Integrin αvβ3, a subtype of the arginine-glycine-aspartate (RGD)-recognizing cell surface integrins, is upregulated on endothelial cells during angiogenesis and on tumor cells. Because of involvement in tumor growth, invasiveness and metastases, and angiogenesis, integrin αvβ3 is an attractive target in cancers. In this study, we applied 68Ga-NODAGA-E[c(RGDyK)]2 for imaging of integrin αvβ3 in patients with neuroendocrine neoplasms (NENs) and its potential use for prognostication. We hypothesized that 68Ga-NODAGA-E[c(RGDyK)]2 PET/CT would show tumor lesion uptake and that higher tumor lesion uptake was associated with a poorer prognosis. Methods: Between December 2017 and November 2020 we prospectively enrolled 113 patients with NEN of all grades (2019 World Health Organization classification) for 68Ga-NODAGA-E[c(RGDyK)]2 PET/CT. The scan was acquired 45 min after injection of 200 MBq of 68Ga-NODAGA-E[c(RGDyK)]2 Board-certified specialists in nuclear medicine and radiology analyzed the PET/CT measuring SUVmax in tumor lesions. Positive tumor lesions were defined as those with tumor-to-liver background ≥ 2. Maximal tumor SUVmax for each patient was used as a predictor of outcome. Patients were followed for at least 1 y to assess progression-free survival and overall survival. Results: Of 113 patients enrolled in the trial, 99 underwent 68Ga-NODAGA-E[c(RGDyK)]2 PET/CT, with 97 patients having evaluable lesions. The patients predominantly had small intestinal (64%) or pancreatic (20%) NEN and most had metastatic disease (93%). Most patients had low-grade tumors (78%), whereas 22% had high-grade tumors. During a median follow-up of 31 mo (interquartile range, 26-38 mo), 62 patients (64%) experienced disease progression and 25 (26%) patients died. In total, 76% of patients had positive tumor lesions, and of the patients with high-grade tumors 91% had positive tumor lesions. High integrin αvβ3 expression, defined as an SUVmax of at least 5.25, had a hazard ratio of 2.11 (95% CI, 1.18-3.78) and 6.95 (95% CI, 1.64-29.51) for progression-free survival and overall survival, respectively (P = 0.01 for both). Conclusion: Tumor lesion uptake of 68Ga-NODAGA-E[c(RGDyK)]2 was evident in patients with all grades of NEN. High uptake was associated with a poorer prognosis. Further studies are warranted to establish whether 68Ga-NODAGA-E[c(RGDyK)]2 PET/CT may become a prediction tool for identification of patients eligible for treatments targeting integrin αvβ3.
Keywords: PET; integrin αvβ3; molecular imaging; neuroendocrine neoplasms; prognosis.
© 2023 by the Society of Nuclear Medicine and Molecular Imaging.