Imaging of Chemokine Receptor 4 Expression in Neuroendocrine Tumors - a Triple Tracer Comparative Approach

Abstract

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.

Impact of Tumor Burden on Quantitative [68Ga] DOTATOC Biodistribution

“…All data was reconstructed using iterative algorithms implemented by the manufacturer. For further details, please refer to [11].…”

Feasibility of CXCR4-Directed Radioligand Therapy in Advanced Diffuse Large B-Cell Lymphoma

“…C-X-C-motif chemokine receptor 4 (CXCR4) is overexpressed on lymphoma cells (3)(4)(5)(6) and has been identified as a potential drug target. Wester et al successfully developed a radiolabeled CXCR4 ligand ( 68 Ga-pentixafor) for PET imaging (5,7,8) that visualizes CXCR4 expression in patients with hematologic and solid malignancies (5,(9)(10)(11)(12)(13)(14)(15)(16)(17). Recently, we and others also reported on experience with 177 Lu-and 90 Y-labeled pentixather (18), the therapeutic counterpart of 68 Ga-pentixafor for CXCR4-targeted radioligand therapy (RLT) in acute leukemia (19) and in patients with advanced multiple myeloma (20,21).…”

Screening of cancer tissue arrays identifies CXCR4 on adrenocortical carcinoma: correlates with expression and quantification on metastases using 64Cu-plerixafor PET

“…One study used 68 Ga-NOTA-NFB, a derivative of the peptide antagonist of CXCR4, T140, to image gliomas [ 76 ]. The most extensive published data have been with a newly developed synthetic pentapeptide labeled with 68 Ga, 68 Ga-pentixafor [ 77 ], which has been evaluated recently in patients with lymphoma [ 78 ], multiple myeloma [ 79 ], small cell lung cancer [ 80 ], glioblastoma [ 81 ], neuroendocrine tumors [ 82 ], and other cancers [ 83 ]. When tissue samples were evaluated, poor correlations were reported for glioblastoma and small cell lung cancer between 68 Ga-pentixafor SUVs and CXCR4 immunoreactivity [ 80 , 81 ].…”

“…When tissue samples were evaluated, poor correlations were reported for glioblastoma and small cell lung cancer between 68 Ga-pentixafor SUVs and CXCR4 immunoreactivity [ 80 , 81 ]. The most recent data for gastro-entero-hepatic neuroendocrine tumors showed a better but still imperfect correspondence between CXCR4 positivity of tumor biopsies and 68 Ga-pentixafor positivity by PET [ 82 ]. Uptake of 68 Ga-pentixafor was also reported very recently for metastases of ACC, although in that study no tissue samples were available for comparing SUVs with CXCR4 expression assessed by independent methods [ 84 ].…”