Abstract
BackgroundLung cancer patients with an activating mutation in the EGFR (epidermal growth factor receptor) can develop resistance to erlotinib treatment, which is often mediated by the T790M resistance mutation in EGFR. The difficulties in obtaining biopsies at progression make it challenging to investigate the appearance of the T790M mutation at progression in large patient cohorts. We have used cell free DNA (cfDNA) from patients treated with erlotinib to investigate if the development of a T790M mutation coincides with the presence of an activating EGFR mutation in the pre-treatment blood sample.MethodsA cohort of 227 NSCLC (non-small cell lung cancer) adenocarcinoma patients was treated with erlotinib irrespective of EGFR-mutational status. Blood samples were drawn immediately before erlotinib treatment was initiated and again at progression. The cobas® EGFR Mutation Test v2 designed for cfDNA was used to identify 42 EGFR mutations.ResultsOf the 227 NSCLC patients, blood samples were available from 144 patients both before erlotinib treatment and at progression (within 1 month before or after clinical progression). One hundred and twenty-eight of the 144 were wild-type EGFR before treatment, and we demonstrate that the T790M mutation was not present at progression in any of these. In contrast, in the 16 patients with an activating EGFR mutation in the pre-treatment blood sample six patients (38%) were identified with a T790M mutation in the progression blood sample.ConclusionThe T790M resistance mutation is only found in the cfDNA of erlotinib-treated NSCLC patients if they have an activating EGFR mutation before treatment.
Highlights
IntroductionLung cancer patients with an activating mutation in the Epidermal growth factor receptor (EGFR) (epidermal growth factor receptor) can develop resistance to erlotinib treatment, which is often mediated by the T790M resistance mutation in EGFR
Lung cancer patients with an activating mutation in the Epidermal growth factor receptor (EGFR) can develop resistance to erlotinib treatment, which is often mediated by the T790M resistance mutation in EGFR
Patients and blood samples From a previously collected cohort, 227 Non-small cell lung cancer (NSCLC) adenocarcinoma patients treated with erlotinib from October 2008 to December 2012 were selected based on the presence of both a biopsy and paired blood samples isolated during treatment [10]
Summary
Lung cancer patients with an activating mutation in the EGFR (epidermal growth factor receptor) can develop resistance to erlotinib treatment, which is often mediated by the T790M resistance mutation in EGFR. A subgroup of NSCLC patients have activating mutations in the EGFR gene, primarily in exon 19 and 21 [1,2,3] This group responds well to EGFR-directed tyrosine kinase inhibitors (TKIs), like erlotinib and gefitinib, and today these agents are part of standard care. Apart from the NSCLC patients with activating EGFR mutations, it has been suggested that a subgroup of the EGFR wild-type patients experience benefit from erlotinib treatment [10]. Demuth et al BMC Cancer (2018) 18:191 investigation of resistance mechanisms for both EGFR wild type and mutation-positive patients is complicated, since re-biopsies from patients with progression are not taken systematically
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