CXCR4-directed PET/CT with [68 Ga]Ga-pentixafor in solid tumors-a comprehensive analysis of imaging findings and comparison with histopathology

Abstract

Background: C-X-C motif chemokine receptor 4 (CXCR4) is overexpressed in various solid cancers and can be targeted by CXCR4-directed molecular imaging. We aimed to characterize the in-vivo CXCR4 expression in patients affected with solid tumors, along with a comparison to ex-vivo findings.

Methods: A total 142 patients with 23 different histologically proven solid tumors were imaged with CXCR4-directed PET/CT using [⁶⁸ Ga]Ga-pentixafor (total number of scans, 152). A semi-quantitative analysis of the CXCR4-positive tumor burden including maximum standardized uptake values (SUV_max) and target-to-background ratios (TBR) using blood pool was conducted. In addition, we performed histopathological staining to determine the immuno-reactive score (IRS) from patients' tumor tissue and investigated possible correlations with SUV_max (by providing Spearman's rho ρ). Based on imaging, we also assessed the eligibility for CXCR4-targeted radioligand therapy or non-radioactive CXCR4 inhibitory treatment (defined as more than five CXCR4-avid target lesions [TL] with SUV_max above 10).

Results: One hundred three of 152 (67.8%) scans showed discernible uptake above blood pool (TBR > 1) in 462 lesions (52 primary tumors and 410 metastases). Median TBR was 4.4 (1.05-24.98), thereby indicating high image contrast. The highest SUV_max was observed in ovarian cancer, followed by small cell lung cancer, desmoplastic small round cell tumor, and adrenocortical carcinoma. When comparing radiotracer accumulation between primary tumors and metastases for the entire cohort, comparable SUV_max was recorded (P > 0.999), except for pulmonal findings (P = 0.013), indicative for uniform CXCR4 expression among TL. For higher IRS, a weak, but statistically significant correlation with increased SUV_max was observed (ρ = 0.328; P = 0.018). In 42/103 (40.8%) scans, more than five TL were recorded, with 12/42 (28.6%) exhibiting SUV_max above 10, suggesting eligibility for CXCR4-targeted treatment in this subcohort.

Conclusions: In a whole-body tumor read-out, a substantial portion of prevalent solid tumors demonstrated increased and uniform [⁶⁸ Ga]Ga-pentixafor uptake, along with high image contrast. We also observed a respective link between in- and ex-vivo CXCR4 expression, suggesting high specificity of the PET agent. Last, a fraction of patients with [⁶⁸ Ga]Ga-pentixafor-positive tumor burden were rendered potentially suitable for CXCR4-directed therapy.

Keywords: C-X-C motif chemokine receptor 4; CXCR4; PET/CT; Radioligand therapy; Solid tumors; Theranostics; [68 Ga]Ga-pentixafor.

Fig. 1

CXCR4-directed PET/CT using [⁶⁸ Ga]Ga-PentixaFor in different solid tumor entities. Maximum intensity projections (MIP) are displayed. Red arrows highlight CXCR4-positive tumor lesions. ACC, adrenocortical carcinoma; NEN, neuroendocrine neoplasia; NSCLC, non-small cell lung carcinoma; SCLC, small cell lung carcinoma. *Not otherwise specified

Fig. 2

Results of the quantitative tumor burden analysis of [⁶⁸ Ga]Ga-PentixaFor PET. Boxplots and whiskers display median and range of SUV_max (A) and TBR (B) for the examined entities. Quantities for all lesions per tumor entity are presented. ACC, adrenocortical carcinoma; CCC, cholangiocellular carcinoma; DSRCT, desmoplastic small round cell tumor; HCC, hepatocellular carcinoma; NEN, neuroendocrine neoplasia; NSCLC, non-small lung cell carcinoma; SCLC, small cell lung carcinoma. *Not otherwise specified

Fig. 3

[.⁶⁸ Ga]Ga-PentixaFor uptake in sites of disease across different compartments. A SUV_max and B TBR. Boxplots display median and interquartile range. Whiskers display 5–95 percentile range. * P < 0.05, ** P < 0.01

Fig. 4

Correlation between immunoreactive score (IRS) and PET parameters. A SUV_max, B SUV_mean, and C SUV_peak. Spearman’s rho and p-values are reported in the graphs

Fig. 5

Concordance of CXCR4-directed immunohistochemistry (IHC) and [.⁶⁸ Ga]Ga-pentixfor PET/CT. Patient with adrenal cortical carcinoma demonstrated increased uptake in sites of disease on maximum intensity projection (MIP, A) and transaxial PET/CT (B), along with high CXCR4 expression on IHC staining (C). SUV_max was 26.9 (TBR: 16.8) and respective immuno-reactive score (IRS) was 12. Patient in B was diagnosed with a neuroendocrine carcinoma, demonstrating no relevant uptake in the primary (D, E SUV_max, 5.5; TBR: 2.5). IHC also revealed no relevant CXCR4 expression (IRS, 1). Magnification of IHC: × 400