ORIGINAL ARTICLE
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Exploring currently available fibroblast activation protein targeting molecules in adrenocortical carcinoma: Navigating theranostic pathways
Sejal Chopra1 . Jaya Shukla1 . Priyavrat Purohit1 . Umanath Adhikari2 . Frank Roesch3 . Euy Sung Moon3 . Yogesh Rathore1 . Nivedita Rana1 . Sanjay Kumar Bhadada2 . Bhagwant Rai Mittal1 . Rama Walia2
Received: 5 January 2025 / Accepted: 11 March 2025 / Published online: 22 March 2025 @ The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2025
Abstract
Introduction Cancer-associated fibroblasts (CAFs) expressing fibroblast activation protein (FAP) in the adrenocortical carcinoma (ACC) microenvironment may be used as potential therapeutic targets. This study investigated the diagnostic potential of four FAPi derivatives i.e. DOTA-FAPi-46 (FAPi46), DOTA.SA.FAPi (SA.FAPi), DATA5m SA.FAPi (DATA. FAPi) and DATA5m C4.FAPi (C4.FAPi) and compared with standard-of-care 18F-FDG (FDG) in ACC.
Methods Thirty histopathological proven cases of localized or metastatic ACC were recruited for both FDG and FAPi PET (number of patients (n)=5 for SA.FAPi, n=5 for DATA.FAPi, n=5 for C4.FAPi and n = 15 for FAPi46). For biodistribu- tion, standardized uptake values (SUV’s) were computed by delineating region-of-interest on various body organs. For comparative analysis in disease identification, lesion tracer uptake was quantified using standardized uptake values corrected for lean body mass (SUL), tumor-to-background ratio (TBR), total lesion glycolysis (TLG for FDG) and total lesion FAP expression (TLF for FAPi).
Results In overall analysis, both FAPi and FDG PET exhibited comparable mean SULpeak [FAPi 4.3 (8.0-1.7) vs FDG 3.9 (8.1-2.5), p-0.271], mean SULavg [2.2 (4.3-1.2) vs 2.2 (3.4-1.3), p-0.897] and mean TBR [1.8 (3.2-1.2) vs 1.9(2.7-1.2), p-0.696]. In volumetric analysis, comparable mean TLF and mean TLG was noted for the cohort [9.3 (53.7-4.5) vs 11.8 (33.0-4.3), p-0.107]. Sub-categorical analysis demonstrated complete concordant findings for both radiotracers in detection of all primary lesions, nodal lesions and distant metastases in lung and peritoneum with discordant findings in liver (22%) and skeletal lesions (33%). For lesion detection, DATA.FAPi and FAPi46 showed 100% concordance with FDG scan find- ings in metastatic disease. SA.FAPi exhibited 33% discordance by detecting an additional skeletal lesion, while C4.FAPi had 10% discordance, missing one liver lesion identified by FDG. Three 68 Ga-FAP derivatives (SA.FAPi, DATA.FAPi, and C4.FAPi) exhibited similar biodistribution, with uptake in the salivary glands, thyroid, liver, pancreas, muscles, and kidneys, and variable uptake in the lacrimal glands, extra-ocular muscles, oral mucosa, and uterus. In contrast, FAPi46 physiologi- cal expression was noted in salivary glands and muscles, with no uptake in other organs. Pancreatic uptake was highest for SA.FAPi (SUVmean 11.8), DATA.FAPi (12.1), and C4.FAPi (10.8), while FAPi46 had the lowest (1.7). Conversely, FAPi46 exhibited the highest muscle uptake (SUVmean 4.3) compared to SA.FAPi (1.7), DATA.FAPi (1.4), and C4.FAPi (1.0). Conclusion All the existing FAP inhibitor molecules were comparable to FDG PET for mapping disease spread and appeared as potential theranostic targets for the management of ACC.
Keywords Adrenocortical carcinoma . 68 Ga-FAPi . FDG . FAPi46 . DOTA.SA.FAPi
Introduction
Adrenocortical carcinoma (ACC) is among the rarest malig- nancies, with an incidence ranging from 0.7 to 2 cases per million annually and a grim 5-year overall survival rate of just 35% [1]. Surgical resection remains the treatment of choice, however, is associated with local recurrence
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and metastatic spread of disease. ACC often presents in an advanced stage, with as many as 70% of patients with stage III or IV disease at the time of diagnosis. Prognosis is quite poor, with 5-year survival rates of 82% for stage I, 61% for stage II, 50% for stage III, and 13% for stage IV [2]. The current treatment regimen for metastatic disease is limited and involves systemic therapy with mitotane alone or in combination with etoposide, doxorubicin, and cispl- atin with a high incidence of toxicity [3, 4]. Moreover, this regime results in complete response in only 1% of the cases and partial response in 23% of participants, with a median progression-free survival of only 5 months. The lack of effective systemic therapies with drastically reduced survival rates requires prompt identification of selective molecules for development of tailored oncology therapeutics.
In the era of precision oncology, the focus has shifted to the tumor microenvironment (TME), a promising tumor component for drug and tracer development. Cancer-asso- ciated fibroblasts (CAFs), a prominent stromal target in the TME, are crucial in tumorigenesis due to their extracellular matrix (ECM) remodeling and role in cancer cell prolifera- tion [5-9]. CAFs are a specialized subset of fibroblasts with a myofibroblastic phenotype characterized by high FAP expression [5, 6, 8]. They are associated with more than 90% of epithelial carcinomas, including lung, breast, pancreatic, colon and ovarian cancer constituting a major component (>90%) of the gross tumor mass [10-13]. Thus, targeting FAP+-CAF’s with specific FAP inhibitors (FAPi) offers a promising approach for developing effective theranostic probes.
Various FAPi molecules have been developed till date, beginning with first-generation compounds using boronic acid warheads, later replaced by more stable carbonyl war- heads [14, 15]. Recent FAPi derivatives are conjugated with the chelator DOTA for theranostic use with isotopes like 68 Ga and 177Lu. FAPi-02, the first DOTA-FAPi using piperidine, showed good tumor uptake but required improve- ments in retention time [16]. Subsequent variants such as FAPi-04, FAPi-21, and FAPi-46 have shown promise in tri- als [17, 18]. Recent advancements introduced squaric acid (SA) motif in DOTA.SA.FAPi (SA.FAPi) for easier cou- pling to the chelator and target without protecting groups [19]. SA may further improve pharmacokinetics, similar to 68 Ga-TRAM.SA.PSMA, 68 Ga-DOTAGA.SA.PSMA, and 68 Ga-NODAGA.SA.PSMA, which have shown high tumor uptake and an excellent tumor-to-background ratio [20]. FAPi derivatives conjugated with DATA5m, a bifunctional version of the hybrid chelator DATA, have also been syn- thesized which can offer facile radiolabeling at room tem- perature [19]. Despite significant advances, finding the ideal theranostic FAPi probe remains an ongoing pursuit.
18F-FDG (FDG) PET is the current standard-of-care in the diagnosis, staging, re-staging and response assessment
in ACC. However, it has the inherent limitation of lacking therapeutic translation. On contrary, various clinical studies have demonstrated the promising potential of FAPi based diagnostics in diverse malignancies [21-24]. Hence, explor- ing FAP assisted theranostics could be pivotal, especially in treating challenging conditions like metastatic ACC where current therapies fall short. This prospective study aims to evaluate the diagnostic potential of four FAPi derivatives i.e. DOTA.FAPi-46 (FAPi46), DOTA.SA.FAPi (SA.FAPi), DATA5m SA.FAPi (DATA.FAPi) and DATA5m C4.FAPi (C4. FAPi) in thirty ACC patients. The diagnostic efficacy of 68 Ga-FAPi PET has been evaluated by comparative analy- sis with FDG PET. The radiosynthesis, quality control and biodistribution of all the derivatives has also been described.
Materials and methods
Materials
FAP derivatives, Hydrochloric acid (HCl) (Merck), C18 car- tridge (Sep-Pak), Sodium Acetate (Sigma Aldrich), Ethanol (Laboratory grade, Honeywell, Riedel-de-Haen™M), Sodium Citrate (Advanced Biochemical Compounds), 0.9% Saline (Otsuka, India), 0.22 um filter (Millex®-GV), Whatmann Paper III strips (Sigma Aldrich), silica-coated Instant Thin Layer Chromatography strips (Sigma Aldrich), Acetoni- trile (Sigma Aldrich), High Purity Liquid Chromatography (HPLC) Water (Merck).
68 Ga-FAP derivatives: Preparation and quality control
Radiosynthesis with 68 Ga
SA.FAPi, DATA.FAPi and C4.FAPi were obtained from Dr. Frank Roesch and Dr. Moon Euy Sung, Mainz, Ger- many. FAPi46 was purchased from Merck, Sigma Aldrich. Radiolabeling of FAP derivatives was performed in a semi- automated iQS® (ITG, isotope technologies Garching GmbH, Germany) Fluidic Labelling Module. 68GaCl3 was eluted using 4 ml 0.05 M HCl from 68Ge-68 Ga radionuclide generator (ITM Medical Isotopes, Munich, Germany). FAP derivative dissolved in 0.25 M Sodium Acetate buffer (pH 8) was added to 68GaCl3 in ratio of 1.0-1.2 nmol/mCi. The reaction mixture was heated at 90 ℃ for 10 min (pH~4) followed by purification using solid-phase extraction (Sep- Pak C-18 column). The radiolabeled product was obtained using 1 mL 50% ethanol as an eluent after passing through 0.22 um Millipore filter. The detailed radiolabeling protocol for each FAP derivative has been mentioned in the Supple- mentary data.
Quality control (QC) of radiolabelled product
The radiochemical purity (RCP) of the radiopharmaceuti- cal was assessed using Instant Thin Layer Chromatography (ITLC) with silica-coated ITLC strip as the stationary phase and sodium citrate (pH 3.5) as the mobile phase. The pres- ence of hydrolysed form in the radiolabelled product was ruled out using paper chromatography with Whatman Paper III as the stationary phase and 50% acetonitrile as the solvent phase. The developed chromatogram was read in a Bismuth Germanate (BGO) based TLC scanner (TLC-204, Comecer).
Clinical study
Study design
This prospective study was duly approved by the Institu- tional Ethics Committee (IEC INT/IEC/2021/SPL-500). Thirty histopathological proven cases of localized or met- astatic ACC were recruited for both FDG and FAPi PET (number of patients (n) =5 for SA.FAPi, n =5 for DATA. FAPi, n=5 for C4.FAPi and n= 15 for FAPi46) for dis- ease evaluation. All the patients were above 18 years of age, and an informed written consent was obtained from them. Patients who refused consent, pregnant and lactating females, or facing difficulty to undergo PET scan due to other serious illness were excluded from the study.
FDG and FAPi PET: Acquisition parameters and scan protocol
All patients underwent both FDG and FAPi PET scans on two different days, within one week interval, for disease evaluation and comparative analysis. For FDG, whole-body (WB) images (Discovery 710, GE Healthcare) were acquired from vertex to mid-thigh, one hour post tracer administra- tion with mean injected activity 302.4±50.1 MBq. Com- puted Tomography (CT) Images were acquired following oral and intravenous contrast media with following param- eters: Matrix-size 512*512; mA 100-350 (auto mA); kV 120; pitch 0.984:1; rotation time 0.75 s and helical thickness 3.75 mm. This was followed by emission PET acquisition for same axial coverage (one minute per bed frame; matrix size 192*192). For 68 Ga-FAPi, WB images (Discovery 710, GE Healthcare) were acquired from vertex to mid-thigh, thirty minutes post tracer administration with mean injected activ- ity 85.6± 18.9 MBq. A low-dose, non-contrast CT (mA 40; kV 120) was acquired followed by PET acquisition for same axial coverage with the above-mentioned parameters (two minutes per bed frame).
Image interpretation
The image reconstruction was performed using Ordered Subset Expectation Maximum (OSEM) using 3 iterations and 24 Subsets and Gaussian filter having full width at half maximum (FWHM) of 5 mm. Both FDG and FAPi scans were reviewed concurrently and co-registered, using carina as a reference anatomical landmark. Two nuclear medicine experts, each with over ten years of experience, indepen- dently interpreted the scans. They were blinded to patient history, clinical outcomes, and results from other imaging modalities to ensure unbiased interpretation. Lesions identi- fied by both interpreters were included in the comparative analysis. Biodistribution of FAP derivatives was noted by drawing region of interests (ROI’s) on various body organs using mean and maximum standardized uptake values (SUV mean, SUVmax). To determine SUV in reference organs, spherical regions of interest (ROIs) with a volume of 1.22 cm3 were delineated on the salivary glands, thyroid, and pancreas. Conversely, spherical ROIs with a volume of 3.52 cm3 were defined on normal brain, liver, kidneys, uterus, psoas major muscle and mediastinal blood pool. For dis- ease identification, a lesion was defined as a focal area of increased radiotracer uptake exceeding blood pool activity (SULavg: 1.7 for FDG, 1.0 for FAPi46, and 1.7 for SA.FAPi, DATA.FAPi, and C4.FAPi), correlating with abnormal CT findings. Tracer avid lesions were categorized anatomically into three groups: local disease (primary/residual/recurrent), nodal lesions, and distant metastases. ROI metrics were represented as SUV adjusted for lean body mass (SUL), SULpeak and SULavg. For tracer uptake comparison, a 3D auto-contour ROI with a 40% SULpeak threshold was drawn around tracer-avid lesions to determine the metabolic tumor volume (MTV). SULavg and MTV were used to calculate total lesion glycolysis (TLG; SULxMTV; grams) for FDG PET. Similarly, total lesion FAP expression (TLF; grams) for FAPi was derived from the product of FAP-expressing tumor volume (FTV), also defined using a 40% SULpeak threshold, and SULavg (Advantage Workstation 4.7, GE Healthcare, USA). The tumor-to-background ratios (TBR) for both trac- ers were also determined using blood pool (BP) as reference background [25].
Statistical analysis
Continuous variables were reported as mean ± standard deviation (SD) for normally distributed data, and as median with inter-quartile range (IQR) for skewed data. Normality of the data was tested using Shapiro-Wilk test (n <50) [26]. Inter-observer agreement in scan interpretation was evalu- ated using Cohen’s weighted kappa statistics, with kappa values below 0.4 indicating weak agreement, values between 0.4 and 0.75 indicating fair to good agreement, and values
of 0.75 or above indicating excellent agreement [27]. Differ- ences in lesion uptake between the two tracers were statisti- cally assessed using Student’s t-test for normally distributed data and Wilcoxon signed-rank test for skewed data, with a p-value of <0.05 indicating statistical significance.
Results
The chemical structure of all the FAP derivatives have been illustrated in Fig. 1. The radiochemical yield (RCY) for all 68 Ga-FAP derivatives was 98.3 ±1.1%. The RCP of the labelled product obtained using ITLC was more than
99%. The radiochromatograms of all the FAP derivatives have been depicted in Supplementary Fig. 1.
Patient demographics
Thirty histopathological proven cases of localized or metastatic ACC were recruited for both FDG and FAPi PET. The mean age of the cohort was 43 + 10 years. Of 30 patients enrolled in this study, 13 had only local diseases, 5 had nodal involvement and 17 had distant metastases with lung and liver being the most common metastatic sites (Table 1).
HO
OH
DOTA.SA.FAPİ
O
N
N
0
N
O
N
N
0
H
H
F
N
N
HO
F
H
N
0
O
0
H
CN
O
0
0
DATA5m SA.FAPi
HOOC
H
O
O
N
H
H
H
O
N
CN
HOOC
N
N
O
N
N
N
F
F
HOOC
COOH
DATA5m.C4.FAPi
N
HOOC
N
H
F
N
N
0
F
N
N
0
0
H
CN
HOOC
0
HO
OH
0
N
N
0
DOTA.FAPi46
O
N
N
0
HO
N
N
N
N
F
CH3
F
N
O
H
CN
O
G Springer
| S.No | Age | Gender | Side | Extent of disease | Surgery | RT* | EDP® |
|---|---|---|---|---|---|---|---|
| 1 | 47 | Male | Right | Local + Distant Mets | Yes | Yes | Yes |
| 2 | 52 | Female | Right | Local | Yes | No | Yes |
| 3 | 58 | Male | Left | Local + Distant Mets | No | No | Yes |
| 4 | 22 | Female | Left | Local | Yes | No | No |
| 5 | 34 | Female | Right | Distant Mets +LNs | Yes | No | Yes |
| 6 | 38 | Female | Right | Local | Yes | Yes | No |
| 7 | 50 | Female | Right | Local + Distant Mets | Yes | No | Yes |
| 8 | 52 | Female | Right | Local + Distant Mets | Yes | No | Yes |
| 9 | 34 | Female | Right | Local | Yes | No | No |
| 10 | 39 | Female | Left | Local | Yes | No | No |
| 11 | 36 | Female | Right | Local + Distant Mets +LNs | Yes | No | Yes |
| 12 | 46 | Male | Right | Local + Distant Mets | Yes | Yes | Yes |
| 13 | 35 | Female | Right | Distant Mets | Yes | No | Yes |
| 14 | 33 | Female | Left | Local | Yes | No | No |
| 15 | 34 | Female | Right | Local + Distant Mets | Yes | No | Yes |
| 16 | 40 | Female | Right | Local | Yes | Yes | No |
| 17 | 60 | Male | Left | Distant Mets | Yes | No | Yes |
| 18 | 58 | Female | Right | Local | Yes | No | Yes |
| 19 | 49 | Female | Right | Local + Distant Mets +LNs | Yes | No | Yes |
| 20 | 47 | Male | Right | Local + Distant Mets | Yes | Yes | Yes |
| 21 | 50 | Female | Left | Distant Mets | Yes | No | Yes |
| 22 | 37 | Female | Right | Distant Mets +LNs | Yes | No | Yes |
| 23 | 23 | Female | Right | Local | Yes | No | No |
| 24 | 57 | Female | Right | Local | Yes | No | No |
| 25 | 32 | Female | Right | Local | Yes | No | No |
| 26 | 51 | Female | Right | Local | Yes | No | No |
| 27 | 48 | Male | Right | Local + Distant Mets | Yes | Yes | Yes |
| 28 | 35 | Female | Right | Distant Mets | Yes | No | Yes |
| 29 | 38 | Female | Right | Local | Yes | No | No |
| 30 | 48 | Female | Left | Local+ Distant Mets +LNs | Yes | No | Yes |
RT =radiotherapy, EDP =etoposide, doxorubicin and cisplatin
Biodistribution analysis: 68 Ga-FAP derivatives
Comparable biodistribution was noted for three 68Ga-FAP derivatives (SA.FAPi, DATA.FAPi, C4.FAPi) with tracer uptake in salivary glands, thyroid, liver, pancreas, muscles and kidneys with variable uptake in lacrimal glands, extra- ocular muscles, oral mucosa and uterus, unlike FAPi46, which demonstrated physiological expression in salivary glands and muscles only, with no uptake in other organs. Pancreatic uptake was similar for SA.FAPi and DATA. FAPi (SUVmean 11.8 vs. 12.1), followed by C4.FAPi (10.8), and was lowest in FAPi46 (1.7), comparable to FDG (1.8) [22]. Blood pool activity was highest in DATA. FAPi (SUVmean 6.6) and lowest in FAPi46 (1.5). Physi- ological muscle uptake was highest in FAPi46 (SUV mean 4.3) followed by SA.FAPi (1.7), DATA.FAPi (1.4) and C4.FAPi (1.0), comparable to FDG (0.8) (Fig. 2) [22].
Disease identification: FAPi vs FDG PET
In 30 patients enrolled for the study, 86 lesions spanning local disease, nodal, and distant metastases were identified. In local disease detection, a perfect agreement (k=1) was observed between both the observers. For distant metasta- ses, a near perfect agreement was observed (k=0.91). For nodal disease, an excellent inter-observer agreement was noted (k=0.85). Lesion-based comparative analysis between both radiotracers demonstrated complete concordant find- ings in detection of all primary lesions, nodal lesions and distant metastases in lung and peritoneum whereas discord- ant findings were noted in liver (22%) and skeletal lesions (33%). In overall analysis, both FAPi and FDG PET exhib- ited comparable mean SULpeak [FAPi 4.3 (8.0-1.7) vs FDG 3.9 (8.1-2.5), p-0.271], mean SULavg [2.2 (4.3-1.2) vs 2.2 (3.4-1.3), p-0.897] and mean TBR [1.8 (3.2-1.2) vs 1.9
Brain
SA.FAPİ
DATA.FAPi
Salivary glands
C4.FAPi
FAPi46
Thyroid
Lung
Liver
Spleen
Pancreas
Blood Pool
Muscles
Kidneys
0
6
12
18
24
30
SUVmax
Brain
SA.FAPİ
DATA.FAPİ
Salivary glands
C4.FAPi
FAPi46
Thyroid
Lung
Liver
Spleen
Pancreas
Blood Pool
Muscles
Kidneys
0
6
12
18
24
30
SUVmean
(2.7-1.2), p-0.696]. In volumetric analysis, comparable mean TLF and mean TLG were noted for the cohort [9.3 (53.7-4.5) vs 11.8 (33.0-4.3), p-0.107] (Table 2).
Site of malignancy
Local (primary/residual/recurrent) disease
Thirteen local adrenal lesions were identified in the study cohort. Both radiotracers detected all primary lesions, yielding 100% concordant scan findings. For local dis- ease, FAPi PET demonstrated lower mean SULpeak 6.2 (20.9-5.8) [vs 14.5 (33.8-5.2); p-0.359], mean SULavg avg 3.3 (5.1-2.0) [vs 5.5 (7.4-2.3); p- 0.154] and mean TLF 346 (1008-24.4) [vs 390 (912-127); p-0.060] in com- parison to FDG although, the difference was statistically
non-significant. On contrary, the mean TBR was higher for FAPi [3.4 (4.6-2.0)] in comparison to FDG PET [2.8 (5.5-1.8), p-0.820] as illustrated in Table 2.
Nodal disease
Six nodal lesions were identified in the cohort with a scan concordance of 100% between both radiotracers. For nodal disease, FAPi PET demonstrated lower mean SULpeak 1.7 (2.1-1.0) [vs 2.7 (2.8-1.3), p-0.062], SULavg 1.3 (1.5-0.8) [vs 1.7 (2.1-1.2), p-0.058] and TBR 0.9 (2.3-0.5) [vs 1.3 (2.1-1.1), p-0.825] in comparison to FDG. On contrary, the mean TLF [3.2 (5.5-0.9)] was higher than the mean TLG [2.8(9.1-1.8), p-0.359] for lymph nodal involvement (Table 2).
| Category of Analysis (n, no of lesions) | Overall (n=86) | Primary (n=13) | Nodal Mets (n=6) | Distant Mets (n=67) | |
|---|---|---|---|---|---|
| SULpeak [Median (IQR)] | 68 Ga-FAPi | 4.3 (8.0-1.7) | 6.3 (20.9-5.8) | 1.7 (2.1-1.0) | 4.0 (7.6-1.7) |
| FDG | 3.9 (8.1-2.5) | 14.5 (33.8-5.2) | 2.7 (2.8-1.3) | 3.8 (7.7-2.2) | |
| p-value | 0.271 | 0.359 | 0.062 | 0.496 | |
| SULavg [Median (IQR)] | 68 Ga-FAPi | 2.2 (4.3-1.2) | 3.4 (5.1-2.0) | 1.3 (1.5-0.8) | 6.3 (8.8-4.4) |
| FDG | 2.2 (3.4-1.3) | 5.5 (7.4-2.3) | 1.7 (2.1-1.2) | 3.6 (4.4-2.0) | |
| p-value | 0.897 | 0.154 | 0.058 | 0.298 | |
| TBRBP [Median (IQR)] | 68 Ga-FAPi | 1.8 (3.2-1.2) | 2.8 (5.5-1.8) | 0.9 (2.3-0.5) | 1.8 (3.2-1.1) |
| FDG | 1.8 (2.7-1.2) | 3.4 (4.6-2.0) | 1.3 (2.1-1.0) | 1.8 (2.6-1.2) | |
| p-value | 0.696 | 0.820 | 0.825 | 0.188 | |
| Volumetric Analysis [Median (IQR)] | TLF (SULxcm3) (SULx MTV) | 9.3 (53.7-4.5) | 346.0 (1008.0-24.4) | 3.3 (5.5-0.9) | 9.2 (47.6-4.6) |
| TLG (SULxcm3)(SUL × MTV) | 11.8 (33.0-4.3) | 390.0 (912.0-126.9) | 2.8 (9.1-1.8) | 9.2 (21.9-4.4) | |
| p-value | 0.107 | 0.060 | 0.359 | 0.125 | |
Distant metastases
Sixty-seven distant metastatic sites were identified in the cohort including forty-six lung, ten liver, three skeletal, and eight peritoneal lesions with 97% concordant scan find- ings. For lesion detection, DATA.FAPi and FAPi46 showed 100% concordance with FDG scan findings. SA.FAPi exhibited 33% discordance by detecting an additional skel- etal lesion, while C4.FAPi had 10% discordance, missing one liver lesion identified by FDG. For distant metastases, higher FAPi avidity was noted compared to FDG with mean SULpeak and SULavg values of 4.0 (7.6-1.7) vs 3.8 (7.7-2.2); p-value 0.496 and 2.2 (4.3-1.2) vs 1.7 (3.4-1.4); p-0.298 respectively. Similar mean TBR were noted for both the radi- otracers [FAPi 1.8 (3.2-1.1) vs FDG 1.8 (2.6-1.2), p-0.825].
In volumetric analysis, mean TLF and TLG values were also comparable [9.2 (47.6-4.6) vs 9.2 (21.9-4.4); p-0.060]. In sub-categorical analysis, liver, skeletal and peritoneal lesions demonstrated higher FAPi avidity in comparison to the lung lesions exhibiting higher FDG avidity. FAPi PET derived mean TBRBp values were higher for liver, skeletal and peritoneal lesions in comparison to lung lesions which demonstrated higher TBRBp for FDG PET. However, the difference in the mean TBRBp was statistically significant for peritoneal lesions only [FAPi 3.7 (5.6-2.5) vs FDG 1.8 (2.0-1.5); p-0.036]. In volumetric analysis, the mean TLF values were higher than the mean TLG values for all the metastatic lesions as depicted in Table 3. The scan images of various FAP derivatives in select cases of ACC are illus- trated in Figs. 3, 4, 5, 6, 7 and 8.
| Site of Distant Metastases (n=67) | Lung (n=46) | Liver (n= 10) | Skeletal (n=3) | Peritoneal (n=8) | |
|---|---|---|---|---|---|
| SUL peak | 68 Ga-FAPi | 2.5 (5.3-1.4) | 9.4 (16.7-4.3) | 7.3±2.3 | 7.3 (12.4-3.2) |
| [Median (IQR)/Mean±S.D.] | FDG | 3.6 (4.5-1.7) | 8.5 (37.1-6.4) | 3.6±2.5 | 5.0 (10.4-3.8) |
| p-value | 0.555 | 0.312 | NA* | 0.438 | |
| SULavg | 68 Ga-FAPi | 1.4 (2.7-0.9) | 4.5 (6.3-2.2) | 3.6±2.5 | 3.5 (4.9-2.8) |
| [[Median (IQR)/Mean±S.D.] | FDG | 1.6 (2.5-1.2) | 7.5 (10.1-5.0) | 2.5±0.5 | 2.8 (7.1-2.5) |
| p-value | 0.347 | 0.156 | NA* | 0.062 | |
| TBRBP | 68 Ga-FAPi | 1.4 (2.0-1.0) | 3.5 (3.9-2.0) | 7.4±3.3 | 3.7 (5.6-2.5) |
| [[Median (IQR)/Mean ± S.D.] | FDG | 1.8 (2.6-1.0) | 2.7 (7.1-1.4) | 3.6±2.5 | 1.8 (2.0-1.5) |
| p-value | 0.418 | 0.483 | NA* | 0.036 | |
| Volumetric Analysis | TLF (SULxcm3)(SUL × MTV) | 7.1 (17.2-4.0) | 250.9 (660.2-42.3) | 9.7±3.1 | 41.0 (72.3-7.4) |
| [Median (IQR)/Mean±S.D.] | TLG (SULxcm3) (SULX MTV) | 6.8 (15.9-3.8) | 32.1 (19.2-504.0) | 3.6±2.5 | 17.1 (158.7-7.8) |
| p-value | 0.074 | 0.109 | NA* | 0.999 |
NA* Not applicable due to small sample size
a
b
d
C
0
FAPi46
FAPİ46
CT
FDG
FDG
a
b
e
C
d
FAPi46
FAPi46
CT
FDG
FDG
a
b
d
C
FAPi46
FAPi46
CT
FDG
FDG
a
b
e
C
d
SA.FAPİ
SA.FAPİ
CT
FDG
FDG
Discussion
Metastatic or recurrent ACC is a highly aggressive malig- nancy, posing substantial challenges in disease manage- ment due to the lack of effective systemic therapies. FDG
10.1 vs FDG SULpeak 6.7; FAPi TBRBp 2.1 vs FDG TBRBp 1.9), aor- tocaval (c: SULpeak 2.2 vs 1.7; TBRBp 1.3 vs 1.2) and para-aortic (d: SULpeak 1.7 vs 1.7; TBRBp 1.6 vs 1.0) lymph nodes
PET is the current standard-of-care for disease evaluation in ACC; however, it is inherently limited by its lack of therapeutic applicability. ACC microenvironment is char- acterized by the presence of CaFs [28]. Hence, investi- gating CAF-FAP-targeted theranostics could be crucial, particularly for managing challenging conditions like
a
b
d
C
DATA.FAPİ
DATA.FAPİ
CT
FDG
FDG
a
b
d
C
C4.FAPİ
C4.FAPİ
CT
FDG
FDG
metastatic ACC, where existing therapies are inadequate. This prospective study assessed the diagnostic perfor- mance of various FAP derivatives in ACC, comparing it with FDG.
Radiosynthesis of all 68 Ga-FAP derivatives is facile using semi-automated module with good RCY and RCP of>98% and 99% respectively (Supplementary Fig. 1).
ill-defined arterial liver lesion in the right lobe (Segment VIII; FAPi SULpeak 13.8 vs FDG SULpeak 3.1; FAPi TBRBp 1.3 vs FDG TBRBP 2.0)
For biodistribution analysis, five recruited patients were randomly assigned to each FAP derivative in this study. Three 68 Ga-FAP derivatives i.e. SA.FAPi (SUVmean: 4.3), DATA.FAPi (4.8) and C4.FAPi (4.5) had a similar physi- ological uptake in the liver while FAPi46 (1.2) demonstrated relatively lower background uptake (vs SUVmean: 3.3) in comparison to FDG [22]. Three 68 Ga-FAP derivatives (SA.
FAPi, DATA.FAPi, C4.FAPi) showed higher physiological pancreatic uptake, but this is unlikely to impede therapeutic use due to rapid clearance. Delayed imaging (2-3 h) may improve lesion delineation due to prolonged tumor reten- tion [24]. The lower liver and pancreatic background uptake of FAPi46 can be advantageous for detecting small liver lesions and pancreatic malignancies. All 68 Ga-FAP deriva- tives showed minimal brain uptake in contrast to FDG hence, making them advantageous for imaging primary diseases or brain metastases. The variable physiological uptake of 68 Ga- FAP derivatives in salivary glands, muscles and pancreas may be linked to their half-maximal inhibitory concentra- tion (IC50) for FAP related prolyl oligopeptidase (PREP) [19]. While these derivatives are selective for FAP, their affinity for PREP or related enzymes such as dipeptidyl peptidase 4 (DPP4) could contribute to this uptake [29-31]. However, the mechanisms underlying their uptake in the extra-ocular muscles, salivary glands and thyroid remains unclear [32-34]. In this study, FAPi46 exhibited favorable biodistribution with minimal physiological uptake and low- est bloodpool activity; therefore, the remaining ten patients underwent imaging with this FAP derivative.
To the best of our knowledge, the utility of 68 Ga-FAPi in ACC is being assessed for the first time in this study. For disease detection, 68 Ga-FAPi and FDG demonstrated similar tracer avidity and TBR. Sub-categorical analysis revealed a higher FDG avidity in local disease. Kaplan et al. have also reported the superiority of FDG over 68 Ga-FAPi in detec- tion of recurrent disease concordant with our study findings [35]. However, in our previous study, we observed a higher 68 Ga-FAPi avidity for local disease in two cases of recurrent ACC [21]. This varying uptake of 68 Ga-FAPi may be attrib- uted to changes in FAPa expression across different meta- static stages. Ding et al., in their study on a breast cancer animal model, demonstrated that FAPa expression changes with disease progression. Early-stage metastases showed higher 68 Ga-FAPi uptake than advanced stages, which had higher FDG avidity [36]. Similarly, in ACC, FAPa expres- sion is significantly elevated in T1, T2, and T3 stages but decreased in the T4 stage [37]. The TNM stage of disease at the time of imaging significantly influences FAPi avidity and hence, may offer critical insights into the optimal timeline of performing 68 Ga-FAPi scans for effective disease detec- tion in ACC.
Both tracers exhibited 100% agreement in nodal disease detection with higher FDG avidity although the difference was statistically insignificant. Serfling et al. reported FDG as superior to 68 Ga-FAPi for detecting nodal metastases [38], while Ballal et al. described a case of NSCLC with no 68 Ga-FAPi uptake in lymph nodes [24]. Conversely, Chen et al. observed better performance with 68 Ga-FAPi com- pared to FDG in identifying nodal metastases [39]. A meta- analysis by Sollini et al. highlighted variable sensitivities
(59%-100%) for FAPi PET in detecting nodal metastases, influenced by cancer biology, lymph node composition, and inflammation [40]. Differential uptake of FDG and 68 Ga- FAPi may also be affected by inflammatory nodes, and the choice of radioisotope (68 Ga/18F) can further impact spatial resolution and detection of smaller tumor clusters [41].
Distant metastases demonstrated greater avidity for 68 Ga- FAPi compared to FDG, consistent with findings from other studies on metastatic disease [21, 22, 39]. Subcategory analysis revealed that the SUL values of 68 Ga-FAPi were higher than those of FDG for liver, skeletal, and peritoneal lesions, aligning with observations reported in previous studies [22, 39]. The mean TLF was found to be compa- rable to the mean TLG for the cohort. Numerous studies have highlighted that TLG and MTV may be more reliable prognostic indicators of overall survival than SUVs in vari- ous cancers, including head and neck, lung, ovarian cancers, and pleural mesothelioma [42-47]. Li C et al. confirmed that TLF strongly correlated with FAP expression, provid- ing a better measure of tumor burden than SUV in non- small cell lung carcinoma (NSCLC). FAP over-expression in ACC is linked to shorter disease-specific survival and poor prognosis [37]. Integrating the volumetric parameter TLF with conventional clinicopathological factors in FAPi-based theranostics could provide a novel approach for prognostic stratification, enhancing treatment planning and response assessment (Fig. 8).
In addition to various FAP ligands, a cyclic peptide FAP2286 has shown promise as a suitable theranostic probe in solid tumors [48]. In this study, three 68 Ga-FAP derivatives (SA.FAPi, DATA.FAPi, C4.FAPi) demonstrated comparable biodistribution patterns, with SA.FAPi showing the lowest blood pool activity. Hence, we further evaluated three FAP derivatives i.e. SA.FAPi, FAPi46 and FAP2286 as potential theranostic probes for ACC. All three FAP-tar- geting molecules localized to lesions; however, 177Lu-SA. FAPi and 177Lu-FAPi46 showed rapid washout and shorter retention (<48 h). In contrast, 177Lu-FAP2286 exhibited favorable pharmacokinetics with prolonged lesion retention (> 10 days), making it ideal for targeted therapy [49]. Addi- tionally, the DOTA(SA.FAPi)2 dimer has also shown prom- ise for therapeutic applications due to its prolonged tumor retention [50]. TLF can serve as a valuable tool for accu- rate patient selection in targeted therapy and the realm of FAPi-aided theranostics can be a potentially game changer in disease management of metastatic ACC by improving prognostication and disease specific survival.
Our study has certain limitations, including a small sam- ple size which may limit the statistical power to detect sig- nificant differences between groups. Therefore, multi-center studies with larger patient populations and power analysis are required to validate the diagnostic performance of 68 Ga- FAPi for routine clinical application. Additionally, not all
nodal and metastatic lesions included in the comparative analysis were biopsy-confirmed. Ethically, obtaining patho- logical confirmation for all analyzed lesions solely to vali- date PET/CT findings may not be justified. Furthermore, the physiological uptake of the radiotracer in areas such as healing wounds, degenerative lesions, muscles, thyroid, sali- vary glands, and the uterus could pose potential challenges in 68 Ga-FAPi PET imaging.
Conclusion
68 Ga-FAPi PET performed similar to the standard-of-care FDG for disease detection in ACC. All the FAP inhibitors emerged as effective molecules for landscaping the disease spread in ACC and FAP appeared as potential therapeutic target for metastatic ACC. The TNM stage of disease sig- nificantly influences FAP expression and hence, may offer critical insights into the optimal timeline of providing FAP targeting therapy to enhance treatment effectiveness. The realm of FAPi-aided theranostics can be a potentially game changer in disease management of metastatic ACC. How- ever, further studies are warranted to assess the role of FAPi targeted therapy, prognostication and impact on survival in ACC.
Supplementary Information The online version contains supplemen- tary material available at https://doi.org/10.1007/s00259-025-07203-4.
Author contributions All authors actively contributed to the study con- ception and design. The DOTA.SA.FAPi, DATA5m.SA.FAPi, DATA 5m.C4.FAPi molecules was provided by Prof. Frank Roesch and Dr. Euy Sung Moon. The patients were referred by Prof. Sanjay Kumar Bhadada and Dr. Rama Walia. The study was performed by Ms. Sejal Chopra under the supervision of Prof. Jaya Shukla, Prof. Bhagwant Rai Mittal and Dr. Rama Walia. The FAPi radiolabelling was performed by Ms. Sejal Chopra and Dr. Yogesh Rathore. The acquisition was performed by Dr. Nivedita Rana. The patient images were interpreted by Dr. Priyavrat Purohit and Dr. Umanath Adhikari. The first draft of manuscript was prepared by Ms. Sejal Chopra. All the authors have read and approved the final manuscript.
Funding The authors would like to acknowledge Postgraduate Institute of Medical Education and Research, Chandigarh (Project ID:9719- 126) for providing financial support to conduct the study.
Data availability The datasets generated during and/or analysed dur- ing the current study are available from the corresponding author on reasonable request.
Declarations
Ethical approval The study was approved by the Institutional Ethics Committee (INT/IEC/2021/SPL-500).
Informed consent An informed written consent for participation in the study and publications of clinical data were taken from the patients enrolled in the study.
Competing interest The authors have no relevant financial or non- financial interests to disclose.
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Authors and Affiliations
Sejal Chopra1 . Jaya Shukla1(D . Priyavrat Purohit1 . Umanath Adhikari2 . Frank Roesch3 . Euy Sung Moon3 . Yogesh Rathore1 . Nivedita Rana1 . Sanjay Kumar Bhadada2 . Bhagwant Rai Mittal1 . Rama Walia2
☒ Jaya Shukla shuklajaya@gmail.com
☒ Rama Walia ramawaliapgimer@gmail.com
1 Department of Nuclear Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
2 Department of Endocrinology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
3 Department of Chemistry, Johannes Gutenberg University, Mainz, Germany