Selection Strategies and Practical Application of BRAF V600E-Mutated Non–Small Cell Lung Carcinoma

Purpose The incidence of BRAF V600E mutation in non–small cell lung carcinoma (NSCLC) is lower than 2%, which poses difficulties in finding legitimate patients for targeted therapy. We investigated the predictive factors pertaining to BRAF V600E and the effectiveness of the VE1 antibody as a screening method for patient selection. Materials and Methods The study was designed into two steps. In a first group, BRAF-mutated NSCLCs were identified from sequencing data to determine the features of BRAF V600E mutation. The results of the first group helped the collection of adenocarcinomas with a papillary or micropapillary pattern but without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) alterations as a second group so that the frequency of BRAF V600E mutation could be calculated. The sensitivity and specificity of the VE1 were compared with BRAF V600E status. Results Among 39 BRAF-mutated NSCLCs in the first group, 20 (51%) were V600E. BRAF V600E mutation was more common in female patients and showed no significant correlation with smoking status. Nineteen cases were adenocarcinomas without EGFR and ALK alterations. The most common patterns of invasion were papillary and micropapillary along with central fibrosis. The sensitivity and specificity of the VE1 were 90.0% and 92.3%, respectively. In the second group, 6.7% of cases were VE1-positive, indicating that the prevalence was significantly higher than that reported in previous studies (0.3%–1.8%). Conclusion BRAF V600E-mutated NSCLCs could be enriched with the application of clinicopathologic parameters, which are not perfect. Therefore, additional VE1 immunohistochemistry may be useful as a screening method.

[1]  Joe Y. Chang,et al.  NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 2.2021. , 2021, Journal of the National Comprehensive Cancer Network : JNCCN.

[2]  A. Jemal,et al.  Cancer Statistics, 2021 , 2021, CA: a cancer journal for clinicians.

[3]  C. Marquette,et al.  Real-world assessment of the BRAF status in non-squamous cell lung carcinoma using VE1 immunohistochemistry: A single laboratory experience (LPCE, Nice, France). , 2020, Lung cancer.

[4]  E. Lee,et al.  Cancer Statistics in Korea: Incidence, Mortality, Survival, and Prevalence in 2017 , 2020, Cancer research and treatment : official journal of Korean Cancer Association.

[5]  Jae Cheol Lee,et al.  Frequency and clinical features of BRAF mutations among patients with stage III/IV lung adenocarcinoma without EGFR/ALK aberrations , 2019, OncoTargets and therapy.

[6]  J. Shih,et al.  Validation of Immunohistochemistry for the Detection of BRAF V600E-Mutated Lung Adenocarcinomas , 2019, Cancers.

[7]  A. Iafrate,et al.  Impact of BRAF Mutation Class on Disease Characteristics and Clinical Outcomes in BRAF-mutant Lung Cancer , 2018, Clinical Cancer Research.

[8]  T. Mitsudomi,et al.  Ground-glass nodules of the lung in never-smokers and smokers: clinical and genetic insights. , 2018, Translational lung cancer research.

[9]  V. Velcheti,et al.  Dabrafenib in combination with trametinib in the treatment of patients with BRAF V600-positive advanced or metastatic non-small cell lung cancer: clinical evidence and experience , 2018, Therapeutic advances in respiratory disease.

[10]  Reena Philip,et al.  FDA Approval Summary: Dabrafenib and Trametinib for the Treatment of Metastatic Non‐Small Cell Lung Cancers Harboring BRAF V600E Mutations , 2018, The oncologist.

[11]  P. A. Futreal,et al.  Genomic Landscape of Atypical Adenomatous Hyperplasia Reveals Divergent Modes to Lung Adenocarcinoma. , 2017, Cancer research.

[12]  B. Taylor,et al.  Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS , 2017, Nature.

[13]  H. Groen,et al.  Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. , 2016, The Lancet. Oncology.

[14]  A. Leroux,et al.  Detection of BRAF Mutations Using a Fully Automated Platform and Comparison with High Resolution Melting, Real-Time Allele Specific Amplification, Immunohistochemistry and Next Generation Sequencing Assays, for Patients with Metastatic Melanoma , 2016, PloS one.

[15]  N. Girard,et al.  Clinical characteristics and outcome of patients with lung cancer harboring BRAF mutations. , 2016, Lung cancer.

[16]  Robert T. Jones,et al.  Cross-reactivity of the BRAF VE1 antibody with epitopes in axonemal dyneins leads to staining of cilia , 2015, Modern Pathology.

[17]  M. Ladanyi,et al.  Clinicopathologic features and outcomes of patients with lung adenocarcinomas harboring BRAF mutations in the Lung Cancer Mutation Consortium , 2015, Cancer.

[18]  M. Ladanyi,et al.  Clinical Characteristics and Course of 63 Patients with BRAF Mutant Lung Cancers , 2014, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[19]  C. Huang,et al.  Coexistence of EGFR with KRAS, or BRAF, or PIK3CA somatic mutations in lung cancer: a comprehensive mutation profiling from 5125 Chinese cohorts , 2014, British Journal of Cancer.

[20]  H. Sasaki,et al.  Usefulness of immunohistochemistry for the detection of the BRAF V600E mutation in Japanese lung adenocarcinoma. , 2013, Lung cancer.

[21]  Jeanne Shen,et al.  Clinical, Pathologic, and Biologic Features Associated with BRAF Mutations in Non–Small Cell Lung Cancer , 2013, Clinical Cancer Research.

[22]  Yi-long Wu,et al.  Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap) , 2013, Annals of oncology : official journal of the European Society for Medical Oncology.

[23]  A. von Deimling,et al.  Diagnostic value of immunohistochemistry for the detection of the BRAFV600E mutation in primary lung adenocarcinoma Caucasian patients. , 2013, Annals of oncology : official journal of the European Society for Medical Oncology.

[24]  A. Yoshizawa,et al.  Clinical significance of BRAF gene mutations in patients with non-small cell lung cancer. , 2011, Anticancer research.

[25]  Antonio Marchetti,et al.  Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  M. Ladanyi,et al.  Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  M. Nikiforova,et al.  The Histopathology of BRAF-V600E–mutated Lung Adenocarcinoma , 2008, The American journal of surgical pathology.

[28]  Y. Nishiwaki,et al.  Prognostic significance of the size of central fibrosis in peripheral adenocarcinoma of the lung. , 2000, The Annals of thoracic surgery.