Prospective Phase II Trial of Prognostication by 68Ga-NOTA-AE105 uPAR PET in Patients with Neuroendocrine Neoplasms: Implications for uPAR-Targeted Therapy

Abstract

The clinical course for patients with neuroendocrine neoplasms (NENs) ranges from indolent to highly aggressive. Noninvasive tools to improve prognostication and guide decisions on treatment are warranted. Expression of urokinase plasminogen activator receptor (uPAR) is present in many cancer types and associated with a poor outcome. Therefore, using an in-house-developed uPAR PET tracer [⁶⁸Ga]Ga-NOTA-Asp-Cha-Phe-D-Ser-D-Arg-Tyr-Leu-Trp-Ser-OH (⁶⁸Ga-NOTA-AE105), we aimed to assess uPAR expression in NENs. We hypothesized that uPAR expression was detectable in a significant proportion of patients and associated with a poorer outcome. In addition, as uPAR-targeted radionuclide therapy has previously proven effective in preclinical models, the study would also indicate the potential for uPAR-targeted radionuclide therapy in NEN patients. Methods: In a prospective clinical phase II trial, we included 116 patients with NENs of all grades, of whom 96 subsequently had uPAR PET/CT performed with evaluable lesions. PET/CT was performed 20 min after injection of approximately 200 MBq of ⁶⁸Ga-NOTA-AE105. uPAR target-to-liver ratio was used to define lesions as uPAR-positive when lesion SUV_max-to-liver SUV_mean ratio was at least 2. Patients were followed for at least 1 y to assess progression-free and overall survival. Results: Most patients had small intestinal NENs (n = 61) and metastatic disease (n = 86). uPAR-positive lesions were seen in 68% (n = 65) of all patients and in 75% (n = 18) of patients with high-grade (grade 3) NENs. During follow-up (median, 28 mo), 59 patients (62%) experienced progressive disease and 28 patients (30%) died. High uPAR expression, defined as a uPAR target-to-liver ratio above median, had a hazard ratio of 1.87 (95% CI, 1.11-3.17) and 2.64 (95% CI, 1.19-5.88) for progression-free and overall survival, respectively (P < 0.05 for both). Conclusion: When ⁶⁸Ga-NOTA-AE105 PET was used to image uPAR in patients with NENs, uPAR-positive lesions were seen in most patients, notably in patients with both low-grade and high-grade NENs. Furthermore, uPAR expression was associated with a worse prognosis. We suggest that uPAR PET is relevant for risk stratification and that uPAR may be a promising target for therapy in patients with NENs.

Keywords: PET; molecular imaging; neuroendocrine neoplasms; prognosis; urokinase plasminogen activator receptor (uPAR).

Graphical abstract

FIGURE 1.

Representative examples of uPAR PET/CT imaging. CT (left column) and uPAR PET (right column) are shown for 4 patients (patients A–D) with high- and low-grade NENS. Top of individual scale bar corresponds to SUV_max of tumor. Pt. #A: Bronchopulmonary NEC (Ki67: 24%). Pt. #B: Orbital metastasis from small intestine NET G2 (Ki-67: 5%); Pt. #C: Large liver metastasis from pancreatic NET G2 (Ki-67: 5%). Pt. #D: Large intramuscular metastasis from primary colon NEC (Ki-67: 90%). BP = bronchopulmonary; SI = small intestine; pNET = pancreatic NET.

FIGURE 2.

Kaplan–Meier plots of OS and PFS using ⁶⁸Ga-NOTA-AE105 uPAR PET. uPAR TLR was dichotomized at median (TLR, 2.47).

FIGURE 3.

Kaplan–Meier plots of OS and PFS using ⁶⁸Ga-NOTA-AE105 uPAR PET. uPAR TLR was dichotomized at 1.32.