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      Early Detection of Erlotinib Treatment Response in NSCLC by 3′-Deoxy-3′-[ 18F]-Fluoro-L-Thymidine ([ 18F]FLT) Positron Emission Tomography (PET)

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          Abstract

          Background

          Inhibition of the epidermal growth factor receptor (EGFR) has shown clinical success in patients with advanced non-small cell lung cancer (NSCLC). Somatic mutations of EGFR were found in lung adenocarcinoma that lead to exquisite dependency on EGFR signaling; thus patients with EGFR-mutant tumors are at high chance of response to EGFR inhibitors. However, imaging approaches affording early identification of tumor response in EGFR-dependent carcinomas have so far been lacking.

          Methodology/Principal Findings

          We performed a systematic comparison of 3′-Deoxy-3′-[ 18F]-fluoro-L-thymidine ([ 18F]FLT) and 2-[ 18F]-fluoro-2-deoxy-D-glucose ([ 18F]FDG) positron emission tomography (PET) for their potential to identify response to EGFR inhibitors in a model of EGFR-dependent lung cancer early after treatment initiation. While erlotinib-sensitive tumors exhibited a striking and reproducible decrease in [ 18F]FLT uptake after only two days of treatment, [ 18F]FDG PET based imaging revealed no consistent reduction in tumor glucose uptake. In sensitive tumors, a decrease in [ 18F]FLT PET but not [ 18F]FDG PET uptake correlated with cell cycle arrest and induction of apoptosis. The reduction in [ 18F]FLT PET signal at day 2 translated into dramatic tumor shrinkage four days later. Furthermore, the specificity of our results is confirmed by the complete lack of [ 18F]FLT PET response of tumors expressing the T790M erlotinib resistance mutation of EGFR.

          Conclusions

          [ 18F]FLT PET enables robust identification of erlotinib response in EGFR-dependent tumors at a very early stage. [ 18F]FLT PET imaging may represent an appropriate method for early prediction of response to EGFR TKI treatment in patients with NSCLC.

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          Most cited references 21

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          Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.

          Most patients with non-small-cell lung cancer have no response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). However, about 10 percent of patients have a rapid and often dramatic clinical response. The molecular mechanisms underlying sensitivity to gefitinib are unknown. We searched for mutations in the EGFR gene in primary tumors from patients with non-small-cell lung cancer who had a response to gefitinib, those who did not have a response, and those who had not been exposed to gefitinib. The functional consequences of identified mutations were evaluated after the mutant proteins were expressed in cultured cells. Somatic mutations were identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib-responsive lung cancer, as compared with none of the seven patients with no response (P<0.001). Mutations were either small, in-frame deletions or amino acid substitutions clustered around the ATP-binding pocket of the tyrosine kinase domain. Similar mutations were detected in tumors from 2 of 25 patients with primary non-small-cell lung cancer who had not been exposed to gefitinib (8 percent). All mutations were heterozygous, and identical mutations were observed in multiple patients, suggesting an additive specific gain of function. In vitro, EGFR mutants demonstrated enhanced tyrosine kinase activity in response to epidermal growth factor and increased sensitivity to inhibition by gefitinib. A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene, which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib. These mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor. Screening for such mutations in lung cancers may identify patients who will have a response to gefitinib. Copyright 2004 Massachusetts Medical Society
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            New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada.

            Anticancer cytotoxic agents go through a process by which their antitumor activity-on the basis of the amount of tumor shrinkage they could generate-has been investigated. In the late 1970s, the International Union Against Cancer and the World Health Organization introduced specific criteria for the codification of tumor response evaluation. In 1994, several organizations involved in clinical research combined forces to tackle the review of these criteria on the basis of the experience and knowledge acquired since then. After several years of intensive discussions, a new set of guidelines is ready that will supersede the former criteria. In parallel to this initiative, one of the participating groups developed a model by which response rates could be derived from unidimensional measurement of tumor lesions instead of the usual bidimensional approach. This new concept has been largely validated by the Response Evaluation Criteria in Solid Tumors Group and integrated into the present guidelines. This special article also provides some philosophic background to clarify the various purposes of response evaluation. It proposes a model by which a combined assessment of all existing lesions, characterized by target lesions (to be measured) and nontarget lesions, is used to extrapolate an overall response to treatment. Methods of assessing tumor lesions are better codified, briefly within the guidelines and in more detail in Appendix I. All other aspects of response evaluation have been discussed, reviewed, and amended whenever appropriate.
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              EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.

              Receptor tyrosine kinase genes were sequenced in non-small cell lung cancer (NSCLC) and matched normal tissue. Somatic mutations of the epidermal growth factor receptor gene EGFR were found in 15of 58 unselected tumors from Japan and 1 of 61 from the United States. Treatment with the EGFR kinase inhibitor gefitinib (Iressa) causes tumor regression in some patients with NSCLC, more frequently in Japan. EGFR mutations were found in additional lung cancer samples from U.S. patients who responded to gefitinib therapy and in a lung adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib, but not in gefitinib-insensitive tumors or cell lines. These results suggest that EGFR mutations may predict sensitivity to gefitinib.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2008
                12 December 2008
                : 3
                : 12
                Affiliations
                [1 ]Max Planck Institute for Neurological Research with Klaus-Joachim-Zülch-Laboratories of the Max Planck Society, Medical Faculty of the University of Cologne, Cologne, Germany
                [2 ]Center for Molecular Medicine Cologne (CMMC), Cologne, Germany
                [3 ]Klinikum Fulda, Fulda, Germany
                [4 ]Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
                [5 ]Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
                [6 ]Department I of Internal Medicine and Center of Integrated Oncology Köln – Bonn, University of Cologne, Cologne, Germany
                [7 ]Chemical Genomics Center of the Max Planck Society, Dortmund, Germany
                Washington University, United States of America
                Author notes

                Conceived and designed the experiments: RTU TZ BN TS YW HB JW AHJ RKT AW. Performed the experiments: RTU MK TS YW CB ST HL MLS HB. Analyzed the data: RTU MLS HB. Contributed reagents/materials/analysis tools: RTU TZ BN MK ST GIS JW AHJ RKT AW. Wrote the paper: RTU TZ BN YW HL MLS HB JW AHJ RKT AW.

                Article
                08-PONE-RA-04439R1
                10.1371/journal.pone.0003908
                2592703
                19079597
                Ullrich et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 6
                Categories
                Research Article
                Cell Biology/Cell Signaling
                Oncology/Lung Cancer
                Radiology and Medical Imaging/PET and SPECT Imaging

                Uncategorized

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