A case of different gene mutations in primary and metastatic lesions after EGFR-TKI treatment of lung cancer

2020 ◽  
Vol 106 (6) ◽  
pp. NP52-NP56
Author(s):  
Shaonan Xie ◽  
Huiyan Deng ◽  
Guangjie Liu ◽  
Qingyi Liu
Keyword(s):  
Lymph Node ◽  
Kinase Inhibitors ◽  
Thoracoscopic Surgery ◽  
Mediastinal Lymph Node ◽  
Main Pulmonary Artery ◽  
Resistance Mechanism ◽  
Growth Factor Receptor ◽  
Gene Mutations ◽  
Egfr Mutations ◽  
Egfr Tki

Background: It remains controversial whether patients with EGFR-mutant lung adenocarcinoma should stop using epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) after progression during treatment. Case report: We report a 35-year-old man with poorly differentiated adenocarcinoma of the left upper lobe and an exon 19 deletion (Ex19Del) mutation found by large-panel next-generation sequencing. The patient underwent video-assisted thoracoscopic surgery 12 months after oral administration of icotinib 125 mg tid, and the left upper lobe and surrounding lymph nodes were removed. Postoperative pathology supported a diagnosis of left upper lobe adenocarcinoma and subcarinal (1/2), main pulmonary artery window (1/2), and left hilar (1/2) lymph node metastases. The EGFR mutations in the residual lesions had disappeared, and Ex19Del mutations were still visible in the mediastinal lymph node metastasis. Conclusion: Spatial heterogeneity of the resistance mechanism may explain why patients who continue to receive EGFR-TKIs in combination with local therapies (e.g., radiotherapy) for progressing lesions may benefit even after progression during EGFR-TKI therapy. The loss of the EGFR mutation allele as a putative resistance mechanism requires additional preclinical and clinical confirmation.

scholarly journals Understanding the Mechanisms of Resistance in EGFR-Positive NSCLC: From Tissue to Liquid Biopsy to Guide Treatment Strategy

2019 ◽  
Vol 20 (16) ◽  
pp. 3951 ◽  
Author(s):  
Marzia Del Re ◽  
Stefania Crucitta ◽  
Giulia Gianfilippo ◽  
Antonio Passaro ◽  
Iacopo Petrini ◽  
...  
Keyword(s):  
Treatment Strategy ◽  
Liquid Biopsy ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Gene Mutations ◽  
Phosphatidyl Inositol ◽  
Egfr Mutations ◽  
Mechanisms Of Resistance ◽  
Alternative Source ◽  
Egfr Mutant

Liquid biopsy has emerged as an alternative source of nucleic acids for the management of Epidermal Growth Factor Receptor (EGFR)-mutant non-Small Cell Lung Cancer (NSCLC). The use of circulating cell-free DNA (cfDNA) has been recently introduced in clinical practice, resulting in the improvement of the identification of druggable EGFR mutations for the diagnosis and monitoring of response to targeted therapy. EGFR-dependent (T790M and C797S mutations) and independent (Mesenchymal Epithelial Transition [MET] gene amplification, Kirsten Rat Sarcoma [KRAS], Phosphatidyl-Inositol 4,5-bisphosphate 3-Kinase Catalytic subunit Alpha isoform [PI3KCA], and RAF murine sarcoma viral oncogene homolog B1 [BRAF] gene mutations) mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKIs) have been evaluated in plasma samples from NSCLC patients using highly sensitive methods (i.e., digital droplet PCR, Next Generation Sequencing), allowing for the switch to other therapies. Therefore, liquid biopsy is a non-invasive method able to detect the molecular dynamic changes that occur under the pressure of treatment, and to capture tumor heterogeneity more efficiently than is allowed by tissue biopsy. This review addresses how liquid biopsy may be used to guide the choice of treatment strategy in EGFR-mutant NSCLC.

Activity of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in patients (pts) with NSCLC with uncommon EGFR mutations: A real-world cohort study (UpSwinG).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9072-9072
Author(s):  
Satoru Miura ◽  
Te-Chun Hsia ◽  
Jen-Yu Hung ◽  
Hyun Ae Jung ◽  
Jin-Yuan Shih ◽  
...  
Keyword(s):  
Real World ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Pathology Reports ◽  
Multi Center Study ◽  
Line Of Therapy ◽  
Ecog Ps ◽  
Egfr Tki ◽  
Egfr Tkis

9072 Background: EGFR TKIs are an established treatment (tx) option for pts with EGFR mutation-positive NSCLC with common mutations (Del19 or L858R); however, 7–23% of NSCLC tumors harbor uncommon EGFR mutations, where EGFR TKI efficacy is less established. These mutations are highly heterogeneous, and developments in detection by NGS are helping to identify mutations with little or no clinical data. Methods: In this non-interventional, global, multi-center study (NCT04179890), existing medical or electronic health records were identified for consecutive EGFR TKI-naïve pts with uncommon EGFR mutations (T790M, ex20ins, major uncommon [G719X, L861Q or S768I], ‘other’ or compound mutations) treated with erlotinib, gefitinib, afatinib, osimertinib or other systemic therapy. Endpoints were time to tx failure (TTF), ORR, OS and duration of response (DoR). Results: Overall, 246 pts (median age: 69.5 yrs; Asian: 84%; brain metastases: 8%; ECOG PS ≥2: 16%) were recruited from 9 countries. Most pts (n=226; 92%) received an EGFR TKI as 1st-line therapy; 132 (54%), 105 (43%) and 7 (3%) received afatinib, 1st-gen TKIs and osimertinib, respectively. 57% of pts received >1 line of therapy. Most pts (73%) had a major uncommon mutation, 9% had other mutations and 33% had a compound mutation; these were detected using PCR (75%) or sequencing (25%), mainly based on tissue biopsy (86%). Pathology reports varied in quality, often lacking detail on specific mutations e.g. 21% of ex18 and 72% of ex20ins were undefined. Median TTF and OS with EGFR TKIs were 9.9 and 24.4 mos; ORR was 42%. In pts treated with 1st-line chemotherapy (n=20), median TTF and ORR were 6.6 mos and 41%. Outcomes were most favorable in major uncommon and compound mutations (Table). TTF appeared to be higher with afatinib vs 1st-gen EGFR TKIs. In most mutation categories, median OS was >2 yrs, possibly reflecting high subsequent therapy uptake. Conclusions: In a real-world setting, EGFR TKIs were the preferred tx option in pts with uncommon EGFR mutations; strongest outcomes were seen in major uncommon and compound mutations, and in pts treated with afatinib. Data were in line with recent analyses of afatinib in uncommon mutations. Tx with an EGFR TKI should be considered as standard for most pts with uncommon mutations. Optimal tx for pts with uncommon mutations requires improvements in pathology reports, with more emphasis on NGS methodology and precise definition of mutations. Clinical trial information: NCT04179890. [Table: see text]

Evaluation of epidermal growth factor receptor (EGFR) mutations as predictive and prognostic indicators in patients with adenocarcinoma of the lung treated with conventional chemotherapy

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7165-7165 ◽  
Author(s):  
T. Fukui ◽  
Y. Ohe ◽  
T. Takano ◽  
K. Tsuta ◽  
K. Nomoto ◽  
...  
Keyword(s):  
Prognostic Value ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Current Smoker ◽  
Egfr Mutations ◽  
Prognostic Indicators ◽  
Survival Duration ◽  
Conventional Chemotherapy ◽  
Adenocarcinoma Of The Lung ◽  
Egfr Tki

7165 Background: EGFR mutations are associated with the responses to EGFR-tyrosine kinase inhibitors (TKI) in patients (pts) with adenocarcinoma of the lung. The E746-A750 deletion and L858R substitution mutations are the most common, as previously described. However, their implications in pts treated with conventional chemotherapy are unclear. To evaluate the predictive and prognostic value of the EGFR mutations, we studied pts with adenocarcinoma of the lung treated with conventional chemotherapy. Methods: We reviewed pts with advanced or recurrent chemotherapy naïve adenocarcinoma of the lung who received systemic chemotherapy between January 1999 and July 2001. Deletion in exon 19 and missense mutation (L858R) in exon 21 from small biopsy or cytology samples were analyzed by a high-resolution DNA melting analysis technique. Results: A total of 101 pts, all Japanese, could be analyzed. Patient characteristics were as follows: median age: 62 (37–84) years; female/ male: 39/ 62; never/ former/ current smoker: 47/ 23/ 31; and platinum-based/ non-platinum regimen: 81/ 20 (18 pts received EGFR-TKI later). 43 pts (42.6%) had EGFR somatic mutations; deletion in 24 pts, and a point mutation (L858R) in 19 pts. PR/ SD/ PD/ NE was observed in 11/ 24/ 7/ 1 pts with EGFR mutations and in 13/ 28/ 15/ 2 pts without the mutations, respectively. The response rate was similar (26% vs. 22%, p = .71) in the two subgroups. The median survival duration of the pts with EGFR mutations was 14.9 months (n = 43, including the 11 pts treated with EGFR-TKI later), as compared with 11.0 months (n = 58, including the 7 pts treated with EGFR-TKI later) in the pts without EGFR mutations (p = .09). Another analysis which handle the start of gefitinib administration as a censoring showed similar results (p = .24). Conclusions: EGFR mutations were not good predictors of tumor response to conventional chemotherapy. The overall survival tended to be longer in the pts with EGFR mutations, but prognostic value of these mutations for survival in pts with advanced adenocarcinoma of the lung was not statistically significant. No significant financial relationships to disclose.

scholarly journals FBXL2 counteracts Grp94 to destabilize EGFR and inhibit EGFR-driven NSCLC growth

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mengmeng Niu ◽  
Jing Xu ◽  
Yang Liu ◽  
Yuhuang Li ◽  
Tao He ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Critical Role ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Inhibitory Effects ◽  
Molecule Inhibitor ◽  
Epidermal Growth ◽  
F Box Protein ◽  
Nsclc Patients ◽  
Egfr Tki

AbstractAbnormal activation of epidermal growth factor receptor (EGFR) drives non-small cell lung cancer (NSCLC) development. EGFR mutations-mediated resistance to tyrosine-kinase inhibitors (TKIs) is a major hurdle for NSCLC treatment. Here, we show that F-box protein FBXL2 targets EGFR and EGFR TKI-resistant mutants for proteasome-mediated degradation, resulting in suppression of EGFR-driven NSCLC growth. Reduced FBXL2 expression is associated with poor clinical outcomes of NSCLC patients. Furthermore, we show that glucose-regulated protein 94 (Grp94) protects EGFR from degradation via blockage of FBXL2 binding to EGFR. Moreover, we have identified nebivolol, a clinically used small molecule inhibitor, that can upregulate FBXL2 expression to inhibit EGFR-driven NSCLC growth. Nebivolol in combination with osimertinib or Grp94-inhibitor-1 exhibits strong inhibitory effects on osimertinib-resistant NSCLC. Together, this study demonstrates that the FBXL2-Grp94-EGFR axis plays a critical role in NSCLC development and suggests that targeting FBXL2-Grp94 to destabilize EGFR may represent a putative therapeutic strategy for TKI-resistant NSCLC.

scholarly journals Preclinical characterization of mobocertinib highlights the putative therapeutic window of this novel EGFR inhibitor to EGFR exon 20 insertion mutations

2020 ◽  
Author(s):  
Pedro E. N. S. Vasconcelos ◽  
Ikei S. Kobayashi ◽  
Susumu S. Kobayashi ◽  
Daniel B. Costa
Keyword(s):  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Therapeutic Window ◽  
Mechanisms Of Resistance ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Exon 20 ◽  
Egfr Tki ◽  
Insertion Mutations ◽  
Egfr Tkis

AbstractBackgroundEpidermal growth factor receptor (EGFR) exon 20 insertion mutations account for 10% of all EGFR mutations and are mostly insensitive to approved EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Novel EGFR-TKIs have been developed or repurposed for these mutants. A limited number of preclinical studies have detailed these EGFR-TKIs. We sought to use commercially available mobocertinib (TAK-788) to characterize the preclinical therapeutic window of this EGFR-TKI against EGFR mutations and to probe possible on-target mechanisms of resistance (EGFR-C797S).MethodsWe used models of EGFR mutations to probe representative 1st, 2nd, 3rd generation, and in-development EGFR exon 20-active (poziotinib, mobocertinib) TKIs. We also introduced EGFR-C797S to these models to identify mechanisms of resistance.ResultsCells driven by the most common EGFR exon 20 insertion mutations (A767_V769dupASV, D770_N771insSVD, H773_V774insH and others) were inhibited by in-development EGFR TKIs at doses below those affecting EGFR-wildtype; albeit more common EGFR mutations (exon 19 deletions and L858R) were inhibited more readily by mobocertinib and poziotinib. Mobocertinib was able to inhibit phosphorylation of EGFR in multiple preclinical models. The presence of EGFR-C797S led to >200-fold resistance in proliferation assays probing mobocertinib and osimertinib. Review of clinical studies of mobocertinib disclosed responses that could be lasting.ConclusionsThis is one of the initial reports to characterize the novel EGFR TKI mobocertinib and highlights its broad activity against EGFR mutants plus the therapeutic window to EGFR exon 20 insertion mutations; as well as EGFR-C797S as a possible mechanism of resistance. Further clinical development of mobocertinib merits continuation.

scholarly journals Diaphragmatic hernia during treatment of lung cancer harboring an EGFR mutation

2021 ◽  
Vol 2021 (7) ◽  
Author(s):  
Aya Konno-Yamamoto ◽  
Osamu Narumoto ◽  
Shota Yamamoto ◽  
Miho Yamaguchi ◽  
Makoto Motoyoshi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Diaphragmatic Hernia ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Metastatic Tumor ◽  
Nonsmall Cell Lung Cancer ◽  
Japanese Woman ◽  
Egfr Mutations ◽  
Egfr Tki

ABSTRACT Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a first-line treatment for patients with nonsmall-cell lung cancer harboring EGFR mutations. We report a 65-year-old Japanese woman with nonsmall-cell lung cancer taking an EGFR-TKI who visited the emergency department with acute nausea and vomiting. Imaging studies demonstrated an incarcerated diaphragmatic hernia. Urgent diagnostic surgery revealed a gap in the diaphragm acting as a hernial orifice, where a metastatic tumor was detected. We consider that regression of the diaphragmatic metastasis by EGFR-TKI therapy resulted in perforation of the diaphragm, causing the diaphragmatic hernia. Gastrointestinal adverse events, e.g. nausea, vomiting and diarrhea, are common during EGFR-TKI treatment. However, this case suggests that in patients with diaphragmatic metastasis, we should consider the rare possibility of diaphragmatic perforation and a subsequent hernia.

scholarly journals Iterative Upgrading of Small Molecular Tyrosine Kinase Inhibitors for EGFR Mutation in NSCLC: Necessity and Perspective

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1500
Author(s):  
Jing Zhu ◽  
Qian Yang ◽  
Weiguo Xu
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Egfr Mutation ◽  
Growth Factor Receptor ◽  
Gene Mutations ◽  
Egfr Mutations ◽  
Convenient Route ◽  
Epidermal Growth ◽  
Nsclc Patients ◽  
Genome Information

Molecular targeted therapy has been reported to have fewer adverse effects, and offer a more convenient route of administration, compared with conventional chemotherapy. With the development of sequencing technology, and research on the molecular biology of lung cancer, especially whole-genome information on non-small cell lung cancer (NSCLC), various therapeutic targets have been unveiled. Among the NSCLC-driving gene mutations, epidermal growth factor receptor (EGFR) mutations are the most common, and approximately 10% of Caucasian, and more than 50% of Asian, NSCLC patients have been found to have sensitive EGFR mutations. A variety of targeted therapeutic agents for EGFR mutations have been approved for clinical applications, or are undergoing clinical trials around the world. This review focuses on: the indications of approved small molecular kinase inhibitors for EGFR mutation-positive NSCLC; the mechanisms of drug resistance and the corresponding therapeutic strategies; the principles of reasonable and precision molecular structure; and the drug development discoveries of next-generation inhibitors for EGFR.

scholarly journals First- or second-generation epidermal growth factor receptor tyrosine kinase inhibitors in a large, real-world cohort of patients with non-small cell lung cancer

2021 ◽  
Vol 13 ◽  
pp. 175883592110357
Author(s):  
Allen Chung-Cheng Huang ◽  
Chi-Hsien Huang ◽  
Jia-Shiuan Ju ◽  
Tzu-Hsuan Chiu ◽  
Pi-Hung Tung ◽  
...  
Keyword(s):  
Real World ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Rank Test ◽  
Third Generation ◽  
Log Rank Test ◽  
Epidermal Growth ◽  
Tki Treatment ◽  
Egfr Tki

Background: There are limited comparisons of first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) in large, real-world cohorts of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor ( EGFR) mutations. Methods: Patients with advanced NSCLC ( N = 612) with common EGFR mutations receiving first-line gefitinib/erlotinib and afatinib were grouped and propensity-score matched. Progression-free survival (PFS), overall survival (OS) and secondary T790M mutations were analyzed. Results: The gefitinib/erlotinib and afatinib groups each contained 206 patients after matching. Compared with gefitinib/erlotinib, patients receiving afatinib achieved longer median PFS (16.3 versus 14.2 months; log-rank test p = 0.020) and had a lower risk of progression [hazard ratio (HR) 0.73 (95% confidence interval (CI), 0.57–0.94); p = 0.017]. Median OS (37.3 versus 34.2 months; log-rank test p = 0.500) and reduction in risk of death [HR 0.89 (95% CI, 0.65–1.23); p = 0.476] did not differ significantly between groups. T790M positivity was significantly higher in the gefitinib/erlotinib than afatinib group (70.9% versus 44.6%, p < 0.001). Multivariate analysis demonstrated that afatinib was independently associated with lower T790M positivity [odds ratio (OR) 0.27 (95% CI, 0.14–0.53); p < 0.001], whereas ⩾12 months PFS after EGFR-TKI treatment [OR 3.00 (95% CI, 1.56–5.98); p = 0.001] and brain metastasis [OR 2.12 (95% CI, 1.08–4.26); p = 0.030] were associated with higher T790M positivity. Sequential third-generation EGFR-TKI treatment was administered to 63 patients, in whom median OS after the second–third-generation and first–third-generation EGFR-TKI sequences were 38.8 and 29.1 months, respectively. Conclusion: Compared with gefitinib/erlotinib, afatinib had a higher treatment efficacy and a lower secondary T790M positivity in a large, real-world cohort of Asian patients with EGFR-mutated NSCLC.

scholarly journals A Case Report of Primary Resistance to EGFR TKI in Lung Adenocarcinoma Due to Coexisting MET Exon 14 Skipping Mutation with Excellent Response to Combination of Gefitinib and Capmatinib

2021 ◽  
Author(s):  
Nirmal Vivek Raut ◽  
Siddharth Srivastava ◽  
Guarav Dilip Gangwani ◽  
Heena Sajid Ali
Keyword(s):  
Kinase Inhibitors ◽  
Single Gene ◽  
Growth Factor Receptor ◽  
Nonsmall Cell Lung Cancer ◽  
Primary Resistance ◽  
Gene Testing ◽  
Comprehensive Genomic Profiling ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Next Generation Sequencing Ngs ◽  
Egfr Tki

AbstractTreatment of nonsmall cell lung cancer (NSCLC) carrying an epidermal growth factor receptor (EGFR) mutation depends on EGFR tyrosine kinase inhibitors (TKIs). However, all patients treated with EGFR TKI eventually develop progressive disease. Approximately, 20% of patients do not respond to EGFR TKIs, which is defined as primary resistance. The prognosis of these patients is similar to NSCLC with nondriver mutations. We report a case of a patient with EGFR exon 21 mutation who rapidly progressed in 15 days on Gefitinib. Next-generation sequencing (NGS) showed a MET exon 14 skip mutation coexisting with EGFR exon 21 mutation, causing primary resistance to EGFR TKI. Based on NGS reports, a treatment combining Gefitinib and Capmatinib, a MET inhibitor, induced a rapid response in the patient, which was sustained at the end of 8 months. This clearly emphasizes the need for comprehensive genomic profiling using NGS over single gene testing.

scholarly journals Better Progression-Free Survival in Elderly Patients with Stage IV Lung Adenocarcinoma Harboring Uncommon Epidermal Growth Factor Receptor Mutations Treated with the First-line Tyrosine Kinase Inhibitors

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 434 ◽  
Author(s):  
Ming-Ju Tsai ◽  
Jen-Yu Hung ◽  
Mei-Hsuan Lee ◽  
Chia-Yu Kuo ◽  
Yu-Chen Tsai ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Egfr Mutations ◽  
First Line ◽  
Free Survival ◽  
Younger Patients ◽  
Epidermal Growth

Patients with lung adenocarcinoma harboring common epidermal growth factor receptor (EGFR) mutations usually have a good response rate (RR) and longer progression-free survival (PFS) to EGFR tyrosine kinase inhibitors (TKIs). However, the treatment efficacy to uncommon EGFR mutations remains controversial. We, therefore, performed a retrospective study, screening 2958 patients. A total of 67 patients with lung adenocarcinoma harboring uncommon EGFR mutations were enrolled and 57 patients with stage IV diseases receiving a first-line EGFR TKI were included for further analyses. The patients were classified into 27 (47%) “a single sensitizing uncommon mutation”, 7 (12%) “multiple sensitizing mutations”, 5 (9%) “a sensitizing mutation and a resistant uncommon mutation”, and 18 (32%) “other resistant uncommon mutations”. No significant difference was noted in PFS or overall survival (OS) between groups. Patients receiving different first-line EGFR TKIs had similar PFS and OS. The elder patients had a significantly poorer performance status than the younger patients but a significantly longer PFS than the younger patients (median PFS: 10.5 vs. 5.5 months, p = 0.0320). In conclusion, this is the first study to identify that elderly patients with stage IV lung adenocarcinoma harboring uncommon EGFR mutation might have a longer PFS. Large-scale prospective studies are mandatory to prove our findings.

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