Abstract 4103: Dynamic co-mutation patterns and therapeutic implications in BRAF-altered malignancies: Evidence from AACR Project GENIE

Abstract Background: BRAF gene alterations result in persistent activation of the MAPK signaling cascade, a well-established oncogenic driver across diverse tumor types. A comprehensive pan-cancer analysis of BRAF alteration types (mutations, CNAs, and fusions), co-mutation landscapes, and actionability in large cohorts remains limited. Methods: We utilized AACR Project GENIE v18.0-public to characterize BRAF alteration prevalence, co-mutations, and actionability. OncoKB levels (L1-L4) defined actionability, and serial samples were analyzed for clonal evolution. Results: Among 204,292 samples, BRAF alterations were detected in 23,363. BRAF mutations were identified in 12,860 samples (7,359 with V600 and 5,501 with non-V600 variants). Prevalence was highest in thyroid cancer (44.9%), melanoma (38.0%), and histiocytosis (33.5%). V600 variants predominated in thyroid cancer (97.2%; 98.4% in papillary and 99.2% in anaplastic) and melanoma (76.7%), while non-V600 variants were enriched in NSCLC (73.3%), endometrial (98.5%), and bladder cancer (96.6%). BRAF copy number alterations (CNAs) were present in 10,274 samples, with the highest prevalence in breast (85.9%), esophagogastric (70.3%), and ovarian (69.6%) cancers. BRAF fusions occurred in 1,153 samples, with the highest prevalence in glioma (16.8%) and prostate cancer (14.2%). Tumor-centric actionability was high in histiocytosis (93.5% actionable), thyroid cancer (91.9%), and melanoma (79.3%), and was substantial in colorectal cancer (50.6%) and glioma (31.6%). Alteration-centric analysis confirmed L1 evidence as highest level for V600 alterations across solid tumors and for fusions (e.g., KIAA1549-BRAF in glioma). Non-V600 alterations showed L2-L4 evidence as highest level (e.g., MEK inhibitors in histiocytoses; investigational RAF inhibitors). Non-V600 tumors showed significantly higher co-mutation burden, with 40 genes enriched, including RTK/RAS (KRAS: 18.5% vs 1.3%; NF1: 18.7% vs 3.6%), chromatin remodeling (ARID1A: 20.1% vs 7.3%), and PI3K/AKT (PIK3CA: 19.8% vs 8.8%). Co-mutation analysis revealed a substantial fraction of events with OncoKB evidence, particularly in RTK/RAS, chromatin, and PI3K/AKT pathways, creating opportunities for rational combination strategies. Serial analysis of 2,314 samples from 1,072 patients demonstrated dynamic evolution of co-mutations, supporting serial profiling to identify emerging therapeutic targets. Conclusions: This study represents the most extensive pan-cancer analysis of BRAF alterations, highlighting their prevalence, co-mutation, and actionability patterns. Non-V600 tumors exhibit higher genomic complexity and actionable co-mutation burden, which could inform combination strategies. The dynamic evolution of co-mutation underscores the need for serial profiling to uncover emerging therapeutic vulnerabilities. Citation Format: Mohamed M. Khamis, Vivek Subbiah, Mohamed Gouda. Dynamic co-mutation patterns and therapeutic implications in BRAF-altered malignancies: Evidence from AACR Project GENIE 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 4103.