Response of Glioblastomas to EGFR Kinase Inhibitors
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《新英格兰医药杂志》
To the Editor: Mellinghoff et al. (Nov. 10 issue)1 identified coexpression of epidermal growth factor receptor (EGFR) deletion mutant variant III (EGFRvIII) and the tumor-suppressor protein PTEN as a molecular signature in pretreatment glioblastoma tissue that predicts sensitivity to EGFR inhibitors. However, several tumors that were responsive to erlotinib in the validation data set exhibited PTEN loss, and one of these did not express EGFRvIII, suggesting that alternative mechanisms of action exist. Although the effects of EGFR inhibitors on EGFR activity and signaling were analyzed in vitro, ideally tissue from patients in the training and validation sets would also be analyzed for molecular effects during therapy in order to correlate clinical with molecular outcomes. We analyzed tissue resected from patients who were undergoing erlotinib or gefitinib therapy, and we did not observe marked inhibition of EGFR phosphorylation.2 However, none of our patients responded robustly to erlotinib or gefitinib. Future studies should use a two-pronged approach in order to identify both pretreatment molecular predictors of outcome and molecular effects during treatment. To expedite clinical trials, investigators might consider biopsy after several weeks of treatment with targeted therapeutics, and they might consider withdrawing therapy if pathway inhibition is not observed.3
Andrew B. Lassman, M.D.
Lauren E. Abrey, M.D.
Memorial Sloan-Kettering Cancer Center
New York, NY 10021
lassmana@mskcc.org
Mark R. Gilbert, M.D.
University of Texas M.D. Anderson Cancer Center
Houston, TX 77030
Dr. Lassman reports owning stock in Genentech; Dr. Abrey reports having received research support from Genentech and serving on a data safety monitoring committee for Genentech.
References
Mellinghoff IK, Wang MY, Vivanco I, et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 2005;353:2012-2024.
Lassman AB, Rossi MR, Razier JR, et al. Molecular study of malignant gliomas treated with epidermal growth factor receptor inhibitors: tissue analysis from North American Brain Tumor Consortium trials 01-03 and 00-01. Clin Cancer Res 2005;11:7841-7850.
Lang FF, Gilbert MR, Puduvalli VK, et al. Toward better early-phase brain tumor clinical trials: a reappraisal of current methods and proposals for future strategies. Neuro-oncol 2002;4:268-77.
The authors reply: Lassman et al. raise two important points. Our study suggests that EGFRvIII and PTEN coexpression is strongly associated with clinical response, but it does not rule out the possibility of additional molecular mechanisms that may sensitize glioblastoma cells to EGFR kinase–inhibitor therapy. Future studies to refine this molecular signature and to identify additional molecular correlates of response are warranted. We also agree with Dr. Lassman and colleagues that it is important to analyze the molecular effects on EGFR, the downstream PI3K signaling pathway, and potentially other signaling networks during treatment. Rational design of clinical trials to optimize tissue sampling at appropriate time points before and during therapy will be critical to the integration of clinical and molecular outcome data and to guide therapeutic decisions in the event of treatment failure.
Ingo K. Mellinghoff, M.D.
Timothy Cloughesy, M.D.
Paul S. Mischel, M.D.
David Geffen UCLA School of Medicine
Los Angeles, CA 90095
pmischel@mednet.ucla.edu
Andrew B. Lassman, M.D.
Lauren E. Abrey, M.D.
Memorial Sloan-Kettering Cancer Center
New York, NY 10021
lassmana@mskcc.org
Mark R. Gilbert, M.D.
University of Texas M.D. Anderson Cancer Center
Houston, TX 77030
Dr. Lassman reports owning stock in Genentech; Dr. Abrey reports having received research support from Genentech and serving on a data safety monitoring committee for Genentech.
References
Mellinghoff IK, Wang MY, Vivanco I, et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 2005;353:2012-2024.
Lassman AB, Rossi MR, Razier JR, et al. Molecular study of malignant gliomas treated with epidermal growth factor receptor inhibitors: tissue analysis from North American Brain Tumor Consortium trials 01-03 and 00-01. Clin Cancer Res 2005;11:7841-7850.
Lang FF, Gilbert MR, Puduvalli VK, et al. Toward better early-phase brain tumor clinical trials: a reappraisal of current methods and proposals for future strategies. Neuro-oncol 2002;4:268-77.
The authors reply: Lassman et al. raise two important points. Our study suggests that EGFRvIII and PTEN coexpression is strongly associated with clinical response, but it does not rule out the possibility of additional molecular mechanisms that may sensitize glioblastoma cells to EGFR kinase–inhibitor therapy. Future studies to refine this molecular signature and to identify additional molecular correlates of response are warranted. We also agree with Dr. Lassman and colleagues that it is important to analyze the molecular effects on EGFR, the downstream PI3K signaling pathway, and potentially other signaling networks during treatment. Rational design of clinical trials to optimize tissue sampling at appropriate time points before and during therapy will be critical to the integration of clinical and molecular outcome data and to guide therapeutic decisions in the event of treatment failure.
Ingo K. Mellinghoff, M.D.
Timothy Cloughesy, M.D.
Paul S. Mischel, M.D.
David Geffen UCLA School of Medicine
Los Angeles, CA 90095
pmischel@mednet.ucla.edu