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This research aims to characterize the distribution of BRAF functional classes in various tumor types and their implications for therapy.

May 30, 2026

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

Key Points

This research aims to characterize the distribution of BRAF functional classes in various tumor types and their implications for therapy.
Comprehensive genomic profiling of 8,337 solid tumor samples using a next-generation sequencing assay.
BRAF alterations classified by functional class and analyzed across tumor lineages using Fisher’s exact test.
Compared distributions of V600E versus non-V600E alterations among BRAF-mutant tumors.
Among 266 BRAF-mutant tumors, Class I alterations accounted for 66.5%, predominantly driven by V600E (59.8%).
40.2% of BRAF-mutant tumors had non-V600E alterations, including Class II mutations and gene fusions.
Significant enrichment of non-V600E alterations was observed in pancreatic, gastric, uterine, breast, and ovarian cancers compared to high-prevalence tumors like melanoma and thyroid (OR ≈ 18.1, p < 0.0001).

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

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