Distribution of BRAF functional classes across select tumor lineages with implications in current targeted therapy paradigms.

Abstract

e15176 Background: BRAF -driven oncogenesis is biologically heterogeneous, and the clinical relevance of non-V600E BRAF alterations remains incompletely integrated into routine practice. Methods: Comprehensive genomic profiling was performed on 8,337 solid tumor samples using a NGS assay capable of detecting BRAF single-nucleotide variants, indels, and gene fusions. Among BRAF -mutant tumors, alterations were classified by functional class and distributions of V600E versus non-V600E alterations were compared across tumor lineages using Fisher’s exact test. Results: Among 266 BRAF -mutant tumors (3.2%), Class I alterations accounted for 66.5%, driven predominantly by V600E (59.8%). Notably, 40.2% of BRAF -mutant tumors harbored non-V600E alterations that fall outside current V600E-directed therapeutic paradigms, including non-V600E codon 600 variants (6.8%), Class II mutations and fusions (24.8%), and Class III variants (9.0%). Among Class II alterations, recurrent events included K601E/N (28.8%) and G469A/V/E (24.2%), along with diverse BRAF fusions (31.8%). Marked tumor-type–specific differences were observed. Tumors with high BRAF prevalence -melanoma (24.2%), thyroid (21.3%), colorectal (7.5%), CNS (5.8%), and lung (3.0%)- were predominantly V600E-driven (60–92%). In contrast, tumors with low BRAF prevalence, including pancreatic (2.8%), gastric (2.2%), uterine (1%), breast (0.4%) and ovary (0.2%) were enriched for non-V600 BRAF biology. In pancreatic cancer, 78% of BRAF -positive tumors harbored Class II alterations, while gastric cancers showed predominantly non-V600 alterations (60% Class II, 40% Class III). Grouped lineage analysis confirmed significant enrichment of non-V600E alterations in pancreatic, gastric, uterine, breast, and ovarian cancers compared with melanoma, thyroid, colorectal, CNS, and lung cancers (OR ≈ 18.1; Fisher’s exact p < 0.0001). Conclusions: BRAF functional class distribution is strongly tumor-type dependent. While tumors with high BRAF prevalence are largely V600E-driven, tumors enriched for non-V600 BRAF alterations occur less frequently overall but represent a disproportionate unmet clinical need, supporting lineage-informed therapeutic development and trials targeting non-V600E BRAF biology. Distribution of BRAF alteration classes across most represented tumor types in the cohort (distributions among BRAF -mutant tumors). Tumor Type Overall N BRAF mutant (%) Overall Class I (%) V600E (%) Non-V600E Codon 600 (%) Class II (Non-Fusion) (%) Class II Fusion (%) Class III (%) Lung 2117 3 70 60 10 19 8 3 Breast 1136 0.4 20 20 0 40 40 0 Colorectal 965 8 81 81 0 11 1 7 Ovary 498 0.2 0 0 0 0 0 100 Head & Neck 366 1 25 25 0 0 25 50 Sarcoma 359 1 50 50 0 0 50 0 Pancreas 318 3 11 11 0 78 0 11 CUP 282 10 75 46 29 11 4 11 CNS 257 6 67 67 0 7 27 0 Gastric 231 2 20 20 0 60 0 40 Biliary Tract 107 4 0 0 0 50 25 25