PET of HER2-positive pulmonary metastases with 18F-ZHER2:342 affibody in a murine model of breast cancer: comparison with 18F-FDG

Abstract

Targeted therapies often depend on the expression of the target present in the tumor. This expression can be difficult to ascertain in widespread metastases. (18)F-FDG PET/CT, although sensitive, is nonspecific for particular tumor markers. Here, we compare the use of a human epidermal growth factor receptor 2 (HER2)-specific (18)F-Z(HER2)(:342)-Affibody and (18)F-FDG in HER2-expressing pulmonary metastases in a murine model of breast cancer.

Methods: The lung metastasis model was established by intravenous injection of MDA-MB-231(HER2)-Luc human breast cancer cells into the tail vein. Bioluminescence imaging was used to evaluate metastasis progression. Uptake of (18)F-Z(HER2)(:342)-Affibody and (18)F-FDG was confirmed by coregistration of the PET images with MR and CT images. At the end of the study, the presence of neoplastic cells and HER2 expression in lung tissues, and distribution of the tracer, were assessed ex vivo by immunohistochemistry and autoradiography.

Results: (18)F-Z(HER2)(:342)-Affibody successfully targeted HER2-positive lesions in the lung and allowed detection of metastases as early as 9 wk after injection of cells. In contrast, (18)F-FDG uptake was often masked by surrounding inflammatory changes and was nonspecific for HER2 expression. HER2 expression at a cellular level correlated well with tracer uptake on autoradiography.

Conclusion: (18)F-Z(HER2)(:342)-Affibody is a promising tracer for evaluation of HER2 status of breast cancer metastases and is more specific for detecting HER2-positive lesions than (18)F-FDG.

Figures

FIGURE 1.

BLI monitoring of metastasis growth. (A) Strong linear correlation (R2 5 0.99) was found between absolute MDA-MB-231HER2-Luc cell number and BLI signal. (B) Total photon flux from BLI signals acquired 9 wk after intravenous injection of MDA-MB-231HER2-Luc cells. Highest ROI signal from either ventral or dorsal position is presented for each individual mouse. Animals indicated by oval shapes were chosen for further imaging studies. (C) Metastasis progression between 9 and 10 wk after cell injection. (D) Representative in vivo images of lungs of mouse number two 10 wk after cell injection.

FIGURE 2.

Contiguous axial PET/MRI sections of mouse 2 collected 9 and 10 wk after cells injection showing rapid metastasis progression. HER2-positive lung metastases were visualized with high tumor-to-background ratio 1 h after 18F-ZHER2:342-Affibody injection. Tracer uptake 10 wk after cell inoculation, indicated by white arrows, was as follows: 6.2 %ID/g (lesion 1), 6.9 %ID/g (lesion 2), and 3.4 %ID/g (lesion 3). TBR = tumor-to-background ratio.

FIGURE 3.

Representative autoradiography (left) with corresponding H&E staining (right) of lung tissue sections of mouse 2 injected with 18F-ZHER2:342-Affibody. Arrows indicate tumor nodules. HER2 expression is heterogeneous. N = normal lung tissue.

FIGURE 4.

Contiguous transaxial PET/CT section of HER2-positive lung metastasis of mouse 2 at 1 h after 18F-FDG injection. Images were collected 9 and 10 wk after cells injection. Increased background activity made evaluation of small pulmonary nodules difficult. Heart and interscapular brown fat had prominent uptake that probably interfered with detection and delineation of most lesions.

FIGURE 5.

Automated segmentation of tumor lesions from MRI slices acquired 10 wk after tumor cells inoculation. Six slices are arranged such that first column shows original images, second column shows delineated tumor regions, and last column shows fused delineated regions onto MR images. Corresponding intensity and geometry-based features are listed in Table 2.

FIGURE 6.

H&E (top) and anti-HER2 (bottom) staining of lung tissue slices.