RET fusion in first/third-generation EGFR-TKIs resistance in advanced non-small cell lung cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20634-e20634 ◽  
Author(s):  
Yu Yao ◽  
Min Zhang ◽  
Xiuju Liu ◽  
Jun Zhao ◽  
Xiangyang Cheng ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Target Therapy ◽  
Small Cell ◽  
Egfr Mutations ◽  
Third Generation ◽  
Small Cell Lung ◽  
Single Nucleotide Variants ◽  
Egfr Tkis

e20634 Background: EGFR-TKIs is the standard first/second-line treatment for EGFR-mutant advanced non-small-cell lung cancer (NSCLC). The mechanisms of EGFR-TKIs resistance are still under exploration. Acquired fusion have been reported contribute to EGFR-TKIs resistance. Here we focus on RET fusion in first/third-generation EGFR-TKIs resistant NSCLC. Methods: We retrospectively reviewed 3600 cases of EGFR-TKIs resistant NSCLC samples from 2016 to 2018 in our institute. Tumor biopsy, ctDNA or pleural effusion samples were analyzed using hybridization capture-based NGS ER-seq method, which enables simultaneously assess single-nucleotide variants (SNV), insertions/deletions (indel), rearrangements and somatic copy-number(CNV) variation at least 59 genes (range 59-1021 genes). Results: Seven cases with RET fusion were identified (7/3600, 0.2%), with co-occurring EGFR mutations. All were adenocarcinoma, median diagnosis age was 55 years old (range 38-84), four male and three female. Most common RET fusion subtype was CCDC6-RET (5/7, 71%), the other was NCOA4-RET (2/7, 29%). The primary EGFR mutation include four EX19del and three L858R. Six patients received prior first and third-generation EGFR-TKIs treatment. The seventh patient had received only gefitinib treatment, EGFR L858R + T790M + NCOA4-RET were discovered in his plasma when disease progression. Interestingly, one patient had EGFR EX19del + T790M + C797S (cis) + CCDC6-RET in plasma after osimertinib resistance. One patient who had EGFR L858R and NCOA4-RET chose lenvatinib, a RET inhibitor, and had a progression free survival of seven months. Conclusions: Broad NGS panel test suggests that RET fusion could be a rare mechanism of EGFR-TKIs resistance, include first and third-generation. There is no currently target treatment strategy available for these patients, and further investigations, like change target therapy drug or combined target therapy are needed.

scholarly journals Integrating Liquid Biopsy and Radiomics to Monitor Clonal Heterogeneity of EGFR-Positive Non-Small Cell Lung Cancer

2020 ◽  
Vol 10 ◽  
Author(s):  
Federico Cucchiara ◽  
Marzia Del Re ◽  
Simona Valleggi ◽  
Chiara Romei ◽  
Iacopo Petrini ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Liquid Biopsy ◽  
Target Therapy ◽  
Case Series ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Clonal Heterogeneity

BackgroundEGFR-positive Non-small Cell Lung Cancer (NSCLC) is a dynamic entity and tumor progression and resistance to tyrosine kinase inhibitors (TKIs) arise from the accumulation, over time and across different disease sites, of subclonal genetic mutations. For instance, the occurrence of EGFR T790M is associated with resistance to gefitinib, erlotinib, and afatinib, while EGFR C797S causes osimertinib to lose activity. Sensitive technologies as radiomics and liquid biopsy have great potential to monitor tumor heterogeneity since they are both minimally invasive, easy to perform, and can be repeated over patient’s follow-up, enabling the extraction of valuable information. Yet, to date, there are no reported cases associating liquid biopsy and radiomics during treatment.Case presentationIn this case series, seven patients with metastatic EGFR-positive NSCLC have been monitored during target therapy. Plasma-derived cell free DNA (cfDNA) was analyzed by a digital droplet PCR (ddPCR), while radiomic analyses were performed using the validated LifeX® software on computed tomography (CT)-images. The dynamics of EGFR mutations in cfDNA was compared with that of radiomic features. Then, for each EGFR mutation, a radiomic signature was defines as the sum of the most predictive features, weighted by their corresponding regression coefficients for the least absolute shrinkage and selection operator (LASSO) model. The receiver operating characteristic (ROC) curves were computed to estimate their diagnostic performance. The signatures achieved promising performance on predicting the presence of EGFR mutations (R2 = 0.447, p <0.001 EGFR activating mutations R2 = 0.301, p = 0.003 for T790M; and R2 = 0.354, p = 0.001 for activating plus resistance mutations), confirmed by ROC analysis.ConclusionTo our knowledge, these are the first cases to highlight a potentially promising strategy to detect clonal heterogeneity and ultimately identify patients at risk of progression during treatment. Together, radiomics and liquid biopsy could detect the appearance of new mutations and therefore suggest new therapeutic management.

scholarly journals Growth Suppression in Lung Cancer Cells Harboring EGFR-C797S Mutation by Quercetin

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1271
Author(s):  
Kuo-Yen Huang ◽  
Tong-Hong Wang ◽  
Chin-Chuan Chen ◽  
Yann-Lii Leu ◽  
Hsin-Jung Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tumor Growth ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Egfr Mutations ◽  
Third Generation ◽  
Small Cell Lung ◽  
Cytotoxic Effects

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are approved treatments for non-small-cell lung cancer (NSCLC) patients harboring activating EGFR mutations. The EGFR C797S mutation is one of the known acquired-resistance mutations to the latest third-generation TKIs. At present, there are no clear options for treating patients who acquire resistance to third-generation TKIs. The acquisition of the EGFR C797S mutation was shown to upregulate the expression of AXL, a receptor tyrosine kinase of the TAM (TYRO3-AXL-MER) family, and the suppression of AXL is effective in reducing the growth of NSCLC cells harboring EGFR C797S. As quercetin was recently shown to inhibit AXL, quercetin may be effective in treating NSCLC cells harboring the EGFR C797S mutation. In this work, the cytotoxic effects of quercetin and its ability to inhibit tumor growth were examined in TKI-resistant NSCLC cells harboring the EGFR C797S mutation. We demonstrated that quercetin exhibited potent cytotoxic effects on NSCLC cells harboring the EGFR C797S mutation by inhibiting AXL and inducing apoptosis. Quercetin inhibited the tumor growth of xenografted NSCLC cells harboring the EGFR C797S mutation and appeared to act synergistically with brigatinib to inhibit of tumor growth in vivo. In summary, herein, we revealed that quercetin is an effective inhibitor for the treatment of non-small-cell lung cancer harboring the EGFR C797S mutation.

Optimal Adjuvant Therapy in Resected Stage IIIA-N2 Non-Small-Cell Lung Cancer Harboring EGFR Mutations

2020 ◽  
Vol 43 (12) ◽  
pp. 686-693
Author(s):  
Miaomiao Wen ◽  
Lei Wang ◽  
Xuejiao Wang ◽  
Sanhu Yang ◽  
Ying Sun ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Adjuvant Therapy ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Stage Iiia ◽  
Egfr Tki ◽  
Egfr Tkis

<b><i>Background:</i></b> Some non-small-cell lung cancer (NSCLC) patients are unexpectedly diagnosed with stage IIIA-N2 disease at the time of thoracoscopy or thoracotomy. Because of the limited statistical evidence of induction chemotherapy for these patients, it is necessary to develop more profound treatment strategies. <b><i>Methods:</i></b> The demographic and clinical characteristics of patients with stage IIIA-N2 NSCLC harboring epidermal growth factor receptor (EGFR) mutations after radical resection were retrospectively reviewed. The patients were divided into 3 groups based on treatment: EGFR tyrosine kinase inhibitors (EGFR-TKIs, erlotinib or gefitinib), adjuvant chemotherapy (docetaxel plus cisplatin), and combination treatment (chemotherapy plus EGFR-TKIs). The effect of adjuvant therapy on survival rate was assessed using univariate and Cox regression analyses. <b><i>Results:</i></b> Patients receiving EGFR-TKIs alone showed significantly improved disease-free survival (DFS; <i>p</i> = 0.025) when compared to those receiving chemotherapy alone. Compared to chemotherapy alone, the combination of chemotherapy and EGFR-TKIs resulted did not significantly improve DFS (<i>p</i> &#x3c; 0.001) and overall survival (OS <i>p</i> &#x3c; 0.001). The combination of EGFR-TKIs with chemotherapy as adjuvant therapy led to improvements in both DFS (<i>p</i> = 0.116) and OS (<i>p</i> = 0.039) compared to patients receiving a EGFR-TKI monotherapy. Toxicities were mild in the 3 treatment groups. <b><i>Conclusions:</i></b> Our study demonstrated that adjuvant EGFR-TKI treatment significantly increased the DFS of patients with stage IIIA-N2 NSCLC when compared with cisplatin-based chemotherapy. The use of EGFR-TKIs and chemotherapy is recommended in the setting of combined-modality therapy.

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