Epidermal Growth Factor Receptor Extracellular Domain Mutations in Glioblastoma Present Opportunities for Clinical Imaging and Therapeutic Development
Authors: Bettina Hentschel
Donald M O&#x27;Rourke
Jianhui Ma
Christos Davatzikos
Sung Min Ha
Ahmed Idbaih
Joerg Felsberg
MacLean P Nasrallah
Spyridon Bakas
Wenya Linda Bi
David A Reardon
Cole J Ferguson
Zev A Binder
Frank B Furnari
Saima Rathore
Michel Bilello
Sonika Dahiya
Stephen J Bagley
Amy Haseley Thorne
Michael Weller
Andrew M Scott
Hamed Akbari
E Paul Wileyto
Laura Orellana
Ciro Zanca
Logan Zhang
Jennifer J D Morrissette
Journal: Cancer cell (2018)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: A289D/T/V; EGFR; EGFR oncogenes; EGFR targeted therapy; GBM
Affiliations: Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Biomedical Image Computing and Analytics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Ludwig Institute for Cancer Research, La Jolla, San Diego 92093, USA., Center for Biomedical Image Computing and Analytics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Division of Neuropathology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63108, USA., Center for Skull Base and Pituitary Surgery, Department of Neurosurgery, Brigham and Woman's Hospital, Harvard Medical Center, Boston, MA 02115, USA., Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Sorbonne Universit√©, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle √©pini√®re, ICM, AP-HP, H√¥pitaux Universitaires Piti√© Salp√™tri√®re - Charles Foix, Service de Neurologie 2-Mazarin, Paris 75013, France., Institute of Neuropathology, Heinrich Heine University, Medical Faculty, Moorenstrasse 5, Duesseldorf 40225, Germany., Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Medical Faculty, H√§rtelstrasse 16, Leipzig 04107, Germany., Department of Neurology, University Hospital and University of Zurich, Zurich 8091, Switzerland., Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA., Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Division of Neuropathology, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Olivia Newton-John Cancer Research Institute, La Trobe University, Melbourne, Australia., Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden; Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden., Ludwig Institute for Cancer Research, La Jolla, San Diego 92093, USA. Electronic address: ., Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Biomedical Image Computing and Analytics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: .

Abstract:  We explored the clinical and pathological impact of epidermal growth factor receptor (EGFR) extracellular domain missense mutations. Retrospective assessment of 260 de novo glioblastoma patients revealed a significant reduction in overall survival of patients having tumors with EGFR mutations at alanine 289 (EGFRA289D/T/V). Quantitative multi-parametric magnetic resonance imaging analyses indicated increased tumor invasion for EGFRA289D/T/V mutants, corroborated in mice bearing intracranial tumors expressing EGFRA289V and dependent on ERK-mediated expression of matrix metalloproteinase-1. EGFRA289V tumor growth was attenuated with an antibody against a cryptic epitope, based on in silico simulation. The findings of this study indicate a highly invasive phenotype associated with the EGFRA289V mutation in glioblastoma, postulating EGFRA289V as a molecular marker for responsiveness to therapy with EGFR-targeting antibodies. 

Retracted: No

PubPeer comments:
 I am at a loss to see how the Kaplan Meier curves in panels 1C, 1D, 1E are all identical (the black lines) when the number of individuals at risk (listed below each panel) is different in each case. Also according to the legend, the graphs are comparing different EGFR mutations to each other, so the plain black  EGFR line in each case should be different, right? Or am I missing something here? Maybe the authors can enlighten me? , 
 The commenter seems to feel that the solid bar, representing wtEGFR, in our survival curves of Figure 1C-E are identical. However, they are incorrect. I can understand why they think so, as they are very similar. But there are shifts in the curve, as they are different populations. The difficulty comes from the fact that each panel only differs from the other by no more than 15 patients, out of a total of greater than 240. So the shifts in the curves are quite minimal, but present. Which is an additional reason that we provided the number at risk below, so you can tell that we are looking at different populations , 
 #1, to further extend what the author just explained: RE: * Also according to the legend, the graphs are comparing different EGFR mutations to each other, so the plain black  EGFR line in each case should be different, right? * No, this is not correct. They don t compare two different mutations to each other; they compare with vs. without mutation. In each panel, the black line show the individuals that do NOT have the mutation plotted in grey. For example, panel E compares with vs. without the G598V mutation. The fraction of the cohort with any of the three mutations is small, and so most of the cohort lacks any of the three mutations, which is why the black lines look so similar in the three panels. Hope that helps. (P.S., If you adjust the image to eliminate the grey, you can see the differences between the black plots. For example, D and E show a vertical drop at the very first timepoint that is absent in C.) ,