TY - JOUR

T1 - Prospective phase II trial of prognostication by 68Ga-NOTA-AE105 uPAR PET in patients with neuroendocrine neoplasms: Implications for uPAR targeted therapy

AU - Carlsen, Esben Andreas

AU - Loft, Mathias

AU - Loft, Annika

AU - Berthelsen, Anne Kiil

AU - Langer, Seppo Wang

AU - Knigge, Ulrich

AU - Kjaer, Andreas

PY - 2022

Y1 - 2022

N2 - The clinical course for patients with neuroendocrine neoplasms (NENs) ranges from indolent to highly aggressive. Non-invasive 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-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 120 patients with NENs of all grades of whom 96 subsequently had uPAR PET/CT performed with evaluable lesions. PET/CT was acquired 20 minutes after injection of approximately 200 MBq 68Ga-NOTA-AE105. uPAR target-to-liver ratio (uPAR TLR) was used to define lesions as uPAR positive when lesion SUVmax /liver SUVmean ≥ 2. Patients were followed for at least 1 year to assess progression-free survival (PFS) and overall survival (OS). RESULTS: The majority of patients had small intestinal NEN (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 disease (NEN G3). During follow-up (median 28 months), 59 patients (62%) experienced progressive disease and 28 patients (30%) died. High uPAR expression, defined as uPAR TLR above median, had a hazard ratio (95% confidence interval) of 1.87 (1.11-3.17) and 2.64 (1.19-5.88) for PFS and OS, respectively (p<0.05 for both). CONCLUSION: Using 68Ga-NOTA-AE105 PET for imaging uPAR in patients with NEN, uPAR positive lesions were seen in the majority of patients and most notably in patients with both low and high grade NEN. Furthermore, uPAR expression was associated with a worse prognosis. We suggest that uPAR PET is relevant for risk stratification and uPAR may be a promising target for therapy in patients with NEN.

AB - The clinical course for patients with neuroendocrine neoplasms (NENs) ranges from indolent to highly aggressive. Non-invasive 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-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 120 patients with NENs of all grades of whom 96 subsequently had uPAR PET/CT performed with evaluable lesions. PET/CT was acquired 20 minutes after injection of approximately 200 MBq 68Ga-NOTA-AE105. uPAR target-to-liver ratio (uPAR TLR) was used to define lesions as uPAR positive when lesion SUVmax /liver SUVmean ≥ 2. Patients were followed for at least 1 year to assess progression-free survival (PFS) and overall survival (OS). RESULTS: The majority of patients had small intestinal NEN (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 disease (NEN G3). During follow-up (median 28 months), 59 patients (62%) experienced progressive disease and 28 patients (30%) died. High uPAR expression, defined as uPAR TLR above median, had a hazard ratio (95% confidence interval) of 1.87 (1.11-3.17) and 2.64 (1.19-5.88) for PFS and OS, respectively (p<0.05 for both). CONCLUSION: Using 68Ga-NOTA-AE105 PET for imaging uPAR in patients with NEN, uPAR positive lesions were seen in the majority of patients and most notably in patients with both low and high grade NEN. Furthermore, uPAR expression was associated with a worse prognosis. We suggest that uPAR PET is relevant for risk stratification and uPAR may be a promising target for therapy in patients with NEN.

U2 - 10.2967/jnumed.121.263177

DO - 10.2967/jnumed.121.263177

M3 - Journal article

C2 - 35058319

VL - 63

SP - 1371

EP - 1377

JO - The Journal of Nuclear Medicine

JF - The Journal of Nuclear Medicine

SN - 0161-5505

IS - 9

ER -