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Background: Positron emission tomography (PET) with 16α-[18F]-fluoro-17β-estradiol ([18F]-FES) can visualize estrogen receptor (ER) expression, but it is challenging to determine the ER status of liver metastases, due to high physiological [18F]-FES uptake. We evaluated whether [18F]-FES-PET can be used to determine the ER status of liver metastases, using corresponding liver biopsies as the gold standard. Methods: Patients with metastatic breast cancer (n = 23) were included if they had undergone a [18F]-FES-PET, liver metastasis biopsy, CT-scan, and [18F]-FDG-PET. [18F]-FES-PET scans were assessed by visual and quantitative analysis, tracer uptake was correlated with ER expression measured by immunohistochemical staining and the effects of region-of-interest size and background correction were determined. Results: Visual analysis allowed ER assessment of liver metastases with 100% specificity and 18% sensitivity. Quantitative analysis improved the sensitivity. Reduction of the region-of-interest size did not further improve the results, but background correction improved ER assessment, resulting in 83% specificity and 77% sensitivity. Using separate thresholds for ER+ and ER− metastases, positive and negative predictive values of 100% and 75%, respectively, could be obtained, although 30% of metastases remained inconclusive. Conclusion: In the majority of liver metastases, ER status can be determined with [18F]-FES-PET if background correction and separate thresholds are applied. [ABSTRACT FROM AUTHOR]

Abstract: NVP-AUY922, a potent heat shock protein (HSP) 90 inhibitor, downregulates the expression of many oncogenic proteins, including the human epidermal growth factor receptor-2 (HER2). Because HER2 downregulation is a potential biomarker for early response to HSP90-targeted therapies, we used the 89Zr-labelled HER2 antibody trastuzumab to quantify the alterations in HER2 expression after NVP-AUY922 treatment with HER2 positron emission tomography (PET) imaging. The HER2 overexpressing human SKOV-3 ovarian tumour cell line was used for in vitro experiments and as xenograft model in nude athymic mice. In vitro HER2 membrane expression was assessed by flow cytometry and a radio-immuno assay with 89Zr-trastuzumab. For in vivo evaluation, mice received 50mg/kg NVP-AUY922 intraperitoneally every other day. 89Zr-trastuzumab was injected intravenously 6d before NVP-AUY922 treatment and after 3 NVP-AUY922 doses. MicroPET imaging was performed at 24, 72 and 144h post tracer injection followed by ex-vivo biodistribution and immunohistochemical staining. After 24h NVP-AUY922 treatment HER2 membrane expression showed profound reduction with flow cytometry (80%) and radio-immuno assay (75%). PET tumour quantification, showed a mean reduction of 41% (p =0.0001) in 89Zr-trastuzumab uptake at 144h post tracer injection after NVP-AUY922 treatment. PET results were confirmed by ex-vivo 89Zr-trastuzumab biodistribution and HER2 immunohistochemical staining. NVP-AUY922 effectively downregulates HER2, which can be monitored and quantified in vivo non-invasively with 89Zr-trastuzumab PET. This technique is currently under clinical evaluation and might serve as an early biomarker for HSP90 inhibition in HER2 positive metastatic breast cancer patients. [Copyright &y& Elsevier]

Purpose: Eftilagimod alpha (efti), a soluble lymphocyte activation gene (LAG-3) protein and MHC class II agonist, enhances innate and adaptive immunity. Active Immunotherapy PAClitaxel (AIPAC) evaluated safety and efficacy of efti plus paclitaxel in patients with predominantly endocrine-resistant, hormone receptor-positive, HER2-negative metastatic breast cancer (ET-resistant HR+ HER2- MBC)., Patients and Methods: Women with HR+ HER2- MBC were randomized 1:1 to weekly intravenous paclitaxel (80 mg/m2) and subcutaneous efti (30 mg) or placebo every 2 weeks for six 4-week cycles, then monthly subcutaneous efti (30 mg) or placebo maintenance. Primary endpoint was progression-free survival (PFS) by blinded independent central review. Secondary endpoints included overall survival (OS), safety/tolerability, pharmacokinetics/pharmacodynamics, and quality of life. Exploratory endpoints included cellular biomarkers., Results: 114 patients received efti and 112 patients received placebo. Median age was 60 years (91.6% visceral disease, 84.1% ET-resistant, 44.2% with previous CDK4/6 inhibitor treatment). Median PFS at 7.3 months was similar for efti and placebo. Median OS was not significantly improved for efti (20.4 vs. 17.5 months; HR, 0.88; P = 0.197) but became significant for predefined exploratory subgroups. EORTC QLQC30-B23 global health status was sustained for efti but deteriorated for placebo. Efti increased absolute lymphocyte, monocyte and secondary target cell (CD4, CD8) counts, plasma IFNγ and CXCL10 levels., Conclusions: Although the primary endpoint, PFS, was not met, AIPAC confirmed expected pharmacodynamic effects and demonstrated excellent safety profile for efti. OS was not significantly improved globally (2.9-month difference), but was significantly improved in exploratory biomarker subgroups, warranting further studies to clarify efti's role in patients with ET-resistant HER2- MBC., (©2023 The Authors; Published by the American Association for Cancer Research.)

Purpose: Determining the estrogen receptor (ER) status is essential in metastatic breast cancer (MBC) management. Whole-body ER imaging with 16α-[ 18 F]fluoro-17β-estradiol positron emission tomography ([ 18 F]FES-PET) is increasingly used for this purpose. To establish the clinical validity of the [ 18 F]FES-PET, we studied the diagnostic accuracy of qualitative and quantitative [ 18 F]FES-PET assessment to predict ER expression by immunohistochemistry in a metastasis., Methods: In a prospective multicenter trial, 200 patients with newly diagnosed MBC underwent extensive workup including molecular imaging. For this subanalysis, ER expression in the biopsied metastasis was related to qualitative whole-body [ 18 F]FES-PET evaluation and quantitative [ 18 F]FES uptake in the corresponding metastasis. A review and meta-analysis regarding [ 18 F]FES-PET diagnostic performance were performed., Results: Whole-body [ 18 F]FES-PET assessment predicted ER expression in the biopsied metastasis with good accuracy: a sensitivity of 95% (95% CI, 89 to 97), a specificity of 80% (66 to 89), a positive predictive value (PPV) of 93% (87 to 96), and a negative predictive value (NPV) of 85% (72 to 92) in 181 of 200 evaluable patients. Quantitative [ 18 F]FES uptake predicted ER immunohistochemistry in the corresponding metastasis with a sensitivity/specificity of 91%/69% and a PPV/NPV of 90%/71% in 156 of 200 evaluable patients. For bone metastases, PPV/NPV was 92%/81%. Meta-analysis with addition of our data has increased diagnostic performance and narrowed the 95% CIs compared with previous studies with a sensitivity/specificity of both 86% (81 to 90 and 73 to 93, respectively)., Conclusion: In this largest prospective series so far, we established the clinical validity of [ 18 F]FES-PET to determine tumor ER status in MBC. In view of the high diagnostic accuracy of qualitatively assessed whole-body [ 18 F]FES-PET, this noninvasive imaging modality can be considered a valid alternative to a biopsy of a metastasis to determine ER status in newly MBC (ClinicalTrials.gov identifier: NCT01957332).

Breast cancer (BC) is a heterogeneous disease in which estrogen receptor (ER) expression plays an important role in most tumors. A clinical dilemma may arise when a metastasis biopsy to determine the ER status cannot be performed safely or when ER heterogeneity is suspected between tumor lesions. Whole-body ER imaging, such as 16α- 18 F-fluoro-17β-estradiol ( 18 F-FES) PET, may have added value in these situations. However, the role of this imaging technique in routine clinical practice remains to be further determined. Therefore, we assessed whether the physician's remaining clinical dilemma after the standard workup was solved by the 18 F-FES PET scan. Methods: This retrospective study included 18 F-FES PET scans of patients who had (or were suspected to have) ER-positive metastatic BC and for whom a clinical dilemma remained after the standard workup. The scans were performed at the University Medical Center of Groningen between November 2009 and January 2019. We investigated whether the physician's clinical dilemma was solved, defined either as solving the clinical dilemma through the 18 F-FES PET results or as basing a treatment decision directly on the 18 F-FES PET results. In addition, the category of the clinical dilemma was reported, as well as the rate of 18 F-FES-positive or -negative PET scans, and any correlation to the frequency of solved dilemmas was determined. Results: One hundred 18 F-FES PET scans were performed on 83 patients. The clinical dilemma categories were inability to determine the extent of metastatic disease or suspected metastatic disease with the standard workup ( n = 52), unclear ER status of the tumor ( n = 31), and inability to determine which primary tumor caused the metastases ( n = 17). The dilemmas were solved by 18 F-FES PET in 87 of 100 scans (87%). In 81 of 87 scans, a treatment decision was based directly on 18 F-FES PET results (treatment change, 51 scans; continuance, 30 scans). The frequency of solved dilemmas was not related to the clinical dilemma category ( P = 0.334). However, the frequency of solved dilemmas was related to whether scans were 18 F-FES-positive ( n = 63) or 18 F-FES-negative ( n = 37; P < 0.001). Conclusion: For various indications, the 18 F-FES PET scan can help to solve most clinical dilemmas that may remain after the standard workup. Therefore, the 18 F-FES PET scan has added value in BC patients who present the physician with a clinical dilemma., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: The androgen receptor (AR) is a potential target in metastatic breast cancer (MBC), and 16β-[ 18 F]-fluoro-5α-dihydrotestosterone positron emission tomography ([ 18 F]-FDHT-PET) can be used for noninvasive visualisation of AR. [ 18 F]-FDHT uptake reduction during AR-targeting therapy reflects AR occupancy and might be predictive for treatment response. We assessed the feasibility of [ 18 F]-FDHT-PET to detect changes in AR availability during bicalutamide treatment and correlated these changes with treatment response., Patients and Methods: Patients with AR + MBC, regardless of oestrogen receptor status, received an [ 18 F]-FDHT-PET at baseline and after 4-6 weeks bicalutamide treatment. Baseline [ 18 F]-FDHT uptake was expressed as maximum standardised uptake value. Percentage change in tracer uptake, corrected for background activity (SUV cor ), 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 [ 18 F]-FDHT-PET in 21 patients detected 341 of 515 lesions found with standard imaging and 21 new lesions. Follow-up [ 18 F]-FDHT-PET was evaluable in 17 patients with 349 lesions, showing a decrease in median SUV cor from 1.3 to 0.7 per-patient and lesion (P < 0.001). Median % reduction per-patient was -45% and per-lesion -39%. In patients with progressive disease (n = 11), median % reduction was -30% versus -53% for patients who showed clinical benefit (in accordance with RECIST (n = 3) or clinical evaluation (n = 3); P = 0.338)., Conclusion: In this feasibility study, a bicalutamide-induced reduction in [ 18 F]-FDHT uptake could be detected by follow-up [ 18 F]-FDHT-PET in patients with AR + MBC. However, this change could not predict bicalutamide response., Clinical Trial Information: NCT02697032., Competing Interests: Conflict of interest statement J.B., C.M.V., H.H.B., B.R., C.D., and A.W.J.M.G. declare no conflict of interest. E.F.J.d.V. reports receiving research funding through grants from ZonMw, the Dutch Cancer Foundation (KWF), MS Research Foundation, and has assisted in conducting contracted research studies funded by Rodin Therapeutics, Lysosomal Ltd, Hoffmann-La Roche, and Ionis Pharmaceuticals. G.A.P.H. reports receiving research funding from The Seerave Foundation and Bristol-Myers Squibb (paid to the institution UMCG) and has served in a consulting/advisory role for Bristol-Myers Squibb, MSD, Novartis, Pfizer, Pierre Fabre, Amgen, and Roche (paid to the institution UMCG). C.P.S. reports receiving research funding from Pfizer, Roche, Genentech, SNS Oncology, G1 Therapeutics, Abbvie, Synthon, and CytoMx Therapeutics (paid to the institution UMCG)., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

It is unknown whether assessment of potential bone lesions in metastatic breast cancer (MBC) by 18 F-FDG PET instead of 99m Tc bone scintigraphy (BS) supports clinically relevant changes in MBC management. Therefore, we retrospectively compared management recommendations based on bone lesion assessment by 18 F-FDG PET plus contrast-enhanced CT (ceCT) or BS plus ceCT, for patients with newly diagnosed MBC. Methods: Baseline ceCT, BS, and 18 F-FDG PET for all patients included in the IMPACT-MBC study (NCT01957332) at the University Medical Center Groningen were reviewed for bone lesions. If bone lesions were found by any imaging modality, virtual MBC management recommendations were made by a multidisciplinary expert panel, based on either 18 F-FDG PET plus ceCT or BS plus ceCT. The panel had access to standard clinicopathologic information and baseline imaging findings outside the skeleton. Clinically relevant management differences between the 2 recommendations were defined either as different treatment intent (curative, noncurative, or unable to determine) or as different systemic or local treatment. If no bone lesions were found by any imaging modality, the patients were included in the analyses without expert review. Results: In total, 3,473 unequivocal bone lesions were identified in 102 evaluated patients (39% by ceCT, 26% by BS, and 87% by 18 F-FDG PET). Additional bone lesions on 18 F-FDG PET plus ceCT compared with BS plus ceCT led to change in MBC management recommendations in 16% of patients (95% CI, 10%-24%). BS also changed management compared with 18 F-FDG PET in 1 patient (1%; 95% CI, 0%-5%). In 26% (95% CI, 19%-36%) of patients, an additional 18 F-FDG PET exam was requested, because BS provided insufficient information. Conclusion: In this exploratory analysis of newly diagnosed MBC patients, 18 F-FDG PET versus BS to assess bone lesions resulted in clinically relevant management differences in 16% of patients. BS delivered insufficient information in over one fourth of patients, resulting in an additional request for 18 F-FDG PET. On the basis of these data, 18 F-FDG PET should be considered a primary imaging modality for assessment of bone lesions in newly diagnosed MBC., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: High physiological 16α-[ 18 F]-fluoro-17β-estradiol ([ 18 F]-FES) uptake in the abdomen is a limitation of this positron emission tomography (PET) tracer. Therefore, we investigated the effect of food intake prior to PET acquisition on abdominal background activity in [ 18 F]-FES-PET scans., Methods: Breast cancer patients referred for [ 18 F]-FES-PET were included. Three groups were designed: (1) patients who consumed a chocolate bar (fatty meal) between tracer injection and imaging ( n = 20), (2) patients who fasted before imaging ( n = 20), and (3) patients without diet restrictions (control group, n = 20). We compared the physiological [ 18 F]-FES uptake, expressed as mean standardized uptake value (SUV mean ), in the abdomen between groups., Results: A significant difference in [ 18 F]-FES uptake in the gall bladder and stomach lumen was observed between groups, with the lowest values for the chocolate group and highest for the fasting group ( p = 0.015 and p = 0.011, respectively). Post hoc analysis showed significant differences in the SUVmean of these organs between the chocolate and fasting groups, but not between the chocolate and control groups., Conclusion: This exploratory study showed that, compared to fasting, eating chocolate decreases physiological gall bladder and stomach [ 18 F]-FES uptake; further reduction through a normal diet was not seen. A prospective study is warranted to confirm this finding.

Rationale: Knowledge on monoclonal antibody biodistribution in healthy tissues in humans can support clinical drug development. Molecular imaging with positron emission tomography (PET) can yield information in this setting. However, recent imaging studies have analyzed the behavior of single antibodies only, neglecting comparison across different antibodies. Methods: We compared the distribution of four 89 Zr-labeled antibodies in healthy tissue in a retrospective analysis based on the recently published harmonization protocol for 89 Zr-tracers and our delineation protocol. Results: The biodistribution patterns of 89 Zr-lumretuzumab, 89 Zr-MMOT0530A, 89 Zr-bevacizumab and 89 Zr-trastuzumab on day 4 after tracer injection were largely similar. The highest tracer concentration was seen in healthy liver, spleen, kidney and intestines. About one-third of the injected tracer dose was found in the circulation, up to 15% in the liver and only 4% in the spleen and kidney. Lower tracer concentration was seen in bone marrow, lung, compact bone, muscle, fat and the brain. Despite low tracer accumulation per gram of tissue, large-volume tissues, especially fat, can influence overall distribution: On average, 5-7% of the injected tracer dose accumulated in fat, with a peak of 19% in a patient with morbid obesity. Conclusion: The similar biodistribution of the four antibodies is probably based on their similar molecular structure, binding characteristics and similar metabolic pathways. These data provide a basis for a prospectively growing, online accessible warehouse of molecular imaging data, which enables researchers to increase and exchange knowledge on whole body drug distribution and potentially supports drug development decisions., Competing Interests: Competing Interests: The UMCG received grants form Roche and Genentech for conduct of the imaging trials. All other authors declare no competing interests.

Unlabelled: Transforming growth factor-β (TGF-β) promotes cancer invasion and metastasis and is therefore a potential drug target for cancer treatment. Fresolimumab, which neutralizes all mammalian active isoforms of TGF-β, was radiolabeled with (89)Zr for PET to analyze TGF-β expression, antibody tumor uptake, and organ distribution., Methods: (89)Zr was conjugated to fresolimumab using the chelator N-succinyldesferrioxamine-B-tetrafluorphenol. (89)Zr-fresolimumab was analyzed for conjugation ratio, aggregation, radiochemical purity, stability, and immunoreactivity. (89)Zr-fresolimumab tumor uptake and organ distribution were assessed using 3 protein doses (10, 50, and 100 μg) and compared with (111)In-IgG in a human TGF-β-transfected Chinese hamster ovary xenograft model, human breast cancer MDA-MB-231 xenograft, and metastatic model. Latent and active TGF-β1 expression was analyzed in tissue homogenates with enzyme-linked immunosorbent assay., Results: (89)Zr was labeled to fresolimumab with high specific activity (>1 GBq/mg), high yield, and high purity. In vitro validation of (89)Zr-fresolimumab showed a fully preserved immunoreactivity and long (>1 wk) stability in solution and in human serum. In vivo validation showed an (89)Zr-fresolimumab distribution similar to IgG in most organs, except for a higher uptake in the liver in all mice and higher kidney uptake in the 10-μg group. (89)Zr-fresolimumab induced no toxicity in mice; it accumulated in primary tumors and metastases in a manner similar to IgG. Both latent and active TGF-β was detected in tumor homogenates, whereas only latent TGF-β could be detected in liver homogenates. Remarkably high (89)Zr-fresolimumab uptake was seen in sites of tumor ulceration and in scar tissue, processes in which TGF-β is known to be highly active., Conclusion: Fresolimumab tumor uptake and organ distribution can be visualized and quantified with (89)Zr-fresolimumab PET. This technique will be used to guide further clinical development of fresolimumab and could possibly identify patients most likely to benefit.