Artificial Intelligence-Guided Molecular Determinants of PI3K Pathway Alterations in Early-Onset Colorectal Cancer Among High-Risk Groups Receiving FOLFOX

<b>Background</b>: Early-onset colorectal cancer (EOCRC), defined as diagnosis before the age of 50, is rising rapidly and disproportionately affects high-risk populations, particularly Hispanic/Latino (H/L) individuals, who experience the steepest increases in incidence and mortality. While prevention and screening strategies have curbed late-onset CRC rates, EOCRC remains outside standard screening guidelines and is projected to become the leading cause of cancer-related death in individuals aged 20-49 by 2030. FOLFOX (folinic acid, fluorouracil, and oxaliplatin) is a standard first-line therapy for microsatellite stable (MSS) CRC lacking actionable driver mutations; however, its efficacy and genomic impact in EOCRC, particularly in underrepresented groups, remain poorly understood. The phosphatidylinositol 3-kinase (PI3K) pathway regulates cell growth, survival, and metabolism, and its alterations have been implicated in therapeutic resistance and adverse outcomes. Yet, the prevalence, clinical relevance, and treatment-specific associations of PI3K pathway alterations in EOCRC remain underexplored. <b>Methods</b>: We analyzed somatic mutation and clinical data from 2515 CRC patients (266 H/L and 2249 Non-Hispanic White [NHW]) across publicly available genomic datasets. Patients were stratified by age at diagnosis (EOCRC < 50 vs. LOCRC ≥ 50), ancestry (H/L vs. NHW), and FOLFOX treatment status. PI3K pathway alterations-including mutations in PIK3CA, PTEN, AKT isoforms, and regulatory genes-were identified using curated pathway definitions. Mutation prevalence was compared across groups using Fisher's exact or chi-squared tests. AI-HOPE-PI3K, a conversational AI platform, was deployed to automate cohort construction, stratify subgroups, and perform post hoc survival analysis. <b>Results</b>: PI3K pathway alterations were observed across all demographic groups. In EO NHW patients treated with FOLFOX, Kaplan-Meier analysis revealed significantly reduced overall survival among those with PI3K pathway alterations (<i>n</i> = 124) compared with their unaltered counterparts (<i>n</i> = 251; <i>p</i> = 0.0008), identifying alterations as a candidate prognostic biomarker in this subgroup. AI-guided subgroup interrogation further highlighted mutation-specific signals: INPP4B and RPTOR emerged as exploratory candidates in EO H/L patients but did not show significant treatment- or ancestry-specific enrichment upon confirmatory testing. Similarly, ancestry-stratified analysis of PIK3R2 mutations revealed comparable rates in EO H/L (1.37%) and EO NHW (1.6%) FOLFOX-treated patients (<i>p</i> = 1.0). Across ancestry and age groups, mutational landscape analysis revealed diverse molecular events-including missense, nonsense, splice-site, frameshift, and in-frame deletions-underscoring the heterogeneity of PI3K pathway dysregulation. <b>Conclusions</b>: This study identifies PI3K pathway alterations as a potential prognostic marker of poor survival in EO NHW patients receiving FOLFOX and uncovers ancestry- and treatment-specific mutational differences in high-risk CRC populations. By integrating clinical, molecular, and treatment variables, the AI-HOPE and AI-HOPE-PI3K platforms enabled rapid, reproducible, and fine-grained analysis of complex datasets. These findings underscore the need for ancestry-informed molecular profiling to optimize therapeutic strategies and highlight AI-guided interrogation as a powerful tool for advancing precision oncology in underrepresented and disproportionately affected CRC populations.