The value of targeting CXCR4 with 68Ga-Pentixafor PET/MRI for Cushing's disease: a retrospective cohort study.

PURPOSE: 68Ga-pentixafor PET/MRI, which targets the C-X-C chemokine receptor type 4 (CXCR4), has been shown to significantly enhance lesion localization accuracy in Cushing’s disease (CD). However, a subgroup of CD tumors exhibits both reduced 68Ga-pentixafor uptake and low CXCR4 expression. In this study, we propose a CXCR4-based stratification of CD patients to evaluate the utility of this stratification for improving lesion localization accuracy, delineating clinical characteristics, predicting survival outcomes, and characterizing mutational features.

METHODS

This retrospective study analyzed 138 patients with surgically and pathologically confirmed CD. Patient subsets underwent 68Ga-Pentixafor PET/MRI (n = 78), CXCR4 immunohistochemistry (n = 116), and targeted gene sequencing (n = 129). Follow-up data were available for 115 patients.

RESULTS

The localization sensitivity and diagnostic accuracy of 68Ga-pentixafor PET/MRI reached 98.7% and 96.3% respectively, when combined with conventional contrast-enhanced MRI. The entire retrospective cohort (n = 138) was stratified into CXCR4-high (n = 95) and CXCR4-low (n = 43) groups using receiver operating characteristic (ROC) analysis. Compared with the CXCR4-high group, the CXCR4-low group exhibited a higher proportion of relapsed tumors (P = 0.005), a lower proportion of hypokalemia (P = 0.005), larger tumor diameter (P = 0.026) and volume (P = 0.013), lower ACTH staining intensity (P < 0.001), and worse progression-free survival (PFS) after 2.5 years (P = 0.041). The prevalence of tumors harboring ubiquitin-specific peptidase 8 (USP8) hotspot mutations was significantly lower in the CXCR4-low group (P = 0.04) among macroadenomas but not among microadenomas.

CONCLUSION

CXCR4-targeted 68Ga-pentixafor PET/MRI helps achieve consistently high accuracy in localizing ACTH-secreting pituitary neuroendocrine tumors. CXCR4 expression demonstrates potential utility for stratifying CD patients, particularly for subtyping macroadenoma.