Reference Detail

Ref Type

Journal Article

PMID

(39516363)

Authors

Özgü E, Kaplan BG, Sivakumar S, Sokol ES, Aydın E, Tokat ÜM, Adibi A, Karakoç EG, Hu J, Kurzrock R, Demiray M

Title

Therapeutic vulnerabilities and pan-cancer landscape of BRAF class III mutations in epithelial solid tumors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
BJC reports	2	1	2024 Oct 08	77	BJC Rep

URL

Abstract Text

Kinase-impaired class III BRAF mutations have recently received attention as a possible prognostic factor and therapeutic target. Class III BRAF variants differ from class I and class II mutations in terms of mechanism of pathway activation and therapeutic vulnerabilities. Genomic landscape analyses of tumors in large real-world cohorts represent a great opportunity to further characterize tumor-related molecular events and treatment vulnerabilities, however, such data is not yet available for tumors with BRAF class III mutations.We investigated the pan-cancer genomic landscape of BRAF class III mutations in 376,302 patients. Patients had comprehensive genomic profiling either by FoundationOne® or FoundationOne®CDx from formalin-fixed, paraffin embedded tissue biopsies. 2 patient cases that harbored BRAF class III mutations who demonstrated dramatic response to anti-EGFR treatment were presented.BRAF class III mutations are likely to co-occur with RAF1, NRAS and HRAS alterations, while concomitant KRAS alterations were rare. Moreover, we found that alterations that predict resistance to anti-EGFR agents were significantly less common in tumors harboring BRAF class III mutations, which is of great importance as anti-EGFR therapies are a potential targeted treatment option in these tumors.Our findings suggest a heterogenous interplay of oncogenic alterations in BRAF class III mutated tumors and have important implications for the molecular mechanisms of carcinogenesis while revealing potential therapeutic vulnerabilities.Tumors harboring BRAF class III (BRAF vIII) mutations comprise a novel subset with distinct genomic heterogeneity. BRAF vIII mutations may sensitize tumors to anti-EGFR treatments. BRAF vIII alterations show significantly less co-occurrence with alterations that predict resistance to anti-EGFR agents. Rare tumors with limited therapy options should be screened for BRAF vIII mutations as they may benefit from anti-EGFR agents.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF D594G	colon carcinoma	predicted - sensitive	Cetuximab + Trametinib	Case Reports/Case Series	Actionable	In a clinical case study, treatment with the combination of Erbitux (cetuximab) and Mekinist (trametinib) resulted in a radiologic complete response after 6 months in a patient with colon carcinoma harboring BRAF D594G (PMID: 39516363).	39516363
BRAF F595L	intrahepatic cholangiocarcinoma	predicted - sensitive	Cetuximab + Trametinib	Case Reports/Case Series	Actionable	In a clinical case study, treatment with the combination of Erbitux (cetuximab) and Mekinist (trametinib) followed by Erbitux (cetuximab) monotherapy resulted in an objective response at a follow-up of 6 months in a patient with intrahepatic cholangiocarcinoma harboring BRAF F595L along with an IDH2 R172W (PMID: 39516363).	39516363