68Ga-FAPI-PET/CT in patients with various gynecological malignancies

Katharina Dendl, Stefan A Koerber, Rebecca Finck, Kgomotso M G Mokoala, Fabian Staudinger, Lisa Schillings, Ulrike Heger, Manuel Röhrich, Clemens Kratochwil, Mike Sathekge, Dirk Jäger, Jürgen Debus, Uwe Haberkorn, Frederik L Giesel, Katharina Dendl, Stefan A Koerber, Rebecca Finck, Kgomotso M G Mokoala, Fabian Staudinger, Lisa Schillings, Ulrike Heger, Manuel Röhrich, Clemens Kratochwil, Mike Sathekge, Dirk Jäger, Jürgen Debus, Uwe Haberkorn, Frederik L Giesel

Abstract

Purpose: 68Ga-FAPI (fibroblast activation protein inhibitor) is a novel and highly promising radiotracer for PET/CT imaging. The aim of this retrospective analysis is to explore the potential of FAPI-PET/CT in gynecological malignancies. We assessed biodistribution, tumor uptake, and the influence of pre- or postmenopausal status on tracer accumulation in hormone-sensitive organs. Furthermore, a comparison with the current standard oncological tracer 18F-FDG was performed in selected cases.

Patients and methods: A total of 31 patients (median age 59.5) from two centers with several gynecological tumors (breast cancer; ovarian cancer; cervical cancer; endometrial cancer; leiomyosarcoma of the uterus; tubal cancer) underwent 68Ga-FAPI-PET/CT. Out of 31 patients, 10 received an additional 18F-FDG scan within a median time interval of 12.5 days (range 1-76). Tracer uptake was quantified by standardized uptake values (SUV)max and (SUV)mean, and tumor-to-background ratio (TBR) was calculated (SUVmax tumor/ SUVmean organ). Moreover, a second cohort of 167 female patients with different malignancies was analyzed regarding their FAPI uptake in normal hormone-responsive organs: endometrium (n = 128), ovary (n = 64), and breast (n = 147). These patients were categorized by age as premenopausal (<35 years; n = 12), postmenopausal (>65 years; n = 68), and unknown menstrual status (35-65 years; n = 87), followed by an analysis of FAPI uptake of the pre- and postmenopausal group.

Results: In 8 out of 31 patients, the primary tumor was present, and all 31 patients showed lesions suspicious for metastasis (n = 81) demonstrating a high mean SUVmax in both the primary (SUVmax 11.6) and metastatic lesions (SUVmax 9.7). TBR was significantly higher in 68Ga-FAPI compared to 18F-FDG for distant metastases (13.0 vs. 5.7; p = 0.047) and by trend for regional lymph node metastases (31.9 vs 27.3; p = 0.6). Biodistribution of 68Ga-FAPI-PET/CT presented significantly lower uptake or no significant differences in 15 out of 16 organs, compared to 18F-FDG-PET/CT. The highest uptake of all primary lesions was obtained in endometrial carcinomas (mean SUVmax 18.4), followed by cervical carcinomas (mean SUVmax 15.22). In the second cohort, uptake in premenopausal patients differed significantly from postmenopausal patients in endometrium (11.7 vs 3.9; p < 0.0001) and breast (1.8 vs 1.0; p = 0.004), whereas no significant difference concerning ovaries (2.8 vs 1.6; p = 0.141) was observed.

Conclusion: Due to high tracer uptake resulting in sharp contrasts in primary and metastatic lesions and higher TBRs than 18F-FDG-PET/CT, 68Ga-FAPI-PET/CT presents a promising imaging method for staging and follow-up of gynecological tumors. The presence or absence of the menstrual cycle seems to correlate with FAPI accumulation in the normal endometrium and breast. This first investigation of FAP ligands in gynecological tumor entities supports clinical application and further research in this field.

Keywords: FAPI; Fibroblast activation protein; Gynecological malignancies; PET; SUV.

Conflict of interest statement

SAK reports grants from Viewray Inc., outside the submitted work.

JD reports grants from Viewray Inc., CRI – The Clinical Research Institute GmbH, Accuray International Sari, RaySearch Laboratories AB, Vision RT Limited, Merck Serono GmbH, Astellas Pharma GmbH, Astra Zeneca GmbH, Siemens Healthcare GmbH, Solution Akademie GmbH, Ergomed PLC Surrey Research Park, Quintiles GmbH, Pharmaceutical Research Associates GmbH, Boehringer Ingelheim Pharma GmbH&CoKG, PTW-Freiburg Dr. Pychlau GmbH, Nanobiotix S.A, outside the submitted work.

UH, CK, and FG are named in a patent application (EP 18155420.5) for quinolone-based FAP-targeting agents for imaging and therapy in nuclear medicine. CK, UH, and FLG also have shares of a consultancy group for iTheranostics.

All other authors declare no potential conflicts of interest relevant to this article.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
a PET-based evaluation of the endometrium, breast, and ovary in 167 female patients with 68Ga-FAPI PET/CT including various malignancies. b Comparison of FAPI-uptake in endometrium, ovary, and breast premenopausal (n = 12) and postmenopausal (n = 68), categorized by age
Fig. 2
Fig. 2
FAPI uptake in primary and metastatic lesions in 31 female patients with different gynecological tumors
Fig. 3
Fig. 3
TBRs of regional lymph node metastases and distant metastases by comparing 68Ga-FAPI-PET/CT and 18F-FDG-PET/CT
Fig. 4
Fig. 4
HE staining (a, c) and FAP immunohistochemistry (b,c) of a retroperitoneal metastasis in a patient diagnosed with leiomyosarcoma of the uterus. The neoplastic cells demonstrated high FAP expression [F], while normal moderate expression was depicted by the stroma (d). As the tumor was characterized by a high amount of angiogenesis beforehand, an example is shown in e, demonstrating strong FAP expression, too. [* presents stroma; --- presents neoplastic cells]. The patient presented a high SUVmax of 9.1 in 68Ga-FAPI-PET/CT [G], 2 days prior to the biopsy, as well
Fig. 5
Fig. 5
Exemplary staining with HE and anti-FAP α monoclonal antibody of a pleural biopsy due to breast cancer. The pleural metastasis, located in the mediastinum, presented a SUVmax of 7.46 in the FAPI-PET/CT 8 months prior to the biopsy (a). The stroma demonstrated markedly strong FAP expression (d), and high-to-moderate expression was observed in neoplastic cells. The depicted cell clusters (b, c) most likely represent tumorous cell nests and demonstrated strong FAP expression as well
Fig. 6
Fig. 6
A 63-year-old woman with metastasized ovarian carcinoma underwent 68Ga-FAPI-PET/CT followed by 18F-FDG-PET/CT 1 month later. Tracer uptake in normal liver parenchyma was markedly different in both tracers: 68Ga-FAPI SUVmax 1.38 vs. 18F-FDG SUVmax 4.34. The quantified uptake in two bone metastases and one liver metastasis presented a rather high FAPI-uptake compared to FDG, respectively
Fig. 7
Fig. 7
A 79-year-old female with metastasized breast and colon cancer underwent within 1.5 years eight 68Ga-FAPI-PET/CT with three different derivates (FAPI-02, FAPI-04, FAPI-46). During that time interval, mainly palbociclib and four cycles of Y-90-FAPI-radioligand therapy were applied. The progression markers CA 15-3 and CA 19-9 were monitored showing a temporary stable and even regredient disease, which is in concordance with FAPI uptake presented in the PET/CT. However, after a while, the patient possibly developed a resistance against palbociclib or radioligand therapy, presenting with possible progressive disease leading to a change of therapy
Fig. 8
Fig. 8
A 58-year-old female patient presented with cervical cancer for pre-radiotherapeutic staging due to a skull metastasis using 68Ga-FAPI-PET/CT. The investigation showed a local relapse with a SUVmax of 14.4. Furthermore, the skull metastasis presented a strong FAPI uptake with a SUVmax of 32.3 enabling precise delineation and radiotherapy planning
Fig. 9
Fig. 9
HE Staining (a) and FAP immunohistochemistry (b) of a high-grade endometrial ovarian adenocarcinoma. Remarkably, the malignant cells (c, d) demonstrated very strong FAP expression (d) compared to presumably uninfiltrated tissue which showed with exception of the stroma scarcely none (e, f) facilitating differentiation between healthy and malignant tissue
Fig. 10
Fig. 10
A 60-year-old patient with metastasized cervical carcinoma underwent 68Ga-FAPI-PET/CT due to monitoring. The local relapse presented a rather strong FAPI uptake with SUVmax 16.90, similar to the exemplary shown liver metastasis in segment II (SUVmax 14.1)

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