Abstract
Integrin α(v)β(3), 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 α(v)β(3) is an attractive target in cancers. In this study, we applied (68)Ga-NODAGA-E[c(RGDyK)](2) for imaging of integrin α(v)β(3) in patients with neuroendocrine neoplasms (NENs) and its potential use for prognostication. We hypothesized that (68)Ga-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 (68)Ga-NODAGA-E[c(RGDyK)](2) PET/CT. The scan was acquired 45 min after injection of 200 MBq of (68)Ga-NODAGA-E[c(RGDyK)](2) Board-certified specialists in nuclear medicine and radiology analyzed the PET/CT measuring SUV(max) in tumor lesions. Positive tumor lesions were defined as those with tumor-to-liver background ≥ 2. Maximal tumor SUV(max) 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 (68)Ga-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 α(v)β(3) expression, defined as an SUV(max) 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 (68)Ga-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 (68)Ga-NODAGA-E[c(RGDyK)](2) PET/CT may become a prediction tool for identification of patients eligible for treatments targeting integrin α(v)β(3.)