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

European Journal of Nuclear Medicine and Molecular Imaging https://doi.org/10.1007/s00259-021-05378-0 ORIGINAL ARTICLE 68 Ga-FAPI-PET/CT in patients with various gynecological malignancies Katharina Dendl 1 & Stefan A. Koerber 2,3,4 & Rebecca Finck 1 & Kgomotso M. G. Mokoala 5 & Fabian Staudinger 1 & Lisa Schillings 6 & Ulrike Heger 6 & Manuel Röhrich 1 & Clemens Kratochwil 1 & Mike Sathekge 5 & Dirk Jäger 7 & Jürgen Debus 2,3,4,8,9,10 & Uwe Haberkorn 1,9,11,12 & Frederik L. Giesel 1,9,11,13 Received: 18 January 2021 / Accepted: 22 April 2021 # The Author(s) 2021 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-FAPIPET/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 This article is part of the Topical Collection on Oncology – General. * Frederik L. Giesel 7 Department of Medical Oncology, Heidelberg University Hospital and National Center for Tumor Diseases (NCT), Heidelberg, Germany 1 Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany 8 2 Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany Heidelberg Ion-Beam Therapy Center (HIT), Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany 9 Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg, Germany German Cancer Consortium (DKTK), partner site, Heidelberg, Germany 10 Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany National Center for Tumor diseases (NCT), Heidelberg, Germany 11 Department of Nuclear Medicine, University of Pretoria & Steve Biko Academic Hospital, Private Bag X169, Pretoria 0001, South Africa Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), Heidelberg, Germany 12 Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany 13 Department of Nuclear Medicine, University Hospital Duesseldorf, Duesseldorf, Germany 3 4 5 6 Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany Eur J Nucl Med Mol Imaging 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-FDGPET/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 . PET . Gynecological malignancies . Fibroblast activation protein . SUV Introduction Regarding all cancer entities in females, breast cancer accounts for approximately 276.000 (30%) of all estimated new cases in the USA in 2020. Moreover, breast (15%), ovary (5%), and uterine corpus cancer (4%) are among the six most frequent cancer-associated deaths [1]. Therefore, a reliable and precise staging tool is of essence. The current most frequently used diagnostical radiotracer for PET/CT regarding oncological malignancies is 18F-FDG, which accumulates in glucose-consuming tissues. Therefore, the accumulation of 18F-FDG is influenced by movement, nutrition, and blood glucose levels. Beyond that, it is limited by high physiological background activity in several organs, low glucose transporter, and hexokinase activity in some malignancies as well as its imprecise differentiation between cancerous growths and acute inflammation and thus its missing specificity [2, 3]. Particularly in gynecological malignancies, several additional pitfalls are commonly encountered, such as potentially false-positive uptake of 18F FDG by the endometrium and ovaries in premenopausal patients as well as physiologic accumulation in several benign diseases including uterine fibroids and benign endometriotic cysts [4]. A novel class of radiotracers, subsumed under the term fibroblast activation protein inhibitor (FAPI), demonstrated highly promising results in previously conducted studies regarding various tumor entities. Fibroblast activation protein (FAP) is a type II serine protease belonging to the dipeptidyl peptidase 4 family with both post-proline dipeptidyl peptidase and endopeptidase activity [5]. Furthermore, FAP is expressed by cancer-associated fibroblasts (CAFs), which are part of the stroma in many tumors promoting cancerous growth and are associated with poor prognosis [6, 7]. FAP is also overexpressed in 90% of all epithelial carcinoma (...truncated)