Added Value of Contrast Enhanced Mammography for Breast Cancer Staging in Patients Referred for a Second Opinion to a Tertiary Cancer Center
Phase: NA
Conditions: Breast Carcinoma, Invasive Breast Carcinoma
Sponsor: M.D. Anderson Cancer Center

PROTOCOL TITLE: Added value of contrast enhanced mammography for breast cancer 
staging referred for a second option to a tertiary cancer center 
Page 1 of 26
PROTOCOL TITLE: 
Added Value of Contrast Enhanced Mammography for Breast Cancer Staging in 
Patients Referred for A Second Opinion to A Tertiary Cancer Center 
PRINCIPAL INVESTIGATOR: 
Name: Olena Weaver, MD 
Department: Breast Imaging 
Telephone Number: (713)471-3613 
Email Address: ooweaver@mdanderson.org 
VERSION NUMBER/DATE: 
4 (07/21/2021) 
REVISION HISTORY 
Revision 
# 
Version Date 
Summary of Changes 
Consent 
Change? 
2 
Responses to SRC questions 
3 
2-2-2021
Responses to IRB 
yes 
4 
7-21-2021
Remove the presence of breast implants as an 
exclusion criterion 
No 

PROTOCOL TITLE: Added value of contrast enhanced mammography for breast cancer 
staging referred for a second option to a tertiary cancer center 
 
Page 2 of 26 
 
Table of Contents 
1.0 
Study Summary ........................................................................................................ 3 
2.0 
Objectives* .............................................................................................................. 5 
3.0 
Background* ............................................................................................................ 5 
4.0 
Study Endpoints* ..................................................................................................... 9 
5.0 
Procedures Involved*............................................................................................... 9 
6.0 
Data and Specimen Banking* ................................................................................ 17 
7.0 
Sharing of Results with Subjects* ......................................................................... 18 
8.0 
Study Timelines* ................................................................................................... 19 
9.0 
Inclusion and Exclusion Criteria* .......................................................................... 19 
10.0 Local Number of Subjects ..................................................................................... 20 
11.0 Recruitment Methods ............................................................................................. 20 
12.0 Withdrawal of Subjects* ........................................................................................ 20 
13.0 Risks to Subjects* .................................................................................................. 20 
14.0 Potential Benefits to Subjects* .............................................................................. 20 
15.0 Data Management* and Confidentiality ................................................................ 21 
16.0 Provisions to Monitor the Data to Ensure the Safety of Subjects* ........................ 22 
17.0 Compensation for Research-Related Injury ........................................................... 23 
18.0 Economic Burden to Subjects ................................................................................ 23 
19.0 Resources Available............................................................................................... 23 
20.0 Multi-Site Research* ............................................................................................. 23 
21.0 References .............................................................................................................. 23 
 
 
 

PROTOCOL TITLE: Added value of contrast enhanced mammography for breast cancer 
staging referred for a second option to a tertiary cancer center 
 
Page 3 of 26 
 
1.0 
Study Summary 
 
Study Title 
Added value of contrast enhanced mammography for breast 
cancer staging in patients referred for a second opinion to a 
tertiary cancer center 
Study Design 
Prospective observational cross-sectional or correlational 
study 
Study Specific 
Abbreviations/ 
Definitions  
CEM: contrast enhanced mammography 
BC: breast cancer 
OSF: outside facility (medical institution or office outside of 
MD Anderson) 
FFDM: full field digital mammogram (2D mammogram) 
LE: low energy images (a part of CEM exam, FFDM 
equivalent) 
DBT: digital breast tomosynthesis (3D mammogram) 
US: ultrasound 
 
 
Primary Objective 
To compare the accuracy of CEM and LE images (equivalent 
of FFDM as the standard of care) for the detection of 
additional cancer sites in the affected breast and in the 
contralateral breast. For the purpose of the study, up to 4 
additional biopsy sites will be included in the analysis. 
Secondary 
Objective(s) 
1. To evaluate the sensitivity, specificity, positive and 
negative predictive value of CEM compared to LE 
CEM images (FFDM equivalent), DBT and 
ultrasound for the detection of additional malignant 
lesions in the ipsilateral and contralateral breast. 
2. To evaluate the difference of the index cancer size 
estimation among CEM, LE images, DBT, and 
ultrasound compared to pathology measurements as 
the ground truth. 
3. To evaluate the incremental cancer detection rate 
provided by CEM, DBT, and US compared to the 
OSF diagnosis. 
 
Exploratory  
Objective(s) 
1. To evaluate the rate of referral to breast MRI in the 
study cohort. 
2. To evaluate the performance of MRI for breast 
cancer diagnosis and compare it with other imaging 
modalities of CEM, LE images, DBT and ultrasound. 
3. To evaluate the feasibility of CEM-guided biopsy of 
CEM- only detected lesions. The technical success of 
CEM guided biopsies will be determined by the 

PROTOCOL TITLE: Added value of contrast enhanced mammography for breast cancer 
staging referred for a second option to a tertiary cancer center 
 
Page 4 of 26 
 
fraction of biopsies that achieve adequate sampling of 
the target. 
Research 
Intervention(s)/ 
Investigational 
Agent(s)  
IV injection of iodinated contrast material 
 
IND/IDE #  
 
Study Population 
• Female patients with known invasive or in-situ breast 
cancer diagnosed at an outside facility and presenting 
to MD Anderson for staging with imaging. 
• Female patients referred from outside institutions 
with imaging findings categorized as highly 
suspicious (BI-RADS 5 or 4C) on outside imaging or 
on re-review by MD Anderson’s radiologists, and 
referred for staging at MDACC. 
Sample Size 
83 
Study Duration for 
individual 
participants 
One diagnostic CEM imaging examination  
In addition, if indicated, one CEM-guided biopsy 
 
 
 
 

PROTOCOL TITLE: Added value of contrast enhanced mammography for breast cancer 
staging referred for a second option to a tertiary cancer center 
 
Page 5 of 26 
 
2.0 
Objectives* 
2.1 
Primary Objectives 
• To compare the accuracy of CEM and LE images 
(equivalent of FFDM as the standard of care) for the 
detection of additional cancer sites in the affected breast 
and in the contralateral breast. 
2.2 Secondary Objectives 
• To evaluate the sensitivity, specificity, positive and negative 
predictive value of CEM compared to LE CEM images 
(FFDM equivalent), DBT and ultrasound for the detection 
of additional malignant lesions in the ipsilateral and 
contralateral breast. 
• To evaluate the difference of the index cancer size 
estimation among CEM, LE images, DBT, and ultrasound 
compared to pathology measurements as the ground truth. 
• To evaluate the incremental cancer detection rate provided 
by CEM, DBT, and US compared to the OSF diagnosis. 
2.3 Exploratory Objectives 
• To evaluate the rate of referral to breast MRI in the study 
cohort. 
• To evaluate the performance of MRI for breast cancer 
diagnosis and compare it with other imaging modalities of 
CEM, LE images, DBT and ultrasound. 
• To evaluate the feasibility of CEM-guided biopsy of CEM- 
only detected lesions. The technical success of CEM guided 
biopsies will be determined by the fraction of biopsies that 
achieve adequate sampling of the target.   
2.4 
Hypothesis 
We hypothesize that CEM will improve the diagnostic accuracy of 
incremental breast cancer detection compared to standard 2D 
mammography and will improve the accuracy of the index cancer size 
estimation. The overarching goal is to determine whether CEM will 
reduce the need for breast MRI and decrease the overall time and cost of 
preoperative imaging evaluation of patients with breast cancer. 
 
3.0 
Background* 
3.1 
Current MDACC practice protocols 
As a major tertiary cancer center, MD Anderson Cancer Center has a 
significant population of patients who present for staging of known breast 

PROTOCOL TITLE: Added value of contrast enhanced mammography for breast cancer 
staging referred for a second option to a tertiary cancer center 
 
Page 6 of 26 
 
cancer (BC) which was already diagnosed at an outside facility (OSF), or 
who have OSF imaging findings that are assigned category 5 (highly 
suspicious with the probability of malignancy >95%) or 4C (suspicious 
with the probability of malignancy 50-95%) according to the American 
College of Radiology (ACR) Breast Imaging Reporting and Database 
System (BI-RADS) on OSF imaging [1]. Precise delineation of the extent 
of disease in the affected breast and evaluation of the contralateral breast 
are crucial for surgical treatment planning in BC patients [2]. Even in 
patients with no known BC, a second opinion at a specialized cancer 
center can make a significant impact on clinical management, changing 
the original interpretation in 36- 47% of lesions [3, 4]. In patients who 
present with known BC at MDACC, the rate of upstaging upon second 
opinion interpretation and possible re-imaging is 25%, which changes 
surgical management in 12% of patients [5]. At the same time, the re-
operation rate after breast conservation surgery in BC patients is 19% 
[5]. This is suboptimal and may be due to underestimation of tumor size, 
but this rate is lower than the national rate, which reaches 30% [2]. 
The current protocol for staging of OSF BC cases consists of a second 
read of interpretable OSF mammograms or repeating technically 
suboptimal mammograms, followed by ultrasound, ultrasound-guided 
and/or stereotactic-guided biopsies, when indicated. Some patients also 
require breast MRI with second look ultrasound and ultrasound- or MRI-
guided biopsies, which prolongs work-up and delays treatment. 
At our institution, using ultrasound and MRI almost doubles the number of 
additional suspicious breast lesions found on mammography. 45% of these 
additional lesions are malignant. The sensitivities of mammography (MG), 
US, and MRI are 36, 71, and 85%, respectively, and their specificities are 
respectively 76, 68, and 39%, making MRI the most sensitive, and the MG 
the most specific modality. 18% of additional malignant lesions at MDA 
are found on MRI only [6]. Unfortunately, the need for breast MRI often 
delays treatment due to the limited availability of magnet time. MRI is also 
an expensive imaging test, further limiting access.   
3.2 
The role of functional imaging 
Functional imaging modalities such as breast MRI and nuclear breast 
imaging (NBI) require IV contrast injections and provide information on 
abnormal vascular architecture and increased vessel wall permeability 
that is common in BC [7]. Breast MRI is the most extensively researched 
among the functional modalities and serves as the gold standard for 
evaluation of new imaging modalities. MRI shows the highest sensitivity in 
detecting additional malignant lesions in the affected breast and the 
contralateral breast [2, 8-10]. MRI is also the most accurate modality for 
the evaluation of the index cancer size, while the conventional imaging 
modalities used for the first line of cancer staging- mammography and 
ultrasound- only modestly correlate with the tumor size on pathology [2, 
11]. These attributes of MRI contribute to improved outcomes of surgical 

PROTOCOL TITLE: Added value of contrast enhanced mammography for breast cancer 
staging referred for a second option to a tertiary cancer center 
 
Page 7 of 26 
 
treatment of BC, in particular, to the decreased need for re-excision for 
positive margins [2, 12, 13]. At the same time, MRI has a high rate of 
false positive results that require additional biopsies and may delay 
cancer treatment [14, 15]. 
Additional limitations of MRI include high cost, long scanning time, and 
limited availability of equipment. There is also a significant patient 
acceptance factor [16]. In one large study, only 51.6% of patients who 
were offered MRI at no cost agreed and successfully completed the MRI 
study. The main reasons for patient refusal were claustrophobia and time 
constraints [17]. 
Dedicated nuclear breast imaging (NBI) is a group of functional imaging 
modalities that depict the distribution of radioactive tracers injected into 
the patient. This group includes breast specific gamma imaging (BSGI), 
molecular breast imaging (MBI), and positron emission mammography 
(PEM) [18]. The role of NBI is evolving. The positive predictive values 
(PPVs) of MBI and BSGI in cancer detection are reported at 35-60% and 
are not affected by breast density, but are affected by lesion size, detecting 
71% of lesions less than 5 mm in size, as opposed to 84-99% of larger 
tumors.  
The disadvantages of NBI are long scanning time, relatively low 
resolution, whole-body radiation, and limited visualization of the 
prepectoral tissues. Yet NBI may be a viable diagnostic option for eligible 
women who cannot tolerate MRI [18]. 
3.3 
Contrast Enhanced Mammography 
CEM is a relatively new imaging technique that is based on 
mammography (MG) but utilizes intravenous contrast that adds functional 
information to morphologic information. Each CEM study has two 
components. The first component is a set of low-energy (LE) images, 
which are equivalent to non-contrast MG and are interpreted as FFDM, 
providing all the benefits of conventional mammography. A set of high-
energy images are also obtained, above the k-edge of iodine (i.e. > 33 
kVp). Then processing is performed to subtract the low-energy from the 
high-energy images and thereby create the second component, subtracted 
contrast images (SCI), which reflect only areas of enhancement. 
Enhancement shows the functional state of the tissues, i.e. tissue 
vascularity and blood vessel permeability that is similar to MRI.  
CEM improves the diagnostic accuracy of MG alone, and even performs 
better than MG combined with DBT or MG with US [19-22]. CEM has 
been shown to be similar in sensitivity, but higher in specificity, than MRI 
for detection of index BC [19, 23]. It also efficiently finds multicentric and 
multifocal BC, as well as cancer in the contralateral breast with similar 
sensitivity but higher specificity than MRI [19, 24]. The higher specificity 
may make CEM more desirable than MRI in pre-operative cancer staging, 
since the high false positive rate currently limits the use of MRI [25]. 

PROTOCOL TITLE: Added value of contrast enhanced mammography for breast cancer 
staging referred for a second option to a tertiary cancer center 
 
Page 8 of 26 
 
CEM is also significantly faster and significantly less costly than MRI 
[16]. It can be easily incorporated into the workflow without any added 
work-up time. In addition, CEM is preferred over MRI by patients [22].  
The main concerns raised about CEM are the need for intravenous 
iodinated contrast administration and the associated risk of contrast-
related complications, as well as increased radiation exposure. However, 
in a recent (2019) systematic literature review of CEM technique 
involving 14,012 patients, only 30 adverse reactions were reported, of 
which 26/30 were mild (pruritus, hives, etc, that resolved promptly without 
treatment); 3/30 cases were moderate (nausea, vomiting, urticaria etc, 
resolved after antihistamines or corticosteroids); and 1/30 cases was 
severe, non-fatal, requiring short-term intensive care [26]. 
As routinely performed, the radiation dose from CEM is approximately 2.3 
mGy for a combination of 2 exposures. This is 1.5 times higher than a 
single exposure of FFDM, but is 25% lower than a combination mode 
mammography, which is the current standard of care at MDACC and 
consists of FFDM and DBT exposures. It is also significantly below the 
FDA allowed maximum glandular dose of 3 mGy per one exposure [27-
29], [personal communication with GE Healthcare engineering team].   
Until recently, no direct method of tissue sampling under direct CEM 
guidance existed, which made it impossible to biopsy CEM-only detected 
lesions, and often required performing breast MRI to search for a 
correlating lesion and for biopsy guidance [30]. This has changed with 
the introduction of the first commercially available CEM-guided biopsy 
device (GE Healthcare Pristina Serena Bright), which has obtained 510(k) 
clearance by the Food and Drug Administration in June 2020. This 
enables direct biopsy of CEM- only detected lesions without the need for 
MRI and MRI- guided biopsies that increase cost and delay patient care 
(Appendix A). 
3.4 
Multiparametric cohort 
We are proposing to add comprehensive multiparametric data collection 
on the study cohort that could aid in patient stratification [ongoing 
MERIT study (PA17-0584)]. This would involve administering a 
questionnaire, collecting blood samples, and archiving raw 
mammographic images, for blood and imaging biomarkers discovery and 
validation. The analysis of the multiparametric data may provide 
additional predictive and prognostic information on BC patients, which 
could be helpful in the choice of therapy and follow-up. 
3.5 
INNOVATION 
The use of CEM as a first line modality in the evaluation of breast cancers 
diagnosed at OSF has not been studied. Our proposed protocol may prove 
beneficial for improving the time and cost-efficiency of imaging work-up, 
as well as for the overall optimization of workflow for the benefit of the 

PROTOCOL TITLE: Added value of contrast enhanced mammography for breast cancer 
staging referred for a second option to a tertiary cancer center 
 
Page 9 of 26 
 
unique population of patients referred from OSF to MD Anderson Cancer 
Center. 
  
4.0 
Study Endpoints* 
4.1 Primary study endpoint: 
Accuracy of CEM for incremental cancer detection in the ipsilateral and 
contralateral breasts. For the purpose of the study, up to 4 additional 
biopsy sites will be included in the analysis. 
4.2 Secondary study endpoints: 
• Sensitivity, specificity, positive and negative predictive value of 
CEM, LE images, DBT, and ultrasound compared to pathology 
measurements as the ground truth. 
• The difference of the largest measurement of the index cancer on 
LE, CEM, DBT and US compared to pathology. 
• Incremental cancer detection rate provided by CEM, DBT and US. 
4.3 
Exploratory Endpoints: 
• Rate of breast MRI utilization and the corresponding diagnosis in 
the study cohort. 
• The fraction of CEM biopsies that achieve adequate sampling of 
the target.   
 
5.0 
Procedures Involved* 
 
5.1 
PROCEDURE TO OBTAIN CONSENT 
Eligible and interested subjects will be consented for study participation.  
A research staff member who is trained in the informed consent process 
will explain the study, invite the patients to enroll, and obtain the informed 
consent of women who wish to participate.  Subjects may be enrolled 
using the approved MD Anderson procedures for remote consenting. 
 
5.2 
PATIENT WORKFLOW (Fig.1) 
 

PROTOCOL TITLE: Added value of contrast enhanced mammography for breast cancer 
staging referred for a second option to a tertiary cancer center 
 
Page 10 of 26 
 
 
Fig. 1. Patient workflow. Research components are represented in blue, 
and standard of care components in black. 
 
5.3 
IMAGING WITH CEM 
Safety checklist and IV injection: 
The imaging technologist, the study personnel, and the radiologist will be 
responsible for ensuring the safe administration of IV contrast. IV contrast 
injections and eligibility screening will be performed in accordance with 
MDACC institutional policies. Contrast safety will be ensured by 
following the current UTMDACC DIVISION OF DIAGNOSTIC 
IMAGING POLICY # 3.30, amendment for CEM (Appendix B). 
The imaging technologist and the study nurse or research coordinator will 
use a patient safety checklist for verifying that the patient has no 
contraindications for the study. 
If a patient passes the safety checklist, an IV catheter will be placed in the 
patient’s forearm or antecubital vein in the mammography suite 
1
• Patients with BC diagnosed at an outside facility and referred for cancer 
staging to MDACC, or patients with BI-RADS 5 or BI-RADS 4C imaging findings
2
• Recruitment and consenting
3
• Contrast-enhanced mammography + DBT (LE + DBT as standard of care, + 
contrast injection as research), questionnaire, blood draw
4
• First clinical read of CEM
5
• Ultrasound (standard of care)
6
• Biopsy with ultrasound, stereotactic, CEM, or MRI guidance (standard of care)
7
• Pathology result
8
• 5 reader image review (LE, DBT, CEM)
9
• Data collection, including outside facility diagnostic imaging results, US and 
MRI results (when available), followed by data analysis

PROTOCOL TITLE: Added value of contrast enhanced mammography for breast cancer 
staging referred for a second option to a tertiary cancer center 
 
Page 11 of 26 
 
immediately before the procedure by a trained nurse, mammography 
technologist, or study coordinator.  The patients will be sitting for the 
injection to minimize vaso-vagal reactions. Low-osmolality iodine-based 
intravenous contrast (Omnipaque 350 mg I/mL; GE Healthcare or 
equivalent) will be injected using a power injector, at a rate of 3 mL/s for 
a total dose of 1.5 mL/kg body weight, but not exceeding 150 ml, followed 
by a 30 mL saline flush [30-32]. 
Imaging technique: 
CEM will be administered using FDA-approved equipment. The study will 
be conducted using a full-field digital mammography system capable of 
providing low- and high-energy exposures to the breast under the same 
compression, as well as producing subtracted contrast images, such as 
Senographe Pristina (GE Healthcare, Buc, FR) or an equivalent system. 
1. The imaging will start with the affected breast 2 min after contrast 
injections and will consist of one high and one low energy exposure in 
succession. The affected breast will be imaged in craniocaudal (CC), 
mediolateral oblique (MLO), and lateromedial (LM) projections (Fig.1).  
CC and MLO images will also be obtained of the unaffected breast (Fig. 
2). 
 
Fig. 2. CEM imaging sequence.  
2. Additional views will be obtained, when needed (e.g. XCCL 
(exaggerated craniocaudal lateral) view), to include all breast tissue per 
clinical protocol. 
3. For those women who have not undergone DBT as a part of their 
screening or diagnostic imaging within 3 month from the study, bilateral 
DBT study will be performed immediately following the CEM study. A 
complete bilateral DBT study will be obtained utilizing DBT projections 
and reconstructed synthetic 2D views. This will include CC, MLO, and LM 
projections of the affected breast, and CC and MLO projections of the 
non-affected breast. 
Patients will be observed for 30 minutes after the contrast injection to 
ensure the absence of symptoms of delayed reaction to iodine-based 
contrast as reported by patients. The patient will be encouraged to drink 
at least 500 ml of water after the procedure. 
Imaging quality assurance: 

PROTOCOL TITLE: Added value of contrast enhanced mammography for breast cancer 
staging referred for a second option to a tertiary cancer center 
 
Page 12 of 26 
 
The images will be immediately sent to the radiologist for quality 
assurance via PACS. Additional images (exaggerated or repeat views) 
may be obtained for technical issues, if necessary. 
OTHER IMAGING STUDIES: 
Decision making algorithm 
 
 
Ultrasound 
Due to a subjective nature of ultrasound, the ultrasound images will not 
be included in the reader study. However ultrasound images and reports 
will be obtained from the patients’ medical records and analyzed to 
provide correlation per lesion with the FFDM, DBT, and CEM studies. 
MRI 
When available, MRI reports and MRI images will be obtained from the 
patients’ medical records and analyzed to correlate with the FFDM, DBT, 
CEM, and ultrasound findings. 
Image-guided biopsies 

PROTOCOL TITLE: Added value of contrast enhanced mammography for breast cancer 
staging referred for a second option to a tertiary cancer center 
 
Page 13 of 26 
 
Ultrasound-guided FNA or core biopsies, as well as stereotactic, or MRI-
guided core biopsies will be performed as a part of routine clinical care, 
when indicated. The biopsies may also be performed using a CEM-guided 
biopsy instrument (GE Healthcare Pristina Serena Bright).   
The following data will be collected from the biopsy reports: 
• Number of core samples 
• Needle gauge 
• Adequacy of sampling, which for stereotactic biopsies will include 
the percent of microcalcifications removed, and the number of 
cores with microcalcifications 
• Concordance with the pathology results. 
 
5.4 
CEM-guided biopsies: 
CEM- guided biopsy device uses a stereotactic technique to target areas 
of abnormal enhancement in the breast. The first commercially available 
CEM-guided biopsy device (GE Healthcare Serena Bright™ CEM biopsy 
system) has been U.S. Food & Drug Administration 510(k) cleared in May 
2020. This system is capable of both conventional stereotactic and CEM-
guided biopsies. For both methods the system uses angular 
mammographic acquisitions in the breast to calculate the target, but for 
stereotactic biopsies it uses the morphologic abnormality in the breast as 
the target, whereas for CEM-guided biopsies it uses the area of suspicious 
enhancement as the target. With the exception of targeting, the biopsy 
procedure and the biopsy needles used for the procedure are identical for 
both methods (Appendix A). 
For those study patients who demonstrate abnormal CEM enhancement 
with no correlate on FFDM or US, GE Healthcare Serena Bright™ CEM 
biopsy system will be used to perform CEM- guided biopsies. CEM- 
guided biopsies may also be utilized for choosing the areas of most 
prominent CEM enhancement as biopsy targets for extensive 
mammographic abnormalities, where precise targeting is difficult. The 
presence of distinct abnormal enhancement within a target is expected to 
correlate with the most metabolically active areas of the lesion [31]. This 
may improve the accuracy of biopsy and decrease the rate of upgrade to 
malignancy at surgery. 
5.5 
Biopsy markers and post-procedure mammograms 
For all biopsy methods a biopsy marker will be placed at the target as the 
standard of care [32]. As a part of the standard of care we will perform a 
post-procedure mammogram after tissue sampling and clip placement 
[32].  
For those patients who undergo CEM-guided biopsies for pathologic 
enhancement, post-procedure CEM images of the biopsied breast will be 
obtained. 

PROTOCOL TITLE: Added value of contrast enhanced mammography for breast cancer 
staging referred for a second option to a tertiary cancer center 
 
Page 14 of 26 
 
The technical success of CEM guided biopsies will be determined by the 
fraction of biopsies that achieve adequate sampling of the target. 
5.6 
Ground truth 
Pathology results from image guided biopsies and surgical pathology 
results will be considered the ground truth.  Breast tissue lesions will be 
categorized as positive if diagnosed as invasive BC or ductal carcinoma in 
situ (DCIS), and otherwise will be categorized as negative, including the 
lesions of uncertain malignant potential without subsequent surgical 
upgrade to invasive cancer or DCIS.  
 
5.7 
Pathology 
As part of the standard of care, the biopsy will be evaluated by a breast 
pathology specialist as part of the routine diagnostic clinical service. After 
the case has been finalized, the slides will be reviewed by the breast 
pathology collaborator for this study in order to record the additional 
information listed below. 
The following parameters will be recorded: 
• Pathologic diagnosis 
• The maximal diameter of the dominant abnormality 
• The maximal diameter of the abnormality with the highest level of 
suspicion (Invasive cancer, in-situ cancer, atypia) 
 
For invasive cancers/DCIS: 
• Histologic/nuclear grade 
• Presence of tumor necrosis for invasive carcinoma and/or 
comedonecrosis for DCIS 
• Architectural growth pattern for DCIS  
• The Presence of lymphovascular invasion 
• Biomarker status (ER, PR, Her-2/neu, Ki-67) 
• Presence of calcifications 
• Tumor infiltrating lymphocyte analysis 
 
 
5.8 
Multiple reader study design  
Low-energy images produced as a part of CEM are of sufficient quality 
for clinical interpretation (equivalent to directly acquired 2D 
mammographic images), and will be interpreted accordingly by 
radiologists. 
The reader study will have 2 components: 

PROTOCOL TITLE: Added value of contrast enhanced mammography for breast cancer 
staging referred for a second option to a tertiary cancer center 
 
Page 15 of 26 
 
1. The first interpretation of the entire CEM study, including all its 
components, will be done clinically by one radiologist after the 
exam is performed. Its results will be actionable and will affect the 
patient’s management. 
2. Multiple reader study. The results of this study will not be used 
for clinical care, and will not be reported to the patients or 
referring clinicians. 
Each patient’s study will contain LE images (FFDM equivalent), DBT 
images, and CEM subtraction images. All these components will be 
separated and presented to radiologists in different combinations for 
within-subject comparison. As a part of the multi-reader component, the 
study images for every patient will be reviewed in 4 sets by 5 radiologists 
each. Images for the same patients will be read by radiologists with an 
interval of at least 2 month to prevent case memorization. 
1. LE (FFDM equivalent) images only 
2. LE (FFDM equivalent) with DBT 
3. LE followed by DBT followed by CEM subtraction images 
4. LE followed by subtraction images (complete CEM study) 
The study radiologists will be aware of the patients’ inclusion criteria, but 
will be blinded to the clinical diagnostic reports, any and all comparison 
images of any modality outside of the assigned protocol, and the 
pathology report.  
5.9 
The sequence of the imaging studies and the parameters to be 
collected are presented below. The reporting will be done using ACR BI-
RADS Fifth edition recommendations.  
 
1. LE images: 
• Laterality  
• Clock position 
• 3 dimensional measurements of the index mass (antero-posterior, 
craniocaudal, transverse), when possible 
• View demonstrating the finding best (CC, MLO, LM) 
• The number, laterality, and clock position of additional lesions 
• Breast density (Bi-RADS A-D) 
• BI-RADS assessment per lesion using the 7-point BI-RADS® scale 
(1, 2, 3, 4a, 4b, 4c, 5) (Fig.3). BI-RADS categories 1-3 will be 
considered negative, and BI-RADS categories 4-5 will be 
considered positive. 
2. DBT images: 
• Laterality  
• Clock position 

PROTOCOL TITLE: Added value of contrast enhanced mammography for breast cancer 
staging referred for a second option to a tertiary cancer center 
 
Page 16 of 26 
 
• 3 dimensional measurements of the index mass in question (antero-
posterior, craniocaudal, transverse), when possible 
• View demonstrating the finding best (CC, MLO, LM) 
• The number, laterality, and clock position of additional lesions 
• BI-RADS assessment using the 7-point BI-RADS® scale (1, 2, 3, 
4a, 4b, 4c, 5) (Fig.3). BI-RADS categories 1-3 will be considered 
negative, and BI-RADS categories 4-5 will be considered positive. 
3. CEM  
• Background enhancement 
• The presence or absence of pathologic enhancement in the area of 
index mass, and the degree of enhancement above background. 
• 3 dimensional diameters of the pathologic enhancement (antero-
posterior, craniocaudal, transverse), when available. 
• The number, laterality, and clock position of additional lesions 
• View demonstrating the finding best (CC, MLO, LM) 
• BI-RADS assessment after adding CEM. BI-RADS categories 1- 3 
will be considered negative, and BI-RADS categories 4-5 will be 
considered positive. 
 
 
 
Fig. 3 BI-RADS assessment categories [1] 
 
A PACS-based MDACC-created and approved software will be utilized 
for data collection by the radiologists and directly transferred for 
statistical analysis. 
 
Lexicon 
There is currently no standard reporting language for contrast enhanced 
mammography. The most commonly used conventional approach to 
reporting will be utilized for the study: for the mammographic findings, 
the BI-RADS mammography lexicon will be utilized; for the enhancement 
patterns, the BI-RADS MRI lexicon will be applied (fig.4) [1, 33]. 

PROTOCOL TITLE: Added value of contrast enhanced mammography for breast cancer 
staging referred for a second option to a tertiary cancer center 
 
Page 17 of 26 
 
 
Fig. 4 MRI descriptors of the BI-RADS lexicon [34] 
 
Follow-up 
We will follow up the study patients for at least 12  months. We will review 
the patients’ medical records, including clinical notes, pathology, and 
radiology reports. This will be done to monitor for possible development 
of new BC or cancer recurrence. Results from biopsy and/or follow-up 
will serve as the ground truth and will be used to determine the true 
positive and true negative. 
 
6.0 
Data and Specimen Banking* 
6.1 
Registration  
 

PROTOCOL TITLE: Added value of contrast enhanced mammography for breast cancer 
staging referred for a second option to a tertiary cancer center 
 
Page 18 of 26 
 
All subjects who have given informed consent and meet eligibility criteria 
must be registered through the MDACC CORe system. 
 
6.2 
Questionnaire  
 
If not already enrolled in the MERIT study (PA17-0584), participants will 
be asked to complete a questionnaire that collects data on personal and 
family history of cancer, health status, breast cancer risk factors, diet, 
weight gain, and physical activity (Appendix C1, C2). The questionnaire 
or a link to the questionnaire may also be sent to the participants at a 
different time from their mammography appointment (before or after) via 
text or email, or through our electronic health record system.  The 
questionnaire data may also be collected via telephone by research staff.  
Essential data elements will be collected from the patients’ medical 
records. 
 
6.3 
Biospecimen Collection 
 
A member of the research staff will collect blood at the time of the CEM 
examination but before contrast is injected. To collect blood specimens, a 
PIVOTM device (Velano Vascular) may be used by trained staff to perform 
the blood draw and the contrast injection through the same IV access to 
avoid multiple patient sticks (Appendix D). 
 
The blood will be delivered to a facility within MD Anderson where it will 
be processed by trained personnel.  Additional details regarding blood 
processing Standard Operating Procedures (SOPs) are described in 
Appendix E.  The McCombs Institute will manage the biospecimens and 
will utilize portions of samples to evaluate candidate biomarkers.   
 
Samples from each patient will be assigned a unique specimen 
identification number.  This number will become a part of the repository 
and will be used to identify the subjects' data in the system. In this way, no 
personal identification information such as name or a social security 
number is necessary. 
 
If the participant is also enrolled in any other McCombs Institute early 
detection study (for example, 2013-0609, PA17-0791), biospecimen 
collection is not required if the last collection was within 30 days. 
7.0 
Sharing of Results with Subjects* 
7.1 The results of the first clinical read of CEM studies will be provided 
within the frame of the clinical workflow, will affect patient care, 
and will be reported to the patient and her referring physician. 
7.2 The results of the multi-reader component will not be shared with the 
patient or her referring provider. 

PROTOCOL TITLE: Added value of contrast enhanced mammography for breast cancer 
staging referred for a second option to a tertiary cancer center 
 
Page 19 of 26 
 
8.0 
Study Timelines* 
8.1 Describe: 
• 
The subject participation will consist of a one-time CEM study. 
The patients’ pertinent clinical information, including imaging, 
pathology and clinical reports will be collected for 12 months. 
• 
In those patients who need a CEM-guided biopsy, the 
participation in the study will also include IV contrast 
administration for the biopsy. 
• 
The study enrollment process is expected to continue for 12 
months. 
• 
March 2022 
9.0 
Inclusion and Exclusion Criteria* 
9.1 
INCLUSION CRITERIA 
• 
Female patients 18 years of age or older with known invasive 
or in-situ BC diagnosed at an outside facility and presenting to 
MD Anderson for staging with imaging. 
• 
Female patients 18 years of age or older referred from outside 
institutions with imaging findings categorized as highly 
suspicious (BI-RADS 5 or 4C) on outside imaging or on re-
review by MD Anderson’s radiologists and referred for staging 
at MDACC. 
• 
Willingness to participate in the study and ability to provide 
informed consent.  
9.2 
EXCLUSION CRITERIA   
• 
 
• 
Breast surgery within 6 months.  
• 
Known allergy to iodine-containing contrast agents. 
• 
History of anaphylactic reaction to any substance that required 
hospitalization or IV placement. 
• 
Renal insufficiency; hyperthyroidism. 
• 
Detection of non-breast primary or metastatic cancer in the 
breast.  
9.3 
PROCEDURE TO OBTAIN CONSENT 
Eligible and interested subjects will be consented for study participation.  
A research staff member who is trained in the informed consent process 
will explain the study, invite the patients to enroll, and obtain the informed 
consent of women who wish to participate.  Subjects may be enrolled 
using the approved MD Anderson procedures for remote consenting. 

PROTOCOL TITLE: Added value of contrast enhanced mammography for breast cancer 
staging referred for a second option to a tertiary cancer center 
 
Page 20 of 26 
 
10.0 Local Number of Subjects 
10.1 83 subjects 
11.0 Recruitment Methods 
Research staff will identify potential subjects via the UT MDACC 
information system. The patients will be approached by either the Clinical 
Cancer Prevention or the Diagnostic Imaging faculty, or qualified 
research staff, for their consent prior to their procedure. This may be done 
before or on the day of their diagnostic mammography appointment at the 
MDACC Nellie B. Connally Breast Imaging Center, or via a telephone 
conversation or a teleconference with a study coordinator, an email, or 
text messaging via MD Anderson approved systems. MyMDAnderson 
website and flyers may be utilized to contact patients. The patients will not 
be compensated for their participation. 
12.0 Withdrawal of Subjects* 
12.1 
The patients may refuse participation at any time for any reason. 
12.2 
The subjects will be withdrawn from the research without their 
consent in the following situations: 
• The patient has consented to the study but is determined to be 
ineligible before CEM is completed 
• The patient does not complete CEM imaging 
• The patient refuses a biopsy or chooses to have a biopsy at an outside 
institution 
• In these cases, the patients’ research files will be removed and any 
collected data will not be used for analysis. 
 
13.0 Risks to Subjects* 
13.1 
The study will require an IV contrast injection, which carries a 
small risk of contrast reaction, which will be minimized by the study 
personnel by patient pre-screening and following MDACC IV contrast 
injection protocols. 
13.2 
The extra imaging study carries small extra dose of ionizing 
radiation, approximately 30% more than a standard 2D mammogram, but 
less than a combination mode 3D mammogram. 
13.3 
CEM may detect abnormalities in the breasts which are not seen 
with mammography or ultrasound and may require CEM- guided biopsies. 
14.0 Potential Benefits to Subjects* 

PROTOCOL TITLE: Added value of contrast enhanced mammography for breast cancer 
staging referred for a second option to a tertiary cancer center 
 
Page 21 of 26 
 
14.1 
CEM is known to have higher sensitivity for cancer detection than 
MG and US and may benefit the study patients by finding BC that were not 
previously seen on other imaging studies.  
14.2 
CEM may eliminate the need for breast MRI, which is a costly and 
time-consuming study that can delay treatment in BC patients. 
14.3 
The presence of a CEM-guided biopsy device can enable direct 
biopsy of CEM- only detected lesions without the need for breast MRI or 
breast MRI-guided biopsies. 
 
15.0 Data Management* and Confidentiality 
15.1 
Statistical considerations 
The primary objective of this study is to compare the accuracy of CEM 
and LE images (FFDM equivalent) for the detection of additional cancer 
sites in the affected breast and in the contralateral breast among patients 
with known BC diagnosed or highly suspicious at an outside facility and 
presenting to MD Anderson for staging imaging.  The images of CEM/LE 
and DBT for each patient will be read/reviewed by 5 radiologists, and the 
majority agreement among 5 radiologists on the lexicon and BI-RADS 
assessment will be used for consensus. If all 5 radiologists disagree, then 
a consensus conference will be held. Pathology results will be considered 
the ground truth. Breast tissue lesions will be categorized as positive if 
determined as invasive cancer or DCIS, and otherwise will be categorized 
as negative that includes the lesions of uncertain malignant potential 
without subsequent surgical upgrade to invasive cancer or DCIS.  
The primary outcome of this study is accuracy determined by comparing 
the CEM/LE results to that of the pathologic evaluations. Specifically, it is 
defined as the number of concordant cases between CEM/LE and 
pathologic evaluation divided by the total sample size. Secondary 
outcomes include sensitivity, specificity, negative predictive value (NPV) 
and positive predictive value (PPV).  Sensitivity (specificity) is defined as 
the number of correctly diagnosed positive (negative) cases divided by the 
total number of confirmed positive (negative) cases, NPV is defined as the 
number of true negative lesions obtained from CEM/LE divided by the 
corresponding total predicted number of negative lesions. The PPV is 
similarly defined for positive breast lesions.  Cancer detection rate is 
defined as number of invasive malignancy or DCIS divided by the total 
sample size. 
A successful CEM guided biopsy is defined as a biopsy which successfully 
sampled the abnormality in question. This procedure will be considered 
feasible if 95% patients or more have successful CEM guided biopsy 
among those who will undergo this procedure, which is similar to the 
success rate of the prone stereotactic vacuum assisted biopsies [41].         

PROTOCOL TITLE: Added value of contrast enhanced mammography for breast cancer 
staging referred for a second option to a tertiary cancer center 
 
Page 22 of 26 
 
15.2 
 Sample size 
In two recent studies, the authors reported the accuracies of 78.0% 
(versus 69.0% for MG) [35] and 79.8% (versus 65.3% for MG) [36], 
respectively.  We utilize these clinical evidences for our sample size 
justifications. Using a two-sided extended McNemar test with a 
significance level of 0.05, a sample size of 83 patients provides 80% 
power to detect an accuracy difference of 12% between the two modalities 
of CEM and FFDM assuming the discordant of 20%. The method 
proposed by Wu (2018) was used to calculate the sample size, where the 
multiple lesions were adjusted via the average number of lesions and the 
variance that were assumed to be 1.4 and 1, respectively [37]. We further 
assumed the intracluster correlation of 0.4, and 0.2 for the intracluster 
correlation of the discordant pairs.   
15.3 
Statistical analysis plan 
Descriptive statistics will be used to summarize clinical variables of 
interest. Specifically, categorical measures will be summarized using 
frequencies and percentages and continuous measures will be summarized 
using means, standard deviations, medians, and ranges. Outcome 
variables of cancer detection rate, accuracy, sensitivity, specificity, PPV, 
and NPV will be estimated along with 95% confidence intervals; and 
compared between the modalities using the McNemar test or the weighted 
generalized score statistic proposed by Kosinski [38], if deemed 
appropriate . To account for multiple lesions, outcome variables will be 
analyzed using generalized liner mix models or extended McNemar’s test 
[39-41], and additional analyses may be further performed if deemed 
appropriate. 
 
16.0 Provisions to Protect the Privacy Interests of Subjects 
Identifiers (name, medical record number) will be collected but will be 
replaced by study numbers in the analytical file.  Scan/report dates will 
also be collected as part of this study, in order to identify different scans 
from the same patient. The key linking these numbers will be retained in a 
restricted database by the investigator.  All study personnel have 
completed training in methods for maintaining the confidentiality of health 
information.  Electronic records will be stored on password protected 
institution computers behind the institution firewall.  Only the PI and 
research staff involved in the study will have access to this data.  
Complete confidentiality will be maintained during this retrospective 
evaluation, manuscript preparation, and submission. 
 
Study sponsors and/or supporters receive limited amounts of PHI. They 
may also view additional PHI in study records during the monitoring 

PROTOCOL TITLE: Added value of contrast enhanced mammography for breast cancer 
staging referred for a second option to a tertiary cancer center 
 
Page 23 of 26 
 
process. MD Anderson’s contracts require sponsors/supporters to protect 
this information and limit how they may use it 
 
17.0 Compensation for Research-Related Injury 
17.1 
The research involves only minimal risk to subjects. The patients 
will not be compensated for their participation. 
18.0 Economic Burden to Subjects 
18.1 
The patients are not expected to encounter out of pocket costs. The 
cost of the imaging and IV contrast for the study is expected to be covered 
by a combination of insurance, GEIK grant, and an internal DICRC grant. 
The costs of biospecimen collection, questionnaire administration, and 
data storage will be covered by the Little Green Book Foundation. 
19.0 Resources Available 
19.1 
A full-field digital mammography system capable of providing low- 
and high-energy exposures to the breast under the same compression, as 
well as producing subtracted contrast images, such as Senographe 
Pristina (GE Healthcare, Buc, FR) 
19.2 
A CEM- guided biopsy device (GE Healthcare, Buc, FR) is 
planned to be installed in November 2020 
19.3 
%FTE is requested for a dedicated clinical mammography 
technologist and a clinical study coordinator 
19.4 
Approximately 5-8 patients per day are seen in the 
multidisciplinary clinic for staging of BC diagnosed at OSF. This results 
in a minimum of 1,305 potentially eligible patients. Recruiting 6% of the 
eligible pool, or 2 patients per week will allow completion of recruitment 
within 12 months. 
 
20.0 Multi-Site Research* 
N/A  
21.0 References 
 
1. 
D'Orsi, C.J., et al., ACR BI-RADS Atlas, Breast Imaging Reporting and Data 
System, 5th edition. 2013, Reston, VA: American College of Radiology. 
2. 
Kuhl, C.K., C. Lehman, and I. Bedrosian, Imaging in Locoregional Management 
of Breast Cancer. Journal of Clinical Oncology, 2020. 38(20): p. 2351-2361. 
3. 
Chang Sen, L.Q., et al., Impact of Second-Opinion Interpretation of Breast 
Imaging Studies in Patients Not Currently Diagnosed With Breast Cancer. J Am 
Coll Radiol, 2018. 15(7): p. 980-987.e1. 

PROTOCOL TITLE: Added value of contrast enhanced mammography for breast cancer 
staging referred for a second option to a tertiary cancer center 
 
Page 24 of 26 
 
4. 
Coffey, K., et al., The Impact of Patient-Initiated Subspecialty Review on Patient 
Care. J Am Coll Radiol, 2018. 15(8): p. 1109-1115. 
5. 
Candelaria, R.P., et al., Incremental Cancer Detection of Locoregional Restaging 
with Diagnostic Mammography Combined with Whole-Breast and Regional 
Nodal Ultrasound in Women with Newly Diagnosed Breast Cancer. Academic 
radiology, 2017. 24(2): p. 191-199. 
6. 
He, H., et al., Incremental cancer detection using breast ultrasonography versus 
breast magnetic resonance imaging in the evaluation of newly diagnosed breast 
cancer patients. The British journal of radiology, 2016. 89(1065): p. 20160401-
20160401. 
7. 
Weidner, N., The importance of tumor angiogenesis: the evidence continues to 
grow. Am J Clin Pathol, 2004. 122(5): p. 675-7. 
8. 
Lehman, C.D., et al., MRI evaluation of the contralateral breast in women with 
recently diagnosed breast cancer. N Engl J Med, 2007. 356(13): p. 1295-303. 
9. 
Houssami, N., et al., Accuracy and surgical impact of magnetic resonance 
imaging in breast cancer staging: systematic review and meta-analysis in 
detection of multifocal and multicentric cancer. J Clin Oncol, 2008. 26(19): p. 
3248-58. 
10. 
Chudgar, A.V., et al., Assessment of disease extent on contrast-enhanced MRI in 
breast cancer detected at digital breast tomosynthesis versus digital 
mammography alone. Clin Radiol, 2017. 72(7): p. 573-579. 
11. 
Choi, W.J., et al., The Accuracy of Breast MR Imaging for Measuring the Size of 
a Breast Cancer: Analysis of the Histopathologic Factors. Clin Breast Cancer, 
2016. 16(6): p. e145-e152. 
12. 
Mann, R.M., et al., The impact of preoperative breast MRI on the re-excision rate 
in invasive lobular carcinoma of the breast. Breast Cancer Res Treat, 2010. 
119(2): p. 415-22. 
13. 
Kuhl, C.K., et al., Impact of Preoperative Breast MR Imaging and MR-guided 
Surgery on Diagnosis and Surgical Outcome of Women with Invasive Breast 
Cancer with and without DCIS Component. Radiology, 2017. 284(3): p. 645-655. 
14. 
Houssami, N. and D.F. Hayes, Review of preoperative magnetic resonance 
imaging (MRI) in breast cancer: should MRI be performed on all women with 
newly diagnosed, early stage breast cancer? CA Cancer J Clin, 2009. 59(5): p. 
290-302. 
15. 
Brennan, M.E., et al., Magnetic resonance imaging screening of the contralateral 
breast in women with newly diagnosed breast cancer: systematic review and 
meta-analysis of incremental cancer detection and impact on surgical 
management. J Clin Oncol, 2009. 27(33): p. 5640-9. 
16. 
Patel, B.K., R.J. Gray, and B.A. Pockaj, Potential Cost Savings of Contrast-
Enhanced Digital Mammography. AJR Am J Roentgenol, 2017. 208(6): p. W231-
W237. 
17. 
Berg, W.A., et al., Reasons women at elevated risk of breast cancer refuse breast 
MR imaging screening: ACRIN 6666. Radiology, 2010. 254(1): p. 79-87. 
18. 
Berg, W.A., Nuclear Breast Imaging: Clinical Results and Future Directions. J 
Nucl Med, 2016. 57 Suppl 1: p. 46S-52S. 

PROTOCOL TITLE: Added value of contrast enhanced mammography for breast cancer 
staging referred for a second option to a tertiary cancer center 
 
Page 25 of 26 
 
19. 
Jochelson, M.S., et al., Bilateral contrast-enhanced dual-energy digital 
mammography: Feasibility and comparison with conventional digital 
mammography and MR imaging in women with known breast carcinoma. 
Radiology, 2013. 266(3): p. 743-51. 
20. 
Cheung, Y.C., et al., Diagnostic performance of dual-energy contrast-enhanced 
subtracted mammography in dense breasts compared to mammography alone: 
interobserver blind-reading analysis. Eur Radiol, 2014. 24(10): p. 2394-403. 
21. 
Mori, M., et al., Diagnostic accuracy of contrast-enhanced spectral 
mammography in comparison to conventional full-field digital mammography in 
a population of women with dense breasts. Breast Cancer, 2017. 24(1): p. 104-
110. 
22. 
Phillips, J., et al., Contrast-enhanced spectral mammography (CESM) versus 
MRI in the high-risk screening setting: patient preferences and attitudes. Clin 
Imaging, 2017. 42: p. 193-197. 
23. 
Sumkin, J.H., et al., Diagnostic Performance of MRI, Molecular Breast Imaging, 
and Contrast-enhanced Mammography in Women with Newly Diagnosed Breast 
Cancer. Radiology, 2019. 293(3): p. 531-540. 
24. 
Kim, E.Y., et al., Diagnostic Value of Contrast-Enhanced Digital Mammography 
versus Contrast-Enhanced Magnetic Resonance Imaging for the Preoperative 
Evaluation of Breast Cancer. J Breast Cancer, 2018. 21(4): p. 453-462. 
25. 
Ali-Mucheru, M., et al., Contrast-Enhanced Digital Mammography in the 
Surgical Management of Breast Cancer. Ann Surg Oncol, 2016. 23(Suppl 5): p. 
649-655. 
26. 
Zanardo, M., et al., Technique, protocols and adverse reactions for contrast-
enhanced spectral mammography (CESM): a systematic review. Insights Imaging, 
2019. 10(1): p. 76. 
27. 
Center for Devices and Radiological Health, O.o.P.E.a.Q., Office of In Vitro 
Diagnostics and Radiological Health, The Mammography Quality Standards Act 
Final Regulations: Preparing for MQSA Inspections; Final Guidance for Industry 
and FDA Document 
O.o.P.E.a.Q. Center for Devices and Radiological Health, Office of In Vitro Diagnostics 
and Radiological Health, Editor. 2001: fda.gov. 
28. 
James, J.R., et al., Breast Radiation Dose With CESM Compared With 2D FFDM 
and 3D Tomosynthesis Mammography. AJR Am J Roentgenol, 2017. 208(2): p. 
362-372. 
29. 
Badr, S., et al., Dual-energy contrast-enhanced digital mammography in routine 
clinical practice in 2013. Diagn Interv Imaging, 2014. 95(3): p. 245-58. 
30. 
Perry, H., et al., Contrast-Enhanced Mammography: A Systematic Guide to 
Interpretation and Reporting. AJR Am J Roentgenol, 2019. 212(1): p. 222-231. 
31. 
Depretto, C., et al., Contrast-enhanced mammography in the evaluation of breast 
calcifications: preliminary experience. Tumori, 2020: p. 300891620919170. 
32. 
Imaging, C.o.P.P.B., ACR PRACTICE PARAMETER FOR THE 
PERFORMANCE OF STEREOTACTIC/TOMOSYNTHESIS-GUIDED BREAST 
INTERVENTIONAL PROCEDURES. 2020. 
33. 
Berg, W.A., Current Status of Supplemental Screening in Dense Breasts. J Clin 
Oncol, 2016. 

PROTOCOL TITLE: Added value of contrast enhanced mammography for breast cancer 
staging referred for a second option to a tertiary cancer center 
 
Page 26 of 26 
 
34. 
Morris, E.A., et al., ACR BI-RADS Magnetic Resonance Imaging, in ACR BI-
RADS Atlas, Breast Imaging Reporting and Data System. 2013, American College 
of Radiology: Reston, VA. 
35. 
Luczyńska, E., et al., Comparison of the Mammography, Contrast-Enhanced 
Spectral Mammography and Ultrasonography in a Group of 116 patients. 
Anticancer Res, 2016. 36(8): p. 4359-66. 
36. 
Luczynska, E., et al., Contrast-enhanced spectral mammography: comparison 
with conventional mammography and histopathology in 152 women. Korean J 
Radiol, 2014. 15(6): p. 689-96.  
37.       Wu, Y., Power calculation of adjusted McNemar's test based on clustered data of 
varying cluster size. Biom J, 2018. 60(6): p. 1190-1200. 
38. 
Kosinski, A.S., A weighted generalized score statistic for comparison of predictive 
values of diagnostic tests. Stat Med, 2013. 32(6): p. 964-77. 
39. 
Genders, T.S.S., et al., Methods for Calculating Sensitivity and Specificity of 
Clustered Data: A Tutorial. Radiology, 2012. 265(3): p. 910-916.  
40.        Obuchowski, N.A., On the comparison of correlated proportions for clustered  
data. Stat     Med, 1998. 17(13): p. 1495-507. 
41. 
Durkalski, V.L., et al., Analysis of clustered matched-pair data. Statistics in 
Medicine, 2003. 22(15): p. 2417-2428.