ABSTRACT
BACKGROUND: The role of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in the treatment of patients with advanced non-small cell lung cancer (NSCLC) and unknown EGFR mutation status has recently been questioned. PATIENTS AND METHODS: We conducted a retrospective study of patients with unknown EGFR mutation status and long-term response (LTR) to gefitinib in the Swiss Iressa expanded access program (EAP). We assessed patient characteristics, and performed Sanger sequencing and next generation sequencing on archived tumor tissue. We hypothesized that EGFR mutations are prevalent in patients with LTR. RESULTS: Of 430 patients in the EAP, 18 (4%) fulfilled our definition of LTR, and 16 of them had archived tumor tissue. Patient characteristics were as expected for age, sex, and smoking history. Median duration of therapy was 38 months (range 24-142 months). Sanger sequencing revealed EGFR exon 18-21 mutations in 6 (38%) of the tumors. Next generation sequencing revealed no further EGFR-mutated cases, but reported in 15 (94%) of the tumors mutations in other genes (ALK, BRAF, DDR2, KEAP1, MET, PTEN, STK11) previously associated with NSCLC. CONCLUSION: Larger studies are needed to define the prognostic values of different driver mutations in patients with NSCLC.
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , ErbB Receptors/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Quinazolines/therapeutic use , Adult , Age Distribution , Aged , Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/epidemiology , DNA Mutational Analysis/methods , Female , Gefitinib , Gene Expression Profiling/methods , Genetic Markers/genetics , Humans , Longitudinal Studies , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , Prevalence , Retrospective Studies , Risk Factors , Sex Distribution , Smoking/epidemiology , Switzerland/epidemiology , Treatment OutcomeABSTRACT
BRAF V600E is an emerging drug target in lung cancer, but the clinical significance of non-V600 BRAF mutations in lung cancer and other malignancies is less clear. Here, we report the case of a patient with metastatic lung adenocarcinoma with BRAF G469L mutation refractory to vemurafenib. We calculated a structure model of this very rare type of mutated BRAF kinase to explain the molecular mechanism of drug resistance. This information may help to develop effective targeted therapies for cancers with non-V600 BRAF mutations.
