PET determination of specific uptake of [11C]-erlotinib by different tumor types expressing EGFR, in vivo through kinetic modeling

Objectives Activating mutations of the epidermal growth factor receptor (EGFR) often occur in non-small cell lung cancer (NSCLC) and in 40% of malignant glioma [1-3]. In this study we (1) investigated [11C]-erlotinib positron emission tomography (PET) imaging as a tool to identify activating mutations of EGFR in both glioma and NSCLC xenografts and (2) performed Logan graphical analysis [4] to compare sensitivity to the Simplified Reference Tissue Model (SRTM) [5].

Methods Specific binding was determined for high and low specific activity (SA) [11C]-erlotinib PET scans in mice bearing synchronous human cancer xenografts with different EGFR expression profiles (mutant EGFR: PC9, HCC827, U87 ΔEGFR; wild type EGFR: U87, SW620). Kinetic modeling using SRTM and Logan plots was used to determine EGFR binding potential (BP). Healthy muscle tissue was used as reference region.

Results Although immunohistochemistry demonstrated constitutive EGFR phosphorylation in all tumors expressing mutant EGFR, SRTM found that only kinase domain mutant NSCLC (HCC827 and PC9) had significantly greater BP in high versus low SA scans (p<0.02 and p=0.075, respectively). See Figure 1. Colon cancer (SW620) and glioblastoma (U87 and U87 ΔEGFR) xenografts were indistinguishable between SA conditions. Logan analyses confirmed these findings with lower sensitivity due to BP underestimation.

Conclusions (1) [11C]-erlotinib is a promising radiotracer that could become a clinical method for assessing EGFR-erlotinib interactions in patients with tumors that harbor EGFR activating kinase domain mutations. (2) As expected, Logan analysis underestimated EGFR BP compared to SRTM; no sensitivity advantage was gained from Logan analysis.

Research Support Yale Clinical Center for Investigation Scholar Award (UL1RR024139/KL2RR024138) to JC, the Kalimeris fund, and the Yale PET Center. JRP is supported by the NSF GRFP (DGE-1122492).