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

• ClinicalTrials.gov Identifier: NCT01315015
• Recruitment Status: Active, not recruiting
• First Posted: March 15, 2011
• Last Update Posted: November 7, 2022
• Sponsor: UMC Utrecht
• Collaborators: Dutch Breast Cancer Screening Organisations; Dutch Reference Centre for Screening; National Institute for Public Health and the Environment (RIVM); The Netherlands Cancer Institute; University Medical Center Nijmegen; Jeroen Bosch Ziekenhuis; Albert Schweitzer Hospital; Hospital Group Twente (ZGT); Amsterdam UMC, location VUmc; Maastricht University Medical Center; ZonMw: The Netherlands Organisation for Health Research and Development; Dutch Cancer Society; Pink Ribbon Inc.; A Sister's Hope; Bayer; Stichting Kankerpreventie Midden-West; Volpara Solutions
• Information provided by (Responsible Party): C.H. van Gils, UMC Utrecht

Tracking Information

• First Submitted Date: March 14, 2011
• First Posted Date: March 15, 2011
• Last Update Posted Date: November 7, 2022
• Actual Study Start Date: November 2011
• Estimated Primary Completion Date: April 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 14, 2011)

The number of interval cancers will be compared between the MRI group and the control group [ Time Frame: 8 years (with an interim analysis every two years; time period between two screening rounds) ]

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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 21, 2012)

• The number of MRI screen-detected tumors will be determined [ Time Frame: 6 years (with an interim analysis every two years; time period between two screening rounds) ]
  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.
• Tumor size, stage and grade distributions, including their histological and molecular subtypes, diagnosed in both study groups will be compared [ Time Frame: 8 years (with an interim analysis every two years; time period between two screening rounds) ]
  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.
• The referral rate in the MRI study group will be determined [ Time Frame: 6 years (with an interim analysis every two years; time period between two screening rounds) ]
  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.
• The positive predictive value (and the amount of false-positive diagnoses) of MRI will be determined using the histological diagnosis as the reference test [ Time Frame: 6 years (with an interim analysis every two years; time period between two screening rounds) ]
  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.
• The number of biopsies per positive MRI will be determined [ Time Frame: 6 years (with an interim analysis every two years; time period between two screening rounds) ]
  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.
• The mortality rate in the MRI group will be compared with the control group using the MISCAN computer simulation program [ Time Frame: 8 years ]
  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.
• The cost-effectiveness of MRI will be estimated using the MISCAN computer simulation program [ Time Frame: 8 years ]
  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.
• The impact of MRI screening on quality of life will be assessed using standardized and validated questionnaires [ Time Frame: 8 years ]
  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.

Original Secondary Outcome Measures (submitted: March 14, 2011)

• Tumor size, stage and grade distributions, including their histological and molecular subtypes, diagnosed in both study groups will be compared [ Time Frame: 8 years (with an interim analysis every two years; time period between two screening rounds) ]
  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.
• The referral rate in the MRI study group will be determined [ Time Frame: 6 years (with an interim analysis every two years; time period between two screening rounds) ]
  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.
• The positive predictive value (and the amount of false-positive diagnosis) of MRI will be determined using the histological diagnosis as the reference test [ Time Frame: 6 years (with an interim analysis every two years; time period between two screening rounds) ]
  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.
• The number of biopsies per positive MRI will be determined [ Time Frame: 6 years (with an interim analysis every two years; time period between two screening rounds) ]
  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.
• The mortality rate in the MRI-group will be compared with the control group using the MISCAN computer simulation program [ Time Frame: 8 years ]
  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.
• The cost-effectiveness of MRI will be estimated using the MISCAN computer simulation program [ Time Frame: 8 years ]
  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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Breast Cancer Screening With MRI in Women Aged 50-75 Years With Extremely Dense Breast Tissue: the DENSE Trial
• Official Title: Breast Cancer Screening With MRI in Women Aged 50-75 Years With Extremely Dense Breast Tissue: the DENSE Trial
• Brief Summary: 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.
• 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
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Screening
• Condition: Breast Cancer

Intervention

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 Name: MR Mammography

Study Arms

• Experimental: Contrast enhanced breast MRI
  The additional MRI will take place biennially after the regular screening mammogram for a study period of 6 years.
  Intervention: Other: Contrast enhanced breast MRI
• No Intervention: Regular breast cancer screening
  No further follow-up until next scheduled screening examination two years later (according to the current Dutch guideline).

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. 2023 Apr 1;58(4):293-298. doi: 10.1097/RLI.0000000000000934. Epub 2022 Oct 17.
• 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: June 3, 2021): 40373
• Original Estimated Enrollment (submitted: March 14, 2011): 14000
• Estimated Study Completion Date: April 2023
• Estimated Primary Completion Date: April 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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)

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 50 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Netherlands

Administrative Information

• NCT Number: NCT01315015
• Other Study ID Numbers: UMCU DENSE; 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 ); UMCU DENSE ( Other Grant/Funding Number: University Medical Center Utrecht )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: C.H. van Gils, UMC Utrecht
• Original Responsible Party: dr. C.H. van Gils, Associate Professor of Clinical Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht
• Current Study Sponsor: UMC Utrecht
• Original Study Sponsor: Same as current

Collaborators

• Dutch Breast Cancer Screening Organisations
• Dutch Reference Centre for Screening
• National Institute for Public Health and the Environment (RIVM)
• The Netherlands Cancer Institute
• University Medical Center Nijmegen
• Jeroen Bosch Ziekenhuis
• Albert Schweitzer Hospital
• Hospital Group Twente (ZGT)
• Amsterdam UMC, location VUmc
• Maastricht University Medical Center
• ZonMw: The Netherlands Organisation for Health Research and Development
• Dutch Cancer Society
• Pink Ribbon Inc.
• A Sister's Hope
• Bayer
• Stichting Kankerpreventie Midden-West
• Volpara Solutions

Investigators

• Principal Investigator: Carla H van Gils, PhD; UMC Utrecht
• Principal Investigator: Wouter B Veldhuis, MD PhD; UMC Utrecht

• PRS Account: UMC Utrecht
• Verification Date: November 2022