10-year molecular landscape of metastatic colorectal cancer in Latin America: Gender and age-specific mutational patterns in a large Colombian cohort (N=2,543).

Abstract

e15597 Background: Molecular profiling of KRAS , NRAS , and BRAF is mandatory for anti-EGFR therapy selection and prognostic stratification in metastatic colorectal cancer (mCRC). While well-characterized in Caucasian and Asian populations, large-scale data from Latin America—a region with unique genetic admixture—remain scarce. We aimed to characterize the mutational prevalence, demographic associations, and testing modalities in the largest Colombian mCRC cohort to date, identifying high-risk biological clusters. Methods: We conducted a retrospective analysis of 2,543 patients with stage IV CRC (2014–2023) at a national reference laboratory. Mutations in KRAS/NRAS (exons 2-4) and BRAF (exons 11, 15) were detected via RT-PCR (IVD/CE-marked). Testing was primarily performed on FFPE tissue (≥10% cellularity); plasma cfDNA was utilized since 2019 when tissue was unavailable. Statistical significance was assessed using 𝜒2 and Fisher’s exact tests. Results: The cohort was balanced by sex (49.3% female; 50.7% male; median age 61). FFPE was the predominant modality (11:1 ratio vs. plasma). Mutational Prevalence: FFPE rates were KRAS 3%, NRAS 8.0%, and BRAF 11.0%. Gender Dimorphism: Overall mutational burden was significantly higher in women (p < 0.05). Specifically, BRAF exon 15 (V600) variants were enriched in women (96.0% vs. 85.0% in men, p = 0.008), whereas exon 11 (non-V600) variants were more frequent in men (15.0% vs. 4.0%, $p = 0.01). Age Interaction: In women, BRAF mutations showed a strong association with age > 50 years (p = 0.002), a pattern not observed in men or for RAS Liquid Biopsy Performance: cfDNA showed lower sensitivity for RAS detection compared to FFPE (p < 0.001), primarily due to the failure to capture low-frequency NRAS . Conclusions: This landmark study reveals significant sex- and age-specific biological clusters in Colombian mCRC patients. The BRAF -age-gender nexus (Women > 50y) likely reflects a high prevalence of the Serrated Pathway, identifying a priority group for BRAF-targeted triplets and immunotherapy (MSI-H-linked). Furthermore, the identification of KRAS G12C and atypical BRAF (Exon 11) variants underscores the need for reflex NGS to personalize therapy. While liquid biopsy is expanding, tissue-based testing remains the gold standard for initial molecular staging in this real-world setting. Variable Total Cohort Women (n=1,253) Men (n=1,290) p-value Median Age (Range) 61 (15–95) 62 (18–95) 60 (15–92) 0.08 Specimen Type - FFPE Tissue 91.7% 91.5% 91.9% NS - Plasma cfDNA 8.3% 8.5% 8.1% NS Mutational Status (FFPE) - KRAS Mutated 52.3% 54.1% 50.5% 0.042 * - NRAS Mutated 8.0% 7.8% 8.2% 0.65 - BRAF Mutated 11.0% 12.8% 9.3% 0.015 * BRAF Subtype (Exon) - Exon 15 (V600) 90.5% 96.0% 85.0% 0.008 * - Exon 11 (Non-V600) 9.5% 4.0% 15.0% 0.012 * Age-Specific BRAF+ - Age >50 years - 14.2% 9.5% 0.002 * - Age <50 years - 8.1% 8.9% 0.45