Early detection of erlotinib treatment response in NSCLC by 3'-deoxy-3'-[F]-fluoro-L-thymidine ([F]FLT) positron emission tomography (PET).
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.
Ullrich
Roland T
RT
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.
Zander
Thomas
T
Neumaier
Bernd
B
Koker
Mirjam
M
Shimamura
Takeshi
T
Waerzeggers
Yannic
Y
Borgman
Christa L
CL
Tawadros
Samir
S
Li
Hongfeng
H
Sos
Martin L
ML
Backes
Heiko
H
Shapiro
Geoffrey I
GI
Wolf
Jürgen
J
Jacobs
Andreas H
AH
Thomas
Roman K
RK
Winkeler
Alexandra
A
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
D015224:Dideoxynucleosides; D019394:Ki-67 Antigen; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; C002854:alovudine