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. 2024 Dec;52(1):342-353.
doi: 10.1007/s00259-024-06891-8. Epub 2024 Aug 29.

Detection of tumour heterogeneity in patients with advanced, metastatic castration-resistant prostate cancer on [68Ga]Ga-/[18F]F-PSMA-11/-1007, [68Ga]Ga-FAPI-46 and 2-[18F]FDG PET/CT: a pilot study

Kim M Pabst #  1   2 , Riccardo Mei #  3   4 , Katharina Lückerath  3   5 , Boris A Hadaschik  5   6 , Claudia Kesch  5   6 , Josefine Rawitzer  5   7 , Lukas Kessler  5   8 , Luisa S Bodensieck  3   5 , Rainer Hamacher  5   9 , Kelsey L Pomykala  5   10   11 , Stefano Fanti  4 , Ken Herrmann  3   5 , Wolfgang P Fendler  3   5
Affiliations

Detection of tumour heterogeneity in patients with advanced, metastatic castration-resistant prostate cancer on [68Ga]Ga-/[18F]F-PSMA-11/-1007, [68Ga]Ga-FAPI-46 and 2-[18F]FDG PET/CT: a pilot study

Kim M Pabst et al. Eur J Nucl Med Mol Imaging. 2024 Dec.

Abstract

Purpose: In metastatic castration-resistant prostate cancer (mCRPC), some patients show low/absent PSMA expression in tumour lesions on positron emission tomography (PET) scans, indicating heterogeneity and heightened risk of non-response to PSMA-RLT (radioligand therapy). Imaging cancer-associated fibroblasts and glucose uptake may further characterise tumour heterogeneity in mCRPC patients. Here, we aimed to evaluate tumour heterogeneity and its potential implications for management in mCRPC patients assessed for PSMA-RLT using [68Ga]Ga-FAPI-46, 2-[18F]FDG and [68Ga]Ga-/[18F]F-PSMA-11/-1007 PET.

Material and methods: Patients with advanced, progressive mCRPC underwent clinical [68Ga]Ga-/[18F]F-PSMA-11/-1007, 2-[18F]FDG and [68Ga]Ga-FAPI-46 PET/CT to evaluate treatment with PSMA-directed RLT. Tumour detection/semiquantitative parameters were compared on a per-lesion/-region basis. Two phenotypes were defined: Criteria for the mixed phenotype were: (a) PSMA-negative findings for lymph node metastases ≥ 2.5 cm, any solid organ metastases ≥ 1.0 cm, or bone metastases with soft tissue component ≥ 1.0 cm, (b) low [68Ga]Ga-/[18F]F-PSMA-11/-1007 uptake and/or (c) balanced tumour uptake of all radioligands. The PSMA-dominant phenotype was assigned if the criteria were not met.

Results: In ten patients, 472 lesions were detected on all imaging modalities (miTNM regions: M1b: 327 (69.3%), M1a: 95 (20.1%), N1: 26 (5.5%), M1c: 18 (3.8%), T: 5 (1.1%) and Tr: 1 (0.2%). [68Ga]Ga-/[18F]F-PSMA-11/-1007 (n = 453 (96.0%)) demonstrates the highest detection rate, followed by [68Ga]Ga-FAPI-46 (n = 268 (56.8%))/2-[18F]FDG (n = 241 (51.1%)). Semiquantitative uptake was highest for [68Ga]Ga-/[18F]F-PSMA-11/-1007 (mean SUVmax (interquartile range): 22.7 (22.5), vs. [68Ga]Ga-FAPI-46 (7.7 (3.7)) and 2-[18F]FDG (6.8 (4.7)). Seven/three patients were retrospectively assigned to the PSMA-dominant/mixed phenotype. Median overall survival was significantly longer for patients who underwent [177Lu]Lu-PSMA-617 RLT and were retrospectively assigned to the PSMA-dominant phenotype (19.7 vs. 9.3 months).

Conclusion: Through whole-body imaging, we identify considerable inter- and intra-patient heterogeneity of mCRPC and potential imaging phenotypes. Regarding uptake and tumour detection, [68Ga]Ga-/[18F]F-PSMA-11/-1007 was superior to [68Ga]Ga-FAPI-46 and 2-[18F]FDG, while the latter two were comparable. Patients who underwent [177Lu]Lu-PSMA-617 RLT based on clinical-decision making had a longer overall survival and could be assigned to the PSMA-dominant phenotype.

Keywords: 18F-FDG; 68Ga-FAPI; MCRPC; PSMA; Prostate cancer.

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Conflict of interest statement

Declarations. Ethics approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of University Duisburg-Essen (permits no. 19–8991-BO/20–9485-BO). Consent to participate: Informed consent was obtained from all individual participants included in the study. Consent to publish: The authors affirm that human research participants provided informed consent for publication of the images in Fig. 3 and Supplemental Fig. 1. Competing interests: K.M.P.: fees from Bayer (research funding), travel fees from IPSEN and Novartis, Clinician Scientist Stipend from the University Medicine Essen Clinician Scientist Academy (UMEA) sponsored by the faculty of medicine and Deutsche Forschungsgemeinschaft (DFG). R.M.: fees from Caelyx and Median Technologies. K.L.: consultant to Sofie Biosciences, Enlaza Therapeutics, research support from Mariana Oncology, Novartis. B.A.H.: Advisory boards for Janssen, Bayer, ABX, Lightpoint, Amgen, MSD, Pfizer, Novartis. Invited speaker for Accord, Astellas, Janssen R&D. Honoraria from Uromed. Research funding from AAA/Novartis, Bristol Myers Squibb, and German Research Foundation. Leadership roles for DKG AUO and DGU. C.K.: research fees from AAA/Novartis, Amen and Curie Therapeutics, travel fees from Amgen, Bayer and Janssen. R.H.: fees from Lilly and PharmaMar, travel fees from Lilly, Novartis and PharmaMar, Clinician Scientist Stipend from the University Medicine Essen Clinician Scientist Academy (UMEA) sponsored by the faculty of medicine and Deutsche Forschungsgemeinschaft (DFG). K.H.: personal fees: Bayer, Sofie Biosciences, SIRTEX, Adacap, Curium, Endocyte, IPSEN, Siemens Healthineers, GE Healthcare, Amgen, Novartis, ymabs, Aktis, Oncology, Pharma15; non-financial support: ABX; grants/personal fees: BTG. W.P.F.: fees from SOFIE Bioscience (research funding), Janssen (consultant, speaker), Calyx (consultant, image review), Bayer (consultant, speaker, research funding), Novartis (speaker, consultant), Telix (speaker), GE Healthcare (speaker), Eczacıbaşı Monrol (speaker), ABX (speaker), Amgen (speaker), Urotrials (speaker). All conflicts of interest were outside the submitted work.

Figures

Fig. 1
Fig. 1
Flow of patients
Fig. 2
Fig. 2
Per-region-based detection efficacy. Per-region-based analysis of detection efficacy (T: primary tumour/local tumour recurrence, N1: regional lymph node metastases, M1a: distant lymph node metastases, M1b: bone metastases, M1c: visceral metastases) for [68Ga]Ga-/[18F]F-PSMA-11/-1007 (white), 2-[18F]FDG (grey) and [68Ga]Ga-FAPI-46 PET (black bars)
Fig. 3
Fig. 3
Heterogeneity of radioligand uptake in patient no. 1. Example of heterogeneity regarding uptake pattern in a pelvic bone metastasis in patient no 1. 2-[18F]FDG uptake was highest in the os sacrum (A, red arrow) and low to moderate uptake in the os ilium (A, white arrow). [18F]F-PSMA-1007 uptake was highest in the os ilium (B, white arrow) and lower in the os sacrum (B, red arrow). [68Ga]Ga-FAPI-46 uptake was only moderate in the os sacrum (C, red arrow) and nearly absent in the os ilium (C, white arrow). After the PET-scans, a biopsy of both regions was performed, revealing a metastasis of prostate adenocarcinoma in the os ilium (D, F; 100-fold magnification) and a metastasis of dedifferentiated prostate cancer in the os sacrum (E,G; 400-fold magnification) which was confirmed by immunohistochemical staining for NKX3.1 (detection of NKX3.1 (brown) in F, absence of NKX3.1 in G). The patient received chemotherapy and died 4 months after imaging
Fig. 4
Fig. 4
Per-lesion-based comparison of SUVmax and SUVmean between [68Ga]Ga-/[18F]F-PSMA-11/-1007, 2-[18F]FDG and [68Ga]Ga-FAPI-46. In the absence of a normal distribution, the Friedman test was used for pairwise comparisons. N = 207 lesions were compared demonstrating uptake of all three radioligands. ***: p < 0.001, **: p < 0.01
Fig. 5
Fig. 5
Per-lesion-based heat maps (SUVmean) to demonstrate heterogeneous uptake and imaging-phenotypes of mCRPC. SUVmean-based heat maps compared uptake of the three radioligands [68Ga]Ga-/[18F]F-PSMA-11/-1007, 2-[18F]FDG and [68Ga]Ga-FAPI-46 in each detected tumour lesion (each row corresponds to one lesion) and defined the imaging phenotype (PSMA-dominant vs. mixed). Negative lesions according to VISION criteria for [68Ga]Ga-/[18F]F-PSMA-11/-1007 and negative lesions (uptake equal to surrounding background) for 2-[18F]FDG and [68Ga]Ga-FAPI-46 [19] are shown in orange boxes, while lesions with tracer uptake are shown in grey scale reflecting the SUVmean of the lesion. Note that the scale for the SUVmean differs between patients to allow visualisation of intra-individual variation in the uptake of the three different radiotracers
Fig. 6
Fig. 6
Kaplan–Meier curves of overall survival by imaging phenotype (PSMA-dominant vs. mixed). Patients with mixed phenotype (orange) demonstrates a significantly lower median overall survival of 9.3 months compared to patients with PSMA-dominant phenotype (black; 19.7 months)
See this image and copyright information in PMC

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