6/7/2017 Disclosure • Research funding or support Industry: – Bayer AG The role of MRI in Screening for – Volpara Solutions Breast Cancer in Dense Breasts: Governmental and charity funding: the DENSE trial - ZonMW Carla H. van Gils, PhD - Dutch Cancer Society - Pink Ribbon / A Sisters Hope Netherlands population-based breast screening program • Nationwide since 1990; fully digital since 2010 Outline • Biennial mammography • 50-75 years • Breast screening in The Netherlands • Participation: 79% • >1.2 mln examinations per year • MRI in dense breasts • DENSE trial • No breast density laws • Breast density not routinely assessed in screening 1
6/7/2017 Breast density distribution in NL Breast density, risk & masking: • ~112,000 examinations, with Volpara measurements • Biennial digital population- 2003-2011 • based screening program 50-75 years VDG 1 VDG2 VDG3 VDG 4 p-trend n=24,210 N=46,426 N=32,330 N=8,932 Extremely dense Total BC /1000 exam. 4.6 8.3 9.4 11.2 <0.001 – category 4 8% Screen-det BC /1000 exam. 4.0 6.4 6.6 6.8 <0.001 Fatty 22% – category 1 Interval BC/1000 exam. 0.7 1.9 2.9 4.4 <0.001 Heterogeneous 29% – category 3 Sensitivity 85.7% 77.6% 69.5% 61.0% <0.001 Scattered 41% VDG = ‘volpara density grade’ measured with Volpara software – category 2 BC/1000 = screen-detected tumors + interval tumors/1000 Sensitivity = # screen-detected tumors/ (# screen-detected tumors + # interval tumors) Wanders et al. Breast Cancer Res Treat 2017;162:95-103 Wanders et al. Breast Cancer Res Treat 2017;162:95-103 Is MRI an option? What is known on use of MRI in dense breasts? • 612 women with ACR density 3/4 and ≥ 1 other risk factor • MRI after 3 annual rounds of Mx+US Study No. Extra cancer 95% CI Recall 95% CI PPV 95% CI Exam. detection rate rate Berg et al. 612 18/1000 (6-30) 23/100 (19-26) 9% (5-14%) 2
6/7/2017 What is known on use of MRI in dense breasts? What is known on use of MRI in dense breasts? • Subgroup: excluding those with BRCA1/2 mutations, chest • radiation or personal history of breast cancer 443 women with a mildly to moderately increased risk • Of which 427 with ACR density 3 or 4 and negative mx+US Study No. Extra cancer 95% CI Recall 95% CI PPV 95% CI Exam. detection rate rate Study No. Extra cancer 95% CI Recall 95% CI PPV 95% CI Berg et al. 612 18/1000 (6-30) 23/100 (19-26) 9% (5-14%) Exam. detection rate rate Melnikow et al. 334 21/1000 (9-43) 23/100 (19-28) 9% (4-17%) subgroup Kuhl et al. (1st 443 25/1000 (13-45) 7/100 (5-10) 33% (18-52%) round) What is known on use of MRI in dense breasts? Current guidelines on MRI for dense breasts For example: • Subgroup: excluding those with BRCA1/2 mutations, chest radiation or personal history of breast cancer Study No. Extra cancer 95% CI Recall 95% CI PPV 95% CI Exam. detection rate rate Kuhl et al. (1st 443 25/1000 (13-45) 7/100 (5-10) 33% (18-52%) round) Melnikow et al. 105 29/1000 (6-81) 9/100 (4-16) 32% (12-66%) subgroup 3
6/7/2017 Current guidelines on MRI for dense breasts What is unknown, and what are the hurdles? • Berg et al. and Kuhl et al.: Promising in relation to extra detection Or: Cave: small numbers of cancers But : • What if density only selection criterium? • What happens after a ‘prevalent’ screening round? • Does extra cancer detection improve health outcomes? (not solely overdiagnosis?) (N.B. not clear for other ‘adjunct’ modalities either) What is known on use of MRI in dense breasts? From the USPSTF: February 2017 • 2120 women at average risk, prevalent and incident rounds • Calculated Gail lifetime risk 6-12%, no significant risk factors • Of which 60% with dense breasts (C or D) and negative mx+US Study No. Extra cancer 95% CI Recall 95% CI PPV 95% CI Exam. detection rate rate Total 3861 15.5/1000 (12-20) 9/100* (8-10) 17%* (14-22) 55% of 48 cancers were in dense breasts Prevalent 2120 22.6/1000 (17-30) 12/100* (11-13) 19%* (15-24) Incident 1741 6.9/1000 (4-13) 5/100* (4-7) 13%* (7-21) 85% of 12 cancers were in dense breasts * BIRADS 3,4,5 are considered as positive 4
6/7/2017 Why important? Set-up of DENSE trial • Paired design: – Extra detection of cancers D ense tissue and • Parallel design: randomized (or comparison cohort) – Extra detection of cancers, but also: E arly breast N eoplasm – To compare interval cancer rates – To compare advanced breast cancer rates S cr E ening) trial – Mortality rates • Long-term: – Not only prevalent, but also incident rounds: • What happens to detection in ongoing screening ClinicalTrials.gov Identifier: NCT01315015 program? • What happens to recall/false-positives? DENSE: MRI screening for women with DENSE trial extremely dense breasts Domain: • RCT with ~7,000 MRI and • Current screening population: 50-75 years 28,000 ‘usual care’ after • With ‘extremely dense’ breasts (Volpara in mammography units) a negative DM and extremely • With a ‘negative’ screening mammography dense breasts Design: • RCT with interval cancer rate as main outcome • 4 Dutch screening organizations, • Other studies: observational paired design (everyone 8 hospitals in various parts of mammography + MRI) – higher detection rate due to the Netherlands overdiagnosis!? Intervention: • Target: contrast-enhanced MRI • ‘Additional contrast-enhanced MRI’ vs ‘no further examination in 4,776 breast screening after negative screening mammography’ participants (to be compared to • 3 screening rounds (prevalent + 2 incident rounds) a 4-fold number of controls) Emaus et al. Radiology 2015;277:527-37 5
6/7/2017 Single-consent prerandomization design Participant selection and recruitment • Breast density is not routinely assessed in NL (no awareness) • Dutch breast cancer screening organization • Living within 60 km of ‘DENSE’ hospital • Disadvantages of classical RCT in case of DENSE: • Extremely dense breasts (Volpara in – Anxiety >40 mammography units) and negative mx – Self-referral induced contamination • Randomization 1:4 • • Therefore: prerandomization + invitation of MRI group only Mail-invitation for MRI by screening organization • (control arm not contacted; its evaluation is registry-based.) Expression of interest to researchers through website or reply card • If positive, contact potential participant by phone to: • – Check eligibility Approval Minister of Health, Welfare and Sports (2011) – Provide further information • – Schedule MRI appointment Comes with a price: – Exclusion and non-participation occur after randomization • Written informed consent just preceding MRI examination – No other information on control group than age, cancer occurrence, tumor characteristics, treatment, mortality Outcomes DENSE trial In 2018 all participants will have undergone • How many tumors detected extra with MRI? their 2-year follow-up • More important, primary outcome: Is the interval cancer rate reduced compared to usual screening? (and the rate of advanced cancers?) • Simulation models for breast cancer mortality reduction • Costs • % false-positives and quality of life 6
6/7/2017 Participation DENSE trial Not interested N=1,872 (23%) Control group Intervention group N≈32,312 (N=8,061) Nonresponders N=913 (11%) Interested in participation N=5,276 (66%) Interested women: - Were slightly younger (median 54 yrs vs 55 yrs) - Lived slightly closer to MRI center (median 24.5 vs 25.5 km) Experience with 1st round MRI and - Were of higher SES: - Q4 SES: 68% interested re-invitation for the 2nd round - Q1 SES: 59% interested Most frequently stated reasons for nonparticipation Participation DENSE trial Not interested Not mutually exclusive N=1,872 (23%) Control group Intervention group • MRI-related inconveniences or contraindications: 27% N≈32,312 (N=8,061) Nonresponders E.g. claustrophobia (12%), refusing contrast (7%), intracorporeal metals N=913 (11%) (3%) Interested in participation N=5,276 (66%) • Anxiety regarding result of supplemental screening: 21% Ineligible N=103 (1%) E.g. emotional burden too high (15%), concerns about false-postives or overdiagnosis (2%) Withdrawal after more Agreed to participate extensive information • Personal health: 21% N=156 (2%) E.g. other diseases (9%), or low estimated risk (7%) Cancelled MRI / no show N=163 (2%) • Practical reasons 14% E.g. time/travel related (12%), financial (<1%) Completed MRI Incomplete MRI • Burden too high – no further explanation 12% N = 4,783 (59%) N=71 (1%) 7
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