Investigation of spleen CXCR4 expression by [68Ga]Pentixafor PET in a cohort of 145 solid cancer patients

Abstract

Background: The chemokine receptor CXCR4 is frequently overexpressed and associated with adverse prognosis in most hematopoietic malignancies and solid cancers. Recently, CXCR4 molecular imaging using the CXCR4-specific positron emission tomography (PET) tracer Pentixafor ([⁶⁸Ga]Pentixafor) has become a well-established method to non-invasively measure CXCR4 expression in vivo. In previous Pentixafor imaging studies, highly variable CXCR4 tracer uptake to the spleen was observed.

Results: We investigated the hypothesis that enhanced spleen [⁶⁸Ga]Pentixafor uptake and thus CXCR4 expression in patients with solid tumors would indicate an activated spleen state and/or an association with clinical and prognostic features and survival parameters. In this retrospective study, [⁶⁸Ga]Pentixafor-PET images and patient records of 145 solid tumor patients representing 27 cancer entities were investigated for an association of spleen [⁶⁸Ga]Pentixafor uptake and clinical characteristics and outcome. Based on this assessment, we did not observe differences in clinical outcomes, measured by progression-free survival, overall survival and remission status neither within the entire cohort nor within subgroups of adrenal cancer, desmoplastic small round cell tumor, neuroendocrine tumors, non-small cell lung cancer, small cell lung cancer and pancreatic adenocarcinoma patients. No tumor entity showed especially high levels of spleen [⁶⁸Ga]Pentixafor uptake compared to others or a control cohort. However, when investigating laboratory parameters, there was a positive correlation of high spleen [⁶⁸Ga]Pentixafor uptake with leukocyte and/or platelet counts in neuroendocrine tumors, non-small cell lung cancer and small cell lung cancer.

Conclusion: Spleen [⁶⁸Ga]Pentixafor uptake was not associated with stage of disease and clinical outcomes in solid tumor patients. We identified positively associated platelet and/or leukocyte counts with spleen [⁶⁸Ga]Pentixafor uptake in neuroendocrine tumors, non-small cell lung cancer and small cell lung cancer, suggesting that splenic CXCR4 expression could possibly play a role in systemic immunity/inflammation in some types of solid tumors or a subgroup of patients within solid tumor entities.

Keywords: CXCR4; Clinical studies; Molecular imaging; PET; Pentixafor; Retrospective studies; Solid tumors; Spleen; Uptake.

Fig. 1

Patients with solid tumors present with different levels of [⁶⁸Ga]Pentixafor uptake in spleen. A Representative image of a 68-year-old female patient presenting with hepatocellular carcinoma and low spleen CXCR4 expression as measured by [⁶⁸Ga]Pentixafor uptake. B Representative image of a 68-year-old male patient presenting with a neuroendocrine tumor and high spleen CXCR4 expression as measured by [⁶⁸Ga]Pentixafor uptake

Fig. 2

Spleen [⁶⁸Ga]Pentixafor uptake levels show a wide variety within different entities, and are not affected by systemic treatment. A Comparison of spleen-to-liver ratios (SUV_maxSpleen/SUV_meanLiver) of patients with adrenal cancer, n = 31; cholangiocarcinoma, n = 4; DSRCT, n = 9; hepatocellular carcinoma, n = 6; mesothelioma, n = 6; neuroendocrine Tumors, n = 25; NSCLC, n = 9; pancreatic adenocarcinoma, n = 9; renal cell carcinoma, n = 4; sarcoma, n = 7; SCLC, n = 13 and control, n = 5. B Comparison of spleen-to-liver ratios (SUV_maxSpleen/SUV_meanLiver) of patients of all tumor entities included in the study, comparing patients without ongoing (no systemic treatment, n = 85) to those with an ongoing systemic therapy or systemic treatment within the last month prior to imaging (systemic treatment, n = 63)

Fig. 3

Spleen [⁶⁸Ga]Pentixafor uptake does not correlate with clinical outcomes in solid tumor patients. A Kaplan–Meier survival curves of progression-free survival (PFS) and overall survival (OS) of all solid tumor patients in the study separated by the median into two groups of low and high spleen-to-liver ratios (SUV_maxSpleen/SUV_meanLiver), PFS: low, n = 61, high, n = 58; OS: low, n = 61, high, n = 54. B Comparison of spleen-to-liver ratios (SUV_maxSpleen/SUV_meanLiver) with remission status of all patients, complete remission (CR), n = 2; partial remission (PR), n = 9; stable disease (SD), n = 15; progressive disease (PD), n = 51. All statistical analyses were performed using log rank (Mantel–Cox) test (A) and one-way ANOVA with Tukey’s correction for multiple comparisons (B). P values as indicated on the graphs

Fig. 4

Spleen [⁶⁸Ga]Pentixafor uptake is positively associated with peripheral blood leukocyte and/or platelet counts in neuroendocrine tumors, NSCLC and SCLC. A Correlation of spleen-to-liver ratio (SUV_maxSpleen/SUV_meanSpleen) with peripheral leucocyte count in patients with neuroendocrine tumors, n = 25 and NSCLC, n = 9. B Correlation of spleen-to-liver ratio (SUV_maxSpleen/SUV_meanSpleen) with peripheral platelet count in patients with adrenal tumors, n = 31; neuroendocrine tumors, n = 25; NSCLC, n = 9 and SCLC, n = 13. All statistical analyses were performed using simple linear regression. R² and P values as indicated on the graphs