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https://www.readbyqxmd.com/read/28940498/twice-weekly-pulse-and-daily-continuous-dose-erlotinib-as-initial-treatment-for-patients-with-epidermal-growth-factor-receptor-mutant-lung-cancers-and-brain-metastases
#1
Kathryn C Arbour, Mark G Kris, Gregory J Riely, Ai Ni, Kathryn Beal, Mariza Daras, Sara A Hayes, Robert J Young, Christopher R Rodriguez, Linda Ahn, William Pao, Helena A Yu
BACKGROUND: In a phase 1 study of pulse/continuous-dose erlotinib, no patient had disease progression in the central nervous system (CNS). This expansion cohort of the phase 1 study tested the same regimen in a cohort of individuals with epidermal growth factor receptor (EGFR)-mutant lung cancers with untreated brain metastases. METHODS: Patients had not received EGFR tyrosine kinase inhibitors or radiation for brain metastases. All received 1200 mg of erlotinib on days 1 and 2 and 50 mg on days 3 to 7 weekly...
September 21, 2017: Cancer
https://www.readbyqxmd.com/read/28932544/the-detectability-of-the-pretreatment-egfr-t790m-mutations-in-lung-adenocarcinoma-using-cast-pcr-and-digital-pcr
#2
Tsutomu Tatematsu, Katsuhiro Okuda, Ayumi Suzuki, Risa Oda, Tadashi Sakane, Osamu Kawano, Hiroshi Haneda, Satoru Moriyama, Hidefumi Sasaki, Ryoichi Nakanishi
BACKGROUND: A gatekeeper T790M mutation is thought to cause resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment. The detection of a 2nd mutation is important for planning the next therapy when patients acquire resistance to the first line EGFR-TKI. METHODS: We used a competitive allele-specific polymerase chain reaction (CAST-PCR) to analyze the incidence and clinical significance of T790M mutations in 153 lung adenocarcinomas with EGFR-activating mutations...
August 2017: Journal of Thoracic Disease
https://www.readbyqxmd.com/read/28919784/durable-complete-remission-of-poor-performance-status-metastatic-lung-adenocarcinoma-patient-treated-with-second-line-erlotinib-a-case-report
#3
Dragana Jovanovic, Ruza Stevic, Marta Velinovic, Milica Kontic, Dragana Maric, Jelena Spasic, Davorin Radosavljevic
This paper presents a rare case of an elderly patient treated with erlotinib for disseminated lung adenocarcinoma with poor performance status (Eastern Cooperative Oncology Group performance status [PS]3). This treatment led to a long duration of complete remission according to Response Evaluation Criteria in Solid Tumors 1.1 - almost 7 years (81 months) of progression-free survival (PFS) and overall survival (OS) of 10 years by March 2017. The treatment with erlotinib started in September 2008 and it was well tolerated with no adverse effects...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28915640/marsdenia-tenacissima-extract-overcomes-axl-and-met-mediated-erlotinib-and-gefitinib-cross-resistance-in-non-small-cell-lung-cancer-cells
#4
Shu-Yan Han, Wei Zhao, Hai-Bo Han, Hong Sun, Dong Xue, Yan-Na Jiao, Xi-Ran He, Shan-Tong Jiang, Ping-Ping Li
Tyrosine kinase inhibitors (TKIs) are an effective treatment strategy for non-small cell lung cancer (NSCLC) patients harboring mutations that result in constitutive activation of the epidermal growth factor receptor (EGFR). However, most patients eventually develop resistance to TKIs. This occurs due to additional EGFR mutations or the activation of bypass signaling pathways. In our previous work, we demonstrated that Marsdenia tenacissima extract (MTE) restored gefitinib sensitivity in resistant NSCLC cells with EGFR T790M or K-ras mutations...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28911086/large-scale-prospective-screening-of-egfr-mutations-in-the-blood-of-advanced-nsclc-patients-to-guide-treatment-decisions
#5
C Mayo-de-Las-Casas, N Jordana-Ariza, M Garzón-Ibañez, A Balada-Bel, J Bertrán-Alamillo, S Viteri-Ramírez, N Reguart, M A Muñoz-Quintana, P Lianes-Barragan, C Camps, E Jantús, J Remon-Massip, S Calabuig, D Aguiar, M L Gil, N Viñolas, A K Santos-Rodríguez, M Majem, B García-Peláez, S Villatoro, A Pérez-Rosado, J C Monasterio, E Ovalle, M J Catalán, R Campos, D Morales-Espinosa, A Martínez-Bueno, M González-Cao, X González, I Moya-Horno, A E Sosa, N Karachaliou, R Rosell, M A Molina-Vila
Background: In a significant percentage of advanced non-small-cell lung cancer (NSCLC) patients, tumor tissue is unavailable or insufficient for genetic analyses. We prospectively analyzed if circulating-free DNA (cfDNA) purified from blood can be used as a surrogate in this setting to select patients for treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Patients and methods: Blood samples were collected in 119 hospitals from 1138 advanced NSCLC patients at presentation (n = 1033) or at progression to EGFR-TKIs (n = 105) with no biopsy or insufficient tumor tissue...
September 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28901258/from-biology-to-therapy-improvements-of-therapeutic-options-in-lung-cancer
#6
Luigi Formisano, Valerie M Jansen, Roberta Marciano, Roberto Bianco
Lung cancer is the leading cause of cancer-related mortality around the world, despite effective chemotherapeutic agents, the prognosis has remained poor for a long time. The discovery of molecular changes that drive lung cancer has led to a dramatic shift in the therapeutic landscape of this disease. In "in vitro" and "in vivo" models of NSCLC (non-small cell lung cancer), angiogenesis blockade has demonstrated an excellent anti-tumor activity, thus, a number of anti-angiogenic drugs have been approved by regulatory authorities for use in clinical practice...
September 12, 2017: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/28899783/induced-sensitivity-to-egfr-inhibitors-is-mediated-by-palmitoylated-cysteine-1025-of-egfr-and-requires-oncogenic-kras
#7
Akriti Kharbanda, Kristin Runkle, Wei Wang, Eric S Witze
Currently, there are no effective therapeutic strategies targeting Kras driven cancers, and therefore, identifying new targeted therapies and overcoming drug resistance have become paramount for effective long-term cancer therapy. We have found that reducing expression of the palmitoyl transferase DHHC20 increases cell death induced by the EGFR inhibitor gefitinib in Kras and EGFR mutant cell lines, but not MCF7 cells harboring wildtype Kras. We show that the increased gefitinib sensitivity in cancer cells induced by DHHC20 inhibition is mediated directly through loss of palmitoylation on a previously identified cysteine residue in the C-terminal tail of EGFR...
September 9, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28884371/egfr-t790m-mutation-testing-of-non-small-cell-lung-cancer-tissue-and-blood-samples-artificially-spiked-with-circulating-cell-free-tumor-dna-results-of-a-round-robin-trial
#8
Jana Fassunke, Michaela Angelika Ihle, Dido Lenze, Annika Lehmann, Michael Hummel, Claudia Vollbrecht, Roland Penzel, Anna-Lena Volckmar, Albrecht Stenzinger, Volker Endris, Andreas Jung, Ulrich Lehmann, Silke Zeugner, Gustavo Baretton, Hans Kreipe, Peter Schirmacher, Thomas Kirchner, Manfred Dietel, Reinhard Büttner, Sabine Merkelbach-Bruse
The European Commision (EC) recently approved osimertinib for the treatment of adult patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) harboring EGFR T790M mutations. Besides tissue-based testing, blood samples containing cell-free circulating tumor DNA (ctDNA) can be used to interrogate T790M status. Herein, we describe the conditions and results of a round robin trial (RRT) for T790M mutation testing in NSCLC tissue specimens and peripheral blood samples spiked with cell line DNA mimicking tumor-derived ctDNA...
September 8, 2017: Virchows Archiv: An International Journal of Pathology
https://www.readbyqxmd.com/read/28881827/structural-basis-of-mutant-selectivity-and-drug-resistance-related-to-co-1686
#9
Xiao-E Yan, Su-Jie Zhu, Ling Liang, Peng Zhao, Hwan Geun Choi, Cai-Hong Yun
Non-small-cell lung cancers (NSCLCs) caused by activating mutations in the kinase domain of epidermal growth factor receptor (EGFR) initially respond to first-generation reversible drugs gefitinib and erlotinib. However, clinical efficacy is limited due to the development of drug-resistance that in more than half of the cases are driven by the secondary T790M mutation. CO-1686 is one of the third generation irreversible inhibitors that inhibits EGFR activating mutants, including those with concurrent T790M, while avoiding the off-target toxicity owing to inhibition of wild-type EGFR in treating EGFR mutation-positive NSCLCs...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28881618/the-prognostic-role-of-pretreatment-epidermal-growth-factor-receptor-t790m-mutation-in-advanced-non-small-cell-lung-cancer-patients-treated-with-egfr-tyrosine-kinase-inhibitors
#10
Guangzhi Ma, Jing Zhang, Liyuan Yin, Hai Jiang, Weiwei Zhang, Yanlin Song, Ming Liu
PURPOSE: The outcome of pretreatment epidermal growth factor receptor (EGFR) T790M mutation in EGFR mutant non-small cell lung cancer (NSCLC) patients treated with EGFR tyrosine kinase inhibitors (TKIs) is controversial, this study aimed to evaluate the prognostic role of pretreatment T790M in advanced NSCLC patients treated with EGFR TKIs. RESULTS: A total of 7 eligible studies containing 179 cases and 281 controls were included in the meta-analysis. The pooled hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were 2...
August 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28880737/cost-effectiveness-of-osimertinib-in-the-uk-for-advanced-egfr-t790m-non-small-cell-lung-cancer
#11
Evelina Bertranou, Carolyn Bodnar, Viktor Dansk, Alastair Greystoke, Samuel Large, Matthew Dyer
AIM: This study presents the cost-utility analysis that was developed to inform the NICE health technology assessment of osimertinib versus platinum-based doublet chemotherapy (PDC) in patients with EGFR-T790M mutation-positive non-small cell lung cancer (NSCLC) who have progressed on epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. METHODS AND MATERIALS: A partitioned survival model with three health states (progression-free, progressed disease, and death) from a UK payer perspective and over lifetime (15 years) was developed...
September 7, 2017: Journal of Medical Economics
https://www.readbyqxmd.com/read/28879074/a-case-report-of-egfr-mutant-lung-adenocarcinoma-that-acquired-resistance-to-egfr-tyrosine-kinase-inhibitors-with-t790m-mutation-and-epithelial-to-mesenchymal-transition
#12
Nana Zhang, Depu Wang, Xiaofeng Li, Zhe Yang, Guanjun Zhang, Yili Wang, Chunbao Wang
Although a secondary mutation and the epithelial-to-mesenchymal transition (EMT) are encountered very often in patients received the EGFR-TKI targeted treatment. The entire detrimental morphological change of the cancer entity was rare reported. Herein we report a case that acquired resistance to EGFR-TKI with T790M mutation and complete EMT morphological change of the tumor tissue. The primary lung tumor from a 52-year-old woman was diagnosed with moderate differentiated adenocarcinoma, with intensively positiveTTF-1 and E-cadherin in differentiated glandular structure but not the budding cancer cell cluster which with an intensive Vimentin staining...
2017: Respiratory Medicine Case Reports
https://www.readbyqxmd.com/read/28874593/egfr-exon-19-deletion-in-pancreatic-adenocarcinoma-responds-to-erlotinib-followed-by-t790m-mediated-resistance
#13
Michael Cecchini, Jeffrey Sklar, Jill Lacy
The prognosis of metastatic pancreatic cancer remains poor despite recent advances in treatment with multidrug chemotherapy regimens. Use of immune checkpoint inhibitors and molecular targeted therapies has so far been disappointing. This report describes a patient with chemotherapy-refractory metastatic pancreatic ductal adenocarcinoma (PDAC) whose tumor was characterized by an activating mutation in exon 19 of the epidermal growth factor receptor (EGFR). He experienced response to erlotinib for 10 months, and then developed disease progression in association with emergence of the T790M mutation...
September 2017: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/28866043/clinical-factors-predicting-detection-of-t790m-mutation-in-rebiopsy-for-egfr-mutant-non-small-cell-lung-cancer
#14
Takahisa Kawamura, Hirotsugu Kenmotsu, Shota Omori, Kazuhisa Nakashima, Kazushige Wakuda, Akira Ono, Tateaki Naito, Haruyasu Murakami, Katsuhiro Omae, Keita Mori, Yusuke Tanigawara, Takashi Nakajima, Yasuhisa Ohde, Masahiro Endo, Toshiaki Takahashi
BACKGROUND: T790M, a secondary epidermal growth factor receptor (EGFR) mutation, accounts for approximately 50% of acquired resistance to EGFR-tyrosine kinase inhibitors (TKIs). To facilitate the use of third-generation EGFR-TKIs to potentially overcome T790M-mediated resistance, we evaluated the clinical factors influencing the incidence of T790M mutation. PATIENTS AND METHODS: We retrospectively screened patients with non-small-cell lung cancer harboring EGFR mutations with progressive disease who were rebiopsied between January 2013 and December 2016...
August 10, 2017: Clinical Lung Cancer
https://www.readbyqxmd.com/read/28860885/osimertinib-in-the-treatment-of-non-small-cell-lung-cancer-design-development-and-place-in-therapy
#15
REVIEW
Mariacarmela Santarpia, Alessia Liguori, Niki Karachaliou, Maria Gonzalez-Cao, Maria Grazia Daffinà, Alessandro D'Aveni, Grazia Marabello, Giuseppe Altavilla, Rafael Rosell
The discovery of epidermal growth factor receptor (EGFR) mutations and subsequent demonstration of the efficacy of genotype-directed therapies with EGFR tyrosine kinase inhibitors (TKIs) marked the advent of the era of precision medicine for non-small-cell lung cancer (NSCLC). First- and second-generation EGFR TKIs, including erlotinib, gefitinib and afatinib, have consistently shown superior efficacy and better toxicity compared with first-line platinum-based chemotherapy and currently represent the standard of care for EGFR-mutated advanced NSCLC patients...
2017: Lung Cancer: Targets and Therapy
https://www.readbyqxmd.com/read/28855040/-detection-and-clinical-significance-of-abundance-of-egfr-mutation
#16
REVIEW
Yi Shao, Diansheng Zhong
Non-small cell lung cancer (NSCLC) patients, with sensitive epidermal growth factor receptor (EGFR) mutations react well to tyrosine kinase inhibitors (TKIs). However, the efficacy of TKIs on patients with the same mutant types differs dramatically. It is implied that the different quantities of mutant alleles could be one of the reasons underlying. Patients with high abundance of EGFR mutation might benefit more from TKIs. There are no universal standards for the definition of EGFR mutant abundance. Abundance could be semi-quantified according to the different sensitivities of detection methods, quantified with quantifying detection techniques such as digital PCR or next generation sequencing, or quantified based on the expression of mutant proteins...
August 20, 2017: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
https://www.readbyqxmd.com/read/28854272/overall-survival-in-egfr-mutated-non-small-cell-lung-cancer-patients-treated-with-afatinib-after-egfr-tki-and-resistant-mechanisms-upon-disease-progression
#17
A J van der Wekken, J L Kuiper, A Saber, M M Terpstra, J Wei, T J N Hiltermann, E Thunnissen, D A M Heideman, W Timens, E Schuuring, K Kok, E F Smit, A van den Berg, H J M Groen
PURPOSE: To determine survival in afatinib-treated patients after treatment with first-generation EGFR tyrosine kinase inhibitors (TKIs) and to study resistance mechanisms in afatinib-resistant tumors. METHODS: Characteristics and survival of patients treated with afatinib after resistance to erlotinib or gefitinib in two large Dutch centers were collected. Whole exome sequencing (WES) and pathway analysis was performed on available pre- and post-afatinib tumor biopsies and normal tissue...
2017: PloS One
https://www.readbyqxmd.com/read/28853575/structure-guided-development-of-covalent-and-mutant-selective-pyrazolopyrimidines-to-target-t790m-drug-resistance-in-epidermal-growth-factor-receptor
#18
Julian Engel, Steven Smith, Jonas Lategahn, Hannah L Tumbrink, Lisa Goebel, Christian Becker, Elisabeth Hennes, Marina Keul, Anke Unger, Heiko Müller, Matthias Baumann, Carsten Schultz-Fademrecht, Georgia Günther, Jan G Hengstler, Daniel Rauh
Reversible epidermal growth factor receptor (EGFR) inhibitors prompt a beneficial clinical response in non-small cell lung cancer patients who harbor activating mutations in EGFR. However, resistance mutations, particularly the gatekeeper mutation T790M, limit this efficacy. Here, we describe a structure-guided development of a series of covalent and mutant-selective EGFR inhibitors that effectively target the T790M mutant. The pyrazolopyrimidine-based core differs structurally from that of aminopyrimidine-based third-generation EGFR inhibitors and therefore constitutes a new set of inhibitors that target this mechanism of drug resistance...
September 18, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28843359/combination-osimertinib-and-gefitinib-in-c797s-and-t790m-egfr-mutated-non-small-cell-lung-cancer
#19
Surein Arulananda, Hongdo Do, Ashan Musafer, Paul Mitchell, Alexander Dobrovic, Thomas John
INTRODUCTION: Osimertinib, a third-generation EGFR tyrosine kinase inhibitor has demonstrated efficacy in tumors harboring the EGFR T790M resistance mutation. Inevitably, resistance to third-generation inhibitors results in disease progression, with the EGFR C797S mutation being one of several resistance pathways identified to date. On the basis of preclinical data, we report what is the first known case of a patient harboring the T790M and C797S mutations in trans treated with combination gefitinib and osimertinib...
August 24, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28841389/osimertinib-as-first-line-treatment-of-egfr-mutation-positive-advanced-non-small-cell-lung-cancer
#20
Suresh S Ramalingam, James C-H Yang, Chee Khoon Lee, Takayasu Kurata, Dong-Wan Kim, Thomas John, Naoyuki Nogami, Yuichiro Ohe, Helen Mann, Yuri Rukazenkov, Serban Ghiorghiu, Daniel Stetson, Aleksandra Markovets, J Carl Barrett, Kenneth S Thress, Pasi A Jänne
Purpose The Osimertinib First Time in Patients Ascending Dose (AURA) study ( ClinicalTrials.gov identifier: NCT01802632) included two cohorts of treatment-naïve patients to examine clinical activity and safety of osimertinib (an epidermal growth factor receptor [EGFR] -tyrosine kinase inhibitor selective for EGFR-tyrosine kinase inhibitor sensitizing [ EGFRm] and EGFR T790M resistance mutations) as first-line treatment of EGFR-mutated advanced non-small-cell lung cancer (NSCLC). Patients and Methods Sixty treatment-naïve patients with locally advanced or metastatic EGFRm NSCLC received osimertinib 80 or 160 mg once daily (30 patients per cohort)...
August 25, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
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