scholarly journals Lung adenocarcinoma in a patient with Li–Fraumeni syndrome bearing a novel germ-line mutation, TP53R333Vfs*12

2020 ◽  
Vol 50 (10) ◽  
pp. 1214-1217 ◽  
Author(s):  
Shodai Takahashi ◽  
Kazuhiro Shimazu ◽  
Koya Kodama ◽  
Koji Fukuda ◽  
Taichi Yoshida ◽  
...  
Keyword(s):  
Bone Metastasis ◽  
Lung Adenocarcinoma ◽  
Egfr Mutation ◽  
Kinase Inhibitor ◽  
Germ Line ◽  
Growth Factor Receptor ◽  
Triple Mutant ◽  
Li Fraumeni Syndrome ◽  
Li Fraumeni ◽  
Egfr Tki

Abstract Germline mutations of TP53 are responsible for Li–Fraumeni syndrome in its 60–80%. We found a novel germline mutation, TP53: c.997del:p.R333Vfs*12 (NM_000546.6, GRCh, 17:7670713..7670713). The proband is a 40-year-old female, who was suffered from osteosarcoma in her right forearm at her age of 11. She was also suffered from lung adenocarcinoma in her right upper lobe and bone metastasis in her right scapula at her age of 37. She was treated with gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) because of EGFR mutation (L747-S752 del). Her bone metastasis became resistant after 1-year treatment. Bone metastasis had an additional EGFR mutation (T790M). The secondary treatment with osimertinib, an another EGFR-TKI, can successfully control the tumors for over 2 years. This TP53 mutation (R333Vfs*12) was first found in lung adenocarcinomas. The therapeutic effect of osimertinib for this triple mutant lung adenocarcinoma is better than the previous report.

Detection of EGFR mutations in NSCLC patients in clinical practice: Comparison between cobas and Scorpion ARMS method.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23101-e23101
Author(s):  
Natsuki Takano ◽  
Satoru Kitazono ◽  
Ryo Ariyasu ◽  
Junji Koyama ◽  
Masafumi Saiki ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Detection Rate ◽  
Egfr Mutation ◽  
Kinase Inhibitor ◽  
De Novo ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Detection Rates ◽  
Initial Biopsy ◽  
Egfr Tki

e23101 Background: Epidermal growth factor receptor (EGFR) mutation is the most important factor for determining the treatment strategy for non-small-cell lung cancers (NSCLCs). Currently, two methods (cobas and Scorpion ARMS) have been approved as companion diagnostics for using EGFR tyrosine kinase inhibitor (TKI). Although there are some differences in the spectrums and sensitivities for detecting EGFRmutations such as exon 19 deletions (ex19del), L858R and T790M mutations, the extent of the differences affecting clinical practice is unclear. Methods: All patients with NSCLC who underwent EGFR mutation tests and treated at our hospital from February 2014 to February 2016 were enrolled. To detect EGFR mutations, the Scorpion ARMS (S) method was used from 2014 to 2015 and thecobasEGFR Mutation Test (C) from 2015 to 2016. We retrospectively investigated the detection rate of each EGFRmutation type and compared the rates between the two methods. Results: A total of 1,287 patients were enrolled. To detect EGFR mutations, 627 patients were tested by the S method and 660 by the C method, respectively. Of 1287 patients, 910 patients underwent initial biopsy, whereas 121 patients underwent re-biopsy after EGFR-TKI failure. EGFRmutations were detected in 130 of 418 (31.1%) patients and 153 of 492 (31.1%) patients by the S and C methods, respectively in the initial biopsy (P = 0.982). However, the detection rate of ex19del was slightly lower in the S method (12.6%) than in the C method (16.3%) (P = 0.105). Conversely, the detection rate of L858R was lower in the C method (13.8%) than in the S method (16.7%), but the difference was not significant (P = 0.252). De novo T790M was detected in one (0.2%) patient by the S method and in none by the C method. In re-biopsy after EGFR-TKI failure, the detection rates of T790M were as follows: 19 of 55 patients (34.5%) by the S method and 20 of 66 (30.3%) by the C method (P = 0.619). Conclusions: The different spectrums and sensitivities of EGFR mutations between the S and C methods were observed; however, they did not significantly affect clinical practice.

Management of medical inoperable and tyrosine kinase inhibitor-naive early-stage lung adenocarcinoma with epidermal growth factor receptor mutations: A retrospective multi-institutional analysis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21082-e21082
Author(s):  
Yue Mei Sun ◽  
Ming Xiu Zhou ◽  
Ming Zeng
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Lung Adenocarcinoma ◽  
Kinase Inhibitor ◽  
Early Stage ◽  
Growth Factor Receptor ◽  
Epidermal Growth ◽  
Egfr Mutant ◽  
Egfr Tki

e21082 Background: The clinical value of combined local radiation and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) and for medical inoperable and TKI-naïve early-stage lung adenocarcinoma patients with EGFR mutations is not yet determined. In this study, we aimed to pool multi-institutional data to compare the therapeutic effect of EGFR-TKI alone and combined radiation and TKI on the survival outcomes in this patient subgroup. Methods: 132 cases of medical non-operable stage I to III EGFR mutant lung adenocarcinoma were retrospectively reviewed based on data from 5 centers. Among the patients, 65 cases received combined radiation and EGFR-TKI therapy (R+TKI) (49.2%), while 67 cases had EGFR-TKI (50.8%) treatment alone. All patients were followed until death. Results: For R+TKI group, the median overall survival (OS) after primary therapy was 42.6 months, while that of the TKI alone group was 29.4 months (log-rank p < .001). In terms of progression-free survival (PFS), the median PFS in these two treatment groups were 24 months and 14.7 months respectively (log-rank p < .001). Multivariate analysis showed that R+TKI was independently associated with improved OS (adjusted HR: 0.420; 95% CI, 0.287 to 0.614; p < .001) and PFS (adjusted HR: 0.420; 95% CI, 0.291 to 0.605; p < .001) compared to TKI alone. Subgroup analysis confirmed the significant OS benefits in stage III patients and RFS benefits in stage II/III patients. Conclusions: Upfront radiation to primary sites with TKI to follow was a feasible option for patients with EGFR-mutant medical inoperable non-small-cell lung carcinoma (NSCLC) during first-line EGFR-TKI treatment, with significantly improved PFS and OS compared with TKI alone

scholarly journals Significance of EGFRGene Mutation in Fresh Cytological Specimens of Lung Adenocarcinoma

1970 ◽  
Vol 2 (2) ◽  
Author(s):  
Xiao Guo ◽  
Rui Wang ◽  
Juan Wu ◽  
Xiaokun Ji ◽  
Heng Wang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Egfr Mutation ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Needle Aspiration ◽  
Chemotherapy Group ◽  
Tissue Specimens ◽  
Medical University

Objective:This paper aims to study the mutation of epidermal growth factor receptor (EGFR) gene in fresh cytological specimens from patients with lung adenocarcinoma, and to determine the prognosis of positive patients by tyrosine kinase inhibitor (TKI). Methods: A total of 313 specimens from needle aspiration and pleural effusion were collected in the Cancer Detection Center of the Fourth Hospital of Hebei Medical University. After HE and immunocytochemistry stainings, the specimens were diagnosed as lung adenocarcinoma by two cytology pathologists. Themutation of 18-21 exon was detectied using ARMS to observe mutations situation. Then, the objective response rate (ORR) and the progression-free survival (PFS) between the targeted group and the chemotherapy group of patients were comparedith. Results: Among 313 cases, 293 cases of lung adenocarcinoma were diagnosed, and DNA specimens were extracted from 288 cases. The success rate was about 98.3%. 130 mutations were found and the rate was 45.1%. EGFR mutation of adenocarcinoma patients mainly occurred to females, nonsmokers, but had nothing to do with age. The ORR was statistically different between the targeted group with chemotherapy (P<0.01), and PFS curve of targeted group was on chemotherapy group. The efficacy and the survival time of targeted group and targeted and chemotherapy group were superior to that of chemotherapy group. The results of the EGFR mutation and the prognosis of the tested positive patients in the fresh cytology samples were consistent with that from previous literatures. Conclusion: The results of the testwere accurate, and fresh cytological specimens can be used as a replacement for tumor tissue specimens.

American Society of Clinical Oncology Provisional Clinical Opinion: Epidermal Growth Factor Receptor (EGFR) Mutation Testing for Patients With Advanced Non–Small-Cell Lung Cancer Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy

2011 ◽  
Vol 29 (15) ◽  
pp. 2121-2127 ◽  
Author(s):  
Vicki Leigh Keedy ◽  
Sarah Temin ◽  
Mark R. Somerfield ◽  
Mary Beth Beasley ◽  
David H. Johnson ◽  
...  
Keyword(s):  
Egfr Mutation ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Mutation Testing ◽  
Phase Iii ◽  
Egfr Mutations ◽  
First Line ◽  
First Line Therapy ◽  
Egfr Tki ◽  
Egfr Mutation Testing

Purpose An American Society of Clinical Oncology (ASCO) provisional clinical opinion (PCO) offers timely clinical direction to ASCO's membership following publication or presentation of potentially practice-changing data from major studies. This PCO addresses the clinical utility of using epidermal growth factor receptor (EGFR) mutation testing for patients with advanced non–small-cell lung cancer (NSCLC) to predict the benefit of taking a first-line EGFR tyrosine kinase inhibitor (TKI). Clinical Context Patients with EGFR-mutated NSCLC have a significantly higher rate of partial responses to the EGFR TKIs gefitinib and erlotinib. In the United States, approximately 15% of patients with adenocarcinoma of the lung harbor activating EGFR mutations. EGFR mutation testing is widespread at academic medical centers and in some locales in community practice. As of yet, there is no evidence of an overall survival (OS) benefit from selecting treatment based on performing this testing. Recent Data One large phase III trial (the Iressa Pan-Asia Study [IPASS] trial), three smaller phase III randomized controlled trials using progression-free survival as the primary end point, and one small phase III trial with OS as the primary end point, all involving first-line EGFR TKIs and chemotherapy doublets, form the basis of this PCO. Provisional Clinical Opinion On the basis of the results of five phase III randomized controlled trials, patients with NSCLC who are being considered for first-line therapy with an EGFR TKI (patients who have not previously received chemotherapy or an EGFR TKI) should have their tumor tested for EGFR mutations to determine whether an EGFR TKI or chemotherapy is the appropriate first-line therapy. NOTE. ASCO's provisional clinical opinions (PCOs) reflect expert consensus based on clinical evidence and literature available at the time they are written and are intended to assist physicians in clinical decision making and identify questions and settings for further research. Because of the rapid flow of scientific information in oncology, new evidence may have emerged since the time a PCO was submitted for publication. PCOs are not continually updated and may not reflect the most recent evidence. PCOs cannot account for individual variation among patients and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It is the responsibility of the treating physician or other health care provider, relying on independent experience and knowledge of the patient, to determine the best course of treatment for the patient. Accordingly, adherence to any PCO is voluntary, with the ultimate determination regarding its application to be made by the physician in light of each patient's individual circumstances. ASCO PCOs describe the use of procedures and therapies in clinical practice and cannot be assumed to apply to the use of these interventions in the context of clinical trials. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of ASCO's PCOs, or for any errors or omissions.

How sensitive are epidermal growth factor receptor-tyrosine kinase inhibitor for lung adenosquamous cell carcinoma harboring EGFR mutation? A bicenter research and pooled analysis of published reports.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20571-e20571
Author(s):  
Yong-Mei Liu ◽  
Xueming Xia ◽  
Wei Du ◽  
Yan Zhang ◽  
Jianlin Xu ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Receptor Tyrosine Kinase ◽  
Egfr Mutation ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Pooled Analysis ◽  
Epidermal Growth ◽  
Egfr Tki

e20571 Background: Lung adenosquamous cell carcinoma (ASC) is a rare subtype of lung cancer. Little is known about the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) for lung ASC with EGFR mutation. Methods: We retrospectively analyzed 44 patients with advanced or recurrent lung ASC harboring EGFR mutation who were treated with EGFR-TKI from two cancer centers to investigate the efficacy. Then a pooled analysis on the efficacy of EGFR-TKI was performed in 74 patients including 30 patients selected from 11 published reports. Results: In our bicenter research, for the ASC patients treated with EGFR-TKI, the objective response rate (ORR), the disease control rate (DCR), the median progression free survival (mPFS) and the median overall survival (mOS) were 54.5%, 79.5%, 8.8 months and 19.43 months, respectively. In pooled analysis, the ORR, DCR, mPFS and mOS of ASC patients were 63.4%, 85.9%, 10.00 months and 21.37 months, respectively. Similar PFS (11.0 vs. 10.0 months; P= 0.771) and OS (23.67 vs. 20.33 months; P= 0.973) were found in patients with deletion in exon 19 and exon 21 L858R mutation. The patients treated with erlotinib or gefitinib had a trend of better OS than those treated with icotinib. Conclusions: EGFR-TKI is an effective treatment for ASC harboring EGFR mutation, comparing with historical data, similar to EGFR-mutated adenocarcinoma (ADC). Further study is needed to identify the different role of the two components of ASC in EGFR treatment.

scholarly journals DARPP-32 promotes ERBB3-mediated resistance to molecular targeted therapy in EGFR-mutated lung adenocarcinoma

Oncogene ◽  
2021 ◽  
Author(s):  
Sk. Kayum Alam ◽  
Yongchang Zhang ◽  
Li Wang ◽  
Zhu Zhu ◽  
Christina E. Hernandez ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Kinase Inhibitor ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Clinical Problem ◽  
Oncogenic Signaling ◽  
Before And After ◽  
Epidermal Growth ◽  
Egfr Tki ◽  
Egfr Tkis

AbstractEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-refractory lung adenocarcinoma (LUAD) progression is a major clinical problem. New approaches to predict and prevent acquired resistance to EGFR TKIs are urgently needed. Here, we show that dopamine and cyclic AMP-regulated phosphoprotein, Mr 32000 (DARPP-32) physically recruits ERBB3 (HER3) to EGFR to mediate switching from EGFR homodimers to EGFR:ERBB3 heterodimers to bypass EGFR TKI-mediated inhibition by potentiating ERBB3-dependent activation of oncogenic signaling. In paired LUAD patient-derived specimens before and after EGFR TKI-refractory disease progression, we reveal that DARPP-32 and kinase-activated EGFR and ERBB3 proteins are overexpressed upon acquired resistance. In mice, DARPP-32 ablation sensitizes gefitinib-resistant xenografts to EGFR TKIs, while DARPP-32 overexpression increases gefitinib-refractory LUAD progression in gefitinib-sensitive lung tumors. We introduce a DARPP-32-mediated, ERBB3-dependent mechanism the LUAD cells use to evade EGFR TKI-induced cell death, potentially paving the way for the development of therapies to better combat therapy-refractory LUAD progression.

scholarly journals SHP2 inhibition enhances the anticancer effect of Osimertinib in EGFR T790M mutant lung adenocarcinoma by blocking CXCL8 loop mediated stemness

2021 ◽  
Author(s):  
Leiming Xia ◽  
Fan Yang ◽  
Suzhi Li ◽  
Chen Kan ◽  
Hong Zheng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Drug Resistance ◽  
Lung Adenocarcinoma ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Cxcl8 Secretion ◽  
The Impact ◽  
Egfr Tki ◽  
Egfr T790m

Abstract Background: Additional epidermal growth factor receptor (EGFR) mutations confer the drug resistance to generations of EGFR targeted tyrosine kinase inhibitor (EGFR-TKI), which is the thorny challenge to propel the treatment of lung adenocarcinoma (LUAD) forward. In the tailored targeting era, the strategy of EGFR-TKI combined regimen was considered the promising approach to conquer the big aforesaid question. The mechanism of SHP2 involved in the cell proliferation, cytokine production, stemness maintenance and drug resistance of LUAD was not yet fully explored.Methods: To determine the impact of SHP2 on the efficacy of EGFR T790M mutant LUAD cells to Osimertinib, SHP2 was tested in Osimertinib treated LUAD cells. Cell proliferation and stemness were tested in SHP2 modified LUAD cells. RNA sequencing were performed to explore the mechanism of SHP2 promoted stemness.Results: This study demonstrated that high SHP2 indicates poor outcome of LUAD patients, and enriched in Osimertinib resistant LUAD cells. Moreover, SHP2 inhibition suppressed the cell proliferation and damaged the stemness of EGFR T790M mutant LUAD. Furthermore, SHP2 facilitates the CXCL8 secretion of EGFR T790M mutant LUAD which derived from a CXCL8-CXCR1/2 positive feedback loop that promoted the stemness and tumorigenesis. Finally, we found SHP2 inhibited ERK-AKT-NFκB and GSK3β-β Catenin pathways in EGFR T790M mutant LUAD cells, inactivation of NF-κB confers to a blockage of CXCL8-CXCR1/2 loop, and stemness limited by restricting GSK3β/β-Catenin signaling.Conclusions: Our data revealed that inhibition of SHP2 enhances the anti-cancer effect of Osimertinib in EGFR T790M mutant LUAD by blocking CXCL8-CXCR1/2 loop mediated stemness, which may provide an alternative option to promote the efficacy of osimertinib in clinic of EGFR T790M mutant LUAD.

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