Breast Cancer Screening With MRI in Women Aged 50-75 Years With Extremely Dense Breast Tissue: the DENSE Trial
Phase: NA
Conditions: Breast Cancer
Sponsor: UMC Utrecht

Study protocol 
 
Official title: Breast Cancer Screening With MRI in Women Aged 50-75 Years With Extremely 
Dense Breast Tissue: the DENSE Trial 
 
NCT number: NCT01315015 
 
Document date: 29 November 2010, revision 7 June 2011 

Protocol
This trial protocol has been provided by the authors to give readers additional information about their work.
Protocol for: Bakker MF, de Lange SV, Pijnappel RM, et al. Supplemental MRI screening for women with extremely 
dense breast tissue. N Engl J Med 2019;381:2091-102. DOI: 10.1056/NEJMoa1903986

WBO aanvraag Eng_VertaalbureauUrgentVertalen_NEJM versie_20190418 
Supplementary File 
 
This supplement contains the following items: 
1. Original protocol, this is also the final protocol. 
This is the protocol that was approved by the Ministry of Health, Welfare and Sport on 11th 
November 2011. For research within the breast cancer screening program in the 
Netherlands a permit is required under the Dutch Population Screening Act. The Ministry 
of Health, Welfare and Sport issued this permit after having been advised by the 
Netherlands Health Council. This advice includes Medical Ethical judgment of the protocol 
and replaces the Ethical Assessment by an Institutional Review Board (IRB). 
 
2. The original statistical analysis plan is also the final statistical analysis plan and is included in 
the protocol (see paragraph 7. ‘Sample size, feasibility’ and paragraph 9. ‘Outcome analysis, 
evaluation’). 

Ministry of Health, Welfare and Sport  
2 
 
Ministry of Health, Welfare and Sport FILE NO.  
(leave blank)  
 
Application form to apply for a permit issued under the Dutch Population Screening Act.  
Please print and send form signed and dated to the Ministry of Health, Welfare and Sport, 
Public Health Department, PO box 20350, 2500 EJ, The Hague.  
The annexes and literature can be sent digitally together with the application form to:  
bevolkingsonderzoek@minvws.nl 
 
Part 1. 
General data  
Sending date: 29 November 2010 
Sending date revision: 7 June 2011 
1. population-
based 
screening 
program title 
Breast cancer screening with MRI of women with high mammographic 
breast density between the age of 50 and 75 
2. applicant  
 
name:  Dr Carla H. van Gils 
 
name contact person: Dr Carla H. van Gils 
 
correspondence address: PO box 85500, Str.6.131 
 
postcode: 3508 GA  
 
city: Utrecht 
 
telefax: 088-755 5485 
 
3. project 
leader  
name: Dr Carla H. van Gils 
 
position: Senior University Lecturer Clinical Epidemiology of Cancer 
 
telephone number: 088-7553014  or  088-7559301 (Sec.)  
 
institution: Julius Center for Health Sciences and Primary Care  
 
correspondence address: PO box 85500 
 
postcode: 3508 GA 
 
city: Utrecht 
 
telefax: 088-755 5485 
 
4. type of 
population-
based 
screening 
program 
 
A permit is required because it is a population-based screening program  
O a. whereby ionising radiation is applied; 
 b. on cancer; 
O c. on diseases or abnormalities which can neither be treated nor 
prevented.  
  
If category a: If the Nuclear Energy Act grants a permit for the X-ray 
machine, enclose a statement of the permit.  

Ministry of Health, Welfare and Sport  
3 
 
If category c: Which exceptional circumstances would warrant the 
research? (max. 10 lines) 
  
The population-based screening program is also a medical scientific 
research:  
 yes, then answer Part 7 as well   
O no 
 
5. starting and 
end date of 
the 
population-
based 
screening 
program 
Starting date:  1 September 2011 
 
End date:  
1 September 2019 
 
6. funding 
If applicable, is the funding complete?  
 yes, for the first screening round, contact person Dr C.H. van Gils 
O no, contact person:  
 
7. signature  
 
applicant:  
 
research or project leader: 
 
Part 2. Justification for the population-based screening program  
 (max. 300 lines)  
 
  
 
1. Motivation, key figures 
 
Breast cancer is one of the most common cancers in women in the 
Netherlands, with an incidence of about 13,000 new invasive tumours per 
year. Each year, 3,180 women die as a result of this disease. In addition, 
breast cancer is sixth on the list of diseases with the greatest burden of 
disease for women (Source: www.nationaalkompas.nl). Over the past 
decades, new treatment options and the population-based mammography 
screening program for breast cancer have made an important contribution 
to the reduction of breast cancer mortality rates (together, reduction of 
25%) (1). However, when we look at the current population-based 
screening program among women between the age of 50 and 75, still a 
third of the breast tumours are diagnosed between two screening rounds, 
the so-called interval cancers. These are tumours detected because they 
are palpable and/or cause complaints. Thus, these tumours did not benefit 
from the population-based screening program, are already at a more 
advanced stage when diagnosed, and have a significantly worse survival 
probability than tumours discovered during the population-based screening 
program (2).  
 
Women with extremely dense breast tissue >75% density, caused by a 
large amount of fibroglandular and stromal tissue in the breast, about 5% of 
all women in the screening age), are a high-risk group for breast cancer. 
Their chances at developing breast cancer is 4 to 6 times higher than those 
of women with low mammographic breast density (primarily fatty tissue in 
the breast) (3). On top of that, it is precisely this group, the highest-risk 

Ministry of Health, Welfare and Sport  
4 
group, where mammographic examination is of limited value because the 
fibroglandular and stromal tissue can easily mask the presence of a 
possible tumour. Various studies have shown that the sensitivity in the 
population-based screening program with mammography is significantly 
lower among women with very dense breasts (4-8). The study conducted 
by Kerlikowske et al. (6) indicates that the mammographic screening 
sensitivity in women aged 50 to 69 years is 65% among women with >75% 
density compared to 89% among women with <25% dense tissue. Or, in 
other words, the risk of an interval cancer for women with >75% density is 
almost 10 times higher than for women with <25% dense tissue. Boyd et al. 
even present a probability of almost 18 times higher for women with >75% 
density at getting interval cancers compared to women with <10% dense 
tissue (4). This dual effect of high breast density on the development of 
cancer on the one hand and on the sensitivity of mammography in this 
group on the other hand, means that the group with the highest risk at 
getting breast cancer is screened using a technique that has limited value 
to them, namely mammography.  
 
Women with very dense breasts could benefit more from sensitive imaging 
techniques, such as digital mammography, ultrasound and magnetic 
resonance imaging (MRI). Digital mammography seems to be more 
sensitive than conventional mammography, but in a large study among 
screening participants, this effect seemed to be limited to women under the 
age of 50 with very dense breasts. There was no difference between the 
digital and conventional mammography for women above the age of 50, 
even for the group with very dense breasts (9). Ultrasound seems to result 
in higher detection rates among women with very dense breasts and a 
higher risk for breast cancer based on the Gail or Claus risk assessment 
models (10). However, the increased sensitivity goes hand in hand with a 
significantly 
higher 
number 
of 
false 
positives. 
Furthermore, 
the 
reproducibility of this technique depends a great deal on the person 
operating the machine, and the ultrasounds are preferably carried out by 
the radiologists themselves instead of technologists, which significantly 
raises the costs of this study.  
 
To this day, the value of MRI for screening purposes has only been 
investigated in (young) women with a BRCA1 or 2 mutation or an otherwise 
very strong family history of breast cancer. In a number of studies where 
women were examined with (digital) mammography, ultrasound as well as 
MRI, the sensitivity of the MRI was significantly higher than that of the other 
techniques (11-14). 
 
2. Objective of the population-based screening study  
 
The proposed experimental population-based screening study entails that 
the participants of the current population-based screening program with the 
highest risk (>75% density) undergo an additional MRI examination if their 
mammographic screening does not show any abnormalities. The aim of this 
is to detect any possible tumours in an earlier stage in this high-risk group 
and to reduce the number of interval cancers in this group, to reduce the 
number of deaths due to breast cancer and to increase the quality of life of 
patients with breast cancer.  
 

Ministry of Health, Welfare and Sport  
5 
This could in particular be effective because the proposed population-
based screening study focuses on the group with the highest risk, for 
whom, at the same time, the effectiveness of the mammography is the 
most limited.   
 
The intended effect on a national level is as follows: 
Every year, there are about 900,000 women in the Netherlands between 
the age of 50 and 75 who are screened using mammography as part of the 
Dutch population-based mammography screening program. About 5% of 
these women have extremely dense breasts (>75% density), so 45,000 
women. It is expected that adding an MRI to the mammography screening 
in this high-risk group will decrease the number of interval cancers from 4.4 
per 1000 screened women to 1.44 per 1000 screened women (1;6) 
(calculations are explained further in section 7.7). On a national level, this 
means that the number of interval cancers per screening round in this 
group decreases from 199 to 65.  
 
The prognosis of patients with tumours discovered through screening is 
better than that of patients with interval cancers, with an estimated 5-year 
survival rate of 95% and 78% respectively (2). On the basis of these 
figures, we estimate that 23 deaths due to breast cancer could be 
prevented per screening round: 134 tumours (199 minus 65) detected now 
through screening instead of in the interval, and of which as a result 
thereof, 17% fewer breast cancer deaths in 5 years (95% minus 78%).  
 
From previous research in the screening population of 50-70 years, we 
know that the average age of women with >75% density is around 53 
years. If we calculate with an average life expectancy of another 27 years, 
an additional 621 extra life years are gained per round with the proposed 
population-based screening study.  
 
In addition, this population-based screening study will have a favourable 
effect on the quality of life of breast cancer patients, considering a large 
part of the interval cancers (67%) will be diagnosed sooner through 
screening, which means an aggressive treatment will be required less 
frequently.  
 
3. Natural course of the disease 
 
About 13,000 women in the Netherlands are diagnosed with breast cancer 
annually (Source: www.ikcnet.nl 2009). Three quarters of these women are 
50 years or older (± 9,750). Important predictive factors for the prognosis of 
breast cancer are tumour diameter, axillary lymph node status and 
histologic tumour grade (1;15). In the Netherlands, women between the age 
of 50 and 75 are screened every two years using mammography as part of 
the Dutch population-based mammography screening program. The 
population-based screening program detects about 5,000 breast tumours 
each year (51% of all tumours among women older than 50) (1). However, 
not all tumours are detected through the population-based screening 
program: Among the participants, about 30% of the tumours are discovered 
in the interval between the screening rounds (the so-called interval 
cancers) (1). This large number of interval cancers is a problem since the 
staging, and with that the prognosis, is less favourable compared to the 

Ministry of Health, Welfare and Sport  
6 
tumours discovered through screening (1;2). In a patient monitoring study 
pilot in the Dutch screening organisation “Zuid-West”, data on the staging 
differences between screening tumours and interval cancers have been 
collected. Interval cancers are more frequently stage III (12%) or IV (15%) 
compared to screen-detected tumours (4% and 6% respectively) (1). A 
Finish study shows that the 5-year survival probability is 95% for women 
with screen-detected tumours and 78% for interval cancers (2). Women 
with very dense breasts have a higher risk of developing screen-detected 
tumours and even more so of developing interval cancer (4;5;7;8). Five per 
cent of all women who participate in the population-based screening 
program have very dense breasts (>75%) and 13% of the interval cancers 
is found in this group (6). 
 
Women with very dense breasts most likely have a higher chance at 
developing interval cancers because the large amount of fibroglandular and 
stromal tissue in the breast could mask the potential presence of a tumour 
during mammographic screening. There are no indications this would be 
caused by tumours growing faster in this group of women (4;16). 
 
 
 
 
4. Treatment options and prognosis  
 
The most commonly used treatments for breast cancer are: surgery, 
radiotherapy, chemotherapy, hormonal therapy and treatment through 
monoclonal antibodies. Most women with breast cancer receive a 
combination of the above-mentioned treatment methods. The choice and 
the sequence of the different treatments depends, among others, on the 
characteristics of the tumour, the stage of the disease, age and 
menopausal status.  
 
The breast cancer prognosis after treatment depends on the stage at 
diagnosis (see graph below). The 10-year survival probability varies from 
very good (>90%) at stage I to very bad at stage IV (<10%) (see graph). 
Treatment is not different for different density categories since there are no 
indicators of differences in prognosis of tumours in the same stage. The 
prognosis of interval cancers, which also occur more frequently among 
women with very dense breasts, is worse than that of tumours discovered 
through regular screening, because the stage at diagnosis is less 
favourable (1;2) (see Section 3. Natural course of the disease).  
 

Ministry of Health, Welfare and Sport  
7 
 
 
 
5/ 6. not applicable 
 
7. Population-based screening program alternatives  
 
Primary prevention 
For breast cancer, no real strong risk factors are known, such as is the 
case with smoking and lung cancer. The known risk factors for  only slightly 
increase the risk of breast cancer and heredity only plays a clear role in 5 to 
10% of the women with breast cancer. Known risk factors are, for example: 
age above 50, various hormonal factors (early age of menarche, late 
menopause, not having children, etc.), being overweight after menopause, 
physical inactivity, alcohol use and having very dense breasts. Of all the 
risk factors, high breast density is, following heredity, associated with 
breast cancer the most. Reducing the density with medicines such as 
Tamoxifen or Raloxifene, could be a way to reduce the risk of developing 
breast cancer for women with very dense breasts (17). However, these 
medicines increase the risk of developing other conditions such as 
endometrial cancer and thromboembolism, and cause vasomotoric side 
effects. It is not yet known how long these medicines need to be taken for 
there to be a protective effect. As a result, these medicines are rarely used, 
even in the United States where these medicines have been approved by 
the FDA (18).  
 
Curative treatment  
In terms of curative treatment, no breakthroughs are expected in the near 
future that could significantly improve the diagnosis of breast cancer 
discovered in a relatively unfavourable stage (stage IIb, III, IV). This makes 
it all the more important to trace breast cancer in an early stage, so the 
prognosis is most favourable. The aim of this screening study is to 
contribute to early detection of breast cancer and with that, enhance the 
survival probability.   
 
 
 

Ministry of Health, Welfare and Sport  
8 
Part 3. Screening strategy 
(max. 150 lines)  
 
 
 
 
 
 
 
1. Target group  
 
The target group of the proposed experimental population-based screening 
study are women at the age of 50 to 75, who participate in the current 
Dutch population-based mammography screening program. Women qualify 
for the examination if their mammographic breast density is higher than 
75% (this is the case for about 5% of the screening participants) and if they 
have a negative (=without abnormalities) screening mammography. This is 
a mammography classified in the population-based screening program as 
BI-RADS (Breast Imaging Reporting Data System) category 1 or 2 
according to the mammographic classification of the American College of 
Radiology (www.acr.org). The breast density is quantified using a method 
developed by N. Karssemeijer (19). This method has been validated 
against MRI for the GE Senographe mammograph (19).  
 
Women with a contraindication to MRI with contrast media (Gadolinium) (for 
example, metal objects in the body such as a pacemaker), cannot take part 
in the trial.   
 
2. Screening method, test characteristics  
 
To this day, the value of MRI for screening purposes has only been 
investigated among (young) women with a BRCA1 or 2 mutation or an 
otherwise very strong family history of breast cancer.  
 
A recent meta-analysis of these studies (20) shows a sensitivity of 94% 
(95%CI 90-97) for MRI and mammography combined and 39% (95%CI 37-
41) for mammography only. The combination with MRI resulted in more 
false positives than mammography only (specificity 77% 95%CI 75-80% 
and 95% 95%CI 93-96% respectively). The specificity did, however, 
improve in the following screening rounds. Although survival data are still 
not available, the more favourable staging of the tumours discovered by 
adding the MRI predicts a significant reduction in breast cancer mortality. 
Based on these data, it is recommended that women with an increased risk 
of developing breast cancer (20-25% or greater) are screened annually with 
mammography and MRI from the age of 30. In the Dutch MRISC study on 
the effect of MRI screening among women with a family history of breast 
cancer, the results were also stratified into two groups of breast density 
(high and low) (21). The mammography and MRI combined led to detecting 
more tumours than mammography only among women with a low as well 
as women with a high breast density. Lehman et al. (22) investigated the 
value of MRI of the contralateral breast of women recently diagnosed with 
breast cancer. This research showed that MRI could identify tumours that 
were missed by mammography (3.1%) with high sensitivity in both dense 
(87%) and nondense (100%) breasts.  
 
Screening with ultrasound also seems to result in higher breast cancer 
detection rates among women with an increased breast density and an 
increased risk -of developing breast cancer based on the Gail or Claus risk 
assessment models (10). Mammography combined with ultrasound had a 

Ministry of Health, Welfare and Sport  
9 
sensitivity of 77.5% compared to a sensitivity of 50% for mammography 
only. However, the increased sensitivity goes hand in hand with a 
significantly increased number of false positives (specificity 89.4% and 
95.5% respectively). We selected MRI (in combination with mammography) 
for this experimental population-based screening study and not ultrasound 
as screening modality among women with very dense breasts for the 
following reasons:  
- 
In several studies where women were examined using (digital) 
mammography, ultrasound as well as MRI, the sensitivity of MRI 
proved to be significantly higher than that of the ultrasound (11-
14;23). For example, in the recent study (2010) by Kuhl et al. (11), 
the sensitivity of the combination of MRI + mammography was 
100% compared to 48% for ultrasound + mammography. The 
positive predictive value of MRI is also considerably higher than 
that of ultrasound (48% versus 36%) (11), and the proportion breast 
cancers after biopsy too (25% versus 15%) (14). Based on this 
literature, the expected effectiveness of screening with MRI among 
women with very dense breasts is significantly higher than that of 
ultrasound.  
- 
The reproducibility of ultrasound is lower and depends a great deal 
on the person operating the machine (24). For this reason, it is 
recommended that ultrasound screening of the breast is carried out 
by radiologists instead of technologists. Taking account of the fact 
that ultrasound screening of the breast is laborious (at least 15 
minutes per breast) (24), the ultrasound screening costs could even 
be slightly higher than that of MRI with contrast (14). 
 
In this experimental population-based screening study, we do not want to 
replace mammography by MRI, considering the sensitivity of the MRI and 
mammography combined are significantly higher than that of the separate 
modalities in studies among women with BRCA1 or 2 mutations (20). In 
addition, DCIS tumours are in general easier to detect by mammography 
(25;26). 
 
3. Cut-off points, positivity criteria  
 
Mammography and MRI results are typically classified in accordance with 
the American College of Radiology classification system, the Breast 
Imaging Reporting and Data System (BI-RADS) (www.acr.org; under 
Quality and Safety resources, BI-RADS atlas). A negative screening 
mammography is an inclusion criterion for this study, which means that per 
definition, all mammographic screenings have been classified as either BI-
RADS 1 (=negative) or 2 (=benign finding). With the MRI assessment, the 
mammography results may be used, as well as those of previous 
examinations. The MRI assessments MRI BI-RADS 1 (=negative) and 2 
(=benign finding) give no indication for further follow-up. These women are 
invited again after 2 years to take part in the population-based screening 
study. With MRI BI-RADS 3 (=probably benign abnormality), the MRI 
examination is repeated after six months. There is a positive finding with 
the MRI if it is classified as MRI BI-RADS 4 (=suspicious abnormality) or 5 
(=highly suggestive of malignancy). These abnormalities will cytologically or 
histologically need to be confirmed. Women with a positive MRI result will 
undergo an ultrasound-guided or MRI-guided biopsy. The MRI BI-RADS 0 

Ministry of Health, Welfare and Sport  
10
result (=incomplete examination) is merely a temporarily result, and 
completion of this examination will take place as soon as possible.   
 
4. Technical realisation  
 
MRI examinations are made no later than 8 weeks after participating in the 
population-based mammography screening program. For premenopausal 
women (women with at least 1 menstruation in the last 30 days), the MRI 
examination is scheduled between day 7 and 14 of the menstrual cycle as 
much as possible to avoid hormonal-induced enhancement.  
 
All women in the MRI group will be scanned according to a “state-of-the-art” 
MRI protocol. Prior to the start of the trial, this protocol is standardised in 
the participating centres. The scans will be interpreted by experienced 
radiologists, using the under 3.3. referred to MRI BI-RADS criteria.  
 
The MRI BI-RADS 3 results will be reassessed centrally before the results 
are reported back to the woman. With this double reading, by definition, the 
highest BI-RADS score is taken as the final result. The reason for 
reassessment of the BI-RADS 3 results is that this is typically the most 
difficult assessment category for the radiologists. This is because this is a 
very heterogeneous group of lesions, for which no clear classification 
category exists. All participating radiologists receive training to standardise 
the MRI procedures and assessment of MRI examinations. 
 
5. Screening interval  
 
The proposed experimental population-based screening study using 
mammography and MRI among women with very dense breasts will run 
parallel to the current Dutch breast cancer screening programme (2 year 
screening interval). This screening interval was chosen in the past based 
on a careful consideration of the costs and benefits. We continue with this, 
because there are no indications that women with very dense breasts in 
this age category develop other tumours (for example, faster-growing 
tumours) compared to women with fatty breasts. Besides, by adopting the 
current screening interval, the existing infrastructure can be used, which 
simplifies the research on the added value of MRI examinations.  
 
6. Diagnosis  
 
The MRI results lead to different strategies for further diagnostic work-up, 
as described in the Netherlands National Breast Cancer Dialogue (in Dutch: 
Nationaal Borstkanker Overleg Nederland, NABON) Mammary Carcinoma 
Directive (27):  
- 
The MRI BI-RADS 0 result (=incomplete examination) is merely a 
temporarily result, and a completion of this examination will take 
place as soon as possible. A reason for a BI-RADS 0 result could be 
a technically incorrect execution of the MRI examination. The 
radiology department of the participating hospitals calls on the 
concerning woman to carry out a new MRI examination.  
- 
When the MRI examination is negative (BI-RADS 1 or 2), further 
work-up is not required. Women with these scores will be invited 
again after 2 years for another mammography as part of the current 

Ministry of Health, Welfare and Sport  
11
population-based mammography screening program and for an MRI 
examination as part of this experimental population-based screening 
study.  
- 
With a BI-RADS 3 (=uncertain; probably benign abnormality) result, 
an MRI examination is repeated after six months. The radiology 
department will contact the woman for this examination.  
- 
A positive MRI examination (BI-RADS 4 or 5) requires a cytologic or 
histologic evaluation. This is done using an ultrasound-guided 
biopsy, or if the abnormality cannot be traced with a second-look 
ultrasound, using an MRI-guided biopsy.  
 
Cytological and histological evaluation is reviewed in the concerning 
centres by experienced mamma-pathologists to determine the subsequent 
clinical strategy. Within the framework of this study, all the material will also 
be evaluated centrally later.  
  
If an abnormality, found using MRI, turns out not to be malignant following 
further examination, the woman is invited again after 2 years for another 
mammography as part of the current population-based screening program 
and for an MRI examination as part of this experimental population-based 
screening study. 
 
Part 4. Scientific appropriateness  
(max. 125 lines)  
 
 
1. Efficacy  
 
The efficacy of adding MRI to the current breast cancer screening 
programme among women with very dense breasts is to this day unclear 
and is to be investigated in this experimental population-based screening 
study. There is, however, strong evidence from the literature that MRI could 
be worthwhile for these women. Different studies show that MRI can 
identify tumours missed by mammography and ultrasound (11-14). The 
value of MRI for screening purposes has been investigated among (young) 
women with a BRCA1 or 2 mutation or an otherwise very strong family 
history of breast cancer. Since young women have dense breasts more 
often, the results of these studies are important to this experimental 
population-based screening study. A recent meta-analysis of these studies 
(20) show a sensitivity of 94% (95%CI 90-97) for the MRI and 
mammography combined, and 39% (95%CI 37-41) for mammography only. 
The combination with MRI did result in more false positives than 
mammography only (specificity 77% 95%CI 75-80% and 95% 95%CI 93-
96% respectively). Nevertheless, the specificity did improve in the following 
screening rounds. Although survival data are still not available, the more 
favourable staging of the tumours discovered by adding the MRI predicts a 
considerable reduction of breast cancer mortality rates. 
 
That is why the American Cancer Society advises to screen women with a 
high risk of developing breast cancer annually with MRI in addition to 
mammography. The first results of the ACRIN 6666 study among women 
with very dense breasts and an increased risk based on the Gail or Claus 
risk assessment models, where MRI is added after three years of screening 
with mammography and ultrasound support these results (23). This study 

Ministry of Health, Welfare and Sport  
12
shows that many more breast cancers at early stages are found by MRI 
compared to mammography and ultrasound and the combination of these 
two. This study also confirms that ultrasound screening or MRI leads to 
more false positive assessments and unnecessary biopsies than screening 
with mammography only.  
 
The drawback of the above-mentioned studies is the cross-sectional 
character, i.e. that all women in the studies have been offered all imaging 
techniques described in the study. Because of this set up, it is not clear 
whether MRI reduces the number of interval cancers, whether there is a 
difference in staging of the tumours found, and whether it does lead to a 
less aggressive treatment.  
 
In a randomised design like we propose in this experimental population-
based screening study, we actually aim to get a better understanding of 
these clinically important outcome measures and the number of false 
positives (and unnecessary biopsies). The randomised design, the outcome 
measures chosen and the size of this experimental population-based 
screening study will generate the necessary weight of evidence on the 
efficacy of adding MRI to the current breast cancer screening programme 
among women with very dense breasts.  
 
2. Other important implications  
 
Investigating the value of adding MRI to the current breast cancer 
screening programme among women with very dense breasts is also 
important for younger women (45-49 years old). These women currently fall 
outside the Dutch population-based mammography screening program 
because it is not cost-effective. The screening is not cost-effective partly 
because, among other reasons, many women in this age group have very 
dense breasts so the sensitivity of mammography screening is limited. If 
this experimental population-based screening study reveals that MRI 
examinations are effective in detecting breast cancer at an early stage 
among women with very dense breasts, then this will also be important 
information for a potential cost-effective strategy for women of the age of 45 
to 49. Another important effect is obtaining more insight into the relationship 
between density and breast cancer risk.  
 
Part 5. Description of the population-based screening study  
(max. 300 lines)   
 
 
 
 
 
1. Design, sites  
 
Described in Part 7.  
 
2. Information, communication, complaints, report  
 
Described in Part 7.  
 
3. Objectives, feasibility, actual results  
 
Objective of this experimental population-based screening study is to detect 
breast cancer in an early and better treatable stage among women with 

Ministry of Health, Welfare and Sport  
13
very dense breasts, which ultimately reduces the number of breast cancer-
related mortalities. The feasibility is described in Section 7. The type of 
results referred to ( Participation rates; Screening Results; Biopsy Rates; 
Detection Rates; Predictive Values; False Negatives and Variation in 
Seriousness of the Disease) will all be evaluated in this experimental 
population-based screening study.  
 
4. Guidelines, working arrangements, quality control, evaluation  
  
The quality of the MRI examinations and their assessment will be monitored 
by working according to the “state-of-the-art” guidelines and by creating 
working arrangements. The working arrangements will be concluded during 
consensus meetings and training sessions where radiologists from all 
participating centres will take part in. The working arrangements will be 
incorporated in a concise document that will be distributed to all the 
centres. This way, we can carry out the MRI reading and assessment 
thereof as standardised as possible. The data collected will be entered into 
an online central database (Research Online). This online database will 
incorporate different validation steps to monitor the quality of the data.  
 
The quality of the experimental population-based screening study will be 
monitored regularly through regular contact between the centres and the 
principal investigators. The principal investigators will also pay a regular 
visit to the centres to stay informed of the process made and any arising 
problems. Besides quality control by the researchers, there will also be an 
on-site 
monitoring, 
recommended 
by 
the 
“Kwaliteitsborging 
van 
mensgebonden onderzoek” (English: Quality Control on Research Involving 
Human Subjects) study group of the Netherlands Federation of University 
Medical Centres (28). Monitoring will consist of 1 visit per year per centre in 
accordance with the on-site monitoring guidelines for studies in the risk 
category: Minimum breach of insignificant risk (28).  
 
Part 6. benefit and harm ratio  
(max. 175 lines)  
 
 
 
 
1. Benefit  
 
The benefit refers to the decline in the number of breast cancer deaths by 
discovering breast cancer in the highest risk groups in an earlier stage than 
is currently the case. The early detection of breast tumours should, 
furthermore, lead to lesser invasive treatments and less burden of disease.  
 
2. Harm 
 
The harms primarily consist of false-positive MRI results and, as a result, 
further follow-up and possible interventions which turned out to be 
unnecessary. This could create stress and loss of trust.   
 
3. Ratio  
 
By selecting the group of women with the highest breast density, , MRI 
examination will take place in a group of women that will benefit from it the 
most, because of their high risk and very limited mammography value. The 

Ministry of Health, Welfare and Sport  
14
ratio of benefit and harm is determined by the sensitivity of MRI in this 
group on the one hand, and the number of false positives on the other 
hand.   
 
Part 7. Medical-scientific research project description  
(max. 525 lines)  
 
 
1. Projectleader  
 
 
Name contact person: Dr Carla H. van Gils 
 
position: 
 
Associate Professor Epidemiology  
 
institution:  
 
Julius Center for Health Sciences and Primary  
 
 
           Care, UMC Utrecht 
 
correspondence address: PO box 85500 
 
postcode:  
 
3508 GA 
 
city:  
 
 
Utrecht 
 
telephone number: 
088-7553014 
 
telefax:  
 
088-7555485 
 
 
2. Problem definition  
 
Women with very dense breast tissue (>75% of the breast consists of 
fibroglandular and stromal tissue) are 4-6 times more likely to develop 
breast cancer than women with little or no dense tissue (3). On top of that, 
the sensitivity of mammographic screening is very limited with these women 
(4-8), so in this group of women, breast cancer presents itself more often as 
interval cancer compared to the group with low breast density. Interval 
cancers are tumours that show itself in between two screening rounds; for 
example, because a woman has complaints. In general, interval cancers 
have a worse prognosis than tumours detected through screening.  
 
The women with the highest risk at developing breast cancer in the 
population-based screening program are momentarily screened using a 
method that has a merely limited value for them, and they could probably 
benefit more from more sensitive screening methods, such as MRI.  
 
 
3. Objective  
 
Our objective is to detect more breast tumours in an earlier stage among 
women who participate in the population-based mammography screening 
program and who have very dense breasts, eventually to reduce the 
number of breast cancer deaths.  
 
 

Ministry of Health, Welfare and Sport  
15
 
4. Research question  
 
1) What is the effectiveness of screening every 2 years using 
mammography combined with MRI compared to mammography 
only in reducing the number of interval cancers (as proxy for breast 
cancer mortality) among women with extremely dense breasts?  
2) What is the cost-effectiveness of each of these strategies?  
3) What is the influence of the MRI examination on the quality of life of 
the participating women?  
4) What is the degree of participation to the MRI study?  
 
 
5. Recent literature  
 
Women with extremely dense breasts (>75%) are 4-6 times more likely to 
develop breast cancer compared to women with <25% dense tissue. This 
relation has been indicated in the past many times before, both in 
premenopausal as well as postmenopausal women, and remains 
unchanged after statistical adjustment for differences in other breast cancer 
risk factors (3;29). The increased risk applies to all breast tumours, even for 
the more aggressive tumours (30). 
 
High breast density makes it substantially harder to detect tumours using 
mammography. This is because the fibroglandular and stromal tissue 
(dense tissue) and tumours block the same amount of X-rays. There is 
strong evidence that women with high mammographic density have a 
higher chance at developing both screen-detected tumours (tumours 
discovered by mammographic screening) and interval tumours. However, 
this effect is stronger for the interval cancers (4;6-8). Our research group 
already showed this difference in the past (8), but was more recently 
confirmed by a study conducted by Boyd et al. in the New England Journal 
of Medicine (4). They found that women with >75% density compared to 
women with <10% dense tissue had a higher risk of developing breast 
cancer (Odds ratio (OR)=4.7; 95% confidence interval (CI)=3.0-7.4). This 
applied to the screen-detected tumours (OR=3.5; 95%CI=2.0-6.2), and to 
the interval cancers, but the latter risk was much stronger (OR=17.8; 
95%CI=4.8-65.9). In an accompanying editorial in the same journal, 
Kerlikowske et al. (6) confirmed again with data of the Breast Cancer 
Surveillance Consortium (BCSC) that the sensitivity of the screening 
programme is very much defined by the degree of breast density. With 
women with low breast density (<25%), the screening sensitivity was 0.91, 
0.94 and 0.86 for women at the age of 40-49, 50-59 and 60-69 respectively. 
With women with very dense breasts, the sensitivity was 0.63, 0.66 and 
0.64 respectively.  
 
There are no studies known on the use of MRI for breast cancer screening 
in this target population. As has been described extensively in Part 3. 
Screening strategy, MRI is in terms of sensitivity the most promising 
screening technique. However, MRI studies have so far been limited to 
women with a BRCA1 or BRCA2 mutation or women with a very strong 
family history of breast cancer. This strategy turned out to be cost-effective 
and the American Cancer Society and American College of Radiologists 
(www.acr.org) now recommends that women, who have a 20-25% lifetime 
risk of developing breast cancer throughout their lives, should get an MRI 

Ministry of Health, Welfare and Sport  
16
each year (in addition to mammography) starting from the age of 30 (31).  
 
 
6. Research design  
 
Design 
The study includes a randomised controlled trial (RCT) with rates of (extra) 
detected tumours, interval cancers and tumour stage distribution as the 
primary outcome measures. Many studies that evaluate the new screening 
methods use a so-called cross-sectional paired design whereby the 
participants receive both the ‘old’ as well as the ‘new’ test. This indicates 
how many more tumours are discovered by the new test compared to the 
old test, but it does not indicate in which stage the tumour with each of the 
tests could be detected. A similar major problem is that the proportion of 
interval cancers cannot be compared between the two tests. This is 
because all tumours detected by one of the two tests will be treated; only 
the tumours that are missed by both tests could appear as interval cancers. 
A decline in the number of interval cancers compared to the old method is 
important to show if the new screening test really is effective and does not 
cause merely more overdiagnosis (in other words, the detection of tumours 
that would never have become symptomatic during a woman’s lifetime). For 
this reason, an RCT with parallel groups is necessary.  
 
For this research proposal a pre-randomisation design has been chosen. 
The researchers are of the opinion that the proposal meets the 
requirements stipulated by the Population Screening Act Committee (32): 
1) It is reasonably likely that the study will lead to important new 
insights (requirement of the importance). 
The importance of this study is described extensively in paragraph 2.1. 
Women with extremely dense breast tissue are more likely to develop 
breast cancer, and mammographic screening has reduced sensitivity 
among these women. The hypothesis is that with an additional MRI 
examination, the sensitivity of the breast screening for these women 
will improve greatly. At this moment, it is not yet possible to make a 
reliable and founded statement on this (see paragraph 4.1). All factors 
that play a role in the consideration whether or not to introduce a new 
screening method are investigated (see paragraph 7.9). The results of 
this project may help ensure that women with extremely dense breast 
tissue will undergo breast cancer screening that is as sensitive as that 
in women with less dense breast tissue.  
     
2) The research questions cannot be answered with a different 
research set up other than pre-randomisation (requirement of 
subsidiarity).  
The researchers are of the opinion that there are no reasonable 
alternatives for the pre-randomisation design. When the classic 
randomisation design is applied, there is also a great risk of 
contamination. Because the control group will also be informed of their 
high breast density and with this, the associated prognostic 
unfavourable combination of increased breast cancer risk with a 
lowered mammographic tumour detection, it is expected that a 
considerable percentage of women in the control group will request 
additional examination (for example, via the general practitioner). The 

Ministry of Health, Welfare and Sport  
17
internal validity of the study will for this reason be compromised, and the 
effect will be diluted. This dilution will be the strongest if the women in 
the control group undergo an additional MRI examination, but also to a 
large degree when they undergo an ultrasound or other additional 
examination. This was also recently observed in a European prostate 
cancer screening trial, where the PSA test was the diagnostic 
intervention (33). The study results showed that there was a strong rise 
in the number of PSA requests in the control group.   
 
With a pre-randomisation design, a setting is created that reflects the 
future practice the most. This way, an impression can be received of the 
acceptance rate of the MRI examination.  
 
3) The disadvantages for and burden on the participants are negligible 
(requirement of proportionality).  
The researchers are of the opinion that not informing the control group 
will not cause important adverse effects for or burden of these 
participants. Actually informing them means the participants are also 
informed of their risks they were not aware of until that moment. To the 
more than 20,000 women in the control group, no other screening 
method can be offered (of course except for the usual mammographic 
screening every 2 years) or a form of risk reduction, which probably 
triggers a lot of unrest.  
 
To be able to answer our research question, we do not need any other 
information from the control group other than on the occurrence of 
breast tumours in between two screening rounds (interval cancers) or 
with later screening rounds or on mortality as a result of breast cancer. 
This data can be obtained by linking the screening data with the data 
from the Dutch Cancer Registry and Statistics Netherlands (CBS) as is 
done now routinely already as part of the evaluation of the Dutch 
population-based mammography screening program (1). This routine 
linkage is also described in the folder of the regular Dutch population-
based mammography screening program. In that same folder, it 
describes how the women can object to such use. The data of both 
study arms are pseudonymized before processing and saving.  
 
The women who are randomised to the intervention group are informed 
of the study, but this takes place after randomisation. Due to the pre-
randomisation design, it is only possible to get permission to agree to 
the result of the randomisation. The researchers are of the opinion that 
the intervention group does not suffer any harm as a result thereof. 
After randomisation, the women invited for MRI receive an extensive 
information package on the study and its benefit-harm ratio.   
 
Sampling frame  
The study population consists of participants of the Dutch population-based 
mammography screening program aged between 50 and 75. They are from 
screening regions located in the operation area of the hospitals where the 
MRI examinations are carried out (see Section 10. Organisation). Women 
with >75% density and a negative mammographic screening (i.e. no reason 
for further diagnostic follow-up) are eligible for this.  
 
 

Ministry of Health, Welfare and Sport  
18
Selection of participants, inclusion and exclusion criteria  
The density is automatically quantified with the help of a full-automatic 
method developed for digital mammography(19). This result will be linked to 
the mammographic screening result. The women with extremely dense 
breasts and a negative screening result (BI-RADS 1 or BI-RADS 2) qualify 
for the study.  
 
The reason to focus on women between the ages of 50 and 75 and not on 
younger women with very dense breasts, is because the first group has a 
higher risk of developing breast cancer, and because the infrastructure for 
screening in this group already exists, so the value of the MRI can be 
examined relatively easily. If we can show that MRI has an added value to 
women with very dense breasts, this will be an important indication for a 
potential future cost-effective strategy for women of 45 to 49 years old.  
 
Women with contraindications for MRI cannot take part in the study. 
Examples of contraindications for contrast MRI are: allergy for gadolinium 
contrast media, presence of iron aneurysm clips, metal chips in the eye and 
pacemakers. Every participant fills out a safety questionnaire to find out if 
there are no contraindications to expose the participant to strong magnetic 
fields and/or contrast medium.  
 
Randomisation and stratification  
The DENSE trial applies the pre-randomisation design, whereby only the 
intervention group is informed about participation in the trial after 
randomisation 
(see 
paragraph 
7.6 
Research 
Method: 
design). 
Randomisation takes place if the breast density is extremely dense and a 
negative mammographic screening examination (BI-RADS mammography 
1 or 2).  
 
Randomisation takes place between:  
Arm I (intervention): additional MRI examination 
Arm II (control; Dutch guideline): no further examination until the following 
screening round 2 years later (unless there is reason to do a breast 
examination in the meantime, because of complaints by the participant for 
instance).  
 
The participants are randomised by a computer-generated randomisation 
sequence, with stratification for screening centre. A screening centre is a 
radiologic partnership assessing the screening mammograms for a certain 
region.  
 
Blinding  
The proposed experimental population-based screening study is a 
pragmatic (in comparison to explanatory) trial whereby two different 
screening strategies, including possible placebo or external effects, are 
compared. The importance of blinding the outcome measure in a pragmatic 
trial depends on the ‘hardness’ with which the outcome measure can be 
determined. In this case, it concerns the presence of breast cancer 
(screening-detected and interval cancers), which will be assessed 
objectively with the help of histology. Thus, blinding in this trial is not 
necessary.  
 

Ministry of Health, Welfare and Sport  
19
Starting and end date project  
Within this experimental population-based screening study, 3 screening 
rounds will be carried out in a period of 6 years. Because of the capacity at 
the MRI centres, it might be necessary to include the screening rounds in 
stages, we pursue a longer period for the entire study, namely from 1 
September 2011 to 1 September 2019. However, the research period per 
participant is still 6 years. For every participant, the intervention in a 
following screening round is the same as in her first screening round, so 
independent of, for example, a possible change in breast density. 
Eventually sensitivity analysis will be carried out to find out whether this has 
possibly influenced the results.  
 
 
 
7. Sample size, feasibility  
 
The sample size is calculated on a minimal detectable difference in the 
interval cancer percentage between the intervention group and the control 
group. The assumptions are based on the report of the National Evaluation 
Team for Breast Cancer Screening in the Netherlands 1990-2007 (1), a 
study by Kerlikowske et al. (6) and a study by Van Gils et al. (34).  
 
Among those aged 49-50, there are 6.2 tumours diagnosed per 1000 
screening examinations: 4.2/1000 by screening and 2/1000 in the interval 
between screenings (interval cancers) (1). In the table below, the expected 
occurrence of breast cancer in the different density categories is based on 
extrapolation of the data collected by Kerlikowske and et al. (6) to the Dutch 
setting. The programme sensitivity (calculated as the number of screen-
detected tumours divided by the total of screen-detected and interval 
tumours) after a screening interval of 2 years is based on data of Van Gils 
et al. (34). 
 
Breast 
density 
Number 
of 
breast 
cancer 
diagnoses 
(screening + interval) 
per 
1000 
examinations* 
 
Programme 
Sensitivity  
(Scr / (Scr+Int))*** 
Proportion 
interval 
cancers  
(=1-Sensitivity) 
total 
6.2** 
 
 
 
 
 
 
<25% 
2.5 
82% 
18% 
25-50% 
5.6 
74% 
26% 
50-75% 
7.6 
66% 
34% 
>75% 
8.0 
45% 
55% 
* relative occurrence of breast cancers between density categories based on data 
from Kerlikowske et al. (6) for women of 50-69 years of age  
** from the National Evaluation Team for Breast Cancer Screening in the 
Netherlands 1990-2007 report (1) 
*** calculated from the article from Van Gils et al. (32) for a 2-year screening 
interval  
 
Within the group with >75% density, the estimated number of interval 
cancers per 1000 mammographic screening examinations is 4.4 (0.55*8.0). 
Our assumption is that the MRI is not hindered by fibroglandular and 

Ministry of Health, Welfare and Sport  
20
stromal tissue, which is why women with >75% density can reach the same 
sensitivity using an MRI as with mammography among women with <25% 
dense tissue (i.e. 82%, see table). By adding MRI, we also expect that the 
proportion of interval cancers decreases to 1.44 per 1000 screening 
examinationss (0.18*8.0).  
 
In the pre-randomisation design, it is necessary to take into account the fact 
that there are women who do not wish to take part after randomisation. 
Because this non-participation only occurs after randomisation, the non-
participants must be included in the analysis according to the intention-to-
treat principle. This means the required sample size becomes larger (35). A 
study by Berg et al. (23) on the added value of MRI in the ACRIN 6666 trial 
showed that 57.9% of the women contacted participated in the MRI 
substudy. For a number of women, money or not having insurance was the 
decisive factor. Without these reasons, the participation level would have 
been 66%. We expect to reach a participation of 66% because the cost of 
MRI examination is covered in our study.  
 
In the intervention group, the expected interval cancer rate is 1.44/1000 
screening examinations among the 66% who participated in the MRI 
examination and 4.4/1000 among the 33% that did not participate in the 
MRI examination. As a result, the interval cancer rate in the intervention 
group is 2.49/1000 screening examinations.  
 
With a 1:4 ratio randomisation, 7,237 women are needed in the intervention 
group (of which 4,776 (66%) actually do take part in the MRI examination) 
and 28,948 women in the control group to show the difference between 
4.4/1000 and 2.49/1000 as statistically significant (1-sided alpha=0.05) with 
a power of 80% after 1 screening round and the subsequent interval. This 
was calculated using the sample size software PASS.   
 
Feasibility  
The experimental population-based screening study will be integrated in the 
infrastructure of the Dutch population-based mammography screening 
program, which is national and entirely digital. We foresee to have to invite 
7,237 women to be able to include 4,776 women (expected participation 
rate 66%) in the intervention group. The total study population (intervention 
and control group) will consist of 36,185 participants. The total target 
population of participants in the Dutch population-based mammography 
screening program with >75% density in the Netherlands is 90,000 in a 
period of 2 years, so we could expand our recruitment if the number of 
people participating is disappointing. We invite women living near the 
participating MRI centres (referred to in Section 10. Organisation). Every 
centre will have to make on average 400 extra MRI examinations per year 
for this experimental population-based screening study. The centres have 
already indicated their desire to participate.  
 
 
 
8. Effectiveness of treatment and practice options  
 
It is known that treating breast cancer in an early stage reduces the 
mortality rate. This is the motivation to conduct a population-based 
screening program on breast cancer in the Netherlands. The recently 

Ministry of Health, Welfare and Sport  
21
updated meta-analysis from Nelson et al. (36) for the US Preventive 
Taskforce 2009 report confirms again that mammographic screening 
reduces the number of deaths due to breast cancer. The relative risk of 
dying because of breast cancer is lower among women invited for 
mammographic screening compared to women in a control group who are 
not invited for screening (50-59 years: 0.89 95%CI 0.75-0.99; 60-69 years: 
0.68 95%CI 0.54-0.87). Furthermore, it is known that with mammographic 
screening, breast tumours among women with extremely dense breasts are 
diagnosed at a later stage compared to breast tumours among women with 
low density.  
 
If we would be in the position to realise that same early detection among 
women with very dense breasts, it may be expected that this would reduce 
the number of deaths due to breast cancer. There are no indications thus 
far that breast tumours among women with very dense breasts have other 
intrinsic characteristics which would give them a more favourable or 
unfavourable prognosis (30;37). 
 
 
 
9. Outcome analysis, evaluation  
 
Indicators of screening effectiveness  
The extra number of tumours detected by MRI, but missed by 
mammography, shall be described as well as the recall rate, the positive 
predictive value (and the false positive percentages) of the MRI and the 
number of biopsies per positive MRI test, with the corresponding 95% 
confidence intervals.  
 
The primary outcome is the comparison of the interval cancer proportions 
between the study groups (Chi-square or Fisher’s exact test in case of 
small numbers). Tumour size, stage and degree of the tumours will be 
compared between the arms as well as the distribution of histological and 
molecular subtypes. With respect to tumour size, the difference between 
means will be tested using the Student’s T-test. If not normally distributed, 
the medians will be calculated and the differences will be tested using the 
Mann-Whitney U test. Differences in stages, grade, histological and 
molecular subtypes are tested using Chi-square or Fisher’s exact test in 
case of small numbers.  
 
A problem already mentioned before, with the single consent version of the 
pre-randomisation design, is the dilution of the effect by non-participation in 
the intervention group after randomisation. Nevertheless, to be able to 
reach a true (nondiluted) estimation of the effect of the MRI, the analysis 
method of Cuzick et al. (35) will be used, which was specifically designed 
for these kinds of screening studies.  
 
Estimation of mortality reduction  
Calculating the actual mortality reduction requires a very long follow-up 
period and an even larger study population than proposed here. Breast 
cancer screening simulation models are a less expensive and faster 
approach to study the mortality reduction rate of this intervention. We use 
the MISCAN simulation programme that was specifically designed to build 
cancer screening models and also to analyse and explain the cancer 

Ministry of Health, Welfare and Sport  
22
screening trial results such as these, and to compare the cost-effectiveness 
of different screening measures (38;39). It is a validated model that has 
been applied numerous of times successfully in evaluating different 
screening strategies. It is also one of the most commonly used breast 
cancer models  by the Cancer Intervention and Surveillance Modelling 
Network (CISNET) consortium sponsored by the National Cancer Institute 
(40). In MISCAN, the individual life courses are generated as a Markov 
process of stages and transitions. For this, the characteristics of the study 
population (demographic data, risk factors) are fed to the model. The 
results of the screening and the scenarios as applied in the proposed 
experimental population-based screening study are estimated for a cohort 
of 1 million women with very dense breasts. The effects on mortality and life 
years gained with the different screening scenarios are estimated at a 
period of 10 years after the start of the screening. The most important 
parameters in the model are the average duration of the preclinical stages 
that can be detected with screening, sensitivity of the screening test and 
improvement in prognosis after detection through screening. Outcomes of 
the model are the number of screen-detected tumours and interval cancers 
(including stage distribution), age-specific breast cancer incidence, stratified 
by stage, and age-specific breast cancer mortality.  
 
Analysis of cost-effectiveness  
The breast cancer simulation model will also be used to predict the costs 
and effects of different screening strategies for a situation in which the 
screening is carried out for 10 years. The costs of the diagnosis and 
treatment of breast cancer will be registered as part of the experimental 
population-based screening study. Costs and effects are calculated for a 
simulated cohort of 1 million women for a period of 10 years after the start 
of the screening. The costs are presented in euros. The effects are 
presented in terms of breast cancer mortality reduction and number of life 
years gained. Cost-effectiveness ratios (CER) are expressed in costs per 
life-year gained and incremental cost-effectiveness ratios (ICER) as extra 
costs per extra life-year gained. For the intervention group, the quality of life 
is assessed using the EuroQol-5D questionnaire. To estimate the number 
of quality-adjusted life years  of the control group, we use the EuroQol-5D 
health status data of the general population of Dutch women of the age 
between 50 and 75 (41). We implement weighting factors with a reduction 
of 10%, 25%, 40% for respectively non-metastatic tumours, tumours with 
metastases in the regional lymph nodes or tumours with distant 
metastases. For this reason, the ICER is expressed in extra costs per 
quality adjusted life-year gained.  
 
Analysis of quality of life  
The effect of MRI screening on the quality of life of the women will be 
assessed using questionnaires. The EuroQol-5D questionnaire is a 
validated and a frequently-used questionnaire that is able to assess the 
quality of life with a few short questions, regarding physical as well as 
psychological consequences (41). 
 
In addition, the psychological consequences the experimental population-
based screening study could cause will also get attention by using the 
‘Consequences of Screening---Breast Cancer’ (COS-BC) questionnaire 
(42). The first part of the questionnaire (COS-BC-1) asks specifically about 

Ministry of Health, Welfare and Sport  
23
the fears and uncertainties during the screening procedure. The second 
part of the questionnaire (COS-BC-2) aims to get the woman to look back 
at the entire period of examinations and have her assess whether it has 
brought about positive and/or negative changes. The great advantage of 
the COS-BC questionnaire in comparison to other validated anxiety 
questionnaires is the fact that it is focussed specifically on breast cancer 
screening.  
 
With three short questions, the screen-specific items questionnaire uncover 
the burden experienced by the MRI examination (43).  
The group of women with MRI-detected breast cancer will be asked to 
answer the EORTC questionnaire once (44). 
 
The goal of the quality of life analysis is to investigate the (changing) quality 
of life in the intervention arm as a whole. Besides, whether differences can 
be observed between participants with false positive, true positive, false 
negative and true negative MRI results will be addressed.  
 
The moments at which time the different questionnaires are conducted is 
indicated in the flowchart (see ‘Flowchart timing of questionnaires’).  
 
Interim analyses 
The first analyses are carried out after the first screening round, namely: 
1. When all women in the intervention group have received an MRI, 
including any possible diagnostic work-up. At that point, the extra number of 
tumours detected by the MRI, and missed by the mammography, can be 
estimated, as well as the recall rate, the positive predictive value and the 
number of biopsies per positive MRI test.  
2. Two years after the last participant has been screened, the difference in 
the proportion of interval cancers is analysed and the tumour size and 
stage between both groups are compared.  
 
An interim analysis on the primary outcome is not possible, because 
information on interval cancers is only available after all participants have 
been screened and followed for two years.   
 
For the false-positive percentage, interim monitoring will take place. From 
the abstract from Berg et al. (23) on the added value of MRI in the ACRIN 
6666 trial, it is possible to calculate that the percentage ‘unjustified’ referrals 
in the entire investigated group is 17% and the percentage ‘unjustified’ 
biopsies is 9%. Based on this, we have decided the following: If after the 
first 750 MRI examinations the number of unjustified referrals is more than 
25% or the number of unjustified biopsies is above 15%, consultation on 
modification of the intervention in relation to the referral criteria is necessary 
and suspending the trial could be considered. A Data Safety and Monitoring 
Board is installed to this end, in any case consisting of an independent 
biostatistician, radiologist and oncologist as its members.  
 
 
 
 
 

Ministry of Health, Welfare and Sport  
24
 
10. Organisation  
 
Steering group: 
 
UMC Utrecht, Julius Center for Health Sciences and Primary Care: 
Prof. P. Peeters (epidemiologist and coordinator of the Cancer 
Epidemiology group) 
Dr C. Van Gils (epidemiologist) 
Dr E. Monninkhof (epidemiologist) 
Dr A. de Wit (coordinator of the Medical Technology Assessment group) 
 
UMC Utrecht Imaging Division: 
Prof. W. Mali (radiologist) 
Prof. M. Van den Bosch (radiologist) 
Dr W. Veldhuis (radiologist) 
 
Dutch Expert Centre for Screening (Dutch: Landelijk Referentie Centrum 
voor Bevolkingsonderzoek, LRCB) 
Prof. G. Den Heeten (Director) 
Dr M. Broeders (epidemiologist) 
 
Radboud University Medical Centre, Radiology Department: 
Prof. N. Karssemeijer (medical physicist) 
 
Screening organization Midden-West: 
A. Bartels-Kortland MSc (Director)  
 
Radiologists of participating centres where the MRI examinations will be 
made: 
Prof. C. Boetes, UMC Maastricht 
A. Obdeijn MSc, Erasmus MC, Rotterdam 
Dr R. Pijnappel, Martini Hospital, Groningen 
Dr C. Loo, Netherlands Cancer Institute (NKI), Amsterdam 
Dr R. Mann, Radboud University Medical Centre, Nijmegen 
Dr W. Veldhuis, Prof. M. van den Bosch, UMC Utrecht 
 
Advisors: 
R. Reij MSc, RIVM, Centre for Population Study  
Prof.  H. De Koning, Erasmus MC, Rotterdam 
Dr M. Tilanus-Linthorst, Erasmus MC, Rotterdam 
Prof. E. Van der Wall, UMC Utrecht, oncology 
Prof. P. Van Diest, UMC Utrecht, pathology 
 
Breast Cancer Patient Association: 
Ms R. van der Heide (former chairman) 
 
 
 
11. Risks  
 
The risks involved for the participants of this experimental population-based 
screening study are as follows:  
1) A participant can experience side effects of the contrast medium used by 
the MRI examination. Millions of MRI examinations are carried out with 

Ministry of Health, Welfare and Sport  
25
Gadolinium-based contrast agent worldwide each year (45). In a recent 
study, 51 side effects were reported after 32,659 injections administered 
with gadolinium-based contrast agent (0.16%), of which 43 mild (0.13%, for 
example nauseous, lightheaded, headache), 6 moderately severe (0.02%, 
for example, shortness of breath, erythema) and 2 severe (0.006%, loss of 
consciousness, cardiac arrest) (46). Extrapolated to the 4,776 patients to 
be scanned for this study, 6 mild side effects are to be expected, 1 
moderately severe and 0-1 severe side effects. These risks are further 
reduced by checking on allergies for the used contrast medium.  
 
There have been reports of Nephrogenic Systemic Fibrosis (NSF) among 
patients 
with 
severe 
kidney 
dysfunction 
(see 
FDA 
website: 
http://www.fda.gov/Drugs/DrugSafety/ucm223966.htm#aihp). NSF is not 
described with patients with normal kidney functions. Severe kidney 
dysfunction is therefore an exclusion criterion for this study.  
 
2) With the MRI examination, there is a chance of a false positive result 
with uncertainty, followed by extensive further and possibly invasive 
examination. How often this will happen in this population is not known and 
is also subject of the trial. The best indication we have comes from a 
recently published abstract (23) on the MRI substudy of the ACRIN 6666 
trial (10). This study shows that based on MRI, 17% of the participants 
underwent further examinations (imaging or biopsy) that were in retrospect 
unnecessary. Nine percent underwent, in retrospect, an unnecessary 
biopsy. Based on histopathological research, it turned out the abnormalities 
of these patients were benign.  
 
Participants will be informed thoroughly on the increased probability of false 
positives. Unnecessary invasive examination will be avoided as much as 
possible by looking back at the original mammographic examination, by 
assessing the MRI BI-RADS 3 results centrally and by scheduling a follow-
up MRI after 6 months for this category and finally, by carrying out a target 
ultrasound before a possible biopsy.  
 
3) There is a chance at being diagnosed with a relative indolent tumour that 
would never have been noticed if an MRI screening had not taken place 
(overdiagnosis). Overdiagnosis is inherent to screening: in the Dutch 
population-based screening program it is estimated that about 8% of the 
breast tumours discovered by screening would never have been diagnosed 
clinically in the absence of a screening programme (47). There are no 
estimates known yet on overdiagnosis in high-risk groups screened by MRI. 
We do not expect the overdiagnosis percentage to be higher in our study 
compared to the current population-based screening program because the 
ductal carcinoma in situ (DCIS) that plays a central role in the 
overdiagnosis problem, is actually easier to detect with mammography than 
with MRI (25;26). Besides, Kuhl et al. (48) have shown that the sensitivity of 
MRI for DCIS is especially high for the high-grade lesions that are most 
likely clinically more relevant.  
 
Overdiagnosis cannot be assessed for an individual, but our research is set 
up to get a better understanding of the degree of overdiagnosis on a 
population level. If the total number of tumours discovered in the MRI group 
(screening tumours) is greater than in the control group but the number of 

Ministry of Health, Welfare and Sport  
26
interval cancers does not decrease proportionally, this could be an 
indication of overdiagnosis.  
 
 
12. Information, consent  
 
The information and consent of the participants will be in accordance with 
the Central Committee on Research involving human subjects (in Dutch: 
Centrale Commissie Mensgebonden Onderzoek (CCMO)) regulations.  
 
Potential participants for the experimental population-based screening 
study will be recruited via the Dutch population-based mammography 
screening program. After randomisation, the intervention group will receive 
an information package through the mail about the study, consisting of the 
following documents: a cover letter from the screening organisation, 
information for the participants with the consent form, flow chart, MRI 
examination questionnaire and the ‘General medical scientific research with 
human subjects brochure’. In the cover letter, the women are asked – even 
if they are not interested in participating – to log in to the website 
www.juliuscentrum.nl/dense-studie. The login codes are provided in the 
information for the participants. If the woman is not interested in the study, 
the procedure is merely unregistering with an option to indicate the reason 
thereof. Women who do wish to participate in the study, register on the 
website and indicate they are interested in participating. Then the woman 
enters her personal data so she can be contacted by telephone by the 
research team. During this telephone conversation, the study is explained 
again and the woman has the opportunity to ask any remaining questions. If 
a woman decides to take part in the study, the study team employee who 
spoke to her will sign the informed consent form. Then this employee will 
send the consent form to the MRI centre, where the participant will be 
asked to sign it before undergoing the MRI examination. If the woman 
indicates over the telephone to want more time to make a decision, a later 
time is agreed on to call again. An appointment is scheduled for the MRI 
examination for those women who do wish to participate in the study. The 
MRI appointment will be confirmed in writing.   
 
The information flowchart is also annexed to the information for the 
participants.  
 
 
13. Ethical assessment  
 
Not submitted for approval by Medical Ethical Committee. 
 
 
14. Funding 
 
This study is financially supported by: 
- 
Utrecht University Medical Center (UMCU) 
- 
Dutch Cancer Society (KWF)  
- 
The 
Netherlands 
Organisation 
for 
Health 
Research 
and 
Development (ZonMw)  
- 
Pink Ribbon Netherlands/A Sister’s Hope 
- 
Bayer Schering Pharma (Bayer is not the sponsor or initiator of this 
research – that is UMC Utrecht). It has been contractually agreed 
with Bayer that all results and any possible intellectual properties as 

Ministry of Health, Welfare and Sport  
27
a result of this research is the property of the provider (UMCU). 
Bayer can not obstruct or postpone publication of the results. It is 
possible to see the contract on demand.  
 
Grant numbers: 
- 
UMCU DENSE 
- 
DCS-UU-2009-4348 
- 
ZONMW-200320002-UMCU 
- 
Pink Ribbon-10074 
- 
BSP-DENSE 
 
 
Part 8. References 
(summary of max. 100 lines)  
 
 
(1)  National evaluation of breast cancer screening in the Netherlands. National 
evaluation of breast cancer screening in the Netherlands 1990-2007. LETB XII.  
2009. Rotterdam. 
 
(2)  Kauhava L, Immonen-Raiha P, Parvinen I, Helenius H, Kaljonen A, Rasanen O, et 
al. Lower costs of hospital treatment of breast cancer through a population-based 
mammography screening programme. Eur J Public Health 2004 Jun;14(2):128-33. 
 
(3)  McCormack VA, dos SS, I. Breast density and parenchymal patterns as markers of 
breast cancer risk: a meta-analysis. Cancer Epidemiol Biomarkers Prev 2006 
Jun;15(6):1159-69. 
 
(4)  Boyd NF, Guo H, Martin LJ, Sun L, Stone J, Fishell E, et al. Mammographic Density 
and the Risk and Detection of Breast Cancer. N Engl J Med 2007 Jan 18;356(3):227-
36. 
 
(5)  Kavanagh AM, Byrnes GB, Nickson C, Cawson JN, Giles GG, Hopper JL, et al. 
Using Mammographic Density to Improve Breast Cancer Screening Outcomes. 
Cancer Epidemiol Biomarkers Prev 2008 Oct 1;17(10):2818-24. 
 
(6)  Kerlikowske K. The mammogram that cried Wolfe. N Engl J Med 2007 Jan 
18;356(3):297-300. 
 
(7)  Mandelson MT, Oestreicher N, Porter PL, White D, Finder CA, Taplin SH, et al. 
Breast density as a predictor of mammographic detection: comparison of interval- 
and screen-detected cancers. J Natl Cancer Inst 2000 Jul 5;92(13):1081-7. 
 
(8)  van Gils CH, Otten JD, Verbeek AL, Hendriks JH, Holland R. Effect of 
mammographic breast density on breast cancer screening performance: a study in 
Nijmegen, Netherlands. J Epidemiol Community Health 1998 Apr;52(4):267-71. 
 
(9)  Pisano ED, Hendrick RE, Yaffe MJ, Baum JK, Acharyya S, Cormack JB, et al. 
Diagnostic accuracy of digital versus film mammography: exploratory analysis of 
selected population subgroups in DMIST. Radiology 2008 Feb;246(2):376-83. 
 (10)  Berg WA, Blume JD, Cormack JB, Mendelson EB, Lehrer D, Bohm-Velez M, et al. 
Combined screening with ultrasound and mammography vs mammography alone in 
women at elevated risk of breast cancer. JAMA 2008 May 14;299(18):2151-63. 
 (11)  Kuhl C, Weigel S, Schrading S, Arand B, Bieling H, Konig R, et al. Prospective 

Ministry of Health, Welfare and Sport  
28
Multicenter Cohort Study to Refine Management Recommendations for Women at 
Elevated Familial Risk of Breast Cancer: The EVA Trial. J Clin Oncol 2010 Mar 
20;28(9):1450-7. 
 (12)  Lord SJ, Lei W, Craft P, Cawson JN, Morris I, Walleser S, et al. A systematic review 
of the effectiveness of magnetic resonance imaging (MRI) as an addition to 
mammography and ultrasound in screening young women at high risk of breast 
cancer. Eur J Cancer 2007 Sep;43(13):1905-17. 
 (13)  Warner E, Plewes DB, Hill KA, Causer PA, Zubovits JT, Jong RA, et al. Surveillance 
of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, 
ultrasound, mammography, and clinical breast examination. JAMA 2004 Sep 
15;292(11):1317-25. 
 (14)  Weinstein SP, Localio AR, Conant EF, Rosen M, Thomas KM, Schnall MD. 
Multimodality screening of high-risk women: a prospective cohort study. J Clin Oncol 
2009 Dec 20;27(36):6124-8. 
 (15)  Tabar L, Chen HH, Duffy SW, Yen MF, Chiang CF, Dean PB, et al. A novel method 
for prediction of long-term outcome of women with T1a, T1b, and 10-14 mm invasive 
breast cancers: a prospective study. Lancet 2000 Feb 5;355(9202):429-33. 
 (16)  Tilanus-Linthorst MM, Obdeijn IM, Hop WC, Causer PA, Leach MO, Warner E, et al. 
BRCA1 mutation and young age predict fast breast cancer growth in the Dutch, 
United Kingdom, and Canadian magnetic resonance imaging screening trials. Clin 
Cancer Res 2007 Dec 15;13(24):7357-62. 
 (17)  Visvanathan K, Chlebowski RT, Hurley P, Col NF, Ropka M, Collyar D, et al. 
American society of clinical oncology clinical practice guideline update on the use of 
pharmacologic interventions including tamoxifen, raloxifene, and aromatase 
inhibition for breast cancer risk reduction. J Clin Oncol 2009 Jul 1;27(19):3235-58. 
 (18)  Ropka ME, Keim J, Philbrick JT. Patient decisions about breast cancer 
chemoprevention: a systematic review and meta-analysis. J Clin Oncol 2010 Jun 
20;28(18):3090-5. 
 (19)  van Engeland S, Snoeren PR, Huisman H, Boetes C, Karssemeijer N. Volumetric 
breast density estimation from full-field digital mammograms. IEEE Trans Med 
Imaging 2006 Mar;25(3):273-82. 
 (20)  Warner E, Messersmith H, Causer P, Eisen A, Shumak R, Plewes D. Systematic 
review: using magnetic resonance imaging to screen women at high risk for breast 
cancer. Ann Intern Med 2008 May 6;148(9):671-9. 
 (21)  Kriege M, Brekelmans CT, Obdeijn IM, Boetes C, Zonderland HM, Muller SH, et al. 
Factors affecting sensitivity and specificity of screening mammography and MRI in 
women with an inherited risk for breast cancer. Breast Cancer Res Treat 2006 
Nov;100(1):109-19. 
 (22)  Lehman CD, Gatsonis C, Kuhl CK, Hendrick RE, Pisano ED, Hanna L, et al. MRI 
evaluation of the contralateral breast in women with recently diagnosed breast 
cancer. N Engl J Med 2007 Mar 29;356(13):1295-303. 
 (23)  Berg W, Zhang Z, Cornack J, Jong R, Barr R, Lehrer D, et al. Supplemental yield 
and performance characteristics of screening MRI after combined ultrasound and 

Ministry of Health, Welfare and Sport  
29
mammography: ACRIN 6666. American College of Radiology Imaging Network. 
2009. http://www.acrin.org/  
 (24)  Gordon PB. Ultrasound for breast cancer screening and staging. Radiol Clin North 
Am 2002 May;40(3):431-41. 
 (25)  Kriege M, Brekelmans CT, Boetes C, Besnard PE, Zonderland HM, Obdeijn IM, et al. 
Efficacy of MRI and mammography for breast-cancer screening in women with a 
familial or genetic predisposition. N Engl J Med 2004 Jul 29;351(5):427-37. 
 (26)  Leach MO, Boggis CR, Dixon AK, Easton DF, Eeles RA, Evans DG, et al. Screening 
with magnetic resonance imaging and mammography of a UK population at high 
familial risk of breast cancer: a prospective multicentre cohort study (MARIBS). 
Lancet 2005 May 21;365(9473):1769-78. 
 (27)  Nationaal Borstkanker Overleg Nederland: Richtlijn mammacarcinoom 2008.  
http://www.oncoline.nl/ 
 (28)  Netherlands Federation of University Medical Centres. Kwaliteitsborging van 
mensgebonden onderzoek. Houten: Badoux Printing House; 2010 Jun.  
 (29)  Vachon CM, van Gils CH, Sellers TA, Ghosh K, Pruthi S, Brandt KR, et al. 
Mammographic density, breast cancer risk and risk prediction. Breast Cancer Res 
2007;9(6):217. 
 (30)  Ziv E, Tice J, Smith-Bindman R, Shepherd J, Cummings S, Kerlikowske K. 
Mammographic density and estrogen receptor status of breast cancer. Cancer 
Epidemiol Biomarkers Prev 2004 Dec;13(12):2090-5. 
 (31)  Saslow D, Boetes C, Burke W, Harms S, Leach MO, Lehman CD, et al. American 
Cancer Society guidelines for breast screening with MRI as an adjunct to 
mammography. CA Cancer J Clin 2007 Mar;57(2):75-89. 
 (32)  Netherlands Health Council. Wet bevolkingsonderzoek: prenatale screening en 
risicoperceptie. The Hague: Netherlands Health Council; 1999: 1999/04WBO. 
(33)  Otto SJ, van der Cruijsen IW, Liem MK, Korfage IJ, Lous JJ, Schröder FZ, de Koning   
           HJ. Effective PSA contamination in the Rotterdam section of the European  
           Randomized Study of Screening for Prostate Cancer. Int J Cancer 2003 105:394- 
           399. 
 (34)  van Gils CH, Otten JD, Hendriks JH, Holland R, Straatman H, Verbeek AL. High 
mammographic breast density and its implications for the early detection of breast 
cancer. J Med Screen 1999;6(4):200-4. 
   (35)  Cuzick J, Edwards R, Segnan N. Adjusting for non-compliance and contamination in  
            randomized clinical trials. Stat Med 1997 May 15;16(9):1017-29. 
 
 (36)  Nelson HD, Tyne K, Naik A, Bougatsos C, Chan BK, Humphrey L. Screening for 
breast cancer: an update for the U.S. Preventive Services Task Force. Ann Intern 
Med 2009 Nov 17;151(10):727-42. 
 (37)  Ma H, Luo J, Press MF, Wang Y, Bernstein L, Ursin G. Is there a difference in the 
association between percent mammographic density and subtypes of breast cancer? 
Luminal A and triple-negative breast cancer. Cancer Epidemiol Biomarkers Prev 

Ministry of Health, Welfare and Sport  
30
2009 Feb;18(2):479-85. 
 (38)  de Gelder R., Bulliard JL, de WC, Fracheboud J, Draisma G, Schopper D, et al. 
Cost-effectiveness of opportunistic versus organised mammography screening in 
Switzerland. Eur J Cancer 2009 Jan;45(1):127-38. 
 (39)  Habbema JD, van Oortmarssen GJ, Lubbe JT, van der Maas PJ. The MISCAN 
simulation program for the evaluation of screening for disease. Comput Methods 
Programs Biomed 1985 May;20(1):79-93. 
 (40)  Mandelblatt JS, Cronin KA, Bailey S, Berry DA, de Koning HJ, Draisma G, et al. 
Effects of mammography screening under different screening schedules: model 
estimates of potential benefits and harms. Ann Intern Med 2009 Nov 
17;151(10):738-47. 
 (41)  Hoeymans N, van LH, Westert GP. The health status of the Dutch population as 
assessed by the EQ-6D. Qual Life Res 2005 Apr;14(3):655-63. 
  (42)   Brodersen J, Thorsen H. Consequences of Screening in Breast Cancer (COS-BC):      
           development of a questionnaire. Scandinavian Journal of Primary Health Care. 2008;   
           26: 251-256. 
 
  (43)   Rijnsburger AJ, Essink-Bot ML, van Dooren S, et al. Impact of screening for breast  
           cancer in high-risk women on health-related quality of life. Br J Cancer 2004; 91: 69– 
           76. 
 
(44)   European Organisation for Research and Treatment of Cancer (EORTC) Study  
           Group on Quality of Life. http://groups.eortc.be/qol. 
 
 (45)  Colletti PM. Nephrogenic systemic fibrosis and gadolinium: a perfect storm. AJR Am 
J Roentgenol 2008 Oct;191(4):1150-3. 
 (46)  Abujudeh HH, Kosaraju VK, Kaewlai R. Acute adverse reactions to gadopentetate 
dimeglumine and gadobenate dimeglumine: experience with 32,659 injections. AJR 
Am J Roentgenol 2010 Feb;194(2):430-4. 
 (47)  de Koning HJ, Draisma G, Fracheboud J, de BA. Overdiagnosis and overtreatment 
of breast cancer: microsimulation modelling estimates based on observed screen 
and clinical data. Breast Cancer Res 2006;8(1):202. 
 (48)  Kuhl CK, Schrading S, Bieling HB, Wardelmann E, Leutner CC, Koenig R, et al. MRI 
for diagnosis of pure ductal carcinoma in situ: a prospective observational study. 
Lancet 2007 Aug 11;370(9586):485-92.