title: Early detection of erlotinib treatment response in NSCLC by 3'-deoxy-3'-[F]-fluoro-L-thymidine ([F]FLT) positron emission tomography (PET).
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.
  
  
  RESULTS
  We performed a systematic comparison of 3'-Deoxy-3'-[(18)F]-fluoro-L-thymidine ([(18)F]FLT) and 2-[(18)F]-fluoro-2-deoxy-D-glucose ([(18)F]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 [(18)F]FLT uptake after only two days of treatment, [(18)F]FDG PET based imaging revealed no consistent reduction in tumor glucose uptake. In sensitive tumors, a decrease in [(18)F]FLT PET but not [(18)F]FDG PET uptake correlated with cell cycle arrest and induction of apoptosis. The reduction in [(18)F]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 [(18)F]FLT PET response of tumors expressing the T790M erlotinib resistance mutation of EGFR.
  
  
  CONCLUSIONS
  [(18)F]FLT PET enables robust identification of erlotinib response in EGFR-dependent tumors at a very early stage. [(18)F]FLT PET imaging may represent an appropriate method for early prediction of response to EGFR TKI treatment in patients with NSCLC.
authors.affiliation: 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.
authors.forename: Roland T
authors.initials: RT
authors.lastname: Ullrich
authors.forename: Thomas
authors.initials: T
authors.lastname: Zander
authors.forename: Bernd
authors.initials: B
authors.lastname: Neumaier
authors.forename: Mirjam
authors.initials: M
authors.lastname: Koker
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimamura
authors.forename: Yannic
authors.initials: Y
authors.lastname: Waerzeggers
authors.forename: Christa L
authors.initials: CL
authors.lastname: Borgman
authors.forename: Samir
authors.initials: S
authors.lastname: Tawadros
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Li
authors.forename: Martin L
authors.initials: ML
authors.lastname: Sos
authors.forename: Heiko
authors.initials: H
authors.lastname: Backes
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wolf
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Jacobs
authors.forename: Roman K
authors.initials: RK
authors.lastname: Thomas
authors.forename: Alexandra
authors.initials: A
authors.lastname: Winkeler
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D015224:Dideoxynucleosides; D015536:Down-Regulation; D055088:Early Detection of Cancer; D066246:ErbB Receptors / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D019394:Ki-67 Antigen / Q000378:metabolism; D008175:Lung Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D049268:Positron-Emission Tomography; D011799:Quinazolines / Q000627:therapeutic use*; D015398:Signal Transduction; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D015224:Dideoxynucleosides; D019394:Ki-67 Antigen; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; C002854:alovudine