Novel FAP ligands enable improved imaging contrast in sarcoma patients due to FAPI-PET/CT

Nowadays, positron emission tomography (PET)/computed tomography (CT) is widely used for clinical cancer imaging. For many malignant tumors, ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) is highly suitable as a PET tracer. Although sarcomas are uncommon, the use of ¹⁸F-FDG-PET/CT for the detection, staging, and oncological management of sarcomas has increased considerably, leading to improved target volume delineation for radiooncological treatment approaches as well as evaluation of treatment response [1‐4]. Moreover, ¹⁸F-FDG-PET/CT provides a useful predictive tool for patients with soft tissue and bone sarcoma. Due to a high mitotic count sustained by intense glycolytic activity, especially high-grade soft tissue sarcomas can be well displayed by hybrid imaging using ¹⁸F-FDG tracer [5]. Although ¹⁸F-FDG-PET/CT represents a highly efficient staging and restaging probe for some sarcoma like rhabdomyosarcoma, physiological uptake within the brain limits the diagnostic value of the tracer, e.g., in the head and neck area [5].

Since the recent development of specific tracers that function as fibroblast activation protein inhibitors (FAPI) for hybrid imaging [6, 7], several studies demonstrated promising results with regard to imaging and tumor characterization. Although ⁶⁸Ga-FAPI-PET/CT also has a high potential for benign diseases [8], its main use continues to be in the imaging of cancers. Kratochwil et al. observed a very high average SUVmax of more than 12 in sarcomas [9]. This is of great interest due to the low uptake of ¹⁸F-fluorodeoxyglucose (FDG) in low-grade sarcoma, demonstrating one of the numerous limitations of conventional FDG-PET/CT [10]. Historically, fibroblast activation protein (FAP) expression was initially described by Rettig et al. in 1988 and was found in malignant cells of many sarcomas [11‐13]. Thus, sarcomas seem to be ideal candidates for using FAPI ligands as a staging probe, for tumor characterization, or even radioligand therapy. Therefore, this retrospective analysis aimed to characterize ⁶⁸Ga-FAPI uptake in a cohort of 15 patients with different sarcomas.

The patients included in the current analysis had a median age of 61 years. Our cohort consisted of several types of sarcoma including five liposarcomas, three undifferentiated pleomorphic sarcomas (UPS), and two leiomyosarcomas (Table 1). 8 out of 15 patients (53.3%) had metastatic disease and local relapse was suspected in three patients. 2 out of the 8 patients with metastatic disease were already metastatic at first diagnosis. Most patients were diagnosed with low-grade sarcoma (80%). For three patients, the grading was not known. The time interval between the initial diagnosis and ⁶⁸Ga-FAPI-PET/CT ranged from 1 to 5 months.

There was a very low background activity with an average normal organ uptake of 2.00 (SUVmax) and 1.34 (SUVmean) for bloodpool; 1.48 (SUVmax) and 0.86 (SUVmean) for normal liver parenchyma; 0.92 (SUVmax) and 0.53 (SUVmean) for normal lung parenchyma; and 1.50 (SUVmax) and 1.02 (SUVmean) for myocardium. ⁶⁸Ga-FAPI-PET/CT detected four primary tumors with a median SUVmax and SUVmean of 7.16 (range 4.64–9.79) and 3.27 (range 2.28–5.51) as well as three local relapses with a median SUVmax and SUVmean of 11.47 (range 6.35–26.24) and 7.03 (range 3.00–13.08), respectively. For metastases, median SUVmax and median SUVmean of 6.29 (range 2.06–37.25) and 3.01 (range 1.45–19.44) were obtained, while the highest uptake was found for lung metastases (median SUVmax: 37.35; median SUVmean: 19.44). Thus, excellent tumor-to-background ratios of more than 7.00 (tumor-to-bloodpool, SUVmax and SUVmean) could be achieved (Fig. 1).

In subgroup analyses with regard to histology, the highest uptake was found for liposarcomas with a median SUVmax and SUVmean of 14.19 and 8.90, respectively. Moreover, ⁶⁸Ga-FAPI uptake was higher for high-grade sarcomas compared to low-grade disease (median SUVmax: 30.21 (range 9.79–44.29) vs. 6.35 (1.89–14.05); median SUVmean: 16.49 (5.91–22.39) vs. 2.90 (1.2–10.01)) (Table 2; Fig. 2).

The current analysis reveals a high intratumoral ⁶⁸Ga-FAPI uptake for sarcomas and sarcoma metastases, indicating a promising clinical application of FAPI-PET/CT for this tumor entity. Compared to data obtained from conventional PET imaging, standardized uptake values probably reached higher levels than using ¹⁸F-FDG tracer: A preliminary report from a prospective trial evaluating the SUVmax of benign and malignant soft tissue lesions for patients undergoing¹⁸F-FDG-PET/CT resulted in a SUV range of 4.1–18.1 for sarcomas [16]. In a histological subgroup analysis of a large retrospective audit of 957 consecutive ¹⁸F-FDG scans of 493 patients, the highest uptake was observed for UPS, angiosarcoma, and leiomyosarcoma (each mean SUVmax <20) [17]. For the current FAPI cohort, the highest SUVmax was obtained for UPS (median SUVmax: 30.21, mean SUVmax 28.10) and liposarcoma (median SUVmax: 26.24, mean SUVmax 26.24) (Table 2). For both, ⁶⁸Ga-FAPI and ¹⁸F-FDG, a significantly higher SUV was found for high-grade sarcoma independent of histological subtype [17]. Moreover, both tracers demonstrated similar intralesional uptake in metastases: the mean SUVmax ranged from 3.56 to 6.16 for ¹⁸F-FDG, which is comparable to intrametastatic ⁶⁸Ga-FAPI uptake (mean SUVmax: 10.5) [18]. Interestingly, Iagaru et al. reported on a very low FDG signal for lung metastases (mean SUVmax: 3.56), while for the current FAPI cohort, the highest uptake was observed for pulmonary lesions (mean SUVmax: 17.34) [18]. Confirmatory studies in this population are scarce; however, this various range of tracer uptake may be explained by different histological subtypes and/or grading as well as a possible increased activity of fibroblasts in the lung parenchyma.

Data obtained from histopathological studies are clearly consistent with our results. Dohi et al. reported on a consistently high expression of FAP in bone and soft tissue tumor cells analyzing various sarcoma types like osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma [12]. In osteosarcoma cells, significant inhibition of cell proliferation, migration, and invasion was observed after a knockdown of the serine protease [19], representing the importance of FAP for the malignant behavior of these tumors after its upregulation. Hereby, FAP most probably affects tumor stage and prognosis as demonstrated in a recently published meta-analysis by Liu et al.: the authors observed that FAP expression was associated with an increased risk for nodal metastases, higher local tumor invasion, and poor survival [20]. Similar results were also obtained for sarcomas like osteosarcoma, for instance. A higher expression of the serine protease was associated with a high histological grade, a more advanced stage, presence of distant metastasis, and a worse progression-free and overall survival [21, 22].

Apart from a high tracer uptake in high-grade sarcoma, a high SUVmax of more than 10 was observed in four patients (2 patients with local relapse, 2 patients with multifocal metastatic disease), while only two of these patients were diagnosed with high-grade disease. After comparison with clinical data, both patients with local relapse showed aggressive courses of disease with multiple relapses (> 10). Although the subgroup was quite small, these results may indicate that ⁶⁸Ga-FAPI-PET/CT might be able to additionally provide a rough assessment of the course of the disease considering a possibly increased presence of cancer-associated fibroblasts within that area.

Within the last years, some advances could be achieved for sarcoma patients due to improved surgery or innovative systemic treatment approaches; however, median overall survival rates range between 18 and 24 months for metastatic disease [23, 24]. Therefore, the current clinical situation and the histopathological background make sarcomas very suitable candidates for FAPI ligands. Apart from diagnostic imaging for staging or restaging, FAPI ligands can be used for radioligand therapy, potentially improving oncological outcomes [25]. Moreover, for all 4 patients undergoing radiotherapy, tumor volume delineation was improved due to an excellent FAPI positivity within the primary tumor or local relapse (Fig. 3).

To the best of our knowledge, this is the first clinical study evaluating ⁶⁸Ga-FAPI uptake in a cohort of patients with sarcoma, although the number of patients included in this retrospective analysis was small and there is a lack of standard of reference to evaluate the performance of the novel tracer. Moreover, no patient received FDG-PET/CT which could be compared with the new hybrid imaging approach. However, the current study shows the potential of the new ligand as a diagnostic or even prognostic agent and may encourage prospective studies in the future.

The current study demonstrated that ⁶⁸Ga-FAPI-PET/CT is a very promising imaging probe for patients with sarcomas. This small case series suggests a high tracer uptake and excellent tumor-to-background ratios. FAPI ligands have the potential for improving the diagnostic and possibly the therapeutic approach for this malignancy; however, larger prospective studies will have to confirm the findings of this study.