BRAF-mutated Non-small Cell Lung Research Articles

Encorafenib and binimetinib as a new regimen for BRAF mutant non-small cell lung cancer

Encorafenib and binimetinib as a new regimen for BRAF mutant non-small cell lung cancer

Radiomic features of primary tumor by lung cancer stage: analysis in BRAF mutated non-small cell lung cancer.

BackgroundThe clinical features and traditional semantic imaging characteristics of BRAF-mutated non-small cell lung cancer (NSCLC) have been previously reported. The radiomic features of BRAF-mutated NSCLC and their role in predicting cancer stage, however, have yet to be investigated. This study’s goal is to assess the differences in CT radiomic features of primary NSCLC driven by BRAF mutation and stratified by tumor-node-metastasis (TNM) staging.MethodsOur IRB approved study included 62 patients with BRAF mutations (V600 in 27 and non-V600 in 35 patients), who underwent contrast-enhanced chest CT. Tumor stage was determined based on the 8th edition of TNM staging. Two thoracic radiologists assessed the primary tumor imaging features such, including tumor size (maximum and minimum dimensions) and density (Hounsfield units, HU). De-identified transverse CT images (DICOM) were processed with 3D slicer (Version 4.7) for manual lesion segmentation and estimation of radiomic features. Descriptive statistics, multivariate logistic regression, and receiver operating characteristics (ROC) were performed.ResultsThere were significant differences in the radiomic features based on cancer stages I-IV with the most significant differences between stage IV and stage I lesions [AUC 0.94 (95% CI: 0.86–0.99), P<0.04]. There were also significant differences in radiomic features between stage IV and combined stages I-III [40/113 radiomic features; AUC 0.71 (95% CI: 0.59–0.85); P<0.04–0.0001]. None of the clinical (0/6) or imaging (0/3) features were significantly different between stage IV and combined stages I–III.ConclusionsThe radiomic features of primary tumor in BRAF driven NSCLC significantly vary with cancer stage, independent of standard imaging and clinical features.

P2.16-08 Clinical Characteristics and Outcomes of Patients with BRAF Mutated Non-Small Cell Lung Cancer

BRAF mutation is a driver oncogene identified in 0.5-2% of non-small cell lung cancer (NSCLC) patients in China, and clinical data are relatively inadequate. This study assessed the clinical characteristics, course of disease and treatment outcomes in patients with BRAF mutated NSCLC in a real-world setting. Between Apr 1, 2017 and Feb 1, 2019, medical data of patients with NSCLC harboring BRAF mutation in our cancer center was retrospective collected. Patient characteristics and treatment outcomes were reviewed. Data cutoff was Apr 1, 2019. A total of 36 patients were identified. BRAF V600E was the most common (31/36, 86.1%), other BRAF molecular subsets were observed in 5 (13.9%) cases including K601E, G469V, G596R and D594N. The majority of patients with BRAF mutation were female (20/36, 55.6%) and non-smokers (20/36, 55.6%), all of them were adenocarcinoma, and median age at diagnosis was 56 (range, 33-79). Twenty-seven patients were recurrent or metastatic NSCLC at data cutoff, most of whom received chemotherapy (16/27, 59.3%) as first-line therapy with median progression-free survival (PFS) of 9.8 months (95%CI 0.0, 21.5) and disease control rate (DCR) of 68.8% (11/16). Eight patients received anti-BRAF targeted therapy (including dabrafenib, trametinib and vemurafenib) in the first-line and showed superior efficacy than those received chemotherapy (median PFS, 15.9 months [95%CI, 4.5, 27.3] vs. 9.8 months [95%CI, 0.0, 21.5], P = 0.183; DCR, 100% vs. 68.8%, P = 0.130). As for distinct molecular subsets, most patients with V600E mutation were female (19/31, 61.3%) and non-smokers (19/31, 61.3%), while four of five (80.0%) patients with non-V600E mutation were male and smokers. All of the 3 patients in non-V600E mutations subgroup with recurrent or metastatic disease received chemotherapy in the first-line, and achieved 2 of SD, 1 of PD. NSCLC with BRAF mutation was associated with specific characteristics, which were variable between molecular subsets. BRAF inhibitors should be considered firstly in treating patients with BRAF-mutated lung cancers. The prognosis value of non-V600E mutations and treatment selection needs more research.

BRAF mutant non-small cell lung cancer and treatment with BRAF inhibitors.

Inhibitors targeting active protein kinases, such as EGFR or ALK, have demonstrated significant efficacy in the treatment of lung cancer. Activating mutations in the MAPK pathway, which includes the enzymes RAS, RAF, MEK, and ERK, result in constitutive signalling, leading to oncogenic cell proliferation and escape from apoptosis; therefore this pathway is a focus of crucial interest for the development of cancer drugs. In melanoma, the most commonly mutated gene is BRAF, with mutations usually occurring in about 50% of all tumours. The BRAF Val600Glu (V600E) mutation constitutes more than 90% of mutations in melanoma. V600E BRAF mutation shows a great dependency on MEK activity, and offers a rational therapeutic strategy for this genetically defined tumour subtype. The use of vemurafenib and dabrafenib, agents that block MAPK signaling in patients with melanoma and the BRAF V600E mutation, has been associated with prolonged survival and progression-free survival. The frequency of V600E BRAF mutation in lung adenocarcinoma is 1.5% to 2.8%. Treatment of V600E BRAF-mutant lung adenocarcinomas with dabrafenib is under evaluation in a phase 2 trial, and could represent another milestone in individualized therapy for lung cancer patients. The next step will be a combination therapy of BRAF inhibitor dabrafenib and MEK inhibitor trametinib.

The Effect of Gefitinib on B-RAF Mutant Non-small Cell Lung Cancer and Transfectants

We previously reported one patient with squamous cell carcinoma of the lung that showed the long-term effect to gefitinib with complete response. In the present report, we examine the epidermal growth factor receptor (EGFR) and K-RAS, HER2, and B-RAF mutations in this patient to find a B-RAF exon11 mutation, resulting in a substitution of valine by phenylalanine at codon 470 (V470F) as a novel type of B-RAF mutation in human cancers. In addition, the fluorescence in situ hybridization analysis for EGFR showed the high polysomy status. B-RAF is a nonreceptor serine/threonine kinase whose kinase domain has a structure similar to other protein kinases, including EGFR members. Of interest, the B-RAF V470F mutation corresponds to a position similar to the EGFR G719X mutation located on the phosphate binding (P)-loop of EGFR that clamps ATP into the catalytic cleft. This observation suggests that gefitinib may have an anti-cancer effect on B-RAF mutant tumors. Indeed, previous reports demonstrated that H1666 cells harboring B-RAF G465V mutations showed sensitivity to gefitinib, inhibiting phosphorylation of ERK1/2. We examined the effect of gefitinib on transient transfectants of the B-RAF mutant, but no drastic inhibition of ERK1/2 phosphorylation that was one of the downstream molecules of B-RAF was induced by gefitinib. In summary, we found a novel B-RAF V470F mutation in lung squamous cell carcinoma that showed response to gefitinib. However, our in vitro investigation did not explain the response observed in this particular patient. Further investigation is necessary to elucidate the mechanism of tumor sensitivity to EGFR tyrosine kinase inhibitors.