European Nuclear Medicine Guide
[68Ga]Ga-FAPI-04
[68Ga]Ga-FAPI-74
[18F]Ga-FAPI-74
This chapter deals with fibroblast activation protein inhibitor (FAPI), a quinoline-based radioligand introduced in 2018 with the potential of wide-ranging theranostic use in clinical oncology and even beyond. The imaging is based on FAP targeting, which is the type II transmembrane serine protease, overexpressed on the surface of tumor-associated fibroblasts (CAFs). Since CAFs are found in the tumor stroma of many epithelial tumors, while fibroblasts in non-active state do not express FAP, FAPI-PET is able to visualize multiple tumor entities with a high target-to-background ratio. Due to the independence from glucose metabolism, fasting is not necessary for FAPI-PET, which provides great clinical advantage comparing with FDG-PET. Furthermore, by binding therapeutic emitters to the DOTA chelator, the ligand is available for theranostic use. FAP ligands also visualize benign processes, such as wound healing, fibrotic or inflammatory processes. In this respect, the diagnostic performance of the tracer needs further validation.
The target molecule of FAP ligand is fibroblast activation protein α (FAPα), a 97 kDa protein with 760 amino acids that have great structural similarities to DPPIV. FAP is a type II transmembrane serine protease with exo- and endopeptidase activity with the ability to cleave a peptide chain at the post-proline site. Ligand binding to FAP leads to a catalytic activation of the molecule to form either a homodimer (FAPα/FAPα) or heterodimer (FAP/FAPβ), followed by a rapid internalization of the ligand-FAP-complex [246]. The main expression site of FAP is the cell membrane of activated fibroblasts (CAFs) in the environment of tumor cells (tumor stroma). Healthy adult body cells, however, do not express FAP, with a few exceptions (e.g. mesenchymal stem cells in the bone marrow). FAP imaging thus serves as tumor-specific and at the same time "pan-tumor" imaging, which, among other things, visualizes epithelial tumors largely independently of tumor entities and metabolic processes. Individual tumor cells of selected tumor entities are also known to express FAP (pancreatic, ovarian, breast cancer, sarcoma) [247].
Epithelial tumors with stronger desmoplastic reactions, such as breast, pancreatic or colon carcinoma, are associated with high FAP expression [248]. Numerous studies have demonstrated higher FAPI tracer accumulation in gastric, pancreatic, colorectal, lung, or hepatic/bile duct cancer, while lymphoma or multiple myeloma show low tracer accumulation [249]. Variable tracer uptake has been observed e.g. in sarcoma, which appears to depend on histological type, which needs further validation [250]. In gynecologic cancers e.g. ovarian or breast cancer, physiological tracer uptake might compromise the image contrast [251]. Overall, especially in those tumors for which FDG-PET is not a primarily suitable diagnostic tool, FAPI-PET might provide a reliable alternative. Multiple studies have demonstrated that FAPI-PET shows higher sensitivity in detecting small lesions in FDG-avid areas such as brain, liver, gastrointestinal tract or head-neck regions, which leads to superior tumor delineation [252].
Compared with radiological imaging modalities such as CT or MRI, FAPI-PET often leads to clear demarcation of tumor lesions, which is particularly advantageous for identifying smaller lesions. For tumors in the lower gastrointestinal tract, more metastatic lesions were detected by FAPI-PET/MRI, which led to a change in the TNM stage and a consecutive change in oncological or radio-oncological treatment strategy in the majority of patients [253]. In hepatocellular carcinoma, high sensitivity of FAPI-PET as well as radiologic imaging modalities especially MRI has been demonstrated (sensitivity: contrast-enhanced CT 96%, MRI 100%, FAPI-PET 96%, FDG-PET 65%), suggesting a potential of strong diagnostic quality of hybrid imaging in terms of FAPI-PET/MRI [254].
Targeted comparisons of CT and MRI have been made primarily in the context of radiotherapy planning [255]. It has been shown that FAPI-PET/CT led to better tumor delineation compared to the corresponding solitary radiologic imaging (MRI or CT) with resulting superior tumor volume determinations.
Initial dosimetric study revealed the effective dose of 1.6 mSv/100 MBq for [68Ga]Ga-FAPI-04, which is thus comparable to other PET tracers such as [18F]F-FDG (2 mSv/100 MBq or lower) or [68Ga]Ga-DOTA-TOC or -DOTA-TATE (2.1 mSv/100 MBq) [256]. NOTA-chelator ligand FAPI-74, which allows both Ga-68 and F-18 radiolabeling, revealed also favorable dosimetric value of 1.6 mSv/100 MBq ([68Ga]Ga-FAPI-74) and 1.4 mSv/100 MBq ([18F]F-FAPI-74), respectively [257]. All mentioned compounds [68Ga]Ga-FAPI have been characterized in terms of stable tracer accumulation and rapid renal elimination, leading to lower radiation exposure[256,257].
In addition to the indications already mentioned, which still need to be validated by extensive patient studies, there are a number of benign conditions in which FAPI-PET can be used as a new diagnostic tool; Accumulation of FAP tracer has been found in organ fibrosis, such as pulmonary fibrosis [261], in ischemic myocardium [262], rheumatoid arthritis [263], Crohn's disease [264], or IgG4-associated diseases [265], among others. In the mentioned diseases, fibrotic tissue alteration led to the correspondingly increased tracer uptake as imaging surrogate. This fact opens the possibility of using FAP imaging to evaluate dynamic disease processes in such diseases non-invasively. In the selected disease entities, surrogates obtained from FAPI-PET appear to have potential prognostic significance. In cardiac ischemia, for example, the FAP-positive region in the post-ischemic myocardium was larger than the infarct area detected by cardiac MRI or SPECT. These areas include viable tissue in the border zone, and thus, the injury volume estimated by FAPI-PET might provide predictive values after acute myocardial infarction [262]. In patients with systemic sclerosis-associated lung fibrosis, FAPI uptake at baseline was associated with progressive disease [263]. A close relationship between inflammatory and fibrotic processes, however, might compromise the diagnostic accuracy in differentiating both disease conditions, which needs further evaluation.
While we have focused on enormous clinical use, including both oncological and non-oncological diseases potentially imaged by FAPI-PET [269], there are also several inherent limitations which should be noted. CAFs are intrinsically heterogeneous in terms of origin, phenotype, and function, and impact the amount of FAP expression. The heterogeneity of FAP expression, especially in non-oncological conditions may lead to false positive findings, as reported in numerous studies and case reports. Most of the false positives are associated with fibrous or sclerotic foci, including post-radiation injury or scar formation, causing activation of quiescent fibroblasts.
Some investigators suggest that the use of delayed static scans are useful for the differentiation of inflammation from malignancy, e.g. in pancreas [270]. It should also be taken into account that a reference histology is not always available and the correlation between FAP ligand accumulation with the degree of tumor differentiation is still not sufficiently clarified.
Well-designed clinical studies in large patient cohorts, as well as thorough histopathological elucidation of the underlying mechanism, are the key to establish this promising imaging modality in the clinical routine. Currently, multiple phase II studies are ongoing, with the near future perspective of phase III studies, so that the clinical use of FAPI will be further developed in a sustainable way.