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FDHT-PET to Predict Bicalutamide Efficacy in Patients with Androgen

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FDHT-PET to Predict Bicalutamide Efficacy in Patients with Androgen University of Groningen Serial [F-18]-FDHT-PET to predict bicalutamide efficacy in patients with androgen receptor positive metastatic breast cancer Boers, Jorianne; Venema, Clasina M; de Vries, Erik F J; Hospers, Geke A P; Boersma, Hendrikus H; Rikhof, Bart; Dorbritz, Christine; Glaudemans, Andor W J M; Schröder, Carolina P Published in: European Journal of Cancer DOI: 10.1016/j.ejca.2020.11.008 IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2021 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Boers, J., Venema, C. M., de Vries, E. F. J., Hospers, G. A. P., Boersma, H. H., Rikhof, B., Dorbritz, C., Glaudemans, A. W. J. M., & Schröder, C. P. (2021). Serial [F-18]-FDHT-PET to predict bicalutamide efficacy in patients with androgen receptor positive metastatic breast cancer. European Journal of Cancer, 144, 151-161. https://doi.org/10.1016/j.ejca.2020.11.008 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 26-09-2021 European Journal of Cancer 144 (2021) 151e161 Available online at www.sciencedirect.com ScienceDirect journal homepage: www.ejcancer.com Original Research Serial [18F]-FDHT-PET to predict bicalutamide efficacy in patients with androgen receptor positive metastatic breast cancer* Jorianne Boers a, Clasina M. Venema a, Erik F.J. de Vries b, Geke A.P. Hospers a, Hendrikus H. Boersma b,c, Bart Rikhof d, Christine Dorbritz e, Andor W.J.M. Glaudemans b, Carolina P. Schro¨der a,* a Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands b Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands c Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands d Department of Internal Medicine, Medical Center Leeuwarden, Leeuwarden, the Netherlands e Medical Imaging Center, Department of Radiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands Received 13 July 2020; received in revised form 11 October 2020; accepted 7 November 2020 KEYWORDS Abstract Background: The androgen receptor (AR) is a potential target in metastatic breast 18 Bicalutamide; cancer (MBC), and 16b-[ F]-fluoro-5a-dihydrotestosterone positron emission tomography 18 18 Metastatic breast ([ F]-FDHT-PET) can be used for noninvasive visualisation of AR. [ F]-FDHT uptake cancer; reduction during AR-targeting therapy reflects AR occupancy and might be predictive for 18 Androgen receptor; treatment response. We assessed the feasibility of [ F]-FDHT-PET to detect changes in [18F]-FDHT-PET AR availability during bicalutamide treatment and correlated these changes with treatment response. * List of where and when the study has been presented in part elsewhere: Part of the data was presented at the AACR virtual annual meeting 2020. * Corresponding author: Department of Medical Oncology, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands. E-mail address: [email protected] (C.P. Schro¨der). https://doi.org/10.1016/j.ejca.2020.11.008 0959-8049/ª 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). 152 J. Boers et al. / European Journal of Cancer 144 (2021) 151e161 Patients and methods: Patients with AR þ MBC, regardless of oestrogen receptor status, received an [18F]-FDHT-PET at baseline and after 4e6 weeks bicalutamide treatment. Base- line [18F]-FDHT uptake was expressed as maximum standardised uptake value. Percentage change in tracer uptake, corrected for background activity (SUVcor), between baseline and follow-up PET scan (% reduction), was assessed per-patient and lesion. Clinical benefit was determined in accordance with Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 or clinical evaluation (absence of disease progression for 24 weeks). Results: Baseline [18F]-FDHT-PET in 21 patients detected 341 of 515 lesions found with stan- dard imaging and 21 new lesions. Follow-up [18F]-FDHT-PET was evaluable in 17 patients with 349 lesions, showing a decrease in median SUVcor from 1.3 to 0.7 per-patient and lesion (P < 0.001). Median % reduction per-patient was À45% and per-lesion À39%. In patients with progressive disease (n Z 11), median % reduction was À30% versus À53% for patients who showed clinical benefit (in accordance with RECIST (n Z 3) or clinical evaluation (n Z 3); P Z 0.338). Conclusion: In this feasibility study, a bicalutamide-induced reduction in [18F]-FDHT uptake could be detected by follow-up [18F]-FDHT-PET in patients with AR þ MBC. However, this change could not predict bicalutamide response. Clinical trial information: NCT02697032. ª 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 1. Introduction showed that [18F]-FDHT uptake reduction during AR- targeting therapy reflects AR occupancy and might be Hormone receptors play a vital role in the development predictive for treatment response [22e25]. This makes of several malignancies [1]. Although oestrogen receptor the follow-up of patients using [18F]-FDHT-PET during (ER) expression is routinely determined in breast cancer AR-targeting treatment a potentially interesting tool for (BC), this is not the case for androgen receptor (AR) BC patients. In addition, the AR/ER ratio and hormone expression [3]. The AR is expressed in 60e85% of all levels may influence treatment response in patients with BCs, with a high prevalence among ER þ tumours BC [26,27]. (85e95%), and lower rates in triple-negative BC Therefore, in this study, we assessed the feasibility of (10e40%) [2e11]. The AR may be a possible target for [18F]-FDHT-PET to detect changes in [18F]-FDHT up- therapeutic strategies in BC patients. Studies with AR- take during treatment with the AR antagonist bicalu- targeting drugs, such as bicalutamide, enzalutamide, tamide in patients with AR þ MBC. In addition, we abiraterone acetate, and orteronel have been conducted evaluated whether a reduction in [18F]-FDHT uptake, in patients with metastatic BC (MBC), including triple- and other exploratory markers including AR/ER ratio, negative [12e14] and ER þ tumours [15e19]. were related to bicalutamide response. Patients with ER À/AR þ tumours show a modest clinical benefit rate from AR-targeting drugs [12e14]. Controversies in (pre)clinical studies exist regarding the 2. Methods effectiveness of this strategy in ER þ(/AR þ) tumours [15e20]. Therefore, the degree of AR blockade will 2.1. Study design and patients possibly lead to more insight into the prediction of treatment response between the patient subgroups. This prospective, single-center study (NCT02697032) Monitoring AR expression during treatment can be was conducted at the University Medical Center Gro- performed by serial biopsies; however a (metastasis) ningen, the Netherlands. The institutional review board biopsy is not always feasible and not necessarily repre- approved the protocol, and patients provided written sentative for the AR status throughout the body, owing informed consent. Postmenopausal patients with AR þ, to heterogeneity. Another approach to obtain (serial) human epidermal growth factor receptor 2enegative assessment of whole-body AR expression is the imaging MBC were eligible, independent of their ER status. technique positron emission tomography (PET) with the Additional inclusion criteria were measurable disease in tracer 16b-[18F]-fluoro-5a-dihydrotestosterone ([18F]- accordance with the Response Evaluation Criteria in FDHT). In previous work, we have shown that AR Solid Tumours (RECIST v1.1) or evaluable disease [28], expression in a metastasis biopsy of BC patients corre- performance status <2, and adequate organ function. lates with tracer uptake on the 16b-[([18F]-FDHT-PET) Exclusion criteria included symptomatic brain metasta- scan [21]. Studies in patients with prostate cancer ses, or a cardiovascular history <6 months before J. Boers et al. / European Journal of Cancer 144 (2021) 151e161 153 screening. In addition, concomitant use of CYP3A4 2.5. Imaging analysis inhibitors was not allowed. Metastatic lesions were identified on CT and bone 2.2. Study procedures scintigraphy. Lesions only present on CT, were consid- ered metastases if they had a minimum diameter of Contrast-enhanced computed tomography (CT) of the 10 mm. An experienced nuclear medicine physician thorax/abdomen and conventional bone scintigraphy (A.G.) visually identified [18F]-FDHT-PET lesions with (with single-photon emission CT if necessary) were tracer uptake above the background signal, which could performed for baseline staging. At baseline, an [18F]- not be attributed to physiological uptake or an artifact. FDHT-PET scan, twelve-lead electrocardiogram, and Liver lesions were excluded due to high physiological peripheral blood to measure testosterone and dihy- [18F]-FDHT uptake. We used syngo.via VB20 imaging drotestosterone levels were obtained. Wherever feasible, software for quantifying tracer uptake. Guided by CT a metastasis biopsy was obtained, except for patients of and/or bone scintigraphy (including lesions not visible which a biopsy was taken in the past 6 months.
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