Clinical trial NCT03703492
Conditions: Breast Cancer Ductal Carcinoma in Situ - Category
Sponsor: University of Wisconsin, Madison
Start date: 2019-01-03; Completion date: 2024-01-02
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This prospective, one-arm study which will enroll participants with biopsy-proven DCIS scheduled for diagnostic breast MRI for preoperative staging/extent of disease evaluation as part of standard of care. Eligible participants will be consented for participation in the research study which includes a directed breast PET/MRI with 18F-FES. 18F-FES uptake of the known malignancy will be measured on the PET/MRI examination using standardized uptake values (SUV) and tumor-to-normal tissue ratios.

Detailed description:
Integrated whole-body magnetic resonance imaging (MRI)-positron emission tomography (PET) scanners have recently been introduced for clinical use. This technology combines the anatomic and perfusion data obtained with Dynamic Contrast Enhanced (DCE) MRI with functional imaging data obtained from PET. For breast imaging, the combination of MRI and PET has important potential to improve diagnostic accuracy and provide molecular characterization of breast cancer. The overall purpose of this research is to determine the technical feasibility of simultaneous breast DCE MRI with 18F-FES PET for measuring estrogen receptor (ER) in patients with ductal carcinoma in situ (DCIS) and identifying patients with low-risk of disease recurrence. The hypothesis is that quantitative 18F-FES uptake parameters from PET/MRI will correlate well with the ER immunohistochemistry score and with low-risk recurrence scores.

Primary Objective 1) To compare quantitative 18F-FES uptake of biopsy-proven DCIS measured using PET/MRI with ER protein levels determined by immunohistochemistry.

Secondary Objectives

1. To determine the optimal cut-point 18F-FES uptake value for distinguishing between ER+ and ER-negative DCIS
2. To determine the test-retest reproducibility of quantitative assessment of tumor 18F-FES uptake
3. To determine the optimal cut-point 18F-FES uptake value for distinguishing between low-risk DCIS and intermediate/high-risk DCIS
4. To estimate the association of quantitative 18F-FES uptake (continuous SUVmax) with research-based Oncotype DX DCIS scores (0-100)
5. To measure the upgrade rate to invasive cancer at surgical excision
6. To correlate tumor 18F-FES uptake with serum estradiol and sex hormone binding globulin levels.

Exploratory Objective

1\) To correlate tumor cell density with 18F-FES uptake on PET/MRI

Arms: arm 1: Directed breast PET/MRI with 18F-FES; 18F-FES uptake of the known malignancy to be measured on the PET/MRI examination
Interventions: intervention 1: (18F)FES intervention 2: Gadobenate dimeglumine
Intervention descriptions: intervention 1: 18F-FES is an investigational new drug which will be used for this study. For complete information, please refer to the Investigator's Brochure: "\[18F\]Fluoroestradiol: An investigational positron emission tomography (PET) radiopharmaceutical for injection, intended for use as an in vivo diagnostic for imaging estrogen receptors in tumors intervention 2: Gadolinium-based intravenous contrast agent used for the MRI portion of this study

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
Hybrid Molecular Imaging of Estrogen Receptor in Breast Cancer Patients 
with Ductal Carcinoma In Situ 
 
 
UWCCC Study # UW18063 
 
UW IRB Tracking # 2018-0814 
 
NCT03703492 
 
 
 
Lead Clinical Investigator: 
Amy Fowler, M.D., Ph.D. 
University of Wisconsin-Madison 
 
Sub-Clinical Investigator: 
Roberta Strigel, M.D., M.S. 
University of Wisconsin-Madison 
 
Study Pathologist: 
Aparna Mahajan, M.D. 
University of Wisconsin-Madison 
 
Study Statistician: 
Emmanuel Sampene, PhD 
 
University of Wisconsin-Madison 
 
Funding Sponsor: 
University of Wisconsin-Madison 
Department of Radiology 
 
Protocol Version Date: 
February 8, 2023 
 


2 
 
Lead Clinical Investigator 
Sub-Clinical Investigator 
Amy Fowler MD, PhD 
Roberta Strigel MD, MS 
Assistant Professor 
Assistant Professor 
Department of Radiology 
Department of Radiology 
University of Wisconsin-Madison 
University of Wisconsin-Madison 
600 Highland Avenue 
600 Highland Avenue 
Madison, WI 53792-3252 
Madison, WI 53792-3252 
 
 
afowler@uwhealth.org 
rstrigel@uwhealth.org 
 
 
 


3 
 
TABLE OF CONTENTS 
 
1. 
PROTOCOL SUMMARY .......................................................................................... 7 
2. 
INTRODUCTION .................................................................................................... 11 
3. 
STUDY AIMS/STUDY OBJECTIVES ..................................................................... 13 
4. 
SELECTION OF PATIENTS .................................................................................. 14 
4.1.1 
Inclusion Criteria: ....................................................................................... 14 
4.1.2 
Exclusion Criteria: ...................................................................................... 14 
5. 
RESEARCH DESIGN AND METHODS ................................................................. 15 
6. 
REGISTRATION PROCEDURES .......................................................................... 21 
6.1 
Patient Recruitment .......................................................................................... 21 
6.2 
Patient Enrollment ............................................................................................ 23 
6.3 
Eligibility Verification ........................................................................................ 23 
6.4 
Registration Content Requirements ................................................................. 23 
6.4.1 
Protocol Number ........................................................................................ 23 
6.4.2 
Investigator Identification ........................................................................... 23 
6.4.3 
Patient Identification .................................................................................. 23 
6.5 
Criteria for Removal from Study ....................................................................... 23 
7. 
TREATMENT/INTERVENTION PLAN ................................................................... 24 
7.1 
Administration Schedule .................................................................................. 24 
7.2 
Dose Modifications ........................................................................................... 24 
7.3 
Supporting Care Guidelines ............................................................................. 24 
7.4 
Duration of Follow-up ....................................................................................... 24 
8. 
ADVERSE EVENT REPORTING REQUIREMENTS ............................................. 25 
8.1 
Purpose ............................................................................................................ 25 
8.2 
Terminology ..................................................................................................... 25 
8.3 
Reporting Procedure ........................................................................................ 26 
8.4 
Additional Adverse Event Information .............................................................. 26 
9. 
MEASUREMENT OF TREATMENT OR INTERVENTION EFFECT ...................... 28 
10. 
STUDY PARAMETERS ....................................................................................... 28 
11. 
DRUG FORMULATION AND PROCUREMENT ................................................. 28 
11.1 
Gadolinium-based intravenous contrast agent .............................................. 28 
11.2 
16α-[18F]-fluoro-17β-estradiol (18F-FES) ....................................................... 28 


4 
 
11.2.1 Other Names ............................................................................................. 28 
11.2.2 Classification ............................................................................................. 28 
11.2.3 Mode of Action ........................................................................................... 28 
11.2.4 Storage and Stability ................................................................................. 29 
11.2.5 Dose Specifics ........................................................................................... 29 
11.2.6 Preparation ................................................................................................ 29 
11.2.7 Route of Administration ............................................................................. 29 
11.2.8 Incompatibilities ......................................................................................... 29 
11.2.9 Availability .................................................................................................. 30 
11.2.10 
Side Effects ............................................................................................ 30 
11.2.11 
Nursing/Patient Implications ................................................................... 30 
12. 
STATISTICAL CONSIDERATIONS .................................................................... 30 
12.1 
Primary Objective .......................................................................................... 30 
12.2 
Secondary Objectives ................................................................................... 31 
12.3 
Evaluation of Toxicity .................................................................................... 32 
13. 
PATHOLOGY REVIEW ....................................................................................... 33 
13.1 
Justification ................................................................................................... 33 
13.2 
Required Pathology Materials ....................................................................... 33 
13.3 
Routing ......................................................................................................... 33 
14. 
RECORDS TO BE KEPT .................................................................................... 34 
14.1 
Images .......................................................................................................... 34 
14.2 
Regulatory and Consent ............................................................................... 34 
14.3 
Confidentiality ............................................................................................... 34 
15. 
PATIENT CONSENT AND PEER JUDGMENT ................................................... 34 
16. 
DATA AND SAFETY MONITORING ................................................................... 35 
16.1 
Risks ............................................................................................................. 36 
16.1.1 MRI ............................................................................................................ 36 
16.1.2 PET ........................................................................................................... 36 
16.1.3 Unexpected findings .................................................................................. 37 
17. 
REFERENCES .................................................................................................... 37 
 
 
 
 


5 
 
ABBREVIATIONS 
AE 
 
 
Adverse event 
AUC  
 
Area under the curve 
CAEPR 
 
Comprehensive Adverse Events and Potential Risks 
CFR  
 
Code of federal regulation 
cGMP  
 
current Good Manufacturing Practice 
CTCAE 
 
Common Terminology Criteria for Adverse Events 
CTEP  
 
Cancer Therapy Evaluation Program  
CIP 
 
 
Cancer Imaging Program 
cm 
 
 
Centimeter 
COV  
 
Coefficient of variation 
CT 
 
 
Computed tomography 
DCE-MRI 
 
Dynamic contrast enhanced magnetic resonance imaging 
DCIS  
 
Ductal carcinoma in situ 
DICOM 
 
Digital imaging and communications in medicine 
DOT  
 
Disease Oriented Team 
DSMC 
 
Data and Safety Monitoring Committee 
DWI  
 
Diffusion weighted imaging 
ECOG/ACRIN 
Eastern Cooperative Oncology Group/American College of   
 
 
 
Radiology Imaging Network 
ERα+  
 
Estrogen receptor alpha-positive 
FDA  
 
U.S. Food and Drug Administration  
FDG  
 
18F-fluorodeoxyglucose 
FES  
 
18F-fluoroestradiol 
GCP  
 
Good Clinical Practice 
GE 
 
 
General Electric 
H&E  
 
hematoxylin and eosin 
HER2  
 
Human epidermal growth factor receptor 2 
HIPAA 
 
Health Insurance Portability and Accountability Act  
HPLC  
 
High performance liquid chromatography  
ICC 
 
 
Intra-class correlation coefficient 
IHC 
 
 
Immunohistochemistry 
IME 
 
 
Important medical event 
IND 
 
 
Investigational new drug 
IRB 
 
 
Institutional review board 
IV 
 
 
Intravenous 
Kg 
 
 
Killogram 
M 
 
 
molar 
MBq  
 
MegaBecquerel 
mCi 
 
 
MilliCurie 
mGy  
 
MilliGray 
mL 
 
 
Milliliter 
mmol  
 
millimole 
mrem  
 
milli Roentgen equivalent man 
MRI 
 
 
Magnetic resonance imaging 


6 
 
MRN  
 
Medical record number 
MR/PET 
 
Magnetic resonance/Positron emission tomography 
mSv  
 
MilliSievert 
MTV  
 
Metabolic tumor volume 
NCI 
 
 
National Cancer Institute 
oz 
 
 
ounce 
PACS  
 
Picture archiving and communication system 
PET  
 
Positron emission tomography 
PET/MRI 
 
Positron Emission Tomography/Magnetic Resonance Imaging 
PSR  
 
Protocol summary report 
PI 
 
 
Principal investigator 
PR 
 
 
Progesterone receptor 
QA 
 
 
Quality Assurance 
QC 
 
 
Quality Control 
ROC  
 
Receiver operator curve 
ROI 
 
 
Region of interest 
SAE  
 
Serious adverse event 
SBP/SHBG  
Sex steroid-binding protein/Sex hormone binding globulin 
SUV  
 
Standard uptake value 
TLU 
 
 
Total lesion uptake 
TRIP  
 
Translational Research Initiatives in Pathology 
USP  
 
United States Pharmacopeia 
UW 
 
 
University of Wisconsin 
UWCCC 
 
University of Wisconsin Carbone Cancer Center 
 
 
 


7 
 
1. 
PROTOCOL SUMMARY 
TITLE OF STUDY 
Hybrid Molecular Imaging of Estrogen Receptor in Breast Cancer Patients with Ductal 
Carcinoma In Situ 
 
CLINICAL PHASE 
Phase 2 
 
INVESTIGATORS 
Lead clinical investigator:  Amy Fowler, MD, PhD, University of Wisconsin-Madison 
Sub-clinical investigator:  Roberta Strigel, MD, MS, University of Wisconsin-Madison 
 
This is an investigator-initiated clinical trial performed at a single clinical site. 
 
PERIOD OF TRIAL 
Planned study conduct duration of approximately 3 years. 
 
STUDY OBJECTIVES 
Integrated whole-body magnetic resonance imaging (MRI)-positron emission tomography 
(PET) scanners have recently been introduced for clinical use.  This technology combines 
the anatomic and perfusion data obtained with Dynamic Contrast Enhanced (DCE) MRI 
with functional imaging data obtained from PET.  For breast imaging, the combination of 
MRI and PET has important potential to improve diagnostic accuracy and provide 
molecular characterization of breast cancer.  The overall purpose of this research is to 
determine the technical feasibility of simultaneous breast DCE MRI with 18F-FES PET for 
measuring estrogen receptor (ER) in patients with ductal carcinoma in situ (DCIS) and 
identifying patients with low-risk of disease recurrence.  We hypothesize that quantitative 
18F-FES uptake parameters from PET/MRI will correlate well with the ER 
immunohistochemistry score and with low-risk recurrence scores.   
 
Primary Objective 
To compare quantitative 18F-FES uptake of biopsy-proven DCIS measured using 
PET/MRI with ER protein levels determined by immunohistochemistry.   
 
Secondary Objectives 
1) To determine the optimal cut-point 18F-FES uptake value for distinguishing 
between ER+ and ER-negative DCIS; 2) to determine the test-retest reproducibility 
of quantitative assessment of tumor 18F-FES uptake; 3) to determine the optimal 
cut-point 18F-FES uptake value for distinguishing between low-risk DCIS and 
intermediate/high-risk DCIS; 4) to estimate the association of quantitative 18F-FES 
uptake (continuous SUVmax) with research-based Oncotype DX DCIS scores (0-
100); 5) to measure the upgrade rate to invasive cancer at surgical excision; 6) to 
correlate tumor 18F-FES uptake with serum estradiol and sex hormone binding 
globulin levels. 
 
Exploratory Objective 


8 
 
To correlate tumor cell density with 18F-FES uptake on PET/MRI. 
 
INCLUSION CRITERIA 
• Women 18 years of age or older 
• Diagnosis of biopsy-proven DCIS without invasion or microinvasion measuring 
at least 1.0 cm in diameter by any imaging modality 
• Undergoing diagnostic breast MRI ordered by the referring clinician for staging 
and extent of disease* 
 
EXCLUSION CRITERIA 
• Inability or unwillingness to provide informed consent to the study 
• Surgery, radiation, neoadjuvant chemo/endocrine therapy for the current 
malignancy prior to study enrollment 
• Patients currently taking or have taken an ER-blocking medication (e.g. 
tamoxifen, raloxifene) within 6 weeks prior to study enrollment 
• Pregnant or lactating women 
• Patient with intolerance or contraindications for MRI or gadolinium-based 
contrast agents 
• Patient girth exceeds the bore of the MRI/PET scanner 
• Patients with a history of allergic reaction attributable to compounds of similar 
chemical or biologic composition to 18F-FES 
• Patients in liver failure as judged by the patient’s physician, due to the 
hepatobiliary clearance of 18F-FES 
• Patients requiring intravenous (IV) conscious sedation for imaging are not 
eligible; patients requiring mild, oral anxiolytics for the clinical MRI will be 
allowed to participate as long as the following criteria are met: 
o The subject has their own prescription for the medication 
o The informed consent process is conducted prior to the self-
administration of this medication 
o They come to the research visit with a driver or an alternative plan for 
transportation (e.g. Uber, taxi, etc.) 
 
STUDY DESIGN 
This is a prospective, one-arm, observational study which will enroll patients with biopsy-
proven DCIS scheduled for diagnostic breast MRI for preoperative staging/extent of 
disease evaluation as part of standard of care.  Eligible patients will be consented for 
participation in the research study which includes a directed breast PET/MRI with 18F-
FES.  18F-FES uptake of the known malignancy will be measured on the PET/MRI 
examination using standardized uptake values (SUV) and tumor-to-normal tissue ratios.  
The proposed work-flow is described in the schema.  
 
 
* Patients with newly diagnosed DCIS from a screening breast MRI are also eligible to participate in this 
study. For these subjects, the research breast PET/MRI should be performed prior to any treatment or 
surgery for DCIS. 
 


9 
 
NUMBER OF SUBJECTS 
We will test the hypothesis that 18F-FES SUVmax from PET/MRI correlates well against 
the ER IHC Allred score.  The correlation of the two measures will be evaluated using 
Spearman correlation analysis.  A sample size of 12 patients achieves 82% power 
(β=0.20) for detecting an expected correlation coefficient (r=0.73) to be significantly 
different from zero with two-tailed α value of 0.05.   
 
We anticipate enrolling approximately 1 subject every 1-2 months .  To measure test-
retest reproducibility, a subset of up to 5 participants with ER+ DCIS will have the option 
to for both test-retest FES scans.  The number of subjects with ER-negative DCIS will be 
limited to ≤3. 
 
 
 


10 
 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical 
Breast MRI 
Directed Research 18F-
FES Breast PET/MRI 
exam 
 
NOTE: If no previous 
breast MRI, the MRI 
component of the 
PET/MRI study is used 
as the clinical breast 
MRI 
Also, PET/CT plus MRI 
scans may be done if 
subjects are unable to 
undergo a PET/MRI 
 
Sub-study (N=5 ER+):  
Repeat 18F-FES Breast 
PET/MRI 
Eligible patient presenting for 
diagnostic breast MRI for 
staging/extent of disease. 
Clinical breast MRI 
interpretation and 
management 
RESEARCH 
STANDARD OF 
CARE 
Breast Surgery and 
Pathologic Analysis 
Research-based 
Oncotype DX DCIS 
Score 
RESEARCH 


11 
 
2. 
INTRODUCTION 
DCIS comprises up to one-fourth of all newly diagnosed cases of breast cancer (1).  The 
incidence of DCIS has markedly increased since the widespread utilization of screening 
mammography.  It is estimated that approximately 63,410 new cases of in situ carcinoma 
will be diagnosed in the United States in 2017 (2).  Despite the high prevalence of DCIS, 
overall treatment outcomes are excellent with 3.3% breast-cancer specific mortality after 
20 years (3). 
 
DCIS is a non-obligate precursor to invasive breast cancer, meaning some disease will 
remain DCIS if not surgically excised while others will progress to invasive cancer (4, 5).  
Small study series of the natural history of DCIS have found that approximately 28% 
(7/25) of untreated DCIS progressed to invasive disease within 15 years (6).  Even cases 
of low nuclear grade DCIS have been shown to develop into invasive breast cancer in 
36% (16/45) of patients undergoing biopsy only (7).  In contrast, data also exist from 
autopsy studies that have found undiagnosed DCIS in up to 15% of women who died 
from causes other than breast cancer (8).   
 
The conventional treatment of DCIS is surgical excision, either through lumpectomy or 
mastectomy (9).  For patients eligible for breast conserving surgery, radiation therapy is 
typically recommended after lumpectomy (10) since adjuvant radiotherapy has been 
shown to reduce the risk of local recurrence (either recurrent DCIS or invasive cancer) by 
approximately 50% (11).  Compilation of data from four randomized trials consisting of 
3,729 women with DCIS have shown that radiation therapy reduced the ten-year rate of 
local recurrence from 28.1% in patients randomized to surgery alone versus 12.9% for 
those randomized to surgery with radiation therapy (11).  Adjuvant endocrine therapy 
(tamoxifen or aromatase inhibitors) can also be considered as an additional systemic risk-
reducing treatment option in women with estrogen receptor (ER) positive DCIS (12-16).             
 
In contrast with invasive breast cancer, use of adjuvant radiotherapy or endocrine therapy 
for DCIS patients has not yet been shown to improve survival (11, 12).  Thus, the potential 
for over-diagnosis and over-treatment of DCIS has become a controversial topic.  
Improved individualized treatment plans for women with DCIS and prevention of over-
treatment in patients with “low-risk” DCIS has been ranked highly as a critical and 
impactful research priority (17-20).  There are ongoing clinical trials evaluating the 
comparative effectiveness of treatments that are alternatives to the standard described 
above.  These include the E4112 trial, which seeks to avoid radiation therapy in women 
with low risk DCIS and the COMET trial which is evaluating endocrine therapy as an 
alternative local control approach for women with ER/PR+ low and intermediate grade 
pure DCIS. 
 
Current approaches for risk stratification are primarily based on clinical and pathological 
factors.  These include patient age, nuclear grade, size, and surgical margin status.  
Prognostic models, such as the University of Southern California/Van Nuys Prognostic 
Index (21) and the Memorial Sloan-Kettering Cancer Center Nomogram (22), have been 
developed that incorporate these clinicopathologic variables.  These models are available 
to clinicians to provide a patient with information regarding the probability of local 


12 
 
recurrence with and without adjuvant therapy to facilitate shared decision-making.  A 
drawback of this approach is that the methods have not been fully validated using 
independent data sets outside of the institutions from which they were developed (23, 
24). 
 
A multigene expression assay has been recently developed that provides a ten-year risk 
estimate of local recurrence for DCIS patients following breast conserving therapy alone 
(25).  The 12-gene Oncotype DX DCIS Score is generated from expression levels of 
seven cancer related genes and five reference genes determined from a patient’s biopsy 
or surgical specimen (25).  The score is a continuous variable from 0 to 100.  Low-risk 
scores are 0 to 38.  Intermediate-risk scores are 39 to 54.  High-risk scores are 55 to 100.  
The score was initially validated using data from the Eastern Cooperative Oncology 
Group (ECOG) E5194 clinical trial, a prospective cohort study of 327 patients deemed to 
have low-risk of local recurrence based on clinicopathologic features treated with breast 
conserving surgery alone.  The 10-year risks (95%CI) of any ipsilateral breast event (local 
recurrence of DCIS or invasive carcinoma) for low, intermediate, and high risk scores 
were 10.6% (6.9-16.2%), 26.7% (16.2-41.9%) and 25.9% (14.8-43%), respectively and 
3.7% (1.8-7.7%), 12.3% (5.1-27.8%), and 19.2% (9.5-36.4%), respectively, for an 
invasive ipsilateral breast event (25).  The DCIS score was further validated in a more 
diverse patient population treated with breast conserving surgery alone, the Ontario DCIS 
cohort (26, 27).  The 10-year risks (95% CI) of any ipsilateral breast event for these 571 
patients with low, intermediate, and high risk scores were 12.7% (9.5-16.9%), 33.0% 
(23.6-44.8%), and 27.8% (20.0-37.8%), respectively (26).  Thus, this genomic test has 
been shown to provide information on local recurrence independent of traditional 
clinicopathologic factors such as age, size, and grade (25, 26) and has been shown to 
have clinical utility in influencing patient management (28, 29).  However, the test is 
expensive (~$3500) and may not be cost effective (30).  Furthermore, it requires a 3-week 
turnaround time (29) and sufficient tissue for analysis which may introduce sampling bias. 
 
An important molecular target in premalignant and malignant breast tissue is ER, which 
drives hormone-dependent breast tumor growth, and can be inhibited by endocrine 
therapy.  As shown in invasive breast cancer, ER appears to be an important prognostic 
factor and predictive biomarker for clinical benefit of adjuvant tamoxifen treatment for 
DCIS (16).  In normal breast tissue, ER is expressed in a minority of cells at low to 
moderate staining intensity.  However, very high levels of ER expression in nearly all cells 
are noted in most premalignant and noninvasive breast lesions (e.g. hyperplasias, atypia, 
lobular carcinoma in situ, and non-comedo DCIS) (31).  The majority of DCIS express ER 
protein (approximately 69%; range 49-97%) (32).  The exception is high grade comedo 
DCIS which can have low or no ER expression.  Semi-quantitative ER levels measured 
by immunohistochemistry in DCIS are inversely related to the histologic grade of DCIS 
and are increased compared to invasive breast cancer (33).  Interestingly, tumors cells at 
sites of focally disrupted myoepithelial cell layers are predominately (86.4%) ER-negative 
(34).   
 
Expression of ER can be measured in patients through the use of a radiolabeled estrogen 
ligand, 16α-18F-fluoro-17β-estradiol (18F-FES), and positron emission tomography (PET) 


13 
 
imaging (35, 36).  Tumoral 18F-FES uptake, as measured by SUVmax with whole body 
PET/CT imaging, correlates well (r=0.56-0.96) with ER expression in invasive breast 
cancer, as measured by radioligand binding in fresh tissue and immunohistochemistry in 
fixed tissue (37, 38).  Overall sensitivity of 18F-FES PET for detection of ER+ breast 
cancer was 84% (95% CI:  73–91) in four published studies involving 114 patients (35, 
37-40).  Overall specificity was high at 98% (95% CI:  90–100) demonstrated by absence 
of 18F-FES uptake (SUVmax less than 1.0) in 51 of 52 histologically benign lesions and 
ER-negative breast cancer in three studies (35, 38-40).  
 
18F-FES PET imaging has been studied as a predictive factor for clinical benefit of 
endocrine therapy in patients with metastatic ER+ breast cancer (35, 36).  Van Kruchten 
et al. combined the results of four single-institution studies and determined that lack of 
response to endocrine therapy was predicted by 18F-FES SUVmax under 1.5 in this 
heterogeneous group of ER+ patients (35).  Using the 1.5 SUVmax threshold, 96 of 114 
patients would have been selected to receive endocrine therapy, and 62 of these would 
have had a clinical benefit (PPV of 65%).  Alternatively, of the 42 patients with 18F-FES 
SUV below 1.5, 37 derived no clinical benefit from endocrine therapy (NPV 88%).   
 
The addition of magnetic resonance imaging (MRI) provides exquisite anatomic detail to 
characterize tumor morphologic characteristics and for functional assessment of lesion 
perfusion (41).  In addition to anatomic data, certain advanced MRI techniques, such as 
diffusion weighted imaging, has potential to distinguish low versus high risk DCIS (42, 
43).  The ECOG/ACRIN trial E4112 titled “Prospective Study of Magnetic Resonance 
Imaging (MRI) and Multiparameter Gene Expression Assay in Ductal Carcinoma In Situ 
(DCIS)” is a multi-institutional study of 368 patients and includes a secondary outcome 
measure assessing the relation between MRI morphologic and kinetic features and DCIS 
score.  
 
To the best of our knowledge, no studies have been performed using 18F-FES in patients 
with DCIS.  This study will investigate the technical feasibility of simultaneous breast DCE 
MRI with 18F-FES PET for quantifying ER in patients with DCIS and identifying patients 
with low-risk of disease recurrence.  If successful, we will pursue further studies using this 
imaging approach for stratifying patients with ER+ DCIS who may avoid radiation therapy 
(as in the E4112 study) and/or surgery (as in the COMET trial) and potentially derive the 
most benefit from endocrine therapy.   
 
3. 
STUDY AIMS/STUDY OBJECTIVES 
The goal of this research is to assess the technical feasibility of simultaneous breast DCE 
MRI with 18F-FES PET for measuring ER in patients with DCIS and identifying patients 
with low-risk of disease recurrence.  We hypothesize that quantitative 18F-FES uptake 
parameters from PET/MRI will correlate well with the ER immunohistochemistry score 
and with low-risk recurrence scores.   
 
3.1  Primary objective:  


14 
 
To measure 18F-FES uptake of biopsy-proven DCIS using breast PET/MRI.  The 
reference standard will be ER expression measured with immunohistochemistry. 
 
3.2  Secondary objectives: 
• Determine the optimal cut-point 18F-FES uptake value for distinguishing between 
ER+ and ER-negative DCIS. 
• Determine the test-retest reproducibility of quantitative assessment of tumor 18F-
FES uptake. 
• Determine the optimal cut-point 18F-FES uptake value for distinguishing between 
low-risk DCIS and intermediate/high-risk DCIS. 
• Estimate the association of quantitative 18F-FES uptake (continuous SUVmax) with 
research-based Oncotype DX DCIS scores (0-100) 
• Measure the upgrade rate to invasive cancer at surgical excision. 
• To correlate tumor 18F-FES uptake with serum estradiol and sex hormone binding 
globulin levels. 
 
3.3  Exploratory objective: 
To correlate tumor cell density with 18F-FES uptake on PET/MRI.   
 
Study duration:  3 years.  Our estimated rate of accrual is approximately 1 participant 
every 1-2 months.   
 
4. 
SELECTION OF PATIENTS 
Study Population: 
Female patients of all races and ethnic backgrounds at least 18 years of age with a current 
diagnosis of DCIS who are undergoing breast MRI for staging and extent of disease 
ordered by their provider as part of routine clinical care. 
 
4.1  Eligibility Criteria 
 
Inclusion Criteria: 
4.1.1  Women 18 years of age or older 
4.1.2  Diagnosis of biopsy-proven DCIS without invasion or microinvasion 
measuring at least 1.0 cm in diameter by any imaging modality 
4.1.3  Undergoing diagnostic breast MRI ordered by the referring clinician for 
staging and extent of disease† 
 
Exclusion Criteria: 
4.1.4  Inability or unwillingness to provide informed consent to the study 
 
† Patients with newly diagnosed DCIS from a screening breast MRI are also eligible to participate in this 
study. For these subjects, the research breast PET/MRI should be performed prior to any treatment or 
surgery for DCIS. 


15 
 
4.1.5 Surgery, radiation, neoadjuvant chemo/endocrine therapy for the current 
malignancy prior to study enrollment 
4.1.6 Patients currently taking or have taken an ER-blocking medication (e.g. 
tamoxifen, raloxifene) within 6 weeks prior to study enrollment 
4.1.7 Pregnant or lactating women 
4.1.8 Patient with intolerance or contraindications for MRI or gadolinium-based 
contrast agents 
4.1.9 Patient girth exceeds the bore of the MRI/PET scanner 
4.1.10 Patients with a history of allergic reaction attributable to compounds of 
similar chemical or biologic composition to FES 
4.1.11 Patients in liver failure as judged by the patient’s physician, due to the 
hepatobiliary clearance of 18F-FES 
4.1.12 Patients requiring intravenous (IV) conscious sedation for imaging are not 
eligible; patients requiring mild, oral anxiolytics for the clinical MRI scan will be 
allowed to participate as long as the following criteria are met: 
4.1.12.1  The patient has their own prescription for the medication 
4.1.12.2  The informed consent process is conducted prior to the self-
administration of the medication. 
4.1.12.3  The patient comes to the research visit with a driver or an 
alternative plan for transportation (e.g. Uber, taxi, etc.). 
 
5. 
RESEARCH DESIGN AND METHODS 
5.1 
Study Design 
This prospective, single-arm, observational, single-institutional research study will 
enroll women with DCIS scheduled for diagnostic breast MRI for preoperative 
staging/extent of disease evaluation.  The proposed work-flow is described in the 
schema above.  Eligible patients will be consented for participation in the research 
study which will involve the simultaneous acquisition of 18F-FES PET imaging data 
during a standard dynamic contrast enhanced clinical breast MRI performed prior 
to surgical excision.  Patients with ER+ DCIS will be offered to participate in an 
optional sub-study which will involve a second (test-retest) 18F-FES PET/MRI 
examination until we have accrued up to 5 patients. The results of the 18F-FES 
PET imaging component of the examination will not be used to guide patient 
management.  However, the clinical breast MRI component of the examination will 
be interpreted and reported with management recommendation as per routine 
clinical care.  Surgical management, radiation therapy, and adjuvant therapy will 
follow standard of care.  A research-based Oncotype DX DCIS score will be 
obtained from the surgical specimen for research purposes only since this test is 
currently not frequently used clinically at our institution (only about 1-5% DCIS 
patients locally).   
 


16 
 
Patients with DCIS may also participate in this study if a clinical breast MRI has 
already been performed.  In this scenario, a research 18F-FES breast PET/MRI will 
be performed on a separate day as the clinical breast MRI exam prior to surgery. 
 
The primary objective is to measure 18F-FES uptake of biopsy-proven DCIS using 
PET/MRI.  The reference standard will be ER expression measured with 
immunohistochemistry.  Secondary objectives include 1) to determine the optimal 
cut-point 18F-FES uptake value for distinguishing between ER+ and ER-negative 
DCIS; 2) to determine the test-retest reproducibility of quantitative assessment of 
tumor 18F-FES uptake; 3) to determine the optimal cut-point 18F-FES uptake value 
for distinguishing between low-risk DCIS and intermediate/high-risk DCIS; 4) to 
estimate the association of quantitative 18F-FES uptake (continuous SUVmax) with 
research-based Oncotype DX DCIS scores (0-100); 5) to measure the upgrade 
rate to invasive cancer at surgical excision; 6) to correlate tumor 18F-FES uptake 
with serum estradiol and sex hormone binding globulin levels.  An exploratory 
objective is to correlate tumor cell density with 18F-FES uptake on PET/MRI. 
 
5.2 
Reference Standard for ER Expression 
The primary objective is to measure 18F-FES uptake of biopsy-proven DCIS using 
PET/MRI.  The reference standard will be ER expression measured with 
immunohistochemistry performed as per the current standard of care.   
 
ER status is reported as positive or negative and includes a percentage of cells 
staining positive as well as intensity of staining.  This information will be obtained 
from the clinical pathology report in the subjects’ electronic medical record and will 
be used to calculate a semi-quantitative Allred score (44).  If the information 
needed to calculate the Allred score is not included in the clinical pathology report, 
a pathologist on the research study team will review the existing ER IHC slides.   
 
The Allred score is the sum of the proportion score and the intensity score (Table 
1) (44).  ER-negative cancers can have either an Allred score of 0 or 2 (1+1).  ER-
positive cancers can have an Allred score of 3, 4, 5, 6, 7, or 8.  An Allred score of 
1 does not exist. 
 
Table 1:  Allred Scoring System 
Percentage of Positive-
Staining Tumor Cells 
Proportion 
Score (PS) 
Average Intensity of 
Positive Tumor Cells  
Intensity 
Score (IS) 
None 
0 
None 
0 
<1% 
1 
Weak 
1 
1-10% 
2 
Intermediate 
2 
10-33% 
3 
Strong 
3 
33-66% 
4 
 
 
66-100% 
5 
 
 
 
5.3 
Study Calendar/Schedule 
 


17 
 
The study calendar/schedule is detailed in Table 2. 
 
Table 2:  Study Calendar/Schedule 
Study Activity 
Baselinea 
Imaging Dayb 
Clinical 
Follow-Upc 
Informed Consenth 
X 
 
 
Demographicsd 
X 
 
 
Medical Historyd 
X 
 
 
Radiology Reportsd 
X 
 
X 
Pathology Reports (Breast biopsy 
and final surgical excision)d 
X 
 
X 
Concomitant Medication Review 
 
X 
 
Pregnancy Screening 
 
X 
 
Day of last menstrual period (if 
premenopausal) 
 
 
X 
 
Height and Weight 
 
X 
 
Blood for Hormone Levels 
 
Xg 
 
18F-FES PET/MRIi 
 
X 
 
Adverse Event Evaluatione 
 
X 
X 
Research-based Oncotype DX DCIS 
Scoref 
 
 
X 
(a) Baseline is defined as the time period from initial subject contact until injection of 18F-FES. 
(b) Imaging Day is defined as the day of the research 18F-FES PET/MRI imaging session. 
(c) Subjects’ medical records are followed until final surgical excision and clinical determination of 
adjuvant therapy plan.  Any standard of care labs, procedures, and/or imaging exams obtained 
during this time period will be reviewed.  Data regarding recommended adjuvant therapy (radiation 
and endocrine therapy) will be recorded.  There are no protocol requirements during this time 
frame. 
(d) Clinical data, including age, race/ethnicity, primary breast cancer data (standard clinical 
histopathology including tumor biomarkers, location, size, and date of biopsy/diagnosis), 
mammographic breast density, and menopausal status will be recorded from the electronic medical 
record. 
(e) Adverse events occurring within one day after 18F-FES infusion will be recorded by the study 
coordinator who will contact the subject within 1 to 3 days. 
(f) Oncotype DX DCIS score will be obtained from the electronic medical record if performed clinically 
(only 1-5% of DCIS patients locally expected) and will also be performed as a separate research-
based assay using the resection specimen. 
(g) Blood sample collected will be up to 10 mLs total. 
(h) During the COVID-19 pandemic, consent procedures will be conducted by phone, when possible, 
to minimize face-to-face contact subjects have with the research team.  An encrypted copy of the 
consent form will be mailed or emailed to subjects prior to the scheduled consent phone call. 
(i) Subjects who are unable to undergo a PET/MRI scan will be invited to undergo a PET/CT along 
with a separate MRI scan   
 
5.4 
Clinical Breast MRI (Standard of Care) 
The clinical breast MRI will be performed and interpreted according to standard 
clinical practice. If additional management recommendations are generated based 
on the clinical breast MRI (i.e. identification of unsuspected suspicious findings 
requiring biopsy), the research examinations will ideally be scheduled prior to the 
date of scheduled intervention(s) but can also be performed after a biopsy 


18 
 
procedure. The patient will be informed of this possibility at the time of initial 
consent. 
 
5.5 
Research Breast 18F-FES PET/MRI 
 
5.5.1 Timing of 18F-FES PET/MRI  
Patients must complete the research breast PET/MRI study prior to 
surgical/oncologic intervention for their biopsy-proven breast cancer as part 
of their routine clinical care.  Ideally, the research breast PET/MRI study 
should be performed prior to any interventions (i.e. biopsies) prompted by 
the clinical breast MRI if performed prior to the research study, but this is 
not required.  If patients are also scheduled for clinical nuclear medicine 
studies using 99mTc-based or 18F-based radiopharmaceuticals, the research 
study should be scheduled on a separate day.  
 
5.5.2 Patient Preparation  
The patient does not need to be fasting for 18F-FES PET/MRI.  Prior to 
arrival, the patient should be well-hydrated (encourage drinking two-three 
8-12 oz glasses of water) unless a fluid-restriction diet is prescribed by the 
patient’s treating physician (e.g., congestive heart failure).  The patient 
should continue to take any of their prescribed medications as scheduled 
by their treating physician. 
 
Upon arrival, subject compliance with pre-procedure instructions will be 
confirmed.   Subject completion of the informed consent documentation will 
also be confirmed. The patient’s height and weight will be measured and 
recorded. Women with childbearing potential will be asked to confirm they 
are not pregnant. If they cannot confirm, they will have a urine pregnancy 
test either at the imaging study visit or within 7 days prior to the imaging 
study visit. 
 
5.5.3 18F-FES Administration  
The patient will have an intravenous line placed, typically in the hand or arm 
opposite to the known primary breast cancer, 18F-FES will be given by 2-
minute infusion, and the dose administered will be approximately 6 mCi ± 
20%.  The injection site will be inspected by the technologist to assess for 
any possible infiltration.  The patient will wait approximately 60 minutes to 
allow for biodistribution and tumor uptake of the radiopharmaceutical prior 
to imaging.  The patient should void prior to image acquisition. 
 
All adverse events occurring within a 24-hour period post-infusion will be 
recorded (a phone call to the participant performed 1 to 3 days after 18F-
FES infusion is acceptable means of collecting this information). The 
adverse events to be specifically monitored during the infusion include 
localized discomfort at the IV injection site, pain, respiratory difficulties, 
flushing, dizziness, pruritus/rash, and any other symptoms that could be 


19 
 
secondary to an anaphylactic reaction. The subject will be instructed to 
report any subjective symptoms or sensory changes noted. 
 
5.5.4 Imaging Quality Assurance (QA)/Quality Control (QC) Procedure 
QA/QC procedures will include review of DICOM files against study 
protocols. The PET/MRI scanner must be kept calibrated in accordance with 
the manufacturer’s recommendations. The scanner should routinely be 
assessed for quantitative integrity and stability by being tested using various 
imaging protocols on a standard phantom. For SUV measurements, this 
assessment should include a comparison against a dose calibrator to 
ensure accuracy; that is, a comparison of the absolute activity measured 
versus the measured activity injected, should be performed. 
 
A daily QC check must be performed at the beginning of the day, including 
PET/MRI scanner and dose calibrator, in accordance with the manufacturer 
recommendations. If any of the QC results are outside of the manufacturer’s 
guidelines, the study must be rescheduled and the problem rectified before 
scanning any patients. 
 
5.5.5 18F-FES PET/MRI Imaging Acquisition 
Image acquisition and reconstruction protocols specific to this research 
study will be available in a separate “Imaging Manual”.  The protocol is 
briefly described here. 
 
The patient will be escorted to the GE Discovery 750W 3T MR scanner 
containing the PET insert and an 8-Channel breast coil qualified for 
PET/MRI located in the basement level of WIMR Tower 1.  Directed breast 
PET/MRI data will be acquired with the patient in the prone position.  
Imaging will be performed by research technologists under guidance of the 
principal and/or collaborating investigators.  MRI-sequences utilized in a 
standard clinical breast MRI will be obtained, including T2-weighted fat 
suppressed and diffusion weighted imaging (DWI) prior to gadolinium 
contrast administration followed by T1-weighted fat suppressed DCE 
imaging.  The MRI sequences will include standard clinical sequences and 
may include research MRI sequences under development and evaluation 
at the University of Wisconsin.  A standard MR-based attenuation correction 
algorithm provided by GE will also be used for this study.  Breast specific 
PET emission data will be acquired simultaneous with the MR images. The 
entire examination is expected to take 30 – 40 minutes.  Post-processing 
includes PET image reconstruction, correction for attenuation, scatter, and 
motion, and co-registration with the MR images.    
 
In the rare instance that the subject is unable to be imaged using the 
simultaneous PET/MRI scanner (e.g. excessive girth, technical issue with 
scanner performance), the subject will undergo two separate scans.  A 
breast MRI (approximately 30 to 40 minutes) will be performed using a 3T 


20 
 
breast MRI scanner (e.g. GE Signa Premier) using MRI sequences as 
described above, and a breast specific PET/CT scan will be performed 
using a PET/CT scanner (e.g. Discovery IQ or GE Discovery 710) located 
in the Department of Radiology in the Wisconsin Institutes for Medical 
Research (WIMR) Tower 1.  The subject will be positioned prone with arms 
overhead.  Following a CT scout (topogram), a directed low-dose, non-
contrast, non-breathhold, non-diagnostic CT scan through the chest/breasts 
will be performed for attenuation correction calculations.  Next, a static PET 
emission scan of the thoracic region to specifically cover the breasts will be 
acquired in 3D acquisition mode.  The entire examination is expected to 
take approximately 15-20 minutes.  Post-processing includes PET image 
reconstruction, correction for attenuation and co-registration with the CT 
images and also with the separately obtained breast MRI. 
 
5.5.6 18F-FES PET/MRI Image Analysis 
Images will be reviewed for general quality.  The known biopsy-proven 
breast cancer(s) will be identified on the MRI/PET examination based on its 
known location from the prior clinical breast MRI, if performed, or the 
patient’s previous imaging, as is typically done in routine clinical practice.  
MRI images will be used to localize the lesion(s), measure the lesion size 
(in three dimensions), and assign the region of interest (ROI) for PET 
imaging analysis.   
  
Quantitative analysis of 18F-FES uptake will be performed at the lesion-
level.  Standardized uptake values (SUV) will be measured by manually 
drawing a region of interest (ROI) to encompass the entire lesion guided by 
the lesion extent visualized on MRI.  For the primary objective, the 
maximum SUV value (SUVmax) will be determined.  For potential exploratory 
analyses, additional uptake values may include SUVpeak (small fixed-size 
ROI centered on most intense part of tumor), SUVmean (average value), 
SUVmin (minimum value), SUVsd (standard deviation), tumor-to-normal 
tissue uptake ratios, FTV (functional tumor volume; i.e. the volume of tumor 
tissue with increased 18F-FES uptake) and TLU (total lesion uptake; i.e. the 
product of FTV × SUVmean).  A research workstation/software (e.g. Mirada 
Medical) will be used to perform these advanced quantitative techniques.     
 
5.6 
Clinical Laboratory Testing 
A blood sample is to be obtained at the time of imaging (drawn prior to 18F-FES 
injection) and submitted for hormonal analysis (estradiol and sex hormone binding 
globulin) by the UW Health clinical laboratory. Results from the UW Health clinical 
laboratory automatically post to the subjects’ medical records. 
 
5.7 
Risk Assessment 
Clinicopathologic-based risk scores will be calculated using the University of 
Southern California/Van Nuys Prognostic Index (21) and the Memorial Sloan-
Kettering Cancer Center Nomogram (22). 


21 
 
 
Genomic-based risk scores will be calculated using the Oncotype DX DCIS test 
(25, 26).  The risk score (0-100) is generated from expression levels of seven 
cancer related genes and five reference genes (Table 3) determined from a 
patient’s biopsy or surgical specimen (25).  Scores are further categorized as low-
risk (0-38), intermediate-risk (39-54), and high-risk (55-100).  Since utilization of 
the Oncotype DX DCIS score for clinical care is variable (only 1-5% of DCIS 
patients locally), we will perform an equivalent “research-based” assay using 
previously published methods (45).  Tissue blocks from the surgical specimen will 
be identified and used for RNA isolation performed by the UW Translational 
Research Initiatives in Pathology (TRIP) Lab.  The Fowler lab will then perform 
quantitative polymerase chain reaction (qPCR) published by Cronin et al (46) and 
will follow the algorithm of Solin et al (25) to calculate the genomic-based risk 
score.  Results of this research assay will not be used to guide clinical 
management.  A batched analysis will be performed after all subjects are enrolled 
for those with sufficient remaining tissue. 
 
Table 3:  12 gene panel included in the Oncotype DX DCIS Score 
Proliferation 
Group 
Hormone Receptor 
Group 
Other 
Reference 
Group 
Ki67 
PR 
GSTM1 
ACTB (β-actin) 
STK15 
 
 
GAPDH 
Survivin 
 
 
RPLP0 
CCNB1 (cyclin B1) 
 
 
GUS 
MYBL2 
 
 
TFRC 
 
5.8 
Repeatability 18F-FES PET/MRI (Optional) 
Up to 5 patients with ER+ DCIS who agree to participate in this optional portion of 
the study will undergo a second (test-retest) 18F-FES PET/MRI examination.  The 
test-retest exam cannot be performed the same day but should be completed prior 
to any therapy or surgical excision.  This will not delay any scheduled routine 
standard of care therapy or procedures for the patient.  This optional sub-study will 
be offered to all patients at the time of consent until we have accrued up to 5 
patients with ER+ DCIS. 
6. 
REGISTRATION PROCEDURES 
Patients must not start protocol procedures prior to registration.  Patients must complete 
the breast PET/MRI study prior to surgical/oncologic intervention for their biopsy-proven 
breast cancer as part of their routine clinical care. 
 
6.1 
Patient Recruitment 
Potentially eligible patients can be identified by several approaches:  study 
coordinator(s) who have access to the clinical breast MRI schedule and the 
schedules from other providers that serve this patient population (e.g. surgeons), 
radiologists who are protocoling clinical breast MRI exams in advance, from 
patients presented at our weekly multidisciplinary and radiologic-pathologic 


22 
 
concordance conferences, and/or through automatic search results of the 
electronic medical record provided by the Biomedical Informatics Services 
delivered to the study investigator(s) and study coordinator(s) via REDCap 
database.  The breast imaging radiologist performing radiologic-pathologic 
concordance after biopsy can also flag patients as potentially eligible. 
 
Recruitment flyers will also be posted in clinics that serve this patient population.  
Patients interested in learning more about the research will be required to respond 
to a research team member(s) noted on the flyer. 
 
Study eligibility will be based on the inclusion and exclusion criteria and will be 
determined by the breast imaging radiologist(s) and/or study coordinator(s).  If a 
patient is potentially eligible for the study, the study coordinator will contact the 
patient by phone prior to their scheduled MRI and outline the research protocol to 
the patient.  If the patient is interested in the study, the study coordinator will 
describe the study in more detail and/or record the subject’s preferred contact 
information and make plans to follow-up with the patient by phone to describe the 
research protocol in more detail.  If they choose, an encrypted version of the 
consent form will be emailed to them to allow additional time to review the form.  If 
the patient indicates they are interested in proceeding with the study, scheduling 
for 18F-FES production with the Radiopharmaceutical Production Facility will be 
coordinated with the patient’s clinical breast MRI appointment. 
 
If the patient is uncertain about participating in the study, they can be offered the 
contact information of an advocate member of the UWCCC Breast Cancer 
Research Advisory Network (BCRAN) to use as a resource for general information 
about participating in clinical research. 
 
The consent process will occur prior to the administration of research procedures.  
During the COVID-19 pandemic, consent procedures will be conducted by phone, 
when possible, to minimize face-to-face contact subjects have with the research 
team.  A copy of the consent form will be mailed or emailed to subjects prior to the 
scheduled consent phone call. If emailed, the consent form will be encrypted.  A 
study team member will call potential subjects at the scheduled time to review the 
information in the consent form including study procedures, risks associated with 
participation, alternatives to participation and whom to contact for additional 
information.  Any questions will be addressed during the course of the phone call 
and subjects will be encouraged to contact the study team with any questions or 
concerns they might have at any time.  Upon completion of the consent process, 
a copy of the signed consent form will be provided in one of the following ways 
depending on each subject preferences and capabilities: 
• 
Electronic signature will be provided using DocuSign 
• 
Subject will be asked to scan a copy of the entire consent document and 
email it back to the study team.  
• 
Subject will be asked to take a photo of the signature page and email a copy 
to the study team.  


23 
 
• 
If subjects are unable to provide an electronic copy of the signed consent 
form, they will be asked to bring a copy of the form to the research visit.    
   
 
Once institutional requirements are met, remote consenting may continue by 
obtaining electronic signature using the DocuSign software platform. 
 
6.2 
Patient Enrollment 
Study enrollment will occur when the patient arrives for and consents to the 
research study.  A study team member will meet with the patient, review the 
research protocol, and answer the potential subject’s questions.  The information 
in the consent form, including study procedures, risks associated with participation, 
alternatives to participation and whom to contact for additional information, will be 
reviewed.  Any questions will be addressed prior to the start of any research 
procedures and all subjects will be reminded that participation is optional and they 
can change their mind at any time and still get clinically required testing completed.  
Those interested in participating will be asked to sign informed consent and HIPAA 
authorization and the subject will be enrolled in the research study.  Subjects will 
be assigned a unique ID number.  Both the MRI screening questionnaire as well 
as the PET screening questionnaire will be reviewed to confirm eligibility criteria.   
 
6.3 
Eligibility Verification 
The patient must meet all of the eligibility requirements listed in Section 4.0.   
 
6.4 
Registration Content Requirements 
6.4.1 
Protocol Number  
6.4.2 
Investigator Identification  
• Investigator’s name 
6.4.3 
Patient Identification  
• Patient’s name 
• Patient’s address 
• Patient’s Medical Record Number (MRN) 
• Patient demographics 
• Gender 
• Birth date  
• Race 
• Ethnicity 
• Date on study 
 
6.5 
Criteria for Removal from Study 
Enrolled patients will be removed from the study in the following circumstances: 
• Subject does not complete the PET/MRI examination per study protocol 
• Positive pre-scan pregnancy test 
• Subject withdraws consent 
• Exclusion criteria are discovered after registration but prior to the PET/MRI 
examination 


24 
 
 
7. 
TREATMENT/INTERVENTION PLAN 
This is an observational study and the results of the 18F-FES PET/MRI will not be used to 
change patient therapy.  The results of the research studies will not be reported by a 
radiologist, will not be part of the patient’s medical record, and will not be available to the 
patient or their physician.  The exception is if the breast MRI component of the breast 
PET/MRI is used as the patient’s clinical examination, then interpretation of the breast 
MRI and management recommendations will be made based on routine clinical practice.  
No medications will be administered as part of the study protocol except intravenous 
injection of a gadolinium-based contrast agent for MRI and 18F-FES PET tracer required 
for PET imaging.   
 
7.1 
Administration Schedule 
For each research breast 18F-FES PET/MRI examination, patients will receive:   
• 
18F-FES, 6 mCi (222 MBq) ± 20%, IV slow infusion over 2 minutes followed 
by saline flush, once  
• Gadolinum intravenous contrast (gadobenate dimeglumine; MultiHance), 
weight-based dosing (0.1 mmol/kg), IV power-injection at 2 cc/second 
followed by a 20 cc saline flush, once 
 
7.2 
Dose Modifications 
There will be no dose modifications for 18F-FES administration. 
 
7.3 
Supporting Care Guidelines 
All supportive measures consistent with optimal patient care will be given 
throughout the study.  Any adverse effects, related or non-related to the injection 
of 18F-FES, will be treated as clinically indicated with no study-related restrictions. 
 
If there is a contrast reaction or extravasation, these will be managed via UW 
Health guidelines.  A physician is always present to manage contrast reactions and 
extravasations, should one occur.  
 
To facilitate clearance of 18F-FES, thus reducing patient radiation dose exposure, 
patients will be instructed to adequately hydrate prior to and after the 
radiopharmaceutical administration unless on a fluid restrictive diet by their treating 
physician. 
 
7.4 
Duration of Follow-up  
Adverse events occurring within 24 hours after 18F-FES infusion will be recorded 
by the study coordinator who will contact the subject within 1 to 3 days after 18F-
FES administration.  Standard of care patient management will occur after the 18F-
FES breast PET/MRI examination.  These visits generally include consultation with 
a surgeon, radiation oncologist, and/or medical oncologist.  Subject’s medical 
records are followed until completion of definitive treatment. 
 


25 
 
8. 
ADVERSE EVENT REPORTING REQUIREMENTS 
8.1 
Purpose 
Adverse event (AE) data collection and reporting, which are required as part 
of every clinical trial, are done to ensure the safety of the patients enrolled, 
as well as those who will enroll in future studies using similar agents.  
 
8.2 
Terminology 
• Adverse Event (AE): Any untoward medical occurrence associated 
with the use of a drug in humans, whether or not considered drug 
related. Therefore, an AE can be ANY unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product.  
• Attribution: An assessment of the relationship between the adverse 
event and the protocol treatment, using the following categories. 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to 
treatment. 
Unlikely 
The AE is doubtfully related to 
treatment. 
Possible 
The AE may be related to treatment. 
Probable 
The AE is likely related to treatment. 
Definite 
The AE is clearly related to treatment. 
• CAEPR (Comprehensive Adverse Events and Potential Risks List): 
An NCI generated list of reported and/or potential AEs associated with 
an agent currently under an NCI IND. Information contained in the 
CAEPR is compiled from the Investigator’s Brochure, the Package 
Insert, as well as company safety reports.  
• CTCAE: The NCI Common Terminology Criteria for Adverse Events 
provides a descriptive terminology that is to be utilized for AE reporting. 
A grade (severity) is provided for each AE term.  
• Hospitalization (or prolongation of hospitalization): For AE reporting 
purposes, a hospitalization is defined as an inpatient hospital stay equal 
to or greater than 24 hours.  
• Life Threatening Adverse Event: Any AE that places the subject at 
immediate risk of death from the AE as it occurred.  
• Serious Adverse Event (SAE): Any adverse event occurring at any 
dose that results in ANY of the following outcomes:  
• Death  
• A life-threatening adverse event  


26 
 
• Inpatient hospitalization or prolongation of existing hospitalization 
(for ≥ 24 hours).  
• A persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions.  
• A congenital anomaly/birth defect.  
• Important Medical Events (IME) that may not result in death, be life 
threatening, or require hospitalization may be considered a serious 
when, based upon medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 
 
8.3 
Reporting Procedure 
Per 21CFR312.32(c), all adverse events deemed both serious and 
unexpected associated with the use of the drug must be reported to the FDA 
and to all participating investigators as soon as possible and in no event 
later than 15 days. 
 
The FDA will be notified of any unexpected fatal or life threatening 
experience associated with the drug as soon as possible but in no event 
later than 7 calendar days.  The University of Wisconsin Health Sciences-
IRB will be notified in accordance with posted institutional policy. 
 
Serious and Non-Serious Adverse events will be recorded, regardless of 
whether or not they are thought to be related to the investigational imaging 
tracer.  While all adverse events will be tabulated and reported in the study 
final report, serious adverse events will be reported in the course of the trial.  
Adverse events that meet criteria of a serious adverse event listed above 
will also be recorded and reported. 
 
The Investigator will inform the IRB of all adverse events attributed to the 
investigational imaging tracer in accordance with posted institutional policy. 
 
8.4 
Additional Adverse Event Information 
CTCAE term (AE description) and grade:  The descriptions and grading 
scales found in the revised NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0 will be utilized for AE reporting.  All appropriate 
treatment areas should have access to a copy of the CTCAE version 5.0.  
A copy of the CTCAE version 5.0 can be downloaded from the CTEP web 
site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.ht
m 
 
The following adverse event information was obtained from the NCI. 
 


27 
 
Condensed risk list – 18F-FES PET 
POSSIBLE, SOME MAY BE SERIOUS 
• Swelling and redness at the site of the medication injection 
• Changes in taste 
 
The only adverse events that have been attributed to PET imaging with 
diagnostic 18F-FES at the levels described in the Investigators Brochure 
have been mild transient disturbances in taste.  Therefore, no significant 
adverse events are expected as a result of the intravenous (IV) 
administration of 18F-FES for typical PET imaging applications.  
 
As with any IV administered agent, 18F-FES could cause an allergic reaction 
that could potentially pose a threat to life (anaphylaxis).  This has not been 
observed in reported human exposure to date.  Reasonable precautions 
should be taken, consistent with normal radiologic and clinical facility 
practice.  The patient should be monitored until the PET procedure is 
completed, and trained personnel and emergency equipment should be 
available per facility standards. 
 
For purposes of informed consent regarding reasonably foreseeable risks 
to subjects in trials utilizing 18F-FES, the following potential adverse events 
are considered extremely rare: 
• 
Injection-related risks that may include infection, or accidental 
extravasation of the dose that may lead to discomfort, localized pain, or 
infection.  
• 
Risks related to allergic reaction/anaphylaxis that may be life 
threatening. 
 
As with all PET imaging agents, 18F-FES is a radiopharmaceutical that 
decays with positron emission.  As such, it poses an intrinsic radiation 
exposure risk.  However, when administered in accordance with the 
Investigator’s Brochure as a PET imaging agent, this risk is felt to be 
extremely small.  The organ and total body doses associated with 18F-FES 
PET imaging are comparable to or lower than those associated with other 
widely used clinical nuclear medicine procedures.   
 
18F-FES in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the 
combination may result in events never previously associated with either 
agent. 
 


28 
 
9. 
MEASUREMENT OF TREATMENT OR INTERVENTION EFFECT 
Not applicable since the research imaging study (PET/MRI) will not be used to guide 
therapy. 
 
10. 
STUDY PARAMETERS 
Information regarding time intervals for performance of the study and contact points is 
included as Table 2 in Section 5.3. 
 
11. 
DRUG FORMULATION AND PROCUREMENT 
11.1 Gadolinium-based intravenous contrast agent 
Gadobenate 
dimuglumine 
(MultiHance) 
is 
the 
gadolinium-based 
intravenous contrast agent used for the MRI portion of this study.  It will be 
obtained from a commercial source (e.g. Bracco Diagnostics, Inc).  This 
agent is used routinely in standard clinical practice at our institution.  Please 
refer to package insert for more comprehensive information. 
 
11.2 16α-[18F]-fluoro-17β-estradiol (18F-FES) 
18F-FES is the radiopharmaceutical which will be used for this study.  For 
complete information, please refer to the Investigator’s Brochure:  
“[18F]Fluoroestradiol: An investigational positron emission tomography 
(PET) radiopharmaceutical for injection, intended for use as an in vivo 
diagnostic for imaging estrogen receptors in tumors (NCI-held IND 79,005)”, 
Edition Number 4, Edition date 2011. 
 
11.2.1 
Other Names 
[F-18]FES, FES 
 
11.2.2 
Classification 
Investigational new drug: Radiopharmaceutical/radiotracer 
In May 2020, 18F-FES was approved by the FDA under the brand 
name “CERIANNA”, but the labelled indication for clinical use is for 
a different breast cancer patient population (recurrent or metastatic) 
than included in this research study (DCIS).  Thus, we will continue 
to perform this research study under our existing approved IND. 
 
11.2.3 
Mode of Action 
18F-FES binds to ER alpha with a binding affinity nearly identical to 
estradiol.  18F-FES binding to sex steroid binding protein (SBP or 
SHBG) is also similar to that of estradiol, providing equivalent 
transport to sites of ER expression, including tumor sites.  In breast 
cancer, the uptake of 18F-FES, measured by whole body PET/CT, 
has been shown to correlate with ER expression in biopsy material 
assayed by in vitro radioligand binding or by IHC.  


29 
 
 
11.2.4 
Storage and Stability 
In accordance with regulations, the Radiopharmaceutical Production 
Facility conducts several quality control tests on the 18F-FES product 
prior to release for human administration.  Once delivered, doses will 
be stored in the appropriate storage area in the nuclear medicine 
facility until they are administered to the patient. The drug solution is 
stored at room temperature in a gray butyl septum sealed, sterile, 
pyrogen-free glass vial with an expiration time of 6 hours. 
 
11.2.5 
Dose Specifics 
The injected dose of 18F-FES will be 6 mCi (222 MBq) ± 20% with a 
specific activity greater than 170 Ci/mmol at the time of injection for 
an activity dose of 6 mCi.  In all cases, less than 5 μg of 18F-FES 
should be injected. 18F-FES is the only active ingredient. There is no 
evidence that nonradioactive and radioactive FES molecules display 
different biochemical behavior.  
 
11.2.6 
Preparation 
Fluorine-18 labeled FES is synthesized with high specific activity so 
the 
quantity 
of 
estrogenic 
material 
injected 
with 
the 
radiopharmaceutical is ≤ 5 μg (≤ 17 nmol).  For a 6 mCi dose, this 
would be 170 Ci/mmol.  Between 3 and 6 mCi of [18F]FES is 
administered in a nominal volume of 10 mL of phosphate buffered 
saline containing less than 15% ethanol (v:v) for a single PET scan. 
 
Specific manufacturing processes will follow our approved Drug 
Master File for 18F-FES.  Briefly, [18F]FES is purified by HPLC using 
an eluent of 50% ethanol, USP in sterile water for injection. The final 
product [18F]FES with a total volume of 10 mL is formulated in 10% 
ethanol for injection, USP and 0.075M saline for injection, USP, 
buffered with 0.075M sodium phosphates injection, USP. The 
concentration of ethanol in the final injectate is less than 15% by 
volume, or a maximum of 1.5 mL of ethanol. This is less than one-
sixth of the amount of ethanol in one alcoholic drink and < 0.025 
mL/kg (< 0.02g/kg) for a standard 56.8-kg woman. 
 
11.2.7 
Route of Administration 
18F-FES is a sterile, intravenously (IV) injectable solution in a volume 
of ≤ 10 mL containing of 0.15 M phosphate buffered saline: < 15% 
ethanol (v:v).  Prior studies have shown that this volume of injectate 
infused over 2 minutes is well tolerated and minimizes local 
saturation of SHBG which could limit systemic delivery of 18F-FES. 
 
11.2.8 
Incompatibilities 
N/A 


30 
 
 
11.2.9 
Availability 
cGMP-grade 18F-FES will be manufactured on-site in the UW-
Madison Radiopharmaceutical Production Facility.  This facility has 
been qualified and approved for production by NCI Cancer Imaging 
Program (CIP) and ECOG-ACRIN for other FES clinical trials.  The 
investigational pharmacist or qualified nuclear medicine technologist 
will be the responsible party designated by the investigator.  
 
11.2.10 
Side Effects 
See Section 8.4 for side effects. The radiation absorbed effective 
dose equivalent to the whole body from intravenously injected 18F-
FES is estimated to be 0.022 mSv/MBq (488 mrem for a 6 mCi 
injection). The critical organ is the liver, with an average absorbed 
dose of 0.13 mGy/MBq. The organ and total body doses associated 
with 18F-FES PET imaging are comparable to or lower than those 
associated with other widely used clinical nuclear medicine 
procedures and are well below the maximum suggested individual 
study and annual total body dose of 30 and 50 mGy, respectively, 
suggested for investigational radiopharmaceuticals by the FDA. 
 
11.2.11 
Nursing/Patient Implications 
Standard safety precautions required when handling radioactive 
materials (predominantly during the injection and uptake period) 
should be followed. 18F-FES requirements are similar to those used 
for other PET tracers, such as 18F-FDG. 
 
11.3 Cerianna (fluoroestradiol F-18) 
If scheduling conflicts do not permit use of locally produced 18F-FES, then 
commercially available 18F-FES (CERIANNA) will be obtained which is FDA 
approved for patients with recurrent or metastatic ER+ breast cancer and is 
being used in a manner that is consistent with its approval. 
 
The use of this product in research is consistent with the criteria for IND 
exemption in accordance with 21 CFR 312.2(b)(1). Cerianna is a lawfully 
marketed drug, and this research is not intended to support a new indication 
or new product labeling.   
 
12. 
STATISTICAL CONSIDERATIONS 
12.1 Primary Objective 
To compare quantitative 18F-FES uptake of biopsy-proven DCIS measured 
using 
PET/MRI 
with 
ER 
protein 
levels 
determined 
by 
immunohistochemistry. 
 


31 
 
The primary objective is to compare 18F-FES SUVmax from PET/MRI with 
the ER immunohistochemistry semi-quantitative score obtained by using 
the Allred score.  We will test the hypothesis that 18F-FES SUVmax from 
PET/MRI correlates well against the ER IHC Allred score.  The correlation 
of the two measures will be evaluated using Spearman correlation. The null 
hypothesis is H0: p0=0.00 and the alternative hypothesis is H1: p1 =0.73. 
 
A sample size of 12 patients achieves 82% power (β=0.20) for detecting an 
expected correlation coefficient (r=0.73) to be significantly different from 
zero with two-tailed α value of 0.05 (http://www.sample-size.net/correlation-
sample-size/).    We anticipate enrolling 1 subject  every 1-2 months.  The 
number of subjects with ER-negative DCIS will be limited to ≤3. 
 
Other measures of 18F-FES uptake including SUVpeak, SUVmean, tumor-to-
normal tissue uptake ratio, and total lesion uptake will also be correlated 
with the ER immunohistochemistry semi-quantitative score obtained by 
using the Allred score.    
 
12.2 Secondary Objectives 
 
1. To determine the optimal cut-point 18F-FES uptake value for 
distinguishing between ER+ and ER-negative DCIS. 
 
Receiver operating characteristic (ROC) curve analysis will be 
performed to determine the optimal cut-point for 18F-FES uptake to 
distinguish ER+ from ER-negative DCIS, as defined by the clinical 
pathology report.  The area under the curve (AUC) for the ROCs and 
their respective two-sided 95% confidence intervals will be 
calculated using logistic regression.  The optimal cut-off point will be 
determined by considering the 18F-FES uptake value with the 
maximum sensitivity and specificity.   
 
2. To determine the test-retest reproducibility of quantitative 
assessment of tumor 18F-FES uptake. 
 
The reproducibility of the two measurements (test-retest) of 18F-FES 
uptake in the subjects (up to 5) who elect to undergo a second 
imaging session will be assessed by intra-class correlation 
coefficient (ICC) and its 95% confidence interval (47). Additionally, 
the coefficient of repeatability (CR) and the Bland-Altman plot will be 
used (48). 
 
3. To determine the optimal cut-point 18F-FES uptake value for 
distinguishing between low-risk DCIS and intermediate/high-risk 
DCIS. 
 


32 
 
ROC curve analysis will be performed to determine the optimal cut-
point for 
18F-FES SUVmax to distinguish low-risk DCIS and 
intermediate/high-risk DCIS.  Risk categories will be determined 
using the Van Nuys Prognostic Index, the Memorial Sloan-Kettering 
Cancer Center Nomogram, and the research-based Oncotype DX 
DCIS score.  Sensitivity and specificity will be determined with two-
sided 95% confidence intervals.  The AUCs for the ROCs and their 
respective two-sided 95% confidence intervals will be calculated 
using logistic regression.   
The optimal cut-off point will be determined by considering the 18F-
FES uptake value with the maximum sensitivity and specificity.   
This analysis will be done separately for each risk assessment 
model. 
 
4. To estimate the association of quantitative 
18F-FES uptake 
(continuous SUVmax) with research-based Oncotype DX DCIS 
scores (0-100). 
 
Scatter plots of continuous quantitative 18F-FES uptake (SUVmax) on 
the y-axis and research-based Oncotype DX DCIS scores (unitless) 
on the x-axis will be created to explore the distribution of the 
measurements.  Pearson’s or Spearman’s rank correlation will be 
used to evaluate the association between quantitative 18F-FES 
uptake and research-based Oncotype DX DCIS score. The 
correlation coefficient (rho) and 95% confidence interval will be 
reported.   
 
5. To determine the upgrade rate to invasive cancer at surgical 
excision. 
 
This percentage will be calculated by dividing the number of patients 
with invasive breast cancer diagnosed at the time of surgical excision 
by the number of patients with percutaneous biopsy-proven DCIS in 
the study. 
 
6. To correlate tumor 18F-FES uptake with serum estradiol and sex 
hormone binding globulin levels. 
 
A correlation analysis of serum estradiol and sex hormone binding 
globulin levels will be performed using Pearson’s or Spearman’s rank 
correlation.  Scatter plots, correlation coefficients (rho) and 95% 
confidence intervals will be reported.   
 
12.3 Secondary Objectives 
To correlate tumor cell density with 18F-FES uptake on PET/MRI.  A strong 
correlation between tumor cell density and detection by 18F-FDG PET/CT 


33 
 
imaging has been reported (49).  A correlation analysis of tumor 18F-FES 
uptake and tumor cell density will be performed using Pearson’s or 
Spearman’s rank correlation.  Scatter plots, correlation coefficients (rho) 
and 95% confidence intervals will be reported. 
 
12.4 Evaluation of Toxicity   
All subjects will be evaluable for toxicity from the time of injection of 18F-FES 
until 24 hours after injection.  For this evaluation, the study coordinator will 
contact the subject within 1 to 3 days after 18F-FES administration. 
 
13. 
PATHOLOGY REVIEW 
13.1 Justification 
The pathology of the biopsy-proven breast cancer will be evaluated per the 
current standard of care (histologic diagnosis, grade, tumor biomarker 
status).  ER status is reported as positive or negative and includes a 
percentage of cells staining positive as well as intensity of staining.  This 
information will be obtained from the clinical pathology report in the subjects’ 
electronic medical record and will be used to calculate a semi-quantitative 
Allred score (44).  If the information needed to calculate the Allred score is 
not included in the clinical pathology report, a pathologist on the research 
study team will review the existing ER IHC slides.  If the information needed 
to determine tumor cell density is not included in the clinical pathology 
report, a pathologist on the research study team will review the existing H&E 
slides. 
 
13.2 Required Pathology Materials 
Pathology reports will be available through the electronic medical record.  
Existing pathology slides (ER IHC and H&E) from the breast biopsy used 
for initial diagnosis will be requested from the Department of Pathology for 
Allred scoring by the research study pathologist if the information needed 
to calculate the Allred score is not included in the clinical pathology report. 
 
For the research-based Oncotype DX DCIS score, a study pathologist will 
review the H&E slides from the surgical specimen and select a block for 
release to the TRIP Laboratory.  We anticipate needing 6 unstained 
sections per patient specimen for sufficient RNA isolation for the assay. 
 
13.3 Routing 
If needed, requested pathology slides will be sent to the research study 
pathologist. 
 


34 
 
14. 
RECORDS TO BE KEPT 
The PI will supervise the data collection and management.  The following types of data 
and materials will be collected: 
 
14.1 Images 
Images from the PET/MRI examinations will be stored on the local picture archiving 
and communication system (PACS) (McKesson, San Francisco, CA).  The local 
PACS system is password protected behind the UWHC Department of Radiology 
firewall.  
 
14.2 Regulatory and Consent 
A research chart will be created for each subject.  The chart will include the signed 
consent form, a copy of the subject’s experimental bill of rights, and a signed 
HIPAA form.  Research charts will be kept in a locked file cabinet within a study 
team members secure office.  An enrollment log will be maintained.  The 
enrollment log will confirm that informed consent was obtained on each subject.  
The patient has the right to decline to participate in the study and to request 
removal from the study at any time.  Informed consent will be provided and signed 
prior to enrollment in the study.  Patients may refuse to answer any questions 
asked during the duration of the study if they are too uncomfortable to answer.  All 
of these potential risks will be described to the patient in the informed consent 
document.  
 
14.3 Confidentiality 
Information about study subjects will be kept confidential and managed according 
to the requirements of the Health Insurance Portability and Accountability Act of 
1996 (HIPAA). Subjects will be assigned a unique study number upon enrollment 
that will be used to label their research data in lieu of directly identifiable 
information.  All subject data collected during participation in the study will be kept 
in a locked file cabinet within a secure office or a password-protected database 
that uses departmental servers and will only be accessible to study team members.  
After the study is completed, all data will be de-identified for the purposes of 
research presentations/publications.  The study breast MRI examinations will be 
archived on the standard clinical PACS system which is password protected 
behind the UWHC firewall.  The study data and records will be maintained for up 
to 5 years after the conclusion of the study, at which point the PI will destroy the 
key to the coded identifiers, thus permanently anonymizing the data. 
 
15. 
PATIENT CONSENT AND PEER JUDGMENT 
Current FDA, state, federal, and institutional regulations concerning informed consent will 
be followed. 
 


35 
 
16. 
DATA AND SAFETY MONITORING 
Safety monitoring of research protocols investigating novel PET tracers utilize a 
combination of tools. These are framed to provide adequate clinical trial oversight 
ensuring that the research team is complying with the conditions of IRB approval and 
FDA requirements. The tools enable frequent evaluations of study-related activities, 
identification of deviations or noncompliance with the conduct of the study or protocol, 
review of adverse events tracking and reporting, and review of drug production and 
accountability. 
 
These tools include: 
• Study visit checklists – Research Coordinators use study visit checklists, 
developed in conjunction with the PI, to ensure that all study required procedures 
and processes are met before, during and after the subject has been enrolled. 
Items listed on these checklists include informed consent obtained, consent 
questions answered (and by whom), medications reviewed, MR safety form, etc. 
These checklists are completed and reviewed by the study coordinator requiring 
signature approval for each study subject to ensure tight adherence to the protocol.  
 
• Safety monitoring – The safety monitoring of subjects enrolled in the research 
includes both internal and external safety checks governing the administration of 
18F-fluoroestradiol (FES). Internal monitoring is performed by co-investigators and 
external monitoring by a team of four physicians, scientists, and staff with the 
appropriate broad clinical and technical expertise. The internal monitoring plan 
includes a brief review of each subject visit after it occurs.  In this regard, the study 
team will discuss data quality, 18F-FES production and administration, and subject 
compliance and tolerance of research procedures.  
 
The external monitoring plan includes a 4-person committee of physicians, 
scientists, and staff with the appropriate expertise (nuclear medicine, oncology, 
research nurse manager, medical physics) that meets annually with 
representatives from the research team, to discuss research progress, AE reports, 
as well as other data reports (note-to-file documentation, protocol deviations, 
reportable events) compiled by the study team.  If an AE occurs, an ad hoc 
committee meeting will be organized to discuss whether the event is considered 
serious, whether it can be attributed to research procedures, whether it constitutes 
an unanticipated problem or non-compliance on the part of the study team, and 
the plan for resolution and a future remediation.  
 
As part of this plan, the monitor(s) will verify that:  
• The rights and well-being of human subjects are protected  
• Reported study data are accurate, complete, and verifiable from source 
documents  
• The conduct of the study is in compliance with the currently approved 
protocol, GCPs, applicable regulatory requirements, and guidelines for 
clinical research studies at the University of Wisconsin-Madison and its 
affiliates  


36 
 
 
16.1 Risks 
16.1.1 
MRI 
The risk from the MRI component of the exam is minimal and is primarily 
related to claustrophobia and discomfort with positioning.  Only staff skilled 
in the placement of IVs will place IVs for the study breast PET/MRI.  Injection 
of gadolinium contrast has common mild side effects, including nausea, 
headache, and hives.  More serious reactions, while rare, can occur, 
including allergic reactions.  Any significant allergic reaction or contrast 
extravasation will be monitored and treated appropriately by clinical staff.   
 
All hardware used to obtain MR images is FDA approved and will be used 
in accordance with the conditions approved by FDA.  The investigational 
software being used in image acquisition is designed to stay within the 
current guidelines for MRI safety, established by the FDA.  In addition, the 
investigational software does not meet the definition of a Significant Risk 
Device as outlined by the FDA under 21 CFR 812.3 as being: 
• Intended as an implant and presents a potential for serious risk to 
the health, safety, or welfare of a subject; 
• Purported or represented to be for use supporting or sustaining 
human life and presents a potential for serious risk to the health, 
safety or welfare of a subject; 
• For a use of substantial importance in diagnosing, curing, mitigating, 
or treating disease, or otherwise preventing impairment of human 
health and presents a potential for serious risk to the health, safety 
or welfare of a subject; or 
• Otherwise presents a potential for serious risk to the health, safety, 
or welfare of a subject. 
 
16.1.2 
PET 
18F-FES has been safely administered to more than 1,000 healthy 
volunteers and breast cancer patients participating in clinical trials 
worldwide as of 2013.  In May 2020, 18F-FES was approved by the FDA 
under the brand name “CERIANNA”, but the labelled indication for clinical 
use is for a different breast cancer patient population (recurrent or 
metastatic) than included in this research study (DCIS).  Thus, we will 
continue to perform this research study under our existing approved IND.  
The only adverse events that have been attributed to 18F-FES at the levels 
described in the Investigators Brochure have been mild transient 
disturbances in taste and injection site pain.   
 
Risks associated with PET imaging result primarily from the radiation dose 
from the radiopharmaceutical.  For this research study, approximately 6 mCi 
of 18F-FES will be administered intravenously which is also the standard 
dose used for other clinical trials using 18F-FES.  The radiation absorbed 
effective dose equivalent to the whole body from intravenously injected FES 


37 
 
is estimated to be 0.022 mSv/MBq (4.88 mSv for a 6 mCi injection).  The 
critical organ is the liver, with an average absorbed dose of 0.13 mGy/MBq.  
For context, the average person in the United States receives an estimated 
effective dose of about 3 mSv per year from naturally occurring radioactive 
materials, such as radon and radiation from outer space.  The organ and 
total body doses associated with FES PET imaging are comparable to or 
lower than those associated with other widely used clinical nuclear medicine 
procedures and are well below the maximum suggested individual study 
and annual total body dose of 30 and 50 mGy, respectively, suggested for 
investigational radiopharmaceuticals by the FDA (50). 
 
16.1.3 
Unexpected findings 
All patients in this study will receive the clinical “gold standard”, diagnostic 
breast MRI and ER measurement via IHC, as part of their clinical care as a 
requirement for enrollment in the study.  Thus, the breast specific 18F-FES 
PET data is not expected to yield any unexpected findings. Subjects will not 
be informed of any unexpected findings on the 18F-FES PET/MRI imaging.     
16.1.4 
CT (performed only in rare instance when subject is unable to be 
imaged using the simultaneous PET/MRI scanner) 
Risks associated with CT include exposure to 1.5 mSv of radiation from the 
low-dose chest CT scan required for attenuation correction calculations.  
Thus, the total whole body effective dose equivalent for breast PET/CT is 
approximately 6.5 mSv.  This corresponds to approximately 2 years of 
natural background radiation and remains well below the annual 
occupational dose limit for radiation workers. 
 
Additionally, subjects may experience discomfort while lying in the PET/CT 
scanner.   
 
 
17. 
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