Acquired EGFR C797S mutation mediates resistance to AZD9291 in non–small cell lung cancer harboring EGFR T790M
Kenneth S. Thress,Cloud P. Paweletz,Enriqueta Felip,Byoung Chul Cho,Daniel Stetson,Brian Dougherty,Zhongwu Lai,Aleksandra Markovets,Ana Vivancos,Yanan Kuang,Dalia Ercan,Sarah E Matthews,Mireille Cantarini,J. Carl Barrett,Pasi A. Jänne,Geoffrey R. Oxnard +15 more
TLDR
Analysis of cell-free plasma DNA collected from subjects with advanced lung cancer whose tumors had developed resistance to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) AZD 9291 provides insight into the diversity of mechanisms through which tumors acquire resistance to AZD9291.Abstract:
Here we studied cell-free plasma DNA (cfDNA) collected from subjects with advanced lung cancer whose tumors had developed resistance to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) AZD9291. We first performed next-generation sequencing of cfDNA from seven subjects and detected an acquired EGFR C797S mutation in one; expression of this mutant EGFR construct in a cell line rendered it resistant to AZD9291. We then performed droplet digital PCR on serial cfDNA specimens collected from 15 AZD9291-treated subjects. All were positive for the T790M mutation before treatment, but upon developing AZD9291 resistance three molecular subtypes emerged: six cases acquired the C797S mutation, five cases maintained the T790M mutation but did not acquire the C797S mutation and four cases lost the T790M mutation despite the presence of the underlying EGFR activating mutation. Our findings provide insight into the diversity of mechanisms through which tumors acquire resistance to AZD9291 and highlight the need for therapies that are able to overcome resistance mediated by the EGFR C797S mutation.read more
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Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer
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References
More filters
Journal ArticleDOI
New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1)
Elizabeth Eisenhauer,P. Therasse,Jan Bogaerts,Lawrence H. Schwartz,Daniel J. Sargent,Robert Ford,Janet Dancey,S. Arbuck,S. Gwyther,Margaret M. Mooney,Larry Rubinstein,Lalitha K. Shankar,Lori E. Dodd,Robert M. Kaplan,Denis Lacombe,Jaap Verweij +15 more
TL;DR: The revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions, and a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included.
Journal ArticleDOI
Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma
Tony Mok,Yi-Long Wu,Sumitra Thongprasert,Chih-Hsin Yang,Da Tong Chu,Nagahiro Saijo,Patrapim Sunpaweravong,Baohui Han,Benjamin Margono,Benjamin Margono,Yukito Ichinose,Yutaka Nishiwaki,Yuichiro Ohe,Jin Ji Yang,Busyamas Chewaskulyong,Haiyi Jiang,Emma Duffield,Claire Watkins,Alison Armour,Masahiro Fukuoka +19 more
TL;DR: Gefit inib is superior to carboplatin-paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia and the presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib.
Journal ArticleDOI
Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors
Lecia V. Sequist,Belinda A. Waltman,Dora Dias-Santagata,Subba R. Digumarthy,Alexa B. Turke,Panos Fidias,Kristin Bergethon,Alice T. Shaw,Scott N. Gettinger,Arjola K. Cosper,Sara Akhavanfard,Rebecca S. Heist,Jennifer S. Temel,James G. Christensen,John C. Wain,Thomas J. Lynch,Kathy Vernovsky,Eugene J. Mark,Michael Lanuti,A. John Iafrate,Mari Mino-Kenudson,Jeffrey A. Engelman +21 more
TL;DR: Detailed genetic and histological analysis of 37 patients with drug-resistant non–small cell lung cancers carrying EGFR mutations provides new insights into the shifting sands of drug resistance evolution in lung cancers and suggests that serial biopsies may be essential in the quest to reverse or even prevent the development ofdrug resistance.
Journal ArticleDOI
Screening for Epidermal Growth Factor Receptor Mutations in Lung Cancer
Rafael Rosell,Teresa Moran,Cristina Queralt,Rut Porta,Felipe Cardenal,Carlos Camps,Margarita Majem,Guillermo Lopez-Vivanco,Dolores Isla,Mariano Provencio,A. Insa,Bartomeu Massuti,José Luis González-Larriba,Luis Paz-Ares,Isabel Bover,Rosario García-Campelo,Miguel Angel Moreno,Silvia Catot,Christian Rolfo,Noemi Reguart,Ramon Palmero,Jose Miguel Sanchez,Roman Bastus,Clara Mayo,Jordi Bertran-Alamillo,Miguel Angel Molina,Jose Javier Sanchez,Miquel Taron +27 more
TL;DR: Large-scale screening of patients with lung cancer for EGFR mutations is feasible and can have a role in decisions about treatment, and the association between the mutations and the outcome of erlotinib treatment is analyzed.
Journal ArticleDOI
AZD9291 in EGFR Inhibitor–Resistant Non–Small-Cell Lung Cancer
Pasi A. Jänne,James Chih-Hsin Yang,Dong Wan Kim,David Planchard,Yuichiro Ohe,Suresh S. Ramalingam,Myung-Ju Ahn,Sang We Kim,Wu Chou Su,Leora Horn,Daniel Haggstrom,Enriqueta Felip,Joo Hang Kim,Paul Frewer,Mireille Cantarini,Kathryn H. Brown,Paul A. Dickinson,Serban Ghiorghiu,Malcolm R Ranson +18 more
TL;DR: AZD9291 was highly active in patients with lung cancer with the EGFR T790M mutation who had had disease progression during prior therapy with EGFR tyrosine kinase inhibitors.
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