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

Purpose:There is a clinical need to identify predictive markers of the responses to EGFR tyrosine-kinase inhibitors (EGFR-TKI). Positron Emission Tomography of deoxy-2-[18F]Fluoro-D-glucose (18FDG-PET/CT) could be a tool of choice for monitoring the early effects of this class of agent on tumor activity. Experimental Design:Using models of human head and neck carcinoma (CAL33 and CAL166 cell lines), we tested first in vitro and in vivo, whether the in vivo changes in 18FDG-PET/CT uptake were associated with the molecular and cellular effects of the EGFR-TKI erlotinib. Then, the pathological and morphological changes and the 18FDG-PET/CT uptake before and after erlotinib exposure in patients were analyzed. Results:Erlotinib strongly inhibited ERK-1/2 phosphorylation in both 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 18FDG 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 18FDG-PET/CT response is a reliable surrogate marker of the effects of erlotinib in head and neck carcinoma.