Acquired EGFR C797G Mutation Detected by Liquid Biopsy as Resistance Mechanism After Treatment With Osimertinib: A Case Report (original) (raw)
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Frontiers in Oncology, 2020
Targeted drug therapy based on the types of epidermal growth factor receptor (EGFR) gene mutations has been widely used in the diagnosis and treatment of patients with non-small cell lung cancer (NSCLC). With the development of next-generation sequencing (NGS) technology, more and more EGFR-tyrosine kinase inhibitor (TKI) resistance mutation sites have been revealed. Here, we report a novel EGFR L858R/A859S/Y891D triple mutation in plasma-derived circulating tumor DNA (ctDNA) was identified in a 53-year-old male patient with NSCLC resistant to osimertinib treatment, using an ultra-deep (20,000×) 160-gene panel through the NGS platform. Our case confirms that dynamic monitoring of liquid biopsy based on ctDNA is conducive to the selection of targeted therapy and the realization of the patient’s full course management.
JAMA oncology, 2018
Osimertinib mesylate is used globally to treat EGFR-mutant non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitor resistance mediated by the EGFR T790M mutation. Acquired resistance to osimertinib is a growing clinical challenge that is poorly understood. To understand the molecular mechanisms of acquired resistance to osimertinib and their clinical behavior. Patients with advanced NSCLC who received osimertinib for T790M-positive acquired resistance to prior EGFR tyrosine kinase inhibitor were identified from a multi-institutional cohort (n = 143) and a confirmatory trial cohort (NCT01802632) (n = 110). Next-generation sequencing of tumor biopsies after osimertinib resistance was performed. Genotyping of plasma cell-free DNA was studied as an orthogonal approach, including serial plasma samples when available. The study and analysis were finalized on November 9, 2017. Mechanisms of resistance and their association with time to treatment discontinuation on osimertinib. Of...
Combination osimertinib and gefitinib in C797S and T790M EGFR mutated non-small-cell lung cancer
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2017
Osimertinib, a third generation Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) has demonstrated efficacy in tumours harbouring the EGFR T790M resistance mutation. Inevitably, resistance to 3(rd) generation inhibitors result in disease progression, with the EGFR C797S mutation being one of several resistance pathways identified to date. Based on preclinical data, we report the first known case of a patient harbouring the T790M and C797S mutations in trans treated with combination gefitinib and osimertinib. On development of progressive disease following multiple therapies, the patient's plasma was sequenced using the Oncomine Lung cfDNA Assay. Subsequent monitoring of circulating tumour (ct) DNA in plasma was performed using droplet digital PCR. Sequencing showed that the T790M and C797S mutations were in trans. Within two weeks of commencement of combination therapy, rapid clinical improvement occurred. Accompanying this, a rapid decline in the C797S mut...
Clinical cancer research : an official journal of the American Association for Cancer Research, 2018
The third generation EGFR tyrosine kinase inhibitor osimertinib is approved to treat EGFR T790M-positive non-small cell lung cancer (NSCLC) patients who have developed resistance to earlier generation drugs. Acquired EGFR C797S mutation has been reported to mediate osimertinib-resistance in some patients. However, the remaining resistance mechanisms are largely unknown. We performed mutation profiling using targeted next-generation sequencing (NGS) for 416 cancer-relevant genes on 93 osimertinib-resistant lung cancer patients' samples, mainly cell-free DNAs (cfDNA), and matched pre-treatment samples of 12 patients. In vitro experiments were conducted to functionally study the secondary EGFR mutations identified. EGFR G796/C797, L792 and L718/G719 mutations were identified in 24.7%, 10.8% and 9.7% of the cases, respectively, with certain mutations co-existing in one patient with different prevalence. L792 and L718 mutants markedly increased the half inhibitory concentration (IC...
2021
Background: Osimertinib efficacy in pre-treated patients with epidermal growth factor receptor (EGFR) T790M-mutated non-small cell lung cancer (NSCLC) has been demonstrated in clinical trials, but real-world data, particularly regarding resistance profile, remains limited. This study aims to analyze the resistance mechanisms acquired after treatment with Osimertinib. Methods: Clinical outcomes and molecular results from re-biopsies at the time of osimertinib progression of EGFR T790M-mutated NSCLC patient were analyzed. Results: Twenty-one patients with stage IV adenocarcinoma were included [median 69 years; 57.1% female; 85.7% never-smokers; 23.8% ECOG performance status (PS) ≥2]. Median PFS and OS were 13.4 (95% CI: 8.0–18.9) and 26.4 (95% IC: 8.9–43.8) months, respectively. At the time of analysis, 10 patients had tumor progression (47.6%). T790M loss occurred in 50%, being associated with earlier progression (median PFS 8.1 vs. 21.4 months, p = 0.011). Diverse molecular alterati...
Experimental Hematology & Oncology, 2019
Cell-free DNA (cfDNA) next-generation sequencing has the potential to capture tumor heterogeneity and genomic evolution under treatment pressure in a non-invasive manner. Here, we report the detection of EGFR L792 mutations, a non-covalent mechanism of osimertinib resistance, using Guardant360 cfDNA testing in a patient with metastatic EGFR-mutant non-small cell lung cancer (NSCLC) whose disease progressed on osimertinib. We subsequently analyzed a large cohort of over 1800 additional patient samples harboring an EGFR T790M mutation and identified a concomitant L792 mutation in a total of 22 (1.2%) cases. In vitro functional assays demonstrated that the EGFR L858R/T790M/L792F/H mutations conferred intermediate-level resistance to osimertinib. Further understanding of potential acquired resistance mechanisms to targeted therapy may help inform treatment strategy in EGFR-mutant NSCLC.
International Journal of Molecular Sciences
Osimertinib is currently the preferred first-line therapy in patients with non-small cell lung cancer (NSCLC) with common epidermal growth factor receptor (EGFR) mutation and the standard second-line therapy in T790M-positive patients in progression to previous EGFR tyrosine kinase inhibitor. Osimertinib is a highly effective treatment that shows a high response rate and long-lasting disease control. However, a resistance to the treatment inevitably develops among patients. Understanding the secondary mechanisms of resistance and the possible therapeutic options available is crucial to define the best management of patients in progression to osimertinib. We provide a comprehensive review of the emerging molecular resistance mechanism in EGFR-mutated NSCLC pre-treated with osimertinib and its future treatment applications.
Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer
British Journal of Cancer
Osimertinib is an irreversible, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that is highly selective for EGFR-activating mutations as well as the EGFR T790M mutation in patients with advanced non-small cell lung cancer (NSCLC) with EGFR oncogene addiction. Despite the documented efficacy of osimertinib in first- and second-line settings, patients inevitably develop resistance, with no further clear-cut therapeutic options to date other than chemotherapy and locally ablative therapy for selected individuals. On account of the high degree of tumour heterogeneity and adaptive cellular signalling pathways in NSCLC, the acquired osimertinib resistance is highly heterogeneous, encompassing EGFR-dependent as well as EGFR-independent mechanisms. Furthermore, data from repeat plasma genotyping analyses have highlighted differences in the frequency and preponderance of resistance mechanisms when osimertinib is administered in a front-line versus second-l...
Lung Cancer, 2017
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Highlights EGFR mutations in cfDNA reveal tumor clonal evolution during osimertinib treatment. Detection of EGFR activating mutation in cfDNA forecasts resistance to osimertinib. EGFR-exon19del amplification is a putative resistance mechanism to osimertinib.