Clinical applications of fibroblast activation protein inhibitor positron emission tomography (FAPI-PET)

Abstract

The discovery of fibroblast activation protein inhibitor positron emission tomography (FAPI-PET) has paved the way for a new class of PET tracers that target the tumor microenvironment (TME) rather than the tumor itself. Although ¹⁸F-fluorodeoxyglucose (FDG) is the most common PET tracer used in clinical imaging of cancer, multiple studies have now shown that the family of FAP ligands commonly outperform FDG in detecting cancers, especially those known to have lower uptake on FDG-PET. Moreover, FAPI-PET will have applications in benign fibrotic or inflammatory conditions. Thus, even while new FAPI-PET tracers are in development and applications are yet to enter clinical guidelines, a significant body of literature has emerged on FAPI-PET, suggesting it will have important clinical roles. This article summarizes the current state of clinical FAPI-PET imaging as well as potential uses as a theranostic agent.

Fig. 1. Chemical structures of the selected FAP tracers.

Chemical structures of the selected FAP tracers for diagnostic use, except (DOTAGA.(SA.FAPi)₂, which is the dimer of the diagnostic tracer DOTA.SA.FAPi and more suitable for therapeutic purposes due to the longer tumor retention.

Fig. 2. Effects of cancer-associated fibroblast (CAF) on immune cells.

Major effects of cancer-associated fibroblast (CAF) on immune cells in the tumor microenvironment. TGF-β transforming growth factor beta, VEGF vascular endothelial growth factor, IL interleukin 6, GM-CSF granulocyte-macrophage colony-stimulating factor, M-CSF macrophage colony-stimulating factor, CCL C-C motif chemokine ligand, CXCL C-X-C motif ligand. BMDSC bone marrow-derived suppressor cells, Tregs regulatory T cells. [From ref. ].

Fig. 3. Head-to-head comparison of ¹⁸F-FDG and ¹⁸F-FAPI-74 PET imaging in selected oncologic patients.

Nine representative oncologic patients who underwent ¹⁸F-FDG and ¹⁸F-FAPI-74 PET imaging. ¹⁸F-FAPI-74 PET outperforms ¹⁸F-FDG PET in detecting primary tumors (patients 11, 39, 50, 58, 79, and 101; solid black arrows), local recurrences (patient 4; blue arrows), abdomen lymph node metastases (patients 4 and 50; green arrows), intrahepatic metastases (patient 50; red arrows), bone metastases (patient 85; arrowheads), and peritoneal metastases (patients 4, 11, 85, 97, and 101; dotted arrows). [From ref. ].

Fig. 4. Example images of 64-year-old woman with recurrent pancreatic ductal adenocarcinoma.

A Maximum-intensity projection (MIP) of ⁶⁸Ga-FAPI PET. B Axial ⁶⁸Ga-FAPI PET/CT images and contrast-enhanced CT (ceCT) images of lesions (arrows: lesions 1 and 2, pulmonary metastasis and mediastinal lymph node metastasis; lesion 3, paraaortic lymph node metastasis) detected by ⁶⁸Ga-FAPI PET. HU: Hounsfield units. [From ref. ].

Fig. 5. A 66-year-old woman underwent preoperative staging after being diagnosed with left ovarian high-grade serous carcinoma.

⁶⁸Ga-FAPI-04 PET/CT demonstrated mild focal uptake (SUVmax, 4.5) in the left primary tumor ((a); dotted arrow head) and distinctive uptake (SUVmax, 9.7) in widespread peritoneal metastasis ((a); solid arrowhead). ¹⁸F-FDG PET/CT revealed high focal uptake (SUVmax, 8.8) in this cystic-solid ovary tumor ((b); dotted arrowhead) and slight and diffuse uptake (SUVmax, 2.5) in the peritoneal metastases ((b); solid arrowhead). For this representative participant, ⁶⁸Ga-FAPI-04 PET/CT detected more metastatic lesions compared with ¹⁸F-FDG PET/CT regarding the peritoneal metastases. [From ref. ].

Fig. 6. Pathological characteristics of fibrosis in different tissues. In tissues such as liver, kidney, lung, heart, and tumor, common events lead to fibrosis progression (and regression).

If the pathological stimulus is persistent and the healing process is dysregulated, the continuous recruitment and activation of inflammatory cells and myofibroblasts can result in fibrosis. Core features of fibrotic processes that are shared by all of these organs include overproduction of cytokines, growth factors, ECM proteins, and ultimately the loss of tissue architecture as well as function. [From ref. ].

Fig. 7. Myocardial perfusion images using 99mTc-tetrofosmin at rest, ⁶⁸Ga-FAPI PET, LGE from CMR, and schematic drawings of LV.

Area of fibroblast activation as indicated by ⁶⁸Ga-FAPI-46 PET signal exceeds infarct area and LGE signal, the most common type of myocardial FAP distribution. HLA 5 horizontal long axis; SA 5 short axis; VLA 5 vertical long axis. [From ref. ].

Fig. 8. Pre- and post-treatment dual-tracer PET/CT in the three participants with different responses undergoing tight control treatment.

Participant 12 is a 55-year-old woman with a 1-month history of rheumatoid arthritis (RA) who was treated with methotrexate, etoricoxib, tripterygium wilfordii, and iguratimod. Participant 17 is a 53-year-old woman with a 1-year history of RA who was treated with methotrexate and etanercept. Participant 18 is a 55-year-old woman with a 19-month history of RA who was treated with methotrexate, etanercept, and tripterygium wilfordii. There is residual active uptake of ⁶⁸Ga-FAPI and ¹⁸F-FDG in three major joints 6 months after treatment in participant 18 (black arrows). Major joints with rheumatoid affection are marked with blue arrows. [Adapted, from ref. ].

Fig. 9. FAP tracer uptake in various non-oncologic diseases.

Reported SUVs of non-oncologic diseases (*SUVmax, **SUVmean, ***SUVpeak, † median, ‡ average). SUV standardized uptake value. [From ref. ].

Fig. 10. ⁶⁸Ga-FAPI tracer uptake in PDAC and in accompaniying pancreatitis.

A, B Average SUVmax and SUVmean 1 h after injection of ⁶⁸Ga-labeled FAPI tracers in 8 PDAC and in accompanying pancreatitis in rest of pancreas. C Exemplary images of tumor-related (red arrow) and pancreatitis-related (yellow arrow) ⁶⁸Ga-FAPI uptake 10, 60, and 180 min after application. D ⁶⁸Ga-FAPI uptake 10, 60, and 180 min after application (SUVmax and SUVmean values) in PDAC lesions of 6 patients. [From ref. ].