Tyrosine Kinase Inhibitors Could Be Effective Against Non-small Cell Lung Cancer Brain Metastases Harboring Uncommon EGFR Mutations

Ma, Chi; Zhang, Juncheng; Tang, Dongjiang; Ye, Xin; Li, Jing; Mu, Ning; Li, Zhi; Liu, Renzhong; Xiang, Lei; Huang, Chuoji; Jiang, Rong

doi:10.3389/fonc.2020.00224

Cited by 19 publications

(14 citation statements)

References 47 publications

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“…Rare EGFR mutations could be classified as “rare” mutation, such as some EGFR exon point mutations of 10% (exon 18, G719X; exon 20, S768I; exon 21, L861Q) and “rarer” EGFR mutations for the others [ 3 , 16 ]. Their clinical presentation is not different, compared to common EGFR mutations, except for CNS metastases, which appear more frequently in uncommon mutations (54%) [ 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. Mechanisms of resistance to EGFR-TKIs are described most of the time for common EGFR mutations.…”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanism of EGFR-TKI Resistance in EGFR-Mutated Non-Small Cell Lung Cancer: Application to Biological Diagnostic and Monitoring

Reita

Pabst

Pencreach

et al. 2021

Cancers

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Non-small cell lung cancer (NSCLC) is the most common cancer in the world. Activating epidermal growth factor receptor (EGFR) gene mutations are a positive predictive factor for EGFR tyrosine kinase inhibitors (TKIs). For common EGFR mutations (Del19, L858R), the standard first-line treatment is actually third-generation TKI, osimertinib. In the case of first-line treatment by first (erlotinib, gefitinib)- or second-generation (afatinib) TKIs, osimertinib is approved in second-line treatment for patients with T790M EGFR mutation. Despite the excellent disease control results with EGFR TKIs, acquired resistance inevitably occurs and remains a biological challenge. This leads to the discovery of novel biomarkers and possible drug targets, which vary among the generation/line of EGFR TKIs. Besides EGFR second/third mutations, alternative mechanisms could be involved, such as gene amplification or gene fusion, which could be detected by different molecular techniques on different types of biological samples. Histological transformation is another mechanism of resistance with some biological predictive factors that needs tumor biopsy. The place of liquid biopsy also depends on the generation/line of EGFR TKIs and should be a good candidate for molecular monitoring. This article is based on the literature and proposes actual and future directions in clinical and translational research.

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Section: Introductionmentioning

confidence: 99%

Molecular Mechanism of EGFR-TKI Resistance in EGFR-Mutated Non-Small Cell Lung Cancer: Application to Biological Diagnostic and Monitoring

Reita

Pabst

Pencreach

et al. 2021

Cancers

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“…CSF liquid biopsy has emerged recently as a novel tool for assessing EGFR mutations in intracranial metastases. A recent study showed that in patients with NSCLC and leptomeningeal metastasis, the rate of uncommon EGFR mutation was high and that the brain metastases with uncommon EGFR mutations seem to respond to EGFR-TKI treatment (16). CSF liquid biopsy could reveal the EGFR genetic profile of the BM and help guide treatment using small-molecule TKI.…”

Section: Discussionmentioning

confidence: 99%

Effective Treatment With Afatinib of Lung Adenocarcinoma With Leptomeningeal Metastasis Harboring the Exon 18 p.G719A Mutation in the EGFR Gene Was Detected in Cerebrospinal Fluid: A Case Report

Wang

et al. 2020

Front. Oncol.

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Background: In patients with lung adenocarcinoma and leptomeningeal metastases, it remains unknown whether non-classical mutations in the epidermal growth factor receptor (EGFR) gene can be detected in the cerebrospinal fluid (CSF) and how it may be used to design directed therapy. Methods: On April 18, 2018, the Interventional Department of Tianjin Huanhu Hospital admitted a 34-years-old male patient with lung adenocarcinoma and leptomeningeal metastasis. An emergency lateral ventriculoperitoneal shunt was performed to relieve the clinical symptoms of intracranial hypertension. Next-generation sequencing (NGS) of the CFS specimens revealed a mutation in EGFR exon 18 p.G719A, and afatinib was administered. Follow-up showed significantly relieved headache, with significantly reduced soft leptomeningeal abnormal enhancement as revealed by enhanced magnetic resonance imaging and significantly smaller tumors in the left lung by chest computed tomography. Carcinoembryonic antigens (CEAs) in cerebrospinal fluid and peripheral blood were significantly reduced. The patient responded well to afatinib, with mild adverse complications. The patient died on October 27, 2019 from respiratory failure as a result of lung infection unrelated to cancer progression. The overall survival (OS) using afatinib was 530 days. Conclusion: CSF can be used as a liquid biopsy for NGS gene detection in patients with lung adenocarcinoma and leptomeningeal metastases. Afatinib exhibits a beneficial effect in patients with lung adenocarcinoma and leptomeningeal metastases harboring the EGFR exon 18 p.G719A mutation.

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“…The availability of targeted therapies highlights the importance of the identification of actionable genomic alterations or resistance mutations in genes, including EGFR , ALK , BRAF and HER2 , which have been detected from CSF ctDNA in several studies [ 20 , 21 , 31 , 32 , 94 , 95 , 96 ]. For example, EGFR–TKI resistance mutation EGFR T790M has been detected in the CSF ctDNA of lung cancer patients [ 94 , 97 ].…”

Section: Clinical Applications Of the Csf Ctdna For Cns Malignanciesmentioning

confidence: 99%

ctDNA-Based Liquid Biopsy of Cerebrospinal Fluid in Brain Cancer

Escudero

Martínez‐Ricarte

Seoane

2021

Cancers

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The correct characterisation of central nervous system (CNS) malignancies is crucial for accurate diagnosis and prognosis and also the identification of actionable genomic alterations that can guide the therapeutic strategy. Surgical biopsies are performed to characterise the tumour; however, these procedures are invasive and are not always feasible for all patients. Moreover, they only provide a static snapshot and can miss tumour heterogeneity. Currently, monitoring of CNS cancer is performed by conventional imaging techniques and, in some cases, cytology analysis of the cerebrospinal fluid (CSF); however, these techniques have limited sensitivity. To overcome these limitations, a liquid biopsy of the CSF can be used to obtain information about the tumour in a less invasive manner. The CSF is a source of cell-free circulating tumour DNA (ctDNA), and the analysis of this biomarker can characterise and monitor brain cancer. Recent studies have shown that ctDNA is more abundant in the CSF than plasma for CNS malignancies and that it can be sequenced to reveal tumour heterogeneity and provide diagnostic and prognostic information. Furthermore, analysis of longitudinal samples can aid patient monitoring by detecting residual disease or even tracking tumour evolution at relapse and, therefore, tailoring the therapeutic strategy. In this review, we provide an overview of the potential clinical applications of the analysis of CSF ctDNA and the challenges that need to be overcome in order to translate research findings into a tool for clinical practice.

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Tyrosine Kinase Inhibitors Could Be Effective Against Non-small Cell Lung Cancer Brain Metastases Harboring Uncommon EGFR Mutations

Cited by 19 publications

References 47 publications

Molecular Mechanism of EGFR-TKI Resistance in EGFR-Mutated Non-Small Cell Lung Cancer: Application to Biological Diagnostic and Monitoring

Molecular Mechanism of EGFR-TKI Resistance in EGFR-Mutated Non-Small Cell Lung Cancer: Application to Biological Diagnostic and Monitoring

Effective Treatment With Afatinib of Lung Adenocarcinoma With Leptomeningeal Metastasis Harboring the Exon 18 p.G719A Mutation in the EGFR Gene Was Detected in Cerebrospinal Fluid: A Case Report

ctDNA-Based Liquid Biopsy of Cerebrospinal Fluid in Brain Cancer

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