Imaging of chemokine receptor 4 expression in neuroendocrine tumors - A triple tracer comparative approach

C-X-C motif chemokine receptor 4 (CXCR4) and somatostatin receptors (SSTR) are overexpressed in gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). In this study, we aimed to elucidate the feasibility of non-invasive CXCR4 positron emission tomography/computed tomography (PET/CT) imaging in GEP-NET patients using [⁶⁸Ga]Pentixafor in comparison to ⁶⁸Ga-DOTA-D-Phe-Tyr3-octreotide ([⁶⁸Ga]DOTATOC) and 18F-fluorodeoxyglucose ([¹⁸F]FDG). Twelve patients with histologically proven GEP-NET (3xG1, 4xG2, 5xG3) underwent [⁶⁸Ga]DOTATOC, [¹⁸F]FDG, and [⁶⁸Ga]Pentixafor PET/CT for staging and planning of the therapeutic management. Scans were analyzed on a patient as well as on a lesion basis and compared to immunohistochemical staining patterns of CXCR4 and somatostatin receptors SSTR2a and SSTR5. [⁶⁸Ga]Pentixafor visualized tumor lesions in 6/12 subjects, whereas [¹⁸F]FDG revealed sites of disease in 10/12 and [⁶⁸Ga]DOTATOC in 11/12 patients, respectively. Regarding sensitivity, SSTR-directed PET was the superior imaging modality in all G1 and G2 NET. CXCR4-directed PET was negative in all G1 NET. In contrast, 50% of G2 and 80% of G3 patients exhibited [⁶⁸Ga]Pentixafor-positive tumor lesions. Whereas CXCR4 seems to play only a limited role in detecting well-differentiated NET, increasing receptor expression could be non-invasively observed with increasing tumor grade. Thus, [⁶⁸Ga]Pentixafor PET/CT might serve as non-invasive read-out for evaluating the possibility of CXCR4-directed endoradiotherapy in advanced dedifferentiated SSTR-negative tumors.