Supplemental Screening for Women With Extremely Dense Breast Tissue: the DENSE-2 Trial (DENSE-2)

Contrast-enhanced Mammography and Abbreviated MRI as Supplemental Screening Modalities for Women Aged 50-75 With Extremely Dense Breast Tissue: the DENSE-2 Trial

Women with extremely dense breasts (nearly all glandular and connective tissue, little fatty tissue) have a 3-6 times higher risk of breast cancer than women with very low breast density. Moreover, due to the masking effect of the dense tissue, any breast tumours present are more difficult to detect in these women. With the results of the DENSE trial, the investigators showed that among women with extremely dense breasts, a combination of MRI and mammography could detect tumours earlier than mammography only. As the implementation of MRI in the screening program induces considerable costs and capacity requirements, the Dutch Ministry of Health would like to investigate whether cheaper and acceptable alternatives can be implemented more easily. In the DENSE-2 study, proposed here, we will investigate contrast-enhanced mammography and an abbreviated form of MRI as alternatives, in a large-scale randomized trial, within the current population-based screening program.

Study Overview

• Status: Recruiting
• Conditions: Breast Cancer
• Intervention / Treatment: Diagnostic test: Contrast-enhanced mammography (CEM); Diagnostic test: Abbreviated MRI (AB-MRI)

Detailed Description

Women with extremely dense breast tissue have a higher risk of developing breast cancer and at the same time, mammography has limited value for these women. Currently, these women are not offered supplemental screening. Therefore, the investigators of the DENSE-2 trial will study supplemental CEM and AB-MRI screening in women with extremely dense breast tissue within the population-based breast cancer screening program because these modalities are expected to have higher diagnostic accuracy than tomosynthesis and ultrasound. In addition, these modalities are expected to be less expensive and require less capacity than a full MRI protocol as examined in the DENSE trial. For both CEM and AB-MRI, no results are currently available from a prospective screening study. The DENSE-2 trial is a randomized controlled trial comparing two intervention arms (CEM [intervention arm A] and abbreviated MRI [intervention arm B]) each with mammography [control arm C].

• Study Type: Interventional
• Enrollment (Estimated): 36000
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Carla van Gils, Prof; Phone Number: 0031-88-7568181; Email: dense-2@umcutrecht.nl
• Study Contact Backup: Name: Evelyn Monninkhof, Dr.; Email: e.monninkhof@umcutrecht.nl

Study Locations

• Netherlands
  • Utrecht, Netherlands
    • Recruiting
    • UMC Utrecht
    • Contact: Sophie van Grinsven, Msc.; Phone Number: 0031-88-7568181; Email: dense-2@umcutrecht.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Participant in the Dutch population-based breast cancer screening program with a negative mammography result (BI-RADS classification 1 or 2).
• Extremely dense breast tissue (assessed with Quantra software, category D).
• Age between 49-72 years (women are invited to the Dutch screening program in the year they turn 50, so the minimum age is 49 years. The maximum age for inclusion is 72 years to ensure that women can still participate in a second round of supplemental screening).
• Living in the service area (travel distance of up to 60 km) of the 15 participating hospitals.
• Absence of breast implants (Quantra cannot provide an accurate density determination for breasts with implants).
• No objection to data sharing.
• Not a participant in the DENSE trial or STREAM trial (participants in the DENSE and STREAM trials are known to the Dutch screening organization).

Exclusion Criteria:

The additional exclusion criteria for the intervention arms are checked after randomization and recruitment (this order is due to the pre-randomization design):

• Presence of in-body metals (only for AB-MRI, this involves specific metals and is asked by telephone).
• Previous allergic reaction to the provided contrast agent.
• Renal insufficiency (glomerular filtration rate <30 ml/min) (only for CEM, is checked for with questionnaire I and possibly renal function measurement).
• Severe claustrophobia (only for AB-MRI).
• Severe obesity (weight >150 kg) (only for AB-MRI).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Screening
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control; This group receives biennial mammography only within the current Dutch National Breast Cancer Screening program. This group will not be informed about the study (pre-randomisation design)
Experimental: Contrast-enhanced Mammography (CEM); This group receives supplemental screening with CEM after a negative mammography result in the Dutch National Breast Cancer screening program	Diagnostic test: Contrast-enhanced mammography (CEM); This intervention group receives supplemental screening with CEM after a negative screening result within the Dutch National Breast Cancer Screening program
Experimental: Abbreviated MRI (AB-MRI); This group receives supplemental screening with AB-MRI after a negative mammography result in the Dutch National Breast Cancer Screening program	Diagnostic test: Abbreviated MRI (AB-MRI); This intervention group receives supplemental screening with AB-MRI after a negative screening result within the Dutch National Breast Cancer Screening program

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Interval Cancer Rate	Measured as a breast cancer diagnosed in between two screening rounds	0 - 3 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cancer detection rate	The number of breast cancers detected by CEM or AB-MRI	0 - 3 year
False positive rate	The number with a false positive result after CEM or AB-MRI	0-5 year
Participant experience with CEM - 1	screen-specific item questionnaire (SSI)	0-5 year
Participant experience with CEM - 2	Self-developed questionnaire	0-5 year
Participant experience with CEM - 3	Focus group interviews	0-5 year
Participant experience with AB-MRI - 1	screen-specific item questionnaire (SSI)	0-5 year
Participant experience with AB-MRI - 2	Self-developed questionnaire	0-5 year
Participant experience with AB-MRI - 3	Focus group interviews	0-5 year
Health-professional experience with CEM	Self-developed questionnaire	0-5 year
Health-professional experience with AB-MRI	Self-developed questionnaire	0-5 year
Estimated rate of overdiagnosis	Simulation with the MISCAN software	0-5 years
Cost-effectiveness	Simulation with the MISCAN software	0-5 year
Breast tumor size	mm	0-5 years
Breast tumor stage	TNM classification	0-5 years
Positive Predictive Value (PPV)	Using the histological diagnosis as the reference test	0-5 year
Biopsy rate	Per 1000 women screened with one of the modalities	0-5 year
Referral rate	Per 1000 women screened per screening modality	0-5 years
Mortality rate	Simulation with MISCAN software	0-5 year
Advanced Cancer detectio Advanced Cancer rate	Advanced cancer is defined as TNM stage II or higher	0 - 3 year

Collaborators and Investigators

• Sponsor: C.H. van Gils
• Collaborators: Radboud University Medical Center; University Medical Center Groningen; Maastricht University Medical Center; Erasmus Medical Center; Catharina Ziekenhuis Eindhoven; Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); St. Antonius Hospital; Albert Schweitzer Hospital; Elisabeth-TweeSteden Ziekenhuis; Rijnstate Hospital; Ziekenhuisgroep Twente; Zuyderland Medical Centre; Antoni van Leeuwenhoek Hospital; Jeroen Bosch Hospital; Bevolkingsonderzoek Nederland; Borstkankervereniging Nederland
• Investigators: Principal Investigator: Carla van Gils, Prof., UMC Utrecht

Study record dates

Study Major Dates

• Study Start (Actual): November 11, 2024
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): September 1, 2031

Study Registration Dates

• First Submitted: October 3, 2024
• First Submitted That Met QC Criteria: October 9, 2024
• First Posted (Actual): October 10, 2024

Study Record Updates

• Last Update Posted (Actual): May 11, 2026
• Last Update Submitted That Met QC Criteria: May 6, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: early detection; breast cancer screening; contrast-enhanced mammography; extremely dense breasts; abbreviated MRI
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms
• Other Study ID Numbers: 05550412310002; Nr. 2024/09 (Other Identifier: Dutch Health Council)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No