising 23,078 tumour samples, 5,879 (26.9%) were classified as EOCRC, and 14,490 (66.3%) as LOCRC. The median age at sequencing was 44 years (range, 17–50) in the EOCRC group and 64 years (range, 51–88) in the LOCRC group. Male predominance was more pronounced in the LOCRC cohort compared with the EOCRC cohort (53.8% vs. 50.5%, respectively; p < 0.001). Genomic profiling demonstrated that BRAF V600E, KRAS G12V, and CDK12 truncating alterations were significantly more prevalent in LOCRC tumors ( BRAF V600E: 8.66% vs. 3.42%, p < 0.0001; KRAS G12V: 8.60% vs. 7.39%, p = 0.0042; CDK12 truncations: 1.58% vs. 1.02%, p = 0.0079). In contrast, KRAS G12D, FBXW7 , NF1 , and POLE oncogenic mutations were enriched in EOCRC ( KRAS G12D: 13.48% vs. 11.26%, p < 0.0001; FBXW7 : 11.13% vs. 9.94%, p = 0.0121; NF1 : 2.64% vs. 2.12%, p = 0.0419; POLE : 1.16% vs. 0.39%, p = 0.0001). No significant differences were observed between groups for KRAS G12C, G12A, or G12S variants, nor for alterations in ARID1A , PIK3CA , PTEN , or POLD1 D402N. Conclusions: The distinct genomic profile of EOCRC, including increased prevalence of KRAS G12D and FBXW7 alterations, underscores potential biological differences from late-onset disease. Incorporating these insights into molecular testing strategies may enhance patient stratification and inform targeted therapeutic development. Alteration ≤50 >50 P-value Evidence level Therapy BRAF-V600E 201 (3.42%) 1254 (8.66%) <0.0001 1 Encorafenib + Cetuximab POLE 54 (1.16%) 43 (0.39%) 0.0001 2 Immunotherapy KRAS-G12D 792 (13.48%) 1631 (11.26%) <0.0001 3 ASP3082; MRTX-1133 KRAS-G12V 434 (7.39%) 1246 (8.60%) 0.0042 3 Daraxonrasib NF1 130 (2.64%) 238 (2.12%) 0.0419 3 Cobimetinib; Trametinib CDK12 47 (1.02%) 166 (1.58%) 0.0079 3 Immunotherapy FBXW7 648 (11.13%) 1420 (9.94%) 0.0121 4 Lunresertib + Camonsertib