Fundamental Concepts in the Application of Plasma Genotyping (Liquid Biopsy) to EGFR Mutation Detection in Non–Small-Cell Lung Cancer

2018 ◽  
pp. 1-12
Author(s):  
Adrian G. Sacher
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Small Cell ◽  
Newly Diagnosed ◽  
Small Cell Lung ◽  
Metastatic Nsclc ◽  
Egfr Kinase

Plasma genotyping has rapidly evolved from an investigational technology into a standard-of-care tool used to direct therapy in metastatic non–small-cell lung cancer (NSCLC). Multiple testing platforms exist for plasma genotyping, each with unique test characteristics and scientific validation. The optimal use and interpretation of plasma genotyping requires understanding of cell-free DNA biology, the assay characteristics of the available testing technologies, and the application of testing in each clinical scenario. Current recommendations for plasma genotyping in metastatic NSCLC are limited to patients with newly diagnosed disease and those with acquired resistance to targeted therapy, in particular, epidermal growth factor receptor (EGFR) kinase inhibitors. In newly diagnosed metastatic NSCLC, under certain circumstances, plasma genotyping is useful for the detection of targetable genomic alterations or nontargetable driver alterations (eg, KRAS) that are mutually exclusive with targetable alterations. In patients with acquired resistance to therapy, such as EGFR T790M-mediated acquired resistance to EGFR kinase inhibitors, plasma genotyping may detect resistance mutations missed by standard tissue genotyping because of tumor heterogeneity. In both scenarios, the high specificity and positive predictive value of validated plasma genotyping assays allow for the reliable selection of therapy on the basis of a positive plasma genotyping result. However, the modest sensitivity of these assays requires that negative results be confirmed by tissue genotyping with repeat biopsy, if necessary. There is considerable potential for plasma genotyping in the detection of early-stage disease, for patients at risk for disease recurrence, and as an integrated biomarker of therapeutic response in clinical trials of novel therapies.

scholarly journals Real-world osimertinib for EGFR mutation-positive non-small-cell lung cancer with acquired T790M mutation

2020 ◽  
Vol 16 (21) ◽  
pp. 1537-1547
Author(s):  
Fumio Imamura ◽  
Madoka Kimura ◽  
Yukihiro Yano ◽  
Masahide Mori ◽  
Hidekazu Suzuki ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Egfr Mutation ◽  
Acquired Resistance ◽  
Small Cell ◽  
Small Cell Lung ◽  
T790m Mutation ◽  
Clinical Trial Registration

Aim: Osimertinib is a key drug for EGFR mutation-positive non-small-cell lung cancer (NSCLC). As the hazards ratio of overall survival in comparison with first-generation EGFR-tyrosine kinase inhibitors was almost similar between FLAURA and ARCHER 1050, salvage use of osimertinib is still a treatment option. Patients & methods: We retrospectively analyzed the clinical courses of EGFR mutation-positive NSCLC patients who were potential candidates for salvage osimertinib. Results: Among 524 patients enrolled from five hospitals, 302 patients underwent biopsy, with 52.6% detection rate of T790M. Osimertinib was administered in 93.6% of the T790M-positive patients. The overall response rate and median progression-free survival time of osimertinib were calculated with 147 patients, to be 55.6% and 17.2 months, respectively. Conclusion: Osimertinib is active for T790M-driven acquired resistance in EGFR-mutant NSCLC, but the detection of T790M was unsatisfactory. Clinical Trial Registration: UMIN000028989 (UMIN Clinical Trials Registry)

scholarly journals Mechanisms of Resistance to EGFR TKIs and Development of a New Generation of Drugs in Non-Small-Cell Lung Cancer

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Takayuki Kosaka ◽  
Ei Yamaki ◽  
Akira Mogi ◽  
Hiroyuki Kuwano
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Clinical Problem ◽  
Small Cell ◽  
Small Cell Lung ◽  
Egfr Tkis

Gefitinib and erlotinib, which are epidermal growth factor receptor- (EGFR-) specific tyrosine kinase inhibitors (TKIs), are widely used as molecularly targeted drugs for non-small-cell lung cancer (NSCLC). Currently, the search forEGFRgene mutations is becoming essential for the treatment of NSCLC since these have been identified as predictive factors for drug sensitivity. On the other hand, in almost all patients responsive to EGFR-TKIs, acquired resistance is a major clinical problem. Mechanisms of acquired resistance reported in the past few years include secondary mutation of theEGFRgene, amplification of theMETgene, and overexpression of HGF; novel pharmaceutical agents are currently being developed to overcome resistance. This review focuses on these mechanisms of acquired resistance to EGFR-TKIs and discusses how they can be overcome.

Role of Cytomorphology in the Era of Liquid Biopsy

2019 ◽  
Vol 63 (6) ◽  
pp. 497-505 ◽  
Author(s):  
Eduardo Clery ◽  
Pasquale Pisapia ◽  
Elena Vigliar ◽  
Umberto Malapelle ◽  
Claudio Bellevicine ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Morphological Changes ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Large Cell ◽  
Small Cell ◽  
Small Cell Lung

In the late stages of non-small cell lung cancer, the detection of sensitizing mutations of the epidermal growth factor receptor (EGFR) is mandatory to select patients’ treatment with first- or second-generation tyrosine kinase inhibitors (TKIs). In patients showing progressive disease, the assessment of the EGFR exon 20 resistance point mutation p.T790M is required for third-generation TKI administration. However, molecular analysis does not capture all the different mechanisms of resistance against these molecules. A variety of morphological changes associated with acquired resistance have also been described. Since an altered morphology may be the only clue to acquired resistance, cytopathology still plays a relevant role in this setting. In this comprehensive review, we have focused on the relevance of squamous cell carcinoma, small cell lung cancer and large-cell neuroendocrine carcinoma transitions from adenocarcinoma resistant to TKIs.

Advances in the Treatment of Non-Small Cell Lung Cancer

2014 ◽  
Vol 12 (5S) ◽  
pp. 764-767 ◽  
Author(s):  
Leora Horn
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Small Cell ◽  
Driver Mutations ◽  
Annual Conference ◽  
Small Cell Lung ◽  
Nccn Guidelines

Clinical trial data continue to emerge on treatments in advanced non-small cell lung cancer (NSCLC), supporting the strategy that histology and molecular driver mutations should guide treatment selection. During her presentation at the NCCN 19th Annual Conference, Dr. Leora Horn highlighted 3 specific areas in which the 2014 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for NSCLC focus attention: updates on the assortment of chemotherapy options, targeted therapies and how acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors appears to have become the catalyst of the development of newer-generations of agents, and the revisited role of newer immunotherapeutic options.

scholarly journals Modern vector in treatment of patients with lung cancer: tyrosine kinase inhibitors in epidermal growth factor receptor mutations (literature review)

2021 ◽  
Vol 26 (2) ◽  
pp. 4-11
Author(s):  
O.M. Smorodska ◽  
Yu.V. Moskalenko ◽  
I.O. Vynnychenko ◽  
O.I. Vynnychenko ◽  
V.V. Kostuchenko
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Small Cell ◽  
Small Cell Lung ◽  
Epidermal Growth ◽  
Egfr Tki

Tumor molecular profiling in patients with non-small cell lung cancer (NSCLC) is used to identify driver mutations, which lead to premature carcinogenesis in more than 80% of adenocarcinoma cases, including epidermal growth factor receptor (EGFR) mutations. Identification of specific somatic aberrations allows to personalize treatment. Personalization of treatment resulted in improvement of NSCLC outcomes. The aim of our study was to consider scientific data on modern concepts of treatment of patients with non-small cell lung cancer with previously detected oncogenic mutations, especially EGFR mutation. In our study we analyzed scientific papers and data of international scientific literature on the problem of lung cancer treatment. Methods used: scientific research, analytical and generalizing. Different drugs are used in treatment of lung cancer. Choice of treatment scheme depends on type and presence of mutations. Patients with advanced non-small-cell lung cancer and detected mutation in the EGFR can be treated with tyrosine kinase inhibitors (TKIs). Nowadays three first generation drugs are recommended by FDA: afatinib, erlotinib, gefitinib. They showed good clinical benefit. Most patients with metastatic NSCLC typically show disease progression after approximately 9 to 13 months of erlotinib, gefitinib, or afatinib therapy. The first and only commercially available third-generation EGFR TKI is оsimertinib - an oral drug, which selectively inhibits both EGFR-TKI and EGFR T790M resistance mutations. Nowadays scientists are in active investigation of mechanisms of acquired resistance to TKIs, but little is known yet. Clinical success can be observed in patients who were treated with TKIs. EGFR T790M is a mutation that leads to acquired resistance to EGFR TKI therapy. Its incidence is approximately 60% after disease progression on TKI drugs (erlotinib, gefitinib, or aphatinib). Third-generation EGFR TKIs demonstrate high efficacy, but acquired resistance development cannot be avoided. Mechanisms of acquired resistance to these agents are still investigated.

Novel ETV1 mutation in small cell lung cancer transformation resistant to EGFR tyrosine kinase inhibitors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e20568-e20568
Author(s):  
Yan Zhou ◽  
Hao Bai ◽  
Lei Cheng ◽  
Baohui Han ◽  
Liwen Xiong
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Small Cell ◽  
Small Cell Lung ◽  
First Line ◽  
Egfr Tyrosine Kinase Inhibitors

e20568 Background: Non-small cell lung cancer (NSCLC) patients harboring mutations in the epidermal growth factor receptor (EGFR) gene dramatically respond to EGFR tyrosine kinase inhibitors (TKIs). However, these patients inevitably developed acquired resistance to TKIs. Among them, small cell lung cancer (SCLC) transformation is a relatively rare mechanism of resistance. However, the mechanism of SCLC transformation is largely unclear. Methods: We performed a 639 cancer-relevant gene panel to detect genetic differences of tissues before and after TKIs resistance caused by SCLC transformation. In vitro experiments were conducted to study the role of ETS variant transcription factor 1 (ETV1) on SCLC transformation and TKIs resistance. Results: We present two EGFR-mutant pulmonary adenocarcinoma (ADC) patients. One with EGFR exon 19 deletion (Ex19del) accepted first-line gefitinib treatment and then received osimertinib(AZD9291) treatment due to acquisition of EGFR-T790M mutation. A novel ETV1 mutation (p.P159S) was detected in SCLC samples after SCLC transformation when not coexisting with T790M. Another patient harbored an EGFR exon 21 mutation (p.L858R) with a long-lasting response to first-line gefitinib and then transformed to SCLC. A previously unreported ETV1 mutation (p.E462Q) was detected in SCLC tissue. In vitro, ETV1 p.E462Q and p.P159S mutations participated in neuroendocrine differentiation by inducing the expression of the neuroendocrine transcription factor, achaete-scute homolog 1 (ASCL1) and promoted H69 cells proliferation. Besides, ETV1 p.E462Q and p.P159S mutations were resistant to first-generation (gefitinib) and third-generation (osimertinib) TKIs after introducing into NCI-H358 cells. Conclusions: Novel ETV1 p.E462Q and p.P159S mutations were found in SCLC tissues of TKIs resistant patients, providing novel understanding of ETV1 involved in acquired resistance to EGFR-TKIs via SCLC transformation.

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