University of Groningen Imaging hormone receptors in metastatic breast cancer patients Venema, Clasina Marieke

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Imaging hormone receptors in metastatic breast cancer patients

Venema, Clasina Marieke

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Venema, C. M. (2018). Imaging hormone receptors in metastatic breast cancer patients. Rijksuniversiteit Groningen.

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517613-L-sub01-bw-Venema 517613-L-sub01-bw-Venema 517613-L-sub01-bw-Venema 517613-L-sub01-bw-Venema Processed on: 7-3-2018 Processed on: 7-3-2018 Processed on: 7-3-2018

Processed on: 7-3-2018 PDF page: 1PDF page: 1PDF page: 1PDF page: 1

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Thesis, University of Groningen, The Netherlands

ISBN: 978-94-028-0983-1

Printing: Ipskamp

The printing of this thesis was financially supported by Graduate

School of Medical Sciences and Stichting Werkgroep Interne

Oncologie, the Faculty of Medical Sciences, University of Groningen,

and is gratefully acknowledged.

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Imaging hormone receptors

in metastatic breast cancer

patients

Proefschrift

ter verkrijging van de graad van doctor aan de

Rijksuniversiteit Groningen

op gezag van de

rector magnificus prof. dr. E. Sterken

en volgens besluit van het College voor Promoties.

De openbare verdediging zal plaatsvinden op

woensdag 9 mei 2018 om 16.15 uur

door

Clasina Marieke Venema

geboren op 10 november 1988

te Alkmaar

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Copromotores C.P. Schroder E.F.J. de Vries

A.W.J.M. Glaudemans Beoordelingscommissie Prof. I.J. de Jong

Prof. R.H.J.A. Slart Prof. S. Sleijfer

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Chapter 1 General introduction and outline of the thesis

The estrogen receptor and molecular imaging

Chapter 2 Recommendations and technical aspects of 16α-

18

F-fluoro-17β-estradiol (FES) PET to image the estrogen

receptor in vivo: the Groningen experience. Clin Nucl

Med 2016; 41:844-851

Chapter 3 Interpretation of pulmonary uptake on FES PET scans

after radiation therapy of the thorax

Chapter 4

18

F-fluoroestradiol positron emission tomography (FES

PET) has added value in staging and therapy decision

making in patients with disseminated lobular breast

cancer. Clin Nucl Med 2017; 42:612-614

Chapter 5 Early identification of patients who benefit from

palbociclib in addition to letrozole: a new role for FES

PET

The androgen receptor and molecular imaging

Chapter 6 Targeting the androgen receptor: a potentially more

valuable therapeutic strategy in breast cancer when

additional tumour characteristics are taken into

account

Chapter 7 Androgen and estrogen receptor imaging in metastatic

breast cancer patients as a surrogate for tissue

biopsies. J Nucl Med 2017; 58: 1906-1912

Chapter 8 Visualizing the effects of bicalutamide on the

androgen receptor availability in metastatic breast

cancer patients

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Med 2016:57: suppl 1: 96S-104S

Chapter 10 Summary and future perspectives

Chapter 11 Nederlandse samenvatting (Dutch summary)

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General introduction and outline of the thesis

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Breast cancer is still the most common cancer in women in the Western World and the most frequent cause of cancer-related death.1 For prognostic and therapeutic purposes knowledge of the expression levels of different receptors in the tumor is important. The estrogen receptor (ER) is expressed in about 70% of breast cancer tumors. Patients with ER positive breast cancer have a more favorable prognosis compared to patients with ER negative breast cancer, and are likely to respond to antihormonal therapy.2 However not all ER positive patients do respond to antihormonal therapy.

Prediction of response and non-response is essential for optimal treatment and for the clinical development of new (combinations of) compounds. In breast cancer, the golden standard for determination of tumor ER expression is by immunohistochemistry on biopsy samples or surgically removed tissue. This technique has proven its value as predictive biomarker to select patients for hormone therapy.3 As tumor receptor status can change over time, current guidelines advise to perform biopsies when a lesion is first suspected, and in the metastatic setting to confirm receptor status, before initiating a new therapy.4 In ER-positive breast cancer, performing a biopsy is a particular challenge. First it is not always safe to biopsy a location or the lesion is difficult to access. And when a lesion is biopsied, sampling errors and complications can occur. Second, response to anti-hormonal treatment can be predicted by tumor ER status, but in the era of known disease heterogeneity, a single biopsy does not necessarily reflect the ER status of all lesions in the body. An alternative way to determine hormone expression is by whole body positron emission tomography (PET) imaging with tracers such as 16α-[18 F]fluoro-17β-estradiol (FES). This tracer has previously shown its ability to visualize and quantify ER-expression in all lesions within an individual patient, but to date is still considered experimental.5

Not only the ER plays a vital role in the development and progression of breast cancer but also the androgen receptor (AR) seems to have a role in breast cancer. Several studies have shown that the AR is present in the majority of breast cancer patients and can be an attractive drug target.6,7 Based on preclinical studies, this offers a potential new treatment strategy.

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The function of AR has mostly been described in prostate cancer, and multiple studies with the 16β-[18F]-fluoro-5α-dihydrotestosterone (FDHT) PET tracer have been performed in patients with prostate cancer to visualize the occupancy of AR during AR-targeted therapy8,9. In breast cancer patients no studies have been performed with FDHT PET. If FDHT-PET can determine the AR status in metastatic breast cancer patients, this technique has the potential to select patients eligible for AR-targeted therapies.

The aim of this thesis is to determine the feasibility of hormone receptor imaging via FES PET and FDHT PET in breast cancer patients and to evaluate the ability of these PET tracers to predict therapy response.

Outline of the thesis

FES is a PET tracer that has been used in a variety of preclinical and clinical studies to detect ER expression, mainly in breast cancer, but also in other oncological indications. Chapter 2 gives an overview of the main indications of FES PET in oncology and provides recommendations on the correct use of this imaging technique. This includes precautions that have to be taken for patient preparation, procedures for the acquisition of the scans, the physiological distribution of the tracer, factors that might influence tracer uptake and guidance for image analysis, quantification of tracer uptake and reporting of the scans.

With increasing experience in performing FES PET scans, also awareness of atypical, non cancer related FES uptake in the lungs of some patients was raised. This uptake is possibly related to previous radiation therapy. We investigated whether radiation therapy could cause enhanced pulmonary tracer uptake on the FES PET scan. While uptake of FES is considered to be ER specific, the influence of radiation therapy on FES PET is still unknown. Chapter 3 describes findings on FES PET scans after radiation therapy in 70 patients who have received radiation therapy and these findings were compared to 39 patients who did not receive radiation therapy prior to their FES PET. The results of this study could guide the interpretation of FES PET scans by nuclear medicine physicians.

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In Chapter 4 we retrospectively analyzed FES PET scans in patients with lobular breast cancer in 4 patients with a clinical dilemma. Lobular breast cancer is the second most common type of invasive breast cancer, accounting for almost ten percent of the invasive lesions. Lobular breast cancer lesions are often difficult to detect with conventional imaging. FES PET may have added value in relation to conventional staging in patients with lobular breast cancer and may support in clinical decision making. In February 2015, the U.S. Food and Drug Administration granted accelerated approval to palbociclib for the use of palbociclib in combination with letrozole in postmenopausal women with ER positive, Human Epidermal Growth factor Receptor 2 (HER2) negative breast cancer as initial endocrine-based therapy. Palbociclib plus letrozole has improved both progression free survival and overall response rate in patients with measurable disease. However, it is still difficult to predict response to this treatment combination. It is presumed that the best biomarker for response to palbociclib is ER expression. In Chapter 5 we describe a feasibility study where we evaluate whether baseline FES PET results can predict treatment response to palbociclib plus letrozole. We hypothesized that lesions with low uptake on FES PET will not respond to the combination of letrozole plus palbociclib.

Chapter 6 comprises preclinical and clinical data on the androgen receptor in breast cancer. We summarized the role of the AR as a potential therapeutic target and performed in addition an in silico analysis of overexpression of AR with mRNA profiles of 7.270 primary breast tumors. As AR expression is not routinely assessed in breast cancers it is difficult to compare survival data. With this dataset we were able to get more uniform data in a large group of patients. In Chapter 7 we investigated whether assessment of AR and ER tumor receptor status by FDHT and FES PET is feasible in metastatic breast cancer patients. We quantified FDHT and FES uptake and correlated this with respectively AR and ER expression on immunohistochemistry of a fresh biopsy of a metastatic lesion. In Chapter 8 we described the effects on FDHT PET scans after treatment of bicalutamide, in AR-positive metastatic breast cancer patients. Bicalutamide is an oral, nonsteroidal AR antagonist, and part of standard of care in

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patients with metastatic prostate cancer but not in breast cancer patients. In a phase II study in patients with metastatic breast cancer, a clinical benefit rate at 6 months was seen in 19% of the patients treated with bicalutamide.10 Although this rate is comparable to other treatment options in triple negative metastatic breast cancer patients, further improvement is clearly wanted. FDHT PET is able to visualize the AR-expression in metastatic breast cancer lesions, and uptake can be blocked by the addition of the AR antagonist flutamide and enzalutamide in prostate cancer patients.8,9 The AR occupancy, as reflected by the reduction in FDHT uptake during treatment with bicalutamide may be predictive of response, similar to change of ER uptake in relation to selective ER degrader therapy.11 The purpose of our study therefore was to evaluate whether FDHT PET imaging in metastatic breast cancer can be used to predict early treatment response to bicalutamide.

Not only FES PET and FDHT PET imaging have been performed in breast cancer patients, but also more PET data is available from other tracers. Chapter 9 describes the process from development of PET tracers to the level of evidence for the use of these tracers in breast cancer. Several breast cancer trials have been performed with the PET tracers FDG, 3-[18 F]-3-deoxythymidine and FES. We studied them to assess how to optimize introducing novel tracers in clinical practice. After defining the gap between a good rationale for a tracer and implementation to the clinic, we propose solutions to fill the gap in order to try to bring more PET tracers to daily clinical practice.

The findings of this thesis are summarized in Chapter 10 followed by future perspectives with regard to the role of molecular imaging of hormone receptors in breast cancer. Chapter 11 contains the Dutch summary.

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14 References

1. World Health Organization, www.who.int/cancer, accessed May 2017 2. Blamey RW, Hornmark-Stenstam B, Ball G, et al. ONCOPOOL-a

European database for 16,944 cases of breast cancer. Eur J Cancer 2010; 46:56-71.

3. Allred DC, Harvey JM, Berardo M, Clark GM. Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol 1998; 11:155-168.

4. National Comprehensive Cancer Network: Clinical practice guidelines in oncology; breast cancer version 1. Accessed: May 2017

www.nccn.org/professionals/physician_gls/f_guidelines.asp#breast 5. van Kruchten M, de Vries EG, Brown M, et al. PET imaging of oestrogen

receptors in patients with breast cancer. Lancet Oncol 2013; 14:e465-475

6. Collins LC, Cole KS, Marotti JD, Hu R, Schnitt SJ, Tamimi RM. Androgen receptor expression in breast cancer in relation to molecular

phenotype: results from the Nurses' Health Study. Mod Pathol. 2011; 24:924-931.

7. Elebro K, Borgquist S, Simonsson M, et al. Combined androgen and estrogen receptor status in breast cancer: Treatment prediction and prognosis in a population-based prospective cohort. Clin Cancer Res 2015; 21:3640-3650.

8. Larson SM, Morris M, Gunther I et al. Tumor localization of 16β-18 F-fluoro-5α-dihydrotestosterone versus 18F-FDG in patients with progressive, metastatic prostate cancer. J Nucl Med 2004; 45:1966-1971

9. Scher HI, Beer TM, Higano CS et al. Antitumour activity of MDV3100 in castration-resistant porstate cancer: a phase 1-2 study. Lancet 2010; 375:1437-1446.

10. Gucalp A, Tolaney S, Isakoff SJ et al. Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic breast cancer. Clin Cancer Res 2013; 19:5505-5512.

11. van Kruchten M, de Vries EG, Glaudemans AW et al. Measuring residual estrogen receptor availability during fulvestrant therapy in patients with metastatic breast cancer. Cancer Discov 2015; 5:72-81

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Chapter 2 Recommendations and technical aspects of 16α-[

18

F]fluoro-17β-estradiol PET to image the estrogen receptor in vivo: the Groningen

experience. Clin Nucl Med 2016; 41: 844-851

Venema CM1, Apollonio G1, Hospers GAP1, Schröder CP1, Dierckx RAJO2,3, de Vries EFJ2, Glaudemans AWJM2

1

From the departments of Medical Oncology and 2Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; and 3Ghent University, Gent, Belgium

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18 Abstract

The estrogen derivative 16α-18F-fluoro-17β-estradiol (FES) is a PET tracer that has been used in a variety of preclinical and clinical studies to detect estrogen receptor (ER) expression, mainly in breast cancer, but also for other oncological indications. As a result of the success of these studies and the potential applications of the tracer, FES starts to be implemented in routine clinical practice. However, the number of centers using this tracer is still limited and many nuclear medicine physicians and medical oncologists are still unaware of the possibilities FES PET imaging offers. The aim of this article is therefore to give an overview of the main indications of FES-PET in oncology and to provide recommendations on correct use of this imaging technique. This includes precautions that have to be taken for patient preparation, procedures for the acquisition of the scans, the physiological distribution of the tracer, factors that might influence tracer uptake and guidance for image analysis, quantification of tracer uptake and reporting of the scans.

Keywords: estrogen receptor expression, imaging, breast cancer, ovarian cancer, FES-PET

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C

ancer is a leading cause of death in the western world1, but remarkable progress has been made in unraveling the molecular pathways that drive tumorigenesis. This has led to the discovery of many novel molecular targets for anticancer treatment and, as a result, in the development of numerous targeted anticancer drugs. These targeted agents interfere with specific molecules that are critical for tumor progression. Personalized medicine aims to identify those patients who are most likely to benefit from a specific treatment. Molecular imaging enables non-invasively determination of the presence of relevant drug targets and other molecular properties in (metastatic) lesions throughout the whole body of an individual patient.2

The estrogen receptor (ER) is over expressed in approximately 70% of patients suffering from primary breast cancer and is an important target for endocrine therapy. Current guidelines recommend the assessment of receptor status (ER, progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER-2)) and grade before starting a new line of therapy.3 ER expression of the tumor is the main indication to start antihormonal treatment, since success rate relies heavily on the ER status of the tumor, both in an adjuvant and in the metastatic setting. Thus assessment of functional ER status provides a rationale for endocrine therapy and is a predictive biomarker for treatment response. The golden standard for assessment of ER expression still remains immunohistochemistry on biopsy samples. Remarkably, this technique uses 1% ER positive cells as a cut-off point for ER positivity.3 Although the specificity of immunohistochemistry is high (almost 100%), it is not always feasible to obtain a suitable biopsy due to the location of the tumor, for safety reasons or because of sampling errors. Moreover, some studies have underlined the possibility of ER expression changing over time, resulting in heterogeneity of ER expression between primary tumor and its metastases, between lesions within a single patient, and even within a single lesion. Discordant ER expression between the primary breast tumor and the metastases was observed in 15-40% of the patients.4,5 In metastatic breast cancer, a single biopsy may therefore not be representative for the ER expression in other metastases throughout the body. Furthermore, performing biopsies from multiple lesions – if

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feasible – is far from patient friendly. PET imaging may overcome these issues and can possibly guide towards more personalized medicine.

The most frequently used tracer for detection of ER expression in breast cancer is 16α-[18F]fluoro-17β-estradiol (FES). With its potential to serve as a prognostic as well as a predictive biomarker FES-PET has gained growing interest in research with over 20 studies registered at clinicaltrials.gov of which 11 are active at this moment (Table 1). However, guidelines on how to correctly acquire, analyze and interpret the scans are not available thus far. Uniformity is essential to compare upcoming studies and for warehousing of all the available data. Besides applications for research purposes, FES-PET is now more and more being introduced in routine clinical practice, especially for patients with a diagnostic dilemma.6

At this moment, FES is produced only in a few institutions worldwide, but this number is growing and more centers in the vicinity of the production sites are able to perform the PET scan. The physical half-life of 18F (110 min) should allow transportation of FES to other hospitals within a traveling distance of a few hours. As more and more nuclear medicine physicians and medical oncologists are getting access to the unique possibilities FES-PET imaging offers, the aim of this article is to give an overview of the main indications of FES-PET in oncology and to provide guidance for the most important aspects of this imaging technique, such as precautions that have to be taken for correct patient preparation, procedures for the acquisition of the scans, the physiological distribution of the tracer, factors that may influence tracer uptake and recommendations for image analysis, quantification of tracer uptake and reporting of the scans. These recommendations are based on extensive experience with FES-PET imaging acquired both in the research and in a clinical setting in Groningen and on available literature data.

Potential indications of FES-PET imaging

Several studies have been performed to assess the potential applications of FES-PET (-CT) as an in vivo imaging tool in oncological diseases (Figure 1). Most frequent settings, and promising indications for clinical use, are summarized below:

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21 Diagnosis and Staging

x Breast cancer: over 20 studies using FES-PET were performed in patients with breast cancer, particularly as a diagnostic tool. As such it has the potential to serve an important role patients with diagnostic dilemmas that cannot be solved by conventional imaging techniques and/or when a biopsy in a suspicious lesion is not feasible.6 Although current guidelines recommend to perform FDG-PET/CT when conventional work up is inconclusive FES-PET may be preferred in patients with ER-positive breast cancer, because FDG-PET cannot differentiate breast cancer metastases from metastases from other tumor types, or from benign, inflammatory or infectious lesions.3

Particularly in a subgroup of patients with lobular breast cancer, which due to the loss of E-Cadherin grows in a less cohesive pattern, it is often difficult to detect the lobular tumor on physical examination and conventional imaging.7 Uptake on FDG PET in lobular breast cancer lesions are often lower compared to ductal breast cancer and hormone negative breast cancer.8.9

An important advantage is that FES-PET is a whole body imaging technique, which is ideal for assessment of heterogeneous ER expression across metastases in the body, and for evaluating the expression of the ER both in the primary tumor and in metastatic disease.10 In 4 clinical trials, an overall specificity of 98% and a sensitivity of 84% of the FES-PET for ER in positive patients was found. In ER-positive breast cancer patients that have high risk to develop metastases or have clinical signs, laboratory values or histology suggestive of the presence of metastases, FES-PET could be a valuable tool for tumor staging, and assessment of the change in ER expression over the time and the heterogeneity in ER status within the same patient.

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Figure 1. Published articles with FES-PET, per indication (based on PubMed search and clinicaltrials.gov)

x Ovarian cancer: There are two known ER subtypes namely ERα and ERβ. In epithelial ovarian cancers both ERα and ERβ are expressed, in respectively 73% and 31% of tumors. Although the affinity of FES for ERα is 6.3 times higher than for ERβ11, FES-PET could be useful in the diagnosis of ovarian cancer in case of diagnostic dilemmas that remained despite conventional work up. In metastatic disease using FES-PET has a sensitivity of 79% and a specificity of 100% for ERα positive metastatic ovarian cancer lesions. Although uptake in metastases in the abdomen and pelvis could be obscured by physiological tracer uptake in the bowel this was mostly solved by the accompanying CT scan.12

x Uterine tumors: FES-PET has been used for the detection of ERα in endometrial carcinoma12, and also in the benign setting of leiomyoma of the uterus, which can metastasize to distant locations (benign metastasizing leiomyoma).14-16 Furthermore, the use of this molecular imaging technique for the differential diagnosis between leiomyoma of the uterus and uterine sarcoma was published.14

x Other tumors: although in this setting only a few studies have been performed, FES-PET could be helpful in all other oncological dilemmas in tumors with high probability of ER expression such as endometrial stromal sarcoma17, gastric carcinoma18, prostate cancer19 and meningeomas20. In gastric carcinoma and prostate cancer, studies on imaging of the ER are still lacking, but might deserve further investigations. Breast cancer (n=54) Uterine tumors (n=4) Ovarian cancer (n=3) Prostate cancer (n=1) Meningiomas (n=1)

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23 Treatment setting and follow-up

x Breast cancer: Next to diagnosing and staging of patients, FES-PET can be used for the selection and early response prediction of antihormonal therapy (this latter still in a research setting). In progressive patients, despite several lines of antihormonal therapy, FES-PET can be used to assess whether metastases still express ER and thus to provide a rationale for another line of antihormonal therapy, or – in case of a negative FES-PET (no ER expression in the metastases) – to switch to another treatment option. Low or absent FES uptake can be considered as a good predictor of endocrine resistance.21,22 For example, in a recent study the value of FES-PET to identify patients with acquired hormone resistant disease (low or absent tracer uptake in metastases) who are unlikely to respond to estradiol therapy was demonstrated.23_{Another study found that the degree of ER blockade}

after institution of tamoxifen treatment predicted responsiveness to anti-estrogen therapy.24 Furthermore molecular imaging could provide an important imaging tool in therapy decision making by measuring the probable responsiveness to intended endocrine drugs: patients with a maximum standardized uptake value (SUVmax) in tumor

metastases below 1.5 are unlikely to respond.22,25,26

FES-PET/CT could guide dose finding strategies as it is able to visualize the pharmacodynamics of ER modulators/degraders. In small patient groups (n= 16-47), the decrease in FES uptake after initiating treatment with an ER antagonist predicted response to tamoxifen and fulvestrant. The quantification of ER binding (receptor saturation) during anti-hormonal therapy can be used to adjust the drug dose in individual patients.26

In addition Yang et al. showed the value of FES-PET imaging to predict response to neoadjuvant chemotherapy, especially when compared to FDG-PET: a low ratio between FES and FDG uptake was correlated with highly proliferative disease that might benefit from chemotherapy, while an high ratio between these two imaging techniques would identify those patients that would benefit from endocrine therapy.27 x Ovarian cancer: Currently, most ovarian cancer patients are treated

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to chemotherapy is still unknown. FES PET might provide a rationale to initiate endocrine treatment in patients ERα-positive lesions. However, clinical studies are required to support this indication.

x Uterine tumors: FES-PET can be used for monitoring treatment response and is able to provide a rationale for ER targeted therapy in endometrial stromal sarcoma patients; however, this finding is, at this moment, only demonstrated by a case report.17

Pharmacokinetics of FES

FES is a fluorinated analogue of estradiol and therefore its biodistribution depends on the presence of functional ER in normal tissue, primary tumor and metastases. The metabolism of FES is similar to that of other estrogens. Several studies have shown that the physiological biodistribution of FES in humans and small animals is similar to that of estradiol: the tracer first accumulates in the liver where it is metabolized into polar conjugates (sulfate and glucuronide), with subsequent excretion into bile. Then its metabolites are excreted by the bile ducts, and pass through the small intestine. Because of the enterohepatic circulation only a small percentage of tracer is distributed in the large intestine, where little uptake can be seen. The main elimination route for estrogens is via urine, while only 7% of the administered tracer is excreted by feces.

FES has chemical properties similar to estradiol, the main and most potent agonist of ER. In the uterus estrogens stimulate the endometrial growth, while in the ovaries the receptor is important to maintain the feedback loop with the pituitary for the synthesis of hormones. In breast tissue, estrogens serve as growth factors for ductal proliferation. As a consequence, specific physiological uptake of FES can be seen in the pituitary gland, uterus, ovaries and in breast tissue of premenopausal women. Uterine FES uptake is roughly SUV 2.5 in the myometrium and SUV 4.0-6.0 in the endometrium.28,29

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Table 1. Active FES studies on clinicaltrials.gov, June 2016

Study No. No. Patients Tumor type Aim Status

NCT02374931 10 Desmoid To establish the avidity of desmoid tumors on 18

F-FES PET/CT imaging

Recruiting

NCT02409316 75 Breast To evaluate the 18F-FES PET/CT uptake as a

preditor of progression-free survival in endocrine refractory recurrent or metastatic breast cancer patients starting a new therapy regimen

Recruiting

NCT02398773 99 Breast To evaluate the predictive value of FES PET/CT to

endocrine therapy in patients with newly diagnosed metastatic breast cancer

Recruiting

NCT01986569 94 Breast To determine a positive and negative percent

agreement between immunohistochemistry and FES

Recruiting

NCT02149173 50 Breast To measure the effect of endocrine targeted

therapy on the estrogen receptor expression and estradiol binding to the receptor using serial FES PET and FDG PET

Recruiting

NCT00816582 100 Breast To determine whether FES can predict clinical

benefit to fulvestrant in postmenopausal women with recurrent or metastatic ER+ breast cancer who are candidates for further hormonal therapy

Recruiting

NCT01957332 200 Breast To evaluate the clinical utility of experimental PET

scans in the setting of MBC at first presentation

Recruiting

NCT02559544 50 Breast To evaluate FES PET/CT uptake as a predictor of

progression free survival in endocrine refractory recurrent or metastatic breast cancer patients starting a new therapy regimen including endocrine targeted therapy

Recruiting

NCT02233621 100 Endome triosis

To assess sensitivity of FES PET for diagnosing endometriosis compared to the gold standard in women care for suspected endometriosis

Recruiting

NCT01720602 15 Breast To assess the change in estrogen receptor

expression measured as the change in SUV using FES PET after 2 and 8 weeks of vorinostat and aromatase inhibitor therapy

Active, not recruiting

NCT01153672 8 Breast To assess the change in estrogen receptor

expression, measured as the change in SUV using FES PET after 2 and 8 weeks of vorinostat and aromatase inhibitor therapy

Active, not recruiting

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26 Technical procedures of FES-PET imaging

Patient preparation

No specific patient preparations have to be made, except when the FES-PET scan is accompanied by a diagnostic CT scan. Then, the same procedural guidelines as for FDG-PET/CT imaging can be followed.29 Some medical aspects have to be taken into account before planning the FES-PET, such as: x A review of the medical history, with specific attention to: current and

previous treatment received, the ER status of the primary tumor, the ER status of metastases (if available), the results of other imaging techniques and the reason for performing the scan (for example diagnostic dilemma or therapy rationale).

x In case of diagnosis and staging, treatment with ER antagonists (e.g. tamoxifen or fulvestrant) should be stopped for ≥5 weeks before performing the scan. Especially for tamoxifen clearance of the drugs may take up to 8 weeks. Aromatase inhibitors as well as luteinizing hormone-releasing hormone (LHRH) agonists can be continued.

x Liver metabolism: despite the rapid hepatic metabolism ofFES, slightly decreased liver function is unlikely to affect quantitative measurements of ER expressing tumors outside the liver. No studies have been performed with patients with severe hepatic impairment.

x If the FES-PET is performed together with a diagnostic CT scan, renal function should be evaluated and kidney failure excluded.

Patient instructions

Other than discomfort at the injection site, adverse events have never been reported. As FES is injected as a bolus, after reaching physiological concentrations, it returns to sub physiological levels within an hour. After injection the patients should be scanned within 120 minutes, but not before 20 minutes as FES concentrations in the blood reaches a peak after 10-20 minutes and remains fairly constant between 20 and 120 minutes.31 In most studies image acquisition is performed 60 +/- 10 minutes after tracer administration for logistical reasons. No results have been published on scanning 20 minutes post injection.

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During the waiting period between injection and scanning, similar instructions have to be followed as for FDG-PET.30 However, patients are allowed to talk and move and theoretically there is no need to fast before the scan. To reduce the radiation burden to the patient and to avoid artifacts due to high radioactivity levels in the urine, drinking 1 liter of water before the procedure and 0.5 liter after tracer injection is suggested. Fasting has been suggested by several studies to reduce bowel accumulation due to bile excretion.13-15

Table 2. Scanning time per bed position, based on administered activity and body weight (mCT Biograph, Siemens)

Activity Body weight 100-150 MBq > 150 MBq 0-60 kg 2 min 1 min 60-90 kg 4 min 2 min > 90 kg 6 min 3 min Tracer production

The production of FES is generally based upon the two-step one-pot radiolabeling procedure starting from the precursor 3-O-(Methoxymethyl)-16,17-O-sulfuryl-16-epiestriol (32). A critical step in the labeling procedure is the hydrolysis step, as incomplete hydrolysis of the intermediate gives rise to the formation of radioactive side-products and low yields. A recent study, however, suggested that this issue can be avoided using another acid for the hydrolysis reaction.33

To allow FES production for clinical studies, the labeling procedure has been adapted to enable fully automated tracer production with either a fixed-tubing or cassette-based synthesis module.34,35 Nowadays not only the cyclic-sulfate precursor is commercially available, but also dedicated disposable labeling kits containing all required chemicals and disposables can be readily purchased. This highly facilitates the production of FES in accordance with Good Manufacturing Practice guidelines. Thus, FES can typically be produced in 20-30% radiochemical yield, which is sufficient for distribution to centers in the vicinity of the production site.

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Figure 2. FES-PET scan of a patient with metastasized breast cancer. (A) low intensity MIP image to analyze the uptake in the liver: in this case homogenous (no liver metastases), (B) high intensity MIP image to analyze all other tissues: multiple bone lesions with high ER expression can be seen.

Image acquisition

FES is a lipophilic radiopharmaceutical with a volume of ≤ 20 mL containing < 10% ethanol, administrated by intravenous injection. The mass injected should be ≤ 5 μg and the administered activity dose is usually a fixed dose of 200 MBq (the drug substance is obtained by dilution of radioactivity with 0,9% NaCl). Higher doses might be safe but have not been tested. The specific activity of FES is typically higher than 25.000 GBq/mmol. Consequently a 200 MBq injection of FES results in less than 3 μg of FES injected. Radiation dosimetry studies show that organ doses due to FES-PET are comparable with those associated with other commonly performed nuclear medicine studies and potential radiation risks are well within acceptable limits. The organs that receive the highest dose are the liver (0.13 mGy/MBq), gall bladder (0.10 mGy/MBq) and urine bladder (0.05 mGy/MBq). The effective dose equivalent is 0.022 mSv/MBq, which corresponds to a radiation burden of 4.4 mSv for an injection of 200 MBq of FES; this is comparable to the radiation burden of FDG.36 The recommended minimum dose is 100 MBq, although this may depend on the performance

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of the PET camera used (e.g. sensitivity, time-of-flight) and the body weight of the patient.

For scan acquisition and processing, the same protocol can be followed as for FDG-PET. During the scan, the arms of the patient should ideally be placed above the head, in order to avoid artifacts. If this is not possible, the arms can be positioned alongside the body. Since FES-PET usually contains insufficient anatomical detail to localize lesions, especially in the abdomen, multimodality imaging (PET/CT) is required to provide anatomical information. For the vast majority of applications, axial anatomical scan coverage from the skull base to mid-thigh is recommended.30 The scanning time per bed position depends on the weight of the patient and administered dose (Table 2, based on mCT Biograph Siemens camera). Interpretation, quantification and reporting:

Some issues should be taken into account when analyzing and reporting a FES-PET scan: the reason why the scan was performed, areas with physiological uptake, metabolism and excretion. Lesions on conventional imaging techniques should be evaluated with FES-PET. Depending on the research question both metastases that show increased ER expression and metastases that do not, have to be examined. Also hitherto unknown lesions, not visible on conventional imaging techniques should be described. Furthermore, if the purpose of the diagnostic imaging was to confirm the ER status for therapy decision making, it is of importance to quantify the overall uptake and (heterogeneity in) ER status of metastases. For the interpretation of the results, the following aspects should be taken into account:

x Physiological uptake of the tracer in the gastrointestinal tract and urinary tract has to be evaluated (see above).

x Best visual analysis method is to first look at low intensity levels at the liver uptake: homogeneous uptake suggests the absence of lesions (although ER-positive lesions with similar uptake as the liver cannot be excluded), “cold spots” could indicate benign cysts, ER negative lesions, but also lesions with low ER expression or even high expression, “hot spots” (uptake > physiological liver uptake) indicate

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ER positive lesions. Care should be taken that the gall bladder has in general higher physiological uptake than the liver. For the evaluation of lesions in all other tissues the intensity level should be put higher (Figure 2).

x In case of ambiguous lesions upon visual analysis of the scan, tracer uptake in the lesion should be quantified as SUVmax. Based on earlier

preclinical and clinical studies that correlated FES PET with immunohistochemistry, a lesion with a SUVmax > 1.5 should be

considered ER positive.

x FES is lipophilic and therefore patients with increased fat mass may have a lower tumor FES uptake than leaner patients, because of an increased pharmacological distribution volume.

x In the majority of patients, uptake at the injection site and in blood vessels can be seen despite extensively flushing or longer administration times. The cause of this accumulation is still unknown, but is probably due to sticking of the tracer to the vessel wall/endothelial cells. As the amount of tracer in these blood vessels is negligible (< 1% of the administered dose) no influence is to be expected for uptake in the tumours (Figure 3).

Figure 3. Physiological distribution of FES-PET with accumulation in the liver (1), excretion by gastrointestinal tract (2), kidneys (3) and bladder (4). In most patients also high uptake is seen in the injected vessel (5).

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In the final scan report, at least the following items have to be mentioned:

x Description of the areas with physiological uptake, metabolism and excretion

x Description of areas with increased (SUVmax > 1.5) ER expression

x Evaluation of ER expression (positive or negative) in lesions observed by other available imaging techniques (CT, MRI, FDG-PET) x If the scan was performed to solve a diagnostic dilemma (Figure 4):

describe if there is FES uptake in the equivocal lesion, if there is uptake quantify it and report if the lesion is ER positive or ER negative

x If the scan was performed to look for heterogeneity within all known metastases: describe which metastases show increased ER expression and which metastases do not

x If the scan was performed for therapy rationale, describe the overall ER status of the metastases

x Describe aspecific findings (see below, factors influencing uptake)

Figure 4 Patient with breast cancer, presenting with coughing and shortness of breath. FDG-PET (left image) was performed to search for metastases. Slightly elevated FDG uptake is visible in mediastinal and hilar lymph nodes, which could be due to metastases but also to inflammation/reactive lymph nodes. FES-PET (right image) shows high ER expression in multiple lymph nodes in mediastinum and hili and also in the neck (left side), in accordance with lymph node metastases with high ER expression (proven by immunohistochemistry).

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32 Factors influencing FES uptake

The accumulation of FES can be affected by both external and intrinsic factors (Table 3).

Intrinsic factors

Based on the results of 312 FES-PET scans various factors might influence FES uptake.37

x Estradiol levels and menopausal status: It is expected that circulating estrogens in premenopausal patients (>30 pg/ml) affect FES uptake, leading to lower accumulation in tumours, due to competition of the tracer with the physiological hormone for the ER binding site. Peterson

et al., however did not show evidence that premenopausal estradiol

levels impacted FES uptake in 82 patients with estradiol levels >30pg/mL.

x SHBG: in analogy with estradiol, circulating FES is mostly bound to one of two proteins in plasma (SHBG and albumin). After injection approximately 45% of the tracer is bound with high affinity but low capacity to SHBG and this percentage depends on the plasma concentration of SHBG. SHBG level is significantly inversely correlated with FES uptake in the tumor.38

x BMI: a significant correlation was also described between BMI and uptake of the tracer. In contrast to what could be expected based on the lipophilic nature of FES, patients with a higher BMI showed a higher tumor uptake of FES. However, this effect did not persist when FES uptake values were adjusted for lean body mass rather than body weight in kilograms.37

x Tumor location: due to high physiological uptake of FES in the liver, FES-PET is not the optimal imaging technique to detect liver metastases. A correlation between the photopenic appearance and the metastatic lesions with tracer accumulation inferior to the physiological distribution in the surrounding healthy liver tissue has been described.6 However, in these cases both ER positive and ER negative hepatic lesions could appear with lower uptake than the uptake in surrounding normal liver parenchyma. Therefore, FES-PET is not recommended when a patient is expected to have only liver metastasis, although occasionally uptake in the liver metastases can be higher than in normal liver tissue. In a recent

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lesion based analysis, performed on 91 patients, it was also demonstrated that uptake of FES in metastases differs per location: an overall lower uptake of FES was found in lung and brain metastases compared to bone lesions or lymph node metastases.39 Furthermore lesions in the gastro-intestinal tract are often difficult to assess due to excretion of the tracer. Bone marrow infiltration can sometimes be seen as a diffuse uptake.

Extrinsic factors

x Previous antihormonal treatment: Since ER antagonists block the binding site of the ER, tracer uptake will be affected. Treatment with ER antagonists (such as fulvestrant and tamoxifen) should therefore be stopped for ≥5 weeks before the FES-PET scan is acquired. Whether this time is sufficient to completely eliminate competitive binding is unknown, particularly for fulvestrant, which has a half-life of 40 days and both blocks and degrades estrogen receptors. A longer drug-free period, therefore, might be needed, but often is not feasible in clinical practice. As aromatase inhibitors do not affect the ER, but inhibit the conversion of testosterone into estrogens by aromatase, its use does not influence the tracer uptake and may therefore be continued.22,39 In some cases it is expected that these type of drugs could even increase uptake, as a result of lower plasma estrogen levels.

x Other therapies: in some patients aspecific uptake can be seen in regions of the body that underwent radiotherapy in the past.40 It remains unclear whether the increased tracer accumulation is due to enhanced extravasation owing to epithelial damage, or to tracer binding to infiltrating immune cells that express ERβ (Figure 5).41

x Resolution of the camera: as in all other nuclear medicine imaging techniques, the detection of lesions depends partially on the size of the tumor in relation to the spatial resolution of the PET camera. Recent developments in hybrid camera imaging led to a better spatial resolution of 2-4 mm and if the ER expression level is high enough even small lesions of a few millimeters can be visualized by FES-PET.

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Table 3

. Factors influencing FES uptake

Intrinsic factors Extrinsic factors

Location of the lesion Previous antihormonal treatment

Menopausal status Previous radiotherapy

SHBG level Spatial resolution of the camera system

BMI

ER status of the primary tumor

ER status of metastases

Figure 5 FES-PET of a patient with metastasized breast cancer and previous radiotherapy. Note the uptake in axillary lymph nodes (1) and in bone metastases (2). Also diffuse heterogeneous uptake in the lungs (3) is visible as result of previous radiotherapy.

Conclusions and future perspectives

Although FES-PET is not yet performed on a large scale, its use is increasing due to the need for better characterization of breast cancer to enable more personalized treatment. Personalized medicine is booming in the oncological world and in this setting, FES-PET seems a promising biomarker to be used for this purpose. If available, FES-PET could thus be considered as a non-invasive method for the detection of lesions expressing ER, mainly in metastatic breast cancer patients. The number of research studies with this tracer is increasing and several multicenter studies are ongoing to reveal the added value of FES-PET for several indications. Most studies are performed in the oncologic setting; however some ongoing studies are

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investigating the feasibility of FES-PET in benign disease. For example, the Vanderbilt-Ingram Cancer Center is trying to establish the avidity of desmoid tumors on FES-PET/CT imaging and correlates FES uptake with degree of ER expression by immunohistochemistry. The purpose of another ongoing study is to assess the sensitivity of FES for diagnosing endometriosis compared to the gold standard, which is histological confirmation at biopsy or excision of lesions performed during laparoscopy, in women suspected of endometriosis and for whom laparoscopy is already scheduled. Not only in detection of disease, but also for the purpose of determining pharmacodynamics of new ER targeted therapies, FES-PET could be of invaluable importance. In a phase I trial in healthy volunteers, FES PET was used to determine ER occupancy in the uterus and brain during targeted treatment with RAD1901.42It may be expected that the interest for this imaging technique will grow in the forthcoming years and that this technique will be implemented in daily clinical practice and even will be included in future diagnostic guidelines. Despite several publications, no specific recommendations were available for nuclear medicine physicians that described how to correctly acquire, analyze and interpret the FES-PET scan. Here, we described the technical aspects of the FES-PET scan that can be used as a first recommendation paper for everyone who wants to implement this imaging technique in his/her imaging facility. Thus, we hope that FES-PET may become available for more patients and can contribute to better diagnosis and treatment selection.

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36 References

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Chapter 3 Enhanced pulmonary uptake on

18

F-FES PET scans after radiation

therapy of the thoracic area: possibly related to fibrosis

C.M. Venema1_{, S.J. van der Veen}2_{, M.D. Dorrius}3_{, A.W.J.M. Glaudemans}4_{, M.}

van Kruchten1, C.P. Schröder1, E.F.J. de Vries4, G.A.P. Hospers1

University of Groningen, University Medical Center Groningen, the Netherlands

1

: Department of Medical Oncology

2

: Department of Radiation Oncology

3

: Department of Radiology

4

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42 Abstract

Purpose The use of 16α-[18F]fluoro-17β-estradiol (FES) positron emission

tomography (PET) in clinical dilemmas and for therapy decision making in lesions expressing estrogen receptors is growing. However, on a considerable number of FES PET scans, previously performed in a research and clinical setting in our institution, FES uptake was noticed in lungs apparently without an oncologic substrate. We hypothesized that this uptake was related to pulmonary fibrosis as a result of radiation therapy. This descriptive study therefore aimed to investigate, based on the experience within our institution, whether radiation therapy in the thoracic area is possibly related to enhanced pulmonary, non-tumor FES uptake. Methods: FES PET/CT scans performed in our institution were retrospectively analyzed from 2008 to 2017. Scans from patients who had received irradiation in the thoracic area prior to the scan, were compared to scans of patients who had never received irradiation in the thoracic area. The primary outcome was the presence of enhanced non-tumor FES uptake in the lungs, defined as visually increased FES uptake in the absence of an oncologic substrate on the concordant (contrast enhanced) CT scan. All CT scans were evaluated by one radiologist, for the presence of fibrosis or oncologic substrates. Results A total of 108 scans were analyzed: 70 scans of patients with previous irradiation in the thoracic area and 38 of patients without. Enhanced non-tumor FES uptake in the lungs was observed in 39/70 irradiated patients (56%), versus in 9/38 (24%) of non-irradiated patients. Fibrosis was present in 37 of the 48 patients with enhanced non-tumor FES uptake (77%), versus in 15/60 (25%) of patients without enhanced non-tumor uptake, irrespective of radiotherapy (p < 0.001). Conclusion After irradiation of the thorax, enhanced non-tumor uptake on FES PET can be observed in the radiation field in a significant proportion of patients. This seems to be related to fibrosis. When interpreting enhanced FES uptake in the lungs, information on recent radiation therapy, or history of pulmonary fibrosis should therefore be taken into consideration.

Keywords: FES PET, estrogen receptor, radiation therapy, pulmonary fibrosis.