Differentiating Between Mixed Neuroendocrine Non-Neuroendocrine Neoplasms (MiNEN) and Other Subtypes of NEN using Fibroblast Activation Protein Inhibitor (FAPI)-Directed PET

Introduction: Fibroblast activation protein (FAP) is overexpressed in highly aggressive gastroenteropancreatic neuroendocrine neoplasms (NEN). We aimed to elucidate the diagnostic performance of non-invasive FAP inhibitor-directed PET using [⁶⁸Ga]FAPI when compared to the reference radiotracer [¹⁸F]FDG in patients with subtypes of poorly differentiated NEN.

Methods: 16 patients with metastasized, high grade NEN [neuroendocrine tumor (NET) G2/G3, n=7; neuroendocrine carcinoma (NEC), n=4, and mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN), n=5] underwent [⁶⁸Ga]FAPI and [¹⁸F]FDG PET/CT without treatment between scans. We compared FAPI-based tumor volume (TV) in patients affected with MiNEN to all other subtypes of NEN and identified patients eligible for a FAP-directed endoradiotherapy (ERT).

Results: [⁶⁸Ga]FAPI visualized tumor lesions in 16/16 subjects (100%), which was comparable to [¹⁸F]FDG (15/16, 93.8%). On a lesion-basis, none of the radiotracers detected significantly more lesions ([¹⁸F]FDG, 9.5±5.3 vs. [⁶⁸Ga]FAPI, 7.3±3.5, P=0.2). MiNEN patients demonstrated significantly higher FAPI-TV (119.9±57.4) when compared to all other subtypes of NEN (33.4±31.6, P=0.001). Based on a visual assessment including intensity of uptake and widespread disease, MiNEN patients (5/5, 100%) were considered eligible for FAPI-directed ERT (all other types, 4/11 (36.4%)).

Conclusions: In aggressive NEN, diagnostic accuracy of [⁶⁸Ga]FAPI-PET/CT is not inferior when compared to [¹⁸F]FDG and may allow to differentiate between patients with MiNEN and other poorly differentiated NEN subtypes. In addition, FAPI-directed ERT may be feasible in patients with MiNEN.