Monitoring of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor-Sensitizing and Resistance Mutations in the Plasma DNA of Patients With Advanced Non-Small Cell Lung Cancer During Treatment With Erlotinib

BACKGROUNDThe feasibility of monitoring epidermal growth factor receptor (EGFR) mutations in plasma DNA from patients with advanced non-small cell lung cancer (NSCLC) during treatment with erlotinib and its relation to disease progression was investigated. METHODSThe amount of EGFR-mutant DNA was tested in plasma DNA from patients with advanced NSCLC with allele-specific polymerase chain reaction assays. Blood samples from 23 patients with adenocarcinoma of NSCLC that carried tyrosine kinase inhibitor-sensitizing EGFR mutations were taken immediately before treatment with erlotinib. Additional blood samples were taken at timed intervals until erlotinib treatment was withdrawn. RESULTSThe amount of plasma DNA with sensitizing EGFR mutations was found to be reduced after the first cycle of erlotinib treatment in 22 of 23 patients (96%). No patients presented with the resistant T790M mutation in the pretreatment sample, but at the time of disease progression the mutation was detected in plasma from 9 patients (39%). The quantitative data from the current study demonstrated that when a T790M mutation emerged in the blood it was accompanied by an increase in the original sensitizing EGFR mutation. When T790M was detected, it was found to be present in all subsequent blood samples from that patient. Most interestingly, the results of the current study demonstrated that monitoring the EGFR mutations in the blood allows for the detection of the T790M mutation up to 344 days before disease progression is clinically evident (range, 15-344 days). CONCLUSIONSThe results of the current study demonstrated that serial monitoring of EGFR mutations in plasma DNA is feasible and may allow for the early detection of resistance mutations. These results warrant further studies to explore the clinical usefulness of such analysis. Cancer 2014;120:3896-3901. (c) 2014 American Cancer Society. Using a new method that allows for the quantification of the level of tumor DNA with epidermal growth factor receptor (EGFR) mutations in a blood sample, the authors were able to monitor the effect of the EGFR-targeting agent erlotinib in patients with lung cancer. Most interestingly, the results of the current study demonstrate that a mutation (T790M) causing erlotinib resistance can be detected in the blood up to 1 year earlier than disease progression can be identified by Response Evaluation Criteria In Solid Tumors (RECIST) criteria.