Clinical Evaluation of Contrast Enhanced Breast CT to Improve Staging and Treatment Follow up in Women With Breast Cancer
Conditions: Breast Cancer
Sponsor: Radboud University Medical Center

NL75855.091.21 / CEBCT vs MR 
 
 
 
PROTOCOL TITLE ‘Clinical evaluation of Contrast Enhanced Breast CT to improve 
Staging and treatment follow up in women with breast cancer’ 
 
Protocol ID 
NL75855.091.21 
Short title 
CEBCT vs MR 
Version 
4.0 
Date 
14-03-2022 
Coordinating 
investigator/project leader 
 
Dr. Ritse Mann 
Ritse.Mann@radboucumc.nl  
024-36 14422 (secretary)  
Principal investigator(s) (in 
Dutch: hoofdonderzoeker/ 
uitvoerder) 
 
Dr. Ritse Mann 
Location Radboudumc 
Location NKI-AVL 
Ritse.Mann@radboucumc.nl  
024-36 14422 (secretary) 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
Radboudumc 
Geert Grooteplein Zuid 10 
6525 GA Nijmegen 
Subsidising party 
ZonMw – VIDI 
Independent expert 
Thierry Boellaard  
tn.boellaard@nki.nl 

NL75855.091.21 / CEBCT vs MR 
 
 
 
PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Head of Department: 
Prof.dr. Mathias Prokop 
 
 
 
 
21-7-2021 
Coordinating Investigator/Project leader: 
Dr. Ritse Mann 
 
 
 
 
21-7-2021 
 
 

NL75855.091.21 / CEBCT vs MR 
 
 
 
TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE 
8 
2. 
OBJECTIVES 
10 
3. 
STUDY DESIGN 
11 
3.1 
Timing of post-contrast scan 
11 
3.2 
CE BCT for staging of Breast cancer (objective a) 
12 
3.3 
CE BCT for evaluation of primary systemic therapy (objective b) 
12 
4. 
STUDY POPULATION 
13 
4.1 
Population (base) 
13 
4.2 
Inclusion criteria 
13 
4.3 
Exclusion criteria 
13 
4.4 
Sample size calculation 
13 
5. 
TREATMENT OF SUBJECTS 
14 
6. 
INVESTIGATIONAL PRODUCT 
14 
7. 
NON-INVESTIGATIONAL PRODUCT 
14 
8. 
METHODS 
15 
8.1 
Study parameters/endpoints 
15 
8.1.1 
Main study parameter/endpoint 
15 
8.1.2 
Secondary study parameters/endpoints (if applicable) 
16 
8.2 
Randomisation, blinding and treatment allocation 
16 
8.3 
Study procedures 
16 
8.4 
Withdrawal of individual subjects 
17 
8.4.1 
Specific criteria for withdrawal 
17 
8.5 
Replacement of individual subjects after withdrawal 
17 
8.6 
Follow-up of subjects withdrawn from treatment 
17 
8.7 
Premature termination of the study 
17 
9. 
SAFETY REPORTING 
17 
9.1 
Temporary halt for reasons of subject safety 
17 
9.2 
AEs, SAEs and SUSARs 
18 
9.2.1 
Adverse events (AEs) 
18 
9.2.2 
Serious adverse events (SAEs) 
18 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) 
18 
9.3 
Annual safety report 
18 
9.4 
Follow-up of adverse events 
18 
10. 
STATISTICAL ANALYSIS 
19 
10.1 
Statistics regarding objective a: 
19 
10.2 
Statistics regarding objective b: 
19 
10.3 
Interim analysis 
20 
11. 
ETHICAL CONSIDERATIONS 
20 
11.1 
Regulation statement 
20 
11.2 
Recruitment and consent 
20 
11.3 
Objection by minors or incapacitated subjects 
20 
11.4 
Benefits and risks assessment, group relatedness 
20 
11.5 
Compensation for injury 
20 
11.6 
Incentives 
21 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
21 
12.1 
Handling and storage of data and documents 
21 

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12.2 
Monitoring and Quality Assurance 
21 
12.3 
Amendments 
21 
12.4 
Annual progress report 
21 
12.5 
Temporary halt and (prematurely) end of study report 
21 
12.6 
Public disclosure and publication policy 
22 
13. 
STRUCTURED RISK ANALYSIS 
22 
13.1 
Synthesis 
22 
14. 
REFERENCES 
22 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ABR 
General Assessment and Registration form (ABR form), the application form 
that is required for submission to the accredited Ethics Committee; in Dutch: 
Algemeen Beoordelings- en Registratieformulier (ABR-formulier) 
AE 
Adverse Event 
AR 
Adverse Reaction 
CA 
Competent Authority 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: Centrale 
Commissie Mensgebonden Onderzoek 
CV 
Curriculum Vitae 
EU 
European Union 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation; in Dutch: Algemene Verordening 
Gegevensbescherming (AVG) 
IC 
Informed Consent 
METC  
Medical research ethics committee (MREC); in Dutch: medisch-ethische 
toetsingscommissie (METC) 
(S)AE 
(Serious) Adverse Event  
SPC 
Summary of Product Characteristics; in Dutch: officiële productinformatie IB1-
tekst 
Sponsor The sponsor is the party that commissions the organisation or performance of 
the research, for example a pharmaceutical 
company, academic hospital, scientific organisation or investigator. A party that 
provides funding for a study but does not commission it is not regarded as the 
sponsor, but referred to as a subsidising party. 
SUSAR  Suspected Unexpected Serious Adverse Reaction 
UAVG 
Dutch Act on Implementation of the General Data Protection Regulation; in 
Dutch: Uitvoeringswet AVG 
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 
 

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SUMMARY 
 
Rationale: Breast CT is a novel modality that has not been largely evaluated in a clinical 
setting. Only recently FDA and CE marked BCT machines have been released, and the 
number of installed bases internationally is below 10 (although rapidly rising). 
Internationally only a few studies on contrast enhanced breast CT have been performed in 
small numbers of patients, albeit with excellent results. Nevertheless, substantial evidence 
for this novel modality is still absent. In particular, the correlation of enhancement and 
histological grade of DCIS, correlation of CEBCT findings with histopathology, and prediction 
and assessment of primary systemic treatment are open fields for which more substantial 
evaluation is clearly needed. 
 
Objectives:  
a. Staging of women with breast cancer, particularly those with extensive carcinoma in 
situ (DCIS).  
 
 
b. Evaluation of women treated with primary systemic therapy.  
 
Study design: Observational cohort study 
 
Study population: Adult women (>18 years old) with breast cancer, scheduled for a pre-
surgery staging contrast enhanced breast MRI and eligible for primary systemic therapy who 
are able to provide informed consent will be enrolled 
 
Intervention: All participants will undergo a bilateral CEBCT scan using a dedicated breast 
CT scanner (Koning, USA). This scanner creates full 3D volumes of the breast using 
conebeam reconstruction. The scanner is designed as an exam table, on which the patient is 
in prone position during image acquisition. Centrally in the table a horizontal CT gantry is 
positioned. A mammographic x-ray tube and an x-ray flat panel detector are mounted on the 
CT gantry and circle the breast during acquisition in 10 seconds. For CEBCT two 
acquisitions need to be obtained (1 before and 1 after contrast), and we will perform the 
CEBCT of both breasts. 
Prior to the examination an iv-canula will be inserted for contrast administration during the 
procedure. Like in (contrast enhanced) mammography the breasts are imaged one at a time. 
The breast to be imaged is suspended through the central table opening into the imaging 
space. In the clinical protocol we will first image the non-affected breast prior to contrast 
administration. Subsequently, the patient is repositioned and the affected breast will be 
imaged. Thereafter an iodinated contrast agent (Iomeron 300) is administered (1.5 ml/kg 
body mass) using a power injector. Considering sufficient of time after contrast administration 
the affected breast will be scanned again. Finally, the non-affected breast is repositioned in 
the gantry, and a post-contrast acquisition of this breast is obtained as well 
 
Main study parameters/endpoints:  
Objective a. 
 
The primary endpoint is the non-inferiority of CEBCT error rate against the golden standard, 
i.e. histopathology, to DCE MRI error rate against the golden standard for tumor staging. 

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As secondary objectives, we will record: 
- 
the concordance of tumor extent between CEBCT and large section histopathology 
- 
the frequency of detection of contralateral cancers with CEBCT. 
 
Objective b. 
 
The primary endpoint is the non-inferiority of CEBCT to predict pCR after primary systemic 
therapy as compared to DCE MRI computed from the area under the receiver operating 
characteristic (ROC) curve (AUC) (or AUROC). 
 
As secondary objectives, we will record: 
- 
the concordance of morphological and enhancement characteristics of cancers on 
CEBCT and their corresponding existing subtyping to the expected response to 
primary systemic therapy 
- 
the potential of CEBCT predicting the response to primary systemic therapy early in 
treatment 
 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: CT imaging is associated with risks related to the use of radiation and 
contrast administration. The risks of this study are reduced as much as possible. In breast 
CT only the breast is exposed to radiation, sparing the rest of the chest to any significant 
amount of radiation. These patients already get numerous mammographic views during 
standard clinical care, and generally receive radiotherapy to the affected breast. There is 
most probably no effect due to the level of additional radiation involved in breast CT imaging, 
considering the course of treatment of the study population (mastectomy or post-surgery 
radiation therapy). 
 
The introduction of an imaging technology that will improve staging and treatment follow up 
of breast cancer detection, will have impact on survival rate and quality of life of breast 
cancer patients. By optimizing the image quality of this modality we will ensure that this 
impact on women’s healthcare is maximized. The research will not be directly beneficial to 
the subjects since the research breast CT results will not influence the subject’s treatment. 

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1. INTRODUCTION AND RATIONALE 
To decide on the most optimal therapy for patients with breast cancer, it is of paramount 
importance to understand the extent and nature of the cancer. For approximately 80% of 
breast cancer patients the primary therapy is surgical, followed by radiotherapy in case of 
breast conserving therapy, and when required systemic therapy.1 
Knowing the extent of tumor, and how it is positioned within the breast, is extremely relevant 
for surgical success, which is defined as the excision of the cancer with no residual 
tumor/DCIS on the inked margin. This is relatively difficult to achieve, the rate of re-excisions 
can be, according to literature, as high as 34%.2, 3 In the Netherlands, the presence of focal 
involvement (<4mm) of a margin is accepted, as it is thought that these represent the basis 
of spicular extensions of the tumor that are in general adequately treated by radiotherapy;19 a 
theory backed by very low numbers of in-breast recurrence.4 Still, even using this very liberal 
approach, the re-excision rate is about 4% in invasive cancers and as high as 19% in DCIS.1 
 
Previous studies using MRI and contrast 
mammography have clearly shown that tumor size 
estimations using a contrast enhanced study 
correspond better to tumor size at final 
histopathology than clinical examination, 
mammography or ultrasound (fig 1).5-11 As we 
previously showed, MRI still outperforms contrast 
mammography, likely due to its 3D nature.12 
Despite the overwhelming evidence that staging of 
all breast cancers is improved with preoperative 
MRI, and that in addition approximately 4% of 
unexpected contra-lateral cancers are detected, the 
indication is worldwide supported mainly for invasive 
lobular breast cancers.13-15 However, this will likely 
change as preliminary results of the currently 
running multi-institutional “Preoperative Breast MRI in Clinical Practice: Multicenter 
International Prospective Meta-Analysis of Individual Data (MIPA)” study unequivocally show 
that in centers with sufficient experience and expertise re-excisions are reduced from 13% to 
8% when using pre-operative MRI for staging, whereas mastectomies do not increase.16 This 
implies that surgeons can use the information obtained with 3D contrast enhanced imaging 
studies to improve the quality of surgical procedures, and it also shows that the correlation of 
tumor size on radiology and pathology is an important measure for the quality of preoperative 
staging (despite the fact that the vastly different shape of the breast in vivo and at pathology 
makes perfect correlation impossible). Still, not-withstanding the clear value of breast MRI, 
over- and underestimation of tumor size does occur in up to 15% of cases.17, 18 Particularly 
DCIS components surrounding the primary tumor are hard to visualize.19 Consequently, the 
higher spatial resolution, as well as the concurrent depiction of calcifications, may further 
improve the quality of pre-operative imaging when shifting from MRI to CEBCT, while 
associated costs and the burden to the patient (due to the open scanner design and the 
shorter examination times) decrease.  
 
The most optimal treatment for patients with breast cancer may not always be primary 
surgery. For ~20% of patients with larger tumors (≥T2) or node positive cancers primary 
systemic therapy (including endocrine, immuno-, and/or chemotherapy) may be used to 
Figure 1: Preoperative evaluation of tumor 
extent using contrast enhanced MRI 

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downstage the tumor.1 The logic behind this approach is primarily that these women will have 
an indication for the systemic therapy in any case, and if not given before surgical treatment, 
it will be given after surgery. 
The advantages of administering systemic therapy before surgery are that it is possible to 1) 
shrink the tumor, thus allowing less aggressive surgery; 2) downstage the axilla, thus 
allowing to prevent axillary clearance in women with initially N+ disease; 3) achieve a 
pathological complete response (pCR) after primary systemic therapy, which is for most 
tumors a good prognostic indicator for disease free survival; 4) monitor response to therapy 
of the primary tumor, allowing for early identification of non-response and therefore allowing 
for a possible switch to more effective therapies.20, 21 These advantages obviously come at a 
risk, as the tumor may progress during the systemic treatment. Fortunately, this is rare 
(<5%), and so far no negative effects of primary systemic therapy on survival have been 
documented.22 In the last decades it has become clear that different molecular subtypes of 
breast cancer respond differently to systemic therapy, with triple negative and HER2+ 
subtypes showing the best results.23 Imaging based studies have shown that morphological 
characteristics of tumors, as well as enhancement characteristics correlate well with these 
subtypes and have a predictive value with regard to treatment response and eventual 
outcome.24-32 The obvious advantage of imaging based response prediction over genomic 
assays is that the whole tumor is evaluated rather than a small sample. When used in 
conjunction with the classical subtyping, it appears that intratumoral heterogeneity is in itself 
an important predictor of response.33-37 Characteristics of the peri-tumoral region also seem 
to be predictive of response.38-40 Unfortunately MRI based predictors are hard to translate to 
clinical practice as many parameters are subjective in nature, and the non-linear relation 
between contrast concentration and enhancement makes quantification difficult.41, 42 Other 
quantitative imaging parameters such as ‘apparent diffusion coefficient’ obtained from 
diffusion weighted MRI and ‘standardized uptake values’ from PET/CT are limited by the 
inherent low signal to noise ratio of these techniques and therefore limited spatial 
resolution.26,27,30 CEBCT will allow showing morphological detail and spatial variation in 
enhancement within breast tumors to an unprecedented level, which may subsequently be 
used to select women with breast cancers for specific forms of primary systemic therapy 
based upon the whole tumor profile.  
In practice, none of the systemic therapies are purely selective for cancer, which implies that 
most have significant toxic side-effects.43-45 Early detection of non-response (which basically 
means that we selected the wrong treatment at the start) is therefore of paramount 
importance. CEBCT will allow for detailed assessment of the response of specific cancers to 
specific systemic therapies, which we will document. In order to use CEBCT as a therapy 
modulating technique a substantial knowledge base needs to be built. 
A directly useful clinical application in this setting is the potentially important role for CEBCT 
in preoperative evaluation of patients treated with some form of primary systemic therapy. 
Breast MRI is not very accurate in the detection of residual disease with a sensitivity of 83% 
and equal specificity.46 Unfortunately, after neoadjuvant chemotherapy, due to the softer and 
often fragmented tumor, surgery is much more challenging, leading to higher rates of re-
excision, or unnecessary aggressive surgical procedures.47,48 Therefore, the very high spatial 
resolution of CEBCT may be exploited to better document the area of residual disease; and 
when specific enough may potentially prevent surgery completely in women who have 
achieved a pCR. 
 

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Breast CT is a novel modality that has not been largely evaluated in a clinical setting. Only 
recently FDA and CE marked BCT machines have been released, and the number of 
installed bases internationally is below 10 (although rapidly rising). 
Internationally only a few studies on contrast enhanced breast CT have been performed in 
small numbers of patients, albeit with excellent results. The first study using CEBCT included 
46 lesions of which 29 were benign, showing that all malignancies were more conspicuous 
on CEBCT than on mammography and on BCT without contrast administration.49 In a small 
study in patients presenting with calcifications Aminololama-Shakeri et al. showed that all 17 
DCIS lesions enhanced and were highly suspicious, whereas benign lesions associated with 
calcifications were far less conspicuous.50 Seifert et al reported on 23 CEBCT examinations 
of patients with known cancers, showing the detection of 3 additional lesions due to the 
performance of CEBCT.51 The largest series published thus far originates from Guangzhou, 
He et al. reported a sensitivity of 98.7% for CEBCT in a series of 270 lesions containing 110 
cancers, which compared favourably with mammography (78.4%), ultrasound (81.1%) and 
non-contrast breast CT (89.2%).52 
Only Wienbeck compared CEBCT directly to breast MRI, showing in a series of 100 lesions 
that CEBCT in experienced hands yields equal accuracy as breast MRI, although according 
to their results, the sensitivity is somewhat lower, whereas the specificity is higher.53 Finally, 
Uhlig et al showed in 23 patients that the mean enhancement in CEBCT is different for 
cancers of different molecular subtypes, thus underscoring the possibility to infer treatment 
selection from CEBCT images.54,55 Consequently, there is a solid basis for the assumptions 
underlying this study, which is further backed by the extensive literature that is available on 
MRI and contrast enhanced mammography. Still substantial evidence for this novel modality 
is absent. In particular, the correlation of enhancement and histological grade of DCIS, 
correlation of CEBCT findings with histopathology, and prediction and assessment of primary 
systemic treatment are open fields for which more substantial evaluation is clearly needed.  
 
 
2. OBJECTIVES 
 
a. Staging of women with breast cancer, particularly those with extensive carcinoma in 
situ (DCIS):  
 
Primary objective a: 
1) The non-inferiority of CEBCT error rate against the golden standard, i.e. 
histopathology, to dynamic contrast enhanced (DCE) MRI error rate against the 
golden standard for tumor staging.  
 
Secondary objective(s) a: 
2) The concordance of tumor extent between CEBCT and large section 
histopathology 
3) The frequency of detection of contralateral cancers with CEBCT in women with 
breast cancer 
 
b. Evaluation of women treated with primary systemic therapy.  
 
Primary objective b: 
1) The non-inferiority of CEBCT to predict pCR after primary systemic therapy as 
compared to DCE MRI computed from the AUROC. 

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Secondary objective(s) b: 
2) The concordance of morphological and enhancement characteristics of cancers 
on CEBCT and their corresponding existing subtyping to the expected response 
to primary systemic therapy? 
3) The potential of CEBCT predicting the response to primary systemic therapy early 
in treatment? 
 
 
3. STUDY DESIGN 
 
All participants will undergo a bilateral CEBCT 
scan using a dedicated breast CT scanner 
(Koning, USA). This scanner creates full 3D 
volumes of the breast using conebeam 
reconstruction (fig 2). The scanner is designed 
as an exam table, on which the patient is in 
prone position during image acquisition. 
Centrally in the table a horizontal CT gantry is 
positioned. A mammographic x-ray tube with a 
0.3 mm focal spot size, and an x-ray flat panel 
detector are mounted on the CT gantry and circle the breast during acquisition in 10 
seconds. For CEBCT two acquisitions need to be obtained (1 before and 1 after contrast), 
and we will perform the CEBCT of both breasts.  
Prior to the examination an iv-canula will be inserted for contrast administration during the 
procedure. Like in (contrast enhanced) mammography the breasts are imaged one at a time. 
The breast to be imaged is suspended through the central table opening into the imaging 
space. The maximum imaging volume is 28 × 28 × 16 cm, which allows the complete 
examination of most breast sizes. In the clinical protocol we will first image the non-affected 
breast prior to contrast administration. Subsequently, the patient is repositioned and the 
affected breast will be imaged. Thereafter an iodinated contrast agent (Iomeron 300) is 
administered (1.5 ml/kg body mass) using a power injector (flow-rate 2.5 ml/s, flush of 30 ml 
saline). To prevent contrast nephropathy the applicable protocols of the relevant hospital 
must be followed, see appendix A (Radboudumc specific) and appendix B (NKI specific). 
Considering sufficient of time after contrast administration the affected breast will be scanned 
again. Finally, the non-affected breast is repositioned in the gantry, and a post-contrast 
acquisition of this breast is obtained as well.   
 
 
3.1 Timing of post-contrast scan 
Based upon timing studies performed for contrast 
enhanced mammography (that uses the same 
type and dose of contrast agent) 2 minutes after 
contrast administration the affected breast will be 
scanned again. Since this timing is not specific 
for CEBCT we will optimize the timing using prior 
developed phantoms (fig 3) and in addition with 
Figure 2: Schematic drawing of the dedicated 
breast CT scanner 
Figure 3: 2 frames form a patient based phantom 
for CE BCT showing the effect of timing on lesion 
conspicuity 

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the initial 30 patients participating in this study (method A). 
 
 
Method A (n=30): 
After the phantom based contrast timing we will verify the results in our first 30 patients. By 
the following scan protocol:  
- 
Pre-contrast scan non-affected breast 
- 
Pre-contrast scan affected breast 
- 
Contrast injections 
- 
Post-contrast scan affected breast after t=70sec 
- 
Post-contrast scan affected breast after t=90sec 
- 
Post-contrast scan affected breast after t=110sec 
- 
Post-contrast scan affected breast after t=130sec 
- 
Post-contrast scan affected breast after t=150sec 
- 
Post-contrast scan non-affected breast  
 
When 30 patients are imaged according Method A, we will perform an interim analysis 
(described in chapter 10.1). This interim analysis is meant to appoint the optimal post-
contrast scan timing. This optimal timing will be used for the remaining participants in Method 
B.   
 
 
3.2 CE BCT for staging of women with breast cancer (objective a) 
Method B (n=383): 
After the interim analysis we will continue with the study, according to the following scan 
protocol: 
- 
Pre-contrast scan non-affected breast 
- 
Pre-contrast scan affected breast 
- 
Contrast injections 
- 
Post-contrast scan affected breast after t= <based on interim analysis Method A> 
- 
Post-contrast scan non-affected breast  
 
Consequently, the acquisition time is <10 minutes in all patients (and <5 minutes in most).  
 
 
3.3 CE BCT for evaluation of primary systemic therapy (objective b) 
The contrast enhanced imaging is necessary for the cancer staging and will be used to come 
to an appropriate treatment plan for the patient. In general, there are two options for the 
patients: 
1. (unilateral) mastectomy and post surgery adjuvant therapy 
2. Primary systemic therapy 
 
Patients in group 1 will reach the end point of the study after the staging imaging, since they 
will undergo mastectomy. Patients in group 2 will be asked to undergo a second CE BCT 
post systemic therapy. This will involve the following scan protocol: 
- 
Pre-contrast scan non-affected breast 
- 
Pre-contrast scan affected breast 
- 
Contrast injections 
- 
Post-contrast scan affected breast after t= <based on interim analysis Method A> 
- 
Post-contrast scan non-affected breast  

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- 
** Post-contrast scan affected breast (after ±5 min) 
 
** This allows for evaluation of changes in enhancement characteristics of the tumor and 
the fibroglandular tissue surrounding the tumor.  
 
 
Post processing, volumetric measures and reader study 
From the obtained pre- and post contrast scans we will generate subtraction images for all 
CEBCT scans to enable detection of even very tiny areas of enhancement, as well as 
maximum intensity projections to provide a global overview of each breast. All CEBCT scans 
will subsequently be independently evaluated by a dedicated breast radiologist on a clinical 
reporting station using software for 3D analysis of the data, allowing MPR in all directions, as 
well as volume rendering and the assessment of slabs in various thicknesses.  
For the studies comparing CEBCT to breast MRI, we will ensure independent blinded 
reading of both modalities by two different radiologists. 
 
 
4. STUDY POPULATION 
4.1 Population (base)  
Women with breast cancer. 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following 
criteria: 
- 
Women >18 years old 
- 
Diagnoses of breast cancer 
- 
Scheduled for a pre-surgery staging contrast enhanced breast MRI 
- 
Eligible for primary systemic therapy 
 
4.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from participation 
in this study: 
- 
Women with suspected or confirmed pregnancy 
- 
Women with prior breast cancer 
- 
Women who are breastfeeding 
- 
Women who are very frail and unable to cooperate 
- 
Women who cannot give informed consent 
- 
Contra indication of iodine contrast (i.e. contrast allergy, renal function impairment 
(GFR <60 ml/min/1.73m2)) 
- 
Contra indication for irradiation (i.e. genetic mutation that predispose to breast 
cancer) 
- 
Male subjects 
 
4.4 Sample size calculation 
Objective a:  
For staging of women with breast cancer, we will conduct a pilot study comparing CT findings 
to large section histopathology in 30 patients. This number is  based upon experience 
obtained in previous studies and it represents a hypothesis generating question. In order to 
compare the accuracy of tumor size estimation of CEBCT and DCE MRI with the golden 

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standard we assume that CEBCT is at least capable of tumor size estimations within 1 cm of 
pathologic size in 74% of patients as we previously documented for breast MRI.35 To 
calculate the sample size we used a one-sided non-inferiority test (McNemar’s test) for the 
difference between two correlated proportions. For a one-sided non-inferiority test of the 
difference between two correlated proportions, a sample size of 344 subjects achieves 80% 
power at a significance level of 0,05 when the non-inferiority difference is -0,04, the treatment 
proportion is 0,74, the standard proportion is 0,74, and the actual difference between the 
proportions is 0 [1] Applying a 10% lost-to-follow up margin implies that we will include 383 
patients undergoing both pre-operative MRI and CEBCT for this comparison (objective a). 
 
Objective b:  
For the evaluation of women treated with primary systemic therapy, we assume that CEBCT 
may directly improve the quality of staging residual cancer after therapy and the selection of 
patients with pCR. Patients will receive both a MRI and CEBCT which means we are dealing 
with paired data. Using radiomics, the data become continuous responses providing a 
likelihood of pCR between 0 and 1. From this the AUC is computed. For MRI an AUC of 0.83 
was reported.63 In order to evaluate non-inferiority of CEBCT, we expect for CEBCT too an 
AUC of 0.83. According to literature, pCR after primary systemic therapy ranges from 15 to 
45% based on the molecular subtypes of breast cancer and the type of systemic treatments 
that the patients undergo [2]. Based on these assumptions a sample of 27 pCR cases and 63 
non-pCR cases results in 80% power to detect a difference of 0,15 between the AUROC of 
MRI and CEBCT measurements using a one-sided z-test at a significance level of 0,05. This 
wide confidence interval is deemed acceptable due to the explorative nature of this part of 
the study. Considering the longitudinal aspect of this study and the sometimes severe side-
effects of chemotherapy which may lead to drop-out of patients, we will apply a margin of 
20% here; thus including 113 patients.  
 
 
NOTE: these 113 cases from objective b are also included in the 383 patients described 
for objective a. 30 additional patients will be included for the interim analysis. So we aim to 
include a total of 413 cases in this study 
 
 
5. TREATMENT OF SUBJECTS  
N/A, observational study 
 
 
6. INVESTIGATIONAL PRODUCT  
N/A, observational study 
 
 
7. NON-INVESTIGATIONAL PRODUCT  
Standard clinical used iodine contrast (see D2 for SMP text). 
 
 

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8. METHODS 
8.1 Study parameters/endpoints 
8.1.1 
Main study parameter/endpoint 
Objective a. 
The primary endpoint is the MRI and CEBCT discordance with the golden standard (i.e size 
estimation within 1 cm from histopathological size). The results will be summarized in the 
following 2x2 table format over all cases: 
 
  
  
  
CEBCT 
No discordance 
with Golden 
standard 
Discordance with 
Golden standard 
Total 
 
 
MRI 
No discordance with 
Golden standard 
A (%) 
B (%) 
A+B (%) 
Discordance with 
Golden standard 
C (%) 
D (%) 
C+D (%) 
Total 
A+C (%) 
B+D (%) 
A+B+C+D 
(100%) 
 
Table 1 Summary table for discordance (error) data where A, B, C and D denote the number 
of cases in each corresponding cell. All percentages are calculated with the grand total, i.e. 
A+B+C+D, as the denominator. The CEBCT error rate is the percentage associated with 
B+D, the MRI error rate is the percentage associated with C+D, and 100%*(B-C)/(A+B+C+D) 
is the CEBCT-MRI error rate difference. 
 
The following hypotheses will be evaluated for the primary analysis: 
 
Null Hypothesis (H0): ƿCEBCT – ƿMRI ≥ ∆ 
  
Alternative Hypothesis (Ha): ƿCEBCT – ƿMRI < ∆,  
 
ƿCEBCT is the error rate for the CEBCT diagnosis compared to the golden standard; ƿMRI is 
the error rate for the MRI diagnosis compared to golden standard; and ∆ is the non-inferiority 
margin. The non-inferiority ∆ will be set at an absolute 4% for this study. 
 
A 2-sided 90% confidence for the CEBCT-MRI error rate difference will be estimated using 
Wald Z statistic. If the upper bound of the 90% CI is less than the non-inferiority margin, 
CEBCT will be considered non-inferior to MRI. 
 
Objective b. 
The primary endpoint of objective B is the non-inferiority of CEBCT to predict pCR after neo-
adjuvant chemotherapy as compared to DCE MRI computed from the AUROC. We will 
estimate AUCs from the radiomics features of both CEBCT and MRI as compared to the 
results of pathologic resection of the tumor (gold standard) in predicting pCR (Yes/No). All 
analysis will be performed for all cases.  
 
We will perform a non-inferiority test for the difference between the paired AUCs of CEBCT 
and MRI across all readers and all cases.  

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Null Hypothesis (H0): AUCCEBCT – AUCMRI ≤ -∆ 
  
Alternative Hypothesis (Ha): AUCCEBCT – AUCMRI > -∆ 
 
AUC is the area under the curve, ∆ is the non-inferiority margin. The non-inferiority ∆ will be 
set at an absolute 0.15 for this study. 
 
The objective will be evaluated at statistical significance level α= 0.05. A two-sided 90% 
confidence interval for the difference between paired AUCs will be computed. If the lower 
bound of the 90% confidence interval is higher than -0.15 we will conclude non-inferiority for 
CEBCT images versus breast MRI images in this pilot study. 
8.1.2 
Secondary study parameters/endpoints (if applicable) 
As secondary objectives, we will record the frequency of contralateral lesions and their final 
pathological outcome, morphological and enhancement characteristics of cancers on CEBCT 
complementary to existing subtyping. 
 
The concordance rates according morphological and enhancement characteristics of 
cancers will be compared using the Fisher exact test for unpaired data and McNemar’s 
test for paired data. 
 
Participant characteristics such as age, ethnicity, race, cup size, family history for breast 
cancer, level of comfort during BCT examination and level of comfort of BCT compared to 
other image modality. 
 
 
8.2 Randomisation, blinding and treatment allocation 
NA 
 
8.3 Study procedures 
The diagnostic work-up will be performed as per standard clinical practice and therefore, in 
addition to the CEBCT examination, will include: 
- objective a: pre-operative breast MRI for breast cancer staging 
- objective b: MRI for evaluation of residual tumor after systemic therapy 
 
CEBCT imaging: 
The CEBCT acquisition will be performed using the Koning dedicated breast computed 
tomography clinical prototype system that is installed at the Radboudumc/NKI. All CEBCT 
acquisitions will be obtained using the standard imaging technique as recommended by the 
manufacturer (49 kVp, 300 projections in 10 seconds covering 360°, 8 ms per projection), 
with the tube current set to a maximum of 100 mA, depending on breast size and density, set 
by using the system’s automatic exposure control (AEC). The tube current used for each 
acquisition will be recorded. For CEBCT two acquisitions need to be obtained (1 before and 
1 after contrast), and CEBCT examination of both breasts will be performed, one at a time. 
Prior to the examination an iv-canula will be inserted for contrast administration during the 
procedure. The breast to be imaged is suspended through the central table opening into the 
imaging space. In the clinical protocol we will first image the non-affected breast prior to 
contrast administration. Subsequently, the patient is repositioned and the affected breast will 

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be imaged. Thereafter an iodinated contrast agent (Iomeron 300) is administered (1.5 ml/kg 
body mass) using a power injector (flow-rate 2.5 ml/s, flush of 30 ml saline). Considering 
sufficient time after contrast administration the affected breast will be scanned again. Finally, 
the non-affected breast is repositioned in the gantry, and a post-contrast acquisition of this 
breast is obtained as well. 
 
Assessment for incidental findings: 
Within 5 days after CEBCT acquisition, the BCT image will be reviewed by one of the breast 
radiologists at Radboudumc/NKI to ensure that no additional lesions previously undetected 
are present. Even though BCT imaging is presently in the research stage, we must ensure 
that any potential additional lesions that might have not been visible in all previous clinical 
images but are visible in the CEBCT image are detected in an appropriate timeframe, and 
not at the delayed stage of the study. If any potential additional lesions are seen, the patient 
will be informed and the appropriate clinical procedures will be followed to validate this 
finding with standard diagnostic techniques (e.g. additional workup, US, biopsy, etc.), as 
appropriate. 
The incidence of these cases and their final outcome will be recorded. Aside from this 
possibility of incidental findings, the results of this research, specifically, the CEBCT imaging, 
will not affect in any way the care provided to the subject. 
 
8.4 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for urgent 
medical reasons. 
8.4.1 
Specific criteria for withdrawal 
The patient will be removed from the study if the BCT images are deemed technically 
unsuitable to use in the study and the scan can be not redone (for the same timepoint). 
 
8.5 Replacement of individual subjects after withdrawal 
The sample size calculation already accounts for possible drop out. Therefor subjects will not 
be replaced in case of withdrawal. 
  
8.6 Follow-up of subjects withdrawn from treatment 
Standard clinical care, not a specific follow-up for this study. 
 
8.7 Premature termination of the study 
NA 
 
 
9. SAFETY REPORTING 
9.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the study if 
there is sufficient ground that continuation of the study will jeopardise subject health or 
safety. The sponsor will notify the accredited METC without undue delay of a temporary halt 
including the reason for such an action. The study will be suspended pending a further 

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positive decision by the accredited METC. The investigator will take care that all subjects are 
kept informed.  
 
9.2 AEs, SAEs and SUSARs 
9.2.1 
Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject during the 
study, whether or not considered related to trial procedure. All adverse events reported 
spontaneously by the subject or observed by the investigator or his staff will be recorded. 
 
9.2.2 
Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalization or prolongation of existing inpatients’ hospitalization; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; or 
- 
any other important medical event that did not result in any of the outcomes listed 
above due to medical or surgical intervention but could have been based upon 
appropriate judgement by the investigator. 
An elective hospital admission will not be considered as a serious adverse event. 
 
The investigator will report all SAEs to the sponsor without undue delay after obtaining 
knowledge of the events. 
 
The sponsor will report the SAEs through the web portal ToetsingOnline to the accredited 
METC that approved the protocol, within 7 days of first knowledge for SAEs that result in 
death or are life threatening followed by a period of maximum of 8 days to complete the initial 
preliminary report. All other SAEs will be reported within a period of maximum 15 days after 
the sponsor has first knowledge of the serious adverse events. 
 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) 
NA 
 
9.3 Annual safety report 
NA 
 
9.4 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been reached. 
Depending on the event, follow up may require additional tests or medical procedures as 
indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the protocol  
 
 
 

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10. STATISTICAL ANALYSIS 
10.1 Statistics regarding objective a:  
We intend to perform a prospective study to compare the accuracy of contrast enhanced 
dedicated breast CT for staging of women with breast cancer. First, we will conduct a pilot 
study comparing CT findings to large section histopathology in 30 patients. This number is 
based upon experience obtained in previous studies and it represents a hypothesis 
generating question. Second, based on the result from the pilot study, we will decide the 
optimal timing for the main prospective study. In order to compare the accuracy of tumor size 
estimation of CEBCT and MRI with the golden standard, we assume that CEBCT is at least 
capable of tumor size estimations within 1 cm of pathologic size in 74% of patients, as we 
previously documented for breast MRI.52 To calculate the sample size we used a one-sided 
non-inferiority test (McNemar’s test) for the difference between two correlated proportions. 
For a one-sided non-inferiority test of the difference between two correlated proportions, a 
sample size of 344 subjects achieves 80% power at a significance level of 0,05 when the 
non-inferiority difference is 4%, the treatment proportion is 0,74, the standard proportion is 
0,74, and the actual difference between the proportions is 0 [1]. Applying a 10% lost-to-follow 
up margin implies that we will include 383 patients undergoing both pre-operative MRI and 
CEBCT for this comparison.  
Based on the distribution of the data, we will apply parametric (paired t-test) or non-
parametric (wilcoxon signed rank test) statistical tests. To compare tumor size 
measurements of CEBCT and large section histopathology pearson’s correlation coefficients 
and a Bland-Altman method will be used. The frequency of detection of contralateral cancers 
with CEBCT is observational and will be of descriptive nature (Contralateral cancer detection 
rate will be expressed as the cancer detection rate per 1000 investigations). All statistical 
analysis will be performed using SPSS statistical software (version 25) or R studio.  
 
10.2 Statistics regarding objective b:  
For the evaluation of women treated with primary systemic therapy, we assume that 
radiomics obtained from CEBCT may directly improve the quality of staging residual cancer 
after therapy and the selection of patients with pCR. Patients will receive both a MRI and 
CEBCT which means we are dealing with paired data. For MRI radiomics an area under the 
curve of 0.83 was reported.46 In order to evaluate non-inferiority of radiomics obtained from 
CEBCT, we expect for CEBCT an area under the curve of 0.83. The non-inferiority ∆ will be 
set at an absolute 0.15 for this pilot study.  
The objective will be evaluated at statistical significance level α= 0.05. A two-sided 90% 
confidence interval for the difference between paired AUCs will be computed. If the lower 
bound of the 90% confidence interval is higher than -0.15 we will conclude non-inferiority for 
CEBCT images versus breast MRI images. 
According to literature, pCR after primary systemic therapy ranges from 15 to 45% based on 
the molecular subtypes of breast cancer and the consequent systemic treatments that the 
patients undergo [2]. Based on these assumptions, a sample of 27 from the positive group 
and 63 from the negative group achieves 80% power to detect a difference of 0,15 between 
the AUC under the null hypothesis of 0,68 and an AUC under the alternative hypothesis of 
0,83 using a one-sided z-test at a significance level of 0,05. Considering the longitudinal 
aspect of this study and the sometimes severe side-effects of chemotherapy which may lead 
to drop-out of patients, we will apply a margin of 20% here; thus including 113 patients. 
All statistical analysis will be performed using SPSS statistical software or R studio. 

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10.3 Interim analysis  
Temporary hold of the study will be done after inclusion of 30 patients. Interim analysis will 
be performed to select the best contrast timing. Based on the outcome of the analysis the 
optimal timing will be applied during the remainder of the study.   
 
 
11. ETHICAL CONSIDERATIONS 
11.1 Regulation statement 
This study will be conducted according to the principles of the Declaration of Helsinki (64th 
WMA General Assembly, Seoul, Korea, October 2013) and in accordance with the Medical 
Research Involving Human Subjects Act (WMO). 
 
11.2 Recruitment and consent 
Patients diagnosed with breast cancer will be informed by their care giver about this study. If 
interested they will receive written information and are asked permission that the research 
coordinator or designee will contact the patient about the willingness to participate. 
Questions arising will be answered and if interested the study visit will be scheduled. Patients 
will have time (2-5 days) to consider participation between first informing by care giver and 
scheduling of pre-surgery staging contrast enhanced breast MRI. When the patients visits 
the hospital: the written informed consent procedure will take place, eligibility evaluated and 
the patient will be enrolled in the study. NOTE: Possible pregnancy is an exclusion condition 
for the study. No pregnancy test will be administered; this criteria will be based on the verbal 
answer of the patient if there is a possibility of pregnancy.  
To inform possible patients about this study, recruitment activities may involve a poster in the 
waiting room, and/or advertisement on web sites. 
 
11.3 Objection by minors or incapacitated subjects 
Minors and/or incapacitated adults will not be asked to participate in this study. 
 
11.4 Benefits and risks assessment, group relatedness 
The introduction of an imaging technology that will improve staging and treatment follow up 
of breast cancer detection, will have impact on survival rate and quality of life of breast 
cancer patients. By optimizing the image quality of this modality we will ensure that this 
impact on women’s healthcare is maximized. The research will not be directly beneficial to 
the subjects since the research breast CT results will not influence the subject’s treatment, if 
any. 
 
11.5 Compensation for injury 
The sponsor/investigator has a liability insurance which is in accordance with article 7 of the 
WMO. 
 
The sponsor (also) has an insurance which is in accordance with the legal requirements in 
the Netherlands (Article 7 WMO). This insurance provides cover for damage to research 
subjects through injury or death caused by the study. 

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The insurance applies to the damage that becomes apparent during the study or within 4 
years after the end of the study. 
 
11.6 Incentives 
No incentives for participation are planned. 
 
 
12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 Handling and storage of data and documents 
Please refer to the Data Management Plan. 
 
12.2 Monitoring and Quality Assurance  
In accordance with the risk-based approach of performing human research as published by 
the NFU, the proposed risk classification for this study is negligible or “verwaarloosbaar”. 
Monitoring will be performed by a certified person, with no relation to this particular study and 
will begin as soon as possible after start of the study. Monitoring is performed for the purpose 
of overseeing the progress of the study and ensuring that it is conducted, recorded and 
reported in accordance with the study protocol, local SOPs, GCP and other applicable 
regulatory requirements. For more details, please refer to the Monitoring Plan. 
 
12.3 Amendments  
Amendments are changes made to the research after a favourable opinion by the accredited 
METC has been given. All amendments will be notified to the METC that gave a favourable 
opinion.  
All substantial amendments will be notified to the METC. Non-substantial amendments will 
not be notified to the accredited METC, but will be recorded and filed by the sponsor.  
 
12.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the accredited 
METC once a year. Information will be provided on the date of inclusion of the first subject, 
numbers of subjects included and numbers of subjects that have completed the trial, serious 
adverse events/ serious adverse reactions, other problems, and amendments.  
 
12.5 Temporary halt and (prematurely) end of study report 
The investigator/sponsor will notify the accredited METC of the end of the study within a 
period of 8 weeks. The end of the study is defined as the last patient’s last visit.  
 
The sponsor will notify the METC immediately of a temporary halt of the study, including the 
reason of such an action.  
 
In case the study is ended prematurely, the sponsor will notify the accredited METC within 15 
days, including the reasons for the premature termination. 
 

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Within one year after the end of the study, the investigator/sponsor will submit a final study 
report with the results of the study, including any publications/abstracts of the study, to the 
accredited METC. 
 
12.6 Public disclosure and publication policy 
The results of this study can be published by the study team during scientific meetings and 
through publications. The anonymized breast CT and clinical diagnostic work-up images 
along with pertinent clinical information (e.g. biopsy outcome) may be used in future studies 
after anonymization with no possibility of reversing the anonymization process, both by the PI 
and others.  
 
 
13. STRUCTURED RISK ANALYSIS  
The mechanism involved in this research is the acquisition of a dedicated breast CT image. 
Dedicated breast CT is based on the same basic physics and technology as body CT, which 
is used millions of times a year world-wide. The x-ray tube voltage of the BCT is ~49 kVp to 
allow separation between fat and fibroglandular tissue, whereas the tube current values are 
chosen depending on breast size and density. The given x-ray dose for one acquisition is on 
average 8.2 mGy, which is about double that of 2-view mammography (~4mGy). Considering 
the different scan protocols, the radiation dose differs: 
- 
Method A: 
 
2 acquisitions of the non-affected breast, and 6 acquisitions of 
the affected breast) 
- 
Method B, gr1:  
2 acquisitions of each breast 
- 
Method B, gr2:  
2 acquisitions of each breast, and 
2 acquisitions of the non-affected breast, 3 of the affected  
breast (after systemic therapy) 
 
Given the clinical nature of the described potential applications, this dose seems very 
acceptable as it may prevent biopsies in women with microcalcifications, and is negligible 
compared to radiotherapy in women with breast cancer. 
 
13.1 Synthesis 
The risks of this study are reduced as much as possible. In breast CT only the breast is 
exposed to radiation, sparing the rest of the chest to any significant amount of radiation. 
Although, these patients already get numerous mammographic views during standard clinical 
care. There is most probably no effect due to the level of additional radiation involved in 
breast 
CT imaging, considering the course of treatment of the study population (mastectomy or 
post-surgery radiation therapy).  
 
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