Breast Cancer Screening With MRI in Women Aged 50-75 Years With Extremely Dense Breast Tissue: the DENSE Trial

The purpose of this study is to determine the cost-effectiveness of biennial screening with mammography and MRI compared to mammography alone in women aged 50-75 years and who show > 75% mammographic density.

Study Overview

• Status: Active, not recruiting
• Conditions: Breast Cancer
• Intervention / Treatment: Other: Contrast enhanced breast MRI

Detailed Description

Women with very high mammographic density have a four to six fold higher breast cancer risk than women with low mammographic density. At the same time, the sensitivity of mammography is seriously impaired in women with high mammographic density, leading to many missed cases. Nevertheless, in the Netherlands this high risk group is currently screened between the age of 50 and 75 years with mammography only. MRI is likely to lead to better detection of breast tumors in women with high mammographic density, because it has a much higher sensitivity than mammography. The DENSE trial investigates the additional value of MRI for breast cancer screening in this risk group. Participants with extremely dense breasts (ACR4) and a negative mammogram are randomized to 'additional MRI' (n=7,237) versus 'current practice' (n=28,948).

• Study Type: Interventional
• Enrollment (Actual): 40373
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • 's-Hertogenbosch, Netherlands
    • Jeroen Bosch Hospital
  • Almelo, Netherlands
    • Hospital Group Twente (ZGT)
  • Amsterdam, Netherlands
    • VU University Medical Center
  • Amsterdam, Netherlands
    • Antoni van Leeuwenhoek Hospital
  • Dordrecht, Netherlands
    • Albert Schweitzer Hospital
  • Hengelo, Netherlands
    • Hospital Group Twente (ZGT)
  • Maastricht, Netherlands
    • Maastricht University Medical Center
  • Nijmegen, Netherlands
    • Radboud University Medical Center
  • Utrecht, Netherlands
    • UMC Utrecht

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Dutch breast cancer screening participants, aged 50-75 years
• > 75% mammographic density
• Negative mammographic examination (BIRADS 1 or 2)

Exclusion Criteria:

Contraindications for MRI

• The presence of intracorporeal metals
• Adverse reaction to a (gadolinium-based) contrast agent in the past
• Severely impaired renal function (GFR < 40 mL/min)
• Pregnant or lactating women
• Claustrophobia
• Adiposity (> 150 kg)

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Contrast enhanced breast MRI; The additional MRI will take place biennially after the regular screening mammogram for a study period of 6 years.	Other: Contrast enhanced breast MRI; Gadolinium contrast is administered as a bolus with a standard dose of 0.1 mL/kg followed by a saline flush of 30 mL.; Other Names: MR Mammography
No Intervention: Regular breast cancer screening; No further follow-up until next scheduled screening examination two years later (according to the current Dutch guideline).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The number of interval cancers will be compared between the MRI group and the control group	The intervention will be carried out for six years, i.e. 3 screening rounds. Given a two year recruitment period, the total study time will be 8 years.	8 years (with an interim analysis every two years; time period between two screening rounds)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The number of MRI screen-detected tumors will be determined	The MRI examination will take place every two years (0, 2 and 4 years after inclusion). Given a two year recruitment period, the total study time will be 6 years.	6 years (with an interim analysis every two years; time period between two screening rounds)
Tumor size, stage and grade distributions, including their histological and molecular subtypes, diagnosed in both study groups will be compared	The intervention will be carried out for six years, i.e. 3 screening rounds. Given a two year recruitment period, the total study time will be 8 years.	8 years (with an interim analysis every two years; time period between two screening rounds)
The referral rate in the MRI study group will be determined	The MRI examination will take place every two years (0, 2 and 4 years after inclusion). Given a two year recruitment period, the total study time will be 6 years.	6 years (with an interim analysis every two years; time period between two screening rounds)
The positive predictive value (and the amount of false-positive diagnoses) of MRI will be determined using the histological diagnosis as the reference test	The MRI examination will take place every two years (0, 2 and 4 years after inclusion). Given a two year recruitment period, the total study time will be 6 years.	6 years (with an interim analysis every two years; time period between two screening rounds)
The number of biopsies per positive MRI will be determined	The MRI examination will take place every two years (0, 2 and 4 years after inclusion). Given a two year recruitment period, the total study time will be 6 years.	6 years (with an interim analysis every two years; time period between two screening rounds)
The mortality rate in the MRI group will be compared with the control group using the MISCAN computer simulation program	The intervention will be carried out for six years, i.e. 3 screening rounds. Given a two year recruitment period, the total study time will be 8 years.	8 years
The cost-effectiveness of MRI will be estimated using the MISCAN computer simulation program	The intervention will be carried out for six years, i.e. 3 screening rounds. Given a two year recruitment period, the total study time will be 8 years.	8 years
The impact of MRI screening on quality of life will be assessed using standardized and validated questionnaires	The intervention will be carried out for six years, i.e. 3 screening rounds. Given a two year recruitment period, the total study time will be 8 years.	8 years

Collaborators and Investigators

• Sponsor: UMC Utrecht
• Collaborators: Bayer; Maastricht University Medical Center; Amsterdam UMC, location VUmc; The Netherlands Cancer Institute; National Institute for Public Health and the Environment (RIVM); ZonMw: The Netherlands Organisation for Health Research and Development; Albert Schweitzer Hospital; Jeroen Bosch Ziekenhuis; University Medical Center Nijmegen; Dutch Cancer Society; Pink Ribbon Inc.; Dutch Breast Cancer Screening Organisations; Dutch Reference Centre for Screening; Hospital Group Twente (ZGT); A Sister's Hope; Stichting Kankerpreventie Midden-West; Volpara Solutions
• Investigators: Principal Investigator: Wouter B Veldhuis, MD PhD, UMC Utrecht; Principal Investigator: Carla H van Gils, PhD, UMC Utrecht

Publications and helpful links

General Publications

• Verburg E, van Gils CH, van der Velden BHM, Bakker MF, Pijnappel RM, Veldhuis WB, Gilhuijs KGA. Validation of Combined Deep Learning Triaging and Computer-Aided Diagnosis in 2901 Breast MRI Examinations From the Second Screening Round of the Dense Tissue and Early Breast Neoplasm Screening Trial. Invest Radiol. 2022 Oct 17. doi: 10.1097/RLI.0000000000000934. Online ahead of print.
• Verburg E, van Gils CH, van der Velden BHM, Bakker MF, Pijnappel RM, Veldhuis WB, Gilhuijs KGA. Deep Learning for Automated Triaging of 4581 Breast MRI Examinations from the DENSE Trial. Radiology. 2022 Jan;302(1):29-36. doi: 10.1148/radiol.2021203960. Epub 2021 Oct 5.
• Veenhuizen SGA, de Lange SV, Bakker MF, Pijnappel RM, Mann RM, Monninkhof EM, Emaus MJ, de Koekkoek-Doll PK, Bisschops RHC, Lobbes MBI, de Jong MDF, Duvivier KM, Veltman J, Karssemeijer N, de Koning HJ, van Diest PJ, Mali WPTM, van den Bosch MAAJ, van Gils CH, Veldhuis WB; DENSE Trial Study Group. Supplemental Breast MRI for Women with Extremely Dense Breasts: Results of the Second Screening Round of the DENSE Trial. Radiology. 2021 May;299(2):278-286. doi: 10.1148/radiol.2021203633. Epub 2021 Mar 16.
• Bakker MF, de Lange SV, Pijnappel RM, Mann RM, Peeters PHM, Monninkhof EM, Emaus MJ, Loo CE, Bisschops RHC, Lobbes MBI, de Jong MDF, Duvivier KM, Veltman J, Karssemeijer N, de Koning HJ, van Diest PJ, Mali WPTM, van den Bosch MAAJ, Veldhuis WB, van Gils CH; DENSE Trial Study Group. Supplemental MRI Screening for Women with Extremely Dense Breast Tissue. N Engl J Med. 2019 Nov 28;381(22):2091-2102. doi: 10.1056/NEJMoa1903986.
• de Lange SV, Bakker MF, Monninkhof EM, Peeters PHM, de Koekkoek-Doll PK, Mann RM, Rutten MJCM, Bisschops RHC, Veltman J, Duvivier KM, Lobbes MBI, de Koning HJ, Karssemeijer N, Pijnappel RM, Veldhuis WB, van Gils CH. Reasons for (non)participation in supplemental population-based MRI breast screening for women with extremely dense breasts. Clin Radiol. 2018 Aug;73(8):759.e1-759.e9. doi: 10.1016/j.crad.2018.04.002. Epub 2018 Jun 18.

Helpful Links

• Click here for more information about this study (website in Dutch language).

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2011
• Primary Completion (Anticipated): April 1, 2023
• Study Completion (Anticipated): April 1, 2023

Study Registration Dates

• First Submitted: March 14, 2011
• First Submitted That Met QC Criteria: March 14, 2011
• First Posted (Estimate): March 15, 2011

Study Record Updates

• Last Update Posted (Actual): November 7, 2022
• Last Update Submitted That Met QC Criteria: November 2, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Breast cancer; Magnetic Resonance Imaging; Secondary prevention; Breast neoplasm; Early detection of cancer; Breast density; Cancer screening test
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms
• Other Study ID Numbers: UMCU DENSE (Other Grant/Funding Number: University Medical Center Utrecht); ZONMW-200320002-UMCU (Other Grant/Funding Number: ZonMw); Pink Ribbon-10074 (Other Grant/Funding Number: Dutch Pink Ribbon / a Sister's hope); BSP-DENSE (Other Grant/Funding Number: Bayer HealthCare, Medical Care); DCS-UU-2009-4348 (Other Grant/Funding Number: Dutch Cancer Society); DCS-UU-2014-6859 (Other Grant/Funding Number: Dutch Cancer Society)