Preclinical and clinical evidence that Deoxy-2-[18F]fluoro-D-glucose positron emission tomography with computed tomography is a reliable tool for the detection of early molecular responses to erlotinib in head and neck cancer.
OBJECTIVE
There is a clinical need to identify predictive markers of the responses to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). Deoxy-2-[(18)F]fluoro-d-glucose positron emission tomography with computed tomography ((18)FDG-PET/CT) could be a tool of choice for monitoring the early effects of this class of agent on tumor activity.


METHODS
Using models of human head and neck carcinoma (CAL33 and CAL166 cell lines), we first tested in vitro and in vivo whether the in vivo changes in (18)FDG-PET/CT uptake were associated with the molecular and cellular effects of the EGFR-TKI erlotinib. Then, the pathologic and morphologic changes and the (18)FDG-PET/CT uptake before and after erlotinib exposure in patients were analyzed.


RESULTS
Erlotinib strongly inhibited extracellular signal-regulated kinase-1/2 (ERK-1/2) phosphorylation both in the preclinical models and in patients. Western blotting, immunofluorescence, and immunohistochemistry showed that erlotinib did not modify Glut-1 expression at the protein level either in cell line models or in tumor tissue from mouse xenografts or in patients. Phospho-ERK-1/2 inhibition was associated with a reduction in (18)FDG uptake in animal and human tumors. The biological volume was more accurate than the standardized uptake value for the evaluation of the molecular responses.


CONCLUSIONS
These results show that the (18)FDG-PET/CT response is a reliable surrogate marker of the effects of erlotinib in head and neck carcinoma.
Vergez
Sébastien
S
Université Paul Sabatier and Institut Claudius Regaud, Toulouse Cedex, France.
Delord
Jean-Pierre
JP
Thomas
Fabienne
F
Rochaix
Philippe
P
Caselles
Olivier
O
Filleron
Thomas
T
Brillouet
Séverine
S
Canal
Pierre
P
Courbon
Frédéric
F
Allal
Ben C
BC
D000368:Aged; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D000069347:Erlotinib Hydrochloride; D005260:Female; D005455:Fluorescent Antibody Technique; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D006258:Head and Neck Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D049268:Positron-Emission Tomography / Q000379:methods*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011799:Quinazolines / Q000627:therapeutic use*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014057:Tomography, X-Ray Computed / Q000379:methods*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D019788:Fluorodeoxyglucose F18; D000069347:Erlotinib Hydrochloride; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3