Supplemental Breast MRI for Women with Extremely Dense Breasts: Results of the Second Screening Round of the DENSE Trial
- Stefanie G. A. Veenhuizen,
- Stéphanie V. de Lange,
- Marije F. Bakker,
- Ruud M. Pijnappel,
- Ritse M. Mann,
- Evelyn M. Monninkhof,
- Marleen J. Emaus,
- Petra K. de Koekkoek-Doll,
- Robertus H. C. Bisschops,
- Marc B. I. Lobbes,
- Mathijn D. F. de Jong,
- Katya M. Duvivier,
- Jeroen Veltman,
- Nico Karssemeijer,
- Harry J. de Koning,
- Paul J. van Diest,
- Willem P. T. M. Mali,
- Maurice A. A. J. van den Bosch,
- Carla H. van Gils ,
- Wouter B. Veldhuis
- For the DENSE Trial Study Group*
Abstract
Background
In the first (prevalent) supplemental MRI screening round of the Dense Tissue and Early Breast Neoplasm Screening (DENSE) trial, a considerable number of breast cancers were found at the cost of an increased false-positive rate (FPR). In incident screening rounds, a lower cancer detection rate (CDR) is expected due to a smaller pool of prevalent cancers, and a reduced FPR, due to the availability of prior MRI examinations.
Purpose
To investigate screening performance indicators of the second round (incidence round) of the DENSE trial.
Materials and Methods
The DENSE trial (ClinicalTrials.gov: NCT01315015) is embedded within the Dutch population–based biennial mammography screening program for women aged 50–75 years. MRI examinations were performed between December 2011 and January 2016. Women were eligible for the second round when they again had a negative screening mammogram 2 years after their first MRI. The recall rate, biopsy rate, CDR, FPR, positive predictive values, and distributions of tumor characteristics were calculated and compared with results of the first round using 95% CIs and χ2 tests.
Results
A total of 3436 women (median age, 56 years; interquartile range, 48–64 years) underwent a second MRI screening. The CDR was 5.8 per 1000 screening examinations (95% CI: 3.8, 9.0) compared with 16.5 per 1000 screening examinations (95% CI: 13.3, 20.5) in the first round. The FPR was 26.3 per 1000 screening examinations (95% CI: 21.5, 32.3) in the second round versus 79.8 per 1000 screening examinations (95% CI: 72.4, 87.9) in the first round. The positive predictive value for recall was 18% (20 of 110 participants recalled; 95% CI: 12.1, 26.4), and the positive predictive value for biopsy was 24% (20 of 84 participants who underwent biopsy; 95% CI: 16.0, 33.9), both comparable to that of the first round. All tumors in the second round were stage 0–I and node negative.
Conclusion
The incremental cancer detection rate in the second round was 5.8 per 1000 screening examinations—compared with 16.5 per 1000 screening examinations in the first round. This was accompanied by a strong reduction in the number of false-positive results.
© RSNA, 2021
Online supplemental material is available for this article.
See also the editorial by Moy and Gao in this issue.
Summary
The cancer detection rate in an incident breast MRI screening round after a negative mammographic examination is 5.8 per 1000 screening examinations—compared with 16.5 per 1000 screening examinations in the prevalent round—which is accompanied by a strong reduction in the number of false-positive results.
Key Results
■ In a prospective trial of 3436 participants, the incremental cancer detection rate in the second round (incidence round) was lower than that in the first round (prevalence round) (5.8 per 1000 screening examinations vs 16.5 per 1000 screening examinations).
■ All MRI-detected cancers in the second round were early stage (0–I) and node negative.
■ The false-positive rate was sharply reduced in the second round compared with the first round (26.3 per 1000 screening examinations vs 79.8 per 1000 screening examinations).
Introduction
Currently, screening mammography is the primary examination standard for early detection of breast cancer in women at average risk (1). However, for women with dense breasts, the sensitivity of mammographic screening has proven to be limited due to the masking effect of dense breast tissue (2,3). Therefore, the Dense Tissue and Early Breast Neoplasm Screening (DENSE) trial investigated the effectiveness of adding a more sensitive screening tool for women with extremely dense breasts: MRI (4). Results of the first screening round (prevalence round) have been published previously (5). In the first round, after a negative screening mammogram, supplemental screening with MRI led to an additional cancer detection rate (CDR) of 16.5 per 1000 screening examinations at the expense of a false-positive rate (FPR) of 79.8 per 1000 screening examinations. Subsequently, compared with the mammography-only group, the interval cancer rate in the group of women invited for MRI was reduced from 5.0 per 1000 screening examinations to 2.5 per 1000 screening examinations. The cancer rate of 2.5 per 1000 screening examinations in the MRI-invitation group consisted of an interval cancer rate of 0.8 per 1000 screening examinations in women who actually underwent MRI (4783 of 8061 invited women, 59%) and 4.9 per 1000 screening examinations in those who did not accept the MRI invitation.
These findings are promising for the early detection of breast cancer in women with dense breasts, but to estimate the long-term benefit and harm of breast MRI screening, information from incidence screening rounds is needed as well. Herein, we present the results of the second round (incidence round) of the DENSE trial, focusing on the recall rate, CDR, FPR, positive predictive values, and tumor characteristics. A reduction in CDR in the incident screening round is expected due to a smaller pool of prevalent cancers, along with a reduction in the FPR due to the availability of prior MRI examinations.
Materials and Methods
Study Design and Participants
The DENSE trial design has been detailed elsewhere (5,6), and the study protocol can be accessed via ClinicalTrials.gov with identifier NCT01315015. This prospective multicenter trial is embedded within the Dutch population–based biennial digital mammography screening program for women between 50 and 75 years of age. Women were eligible for the DENSE trial if they had a negative mammography result (American College of Radiology Breast Imaging Reporting and Data System [BI-RADS] category 1 or 2) and extremely dense breast tissue, which is defined as density category 4 or d, measured with Volpara imaging software (version 1.5, Volpara Health Technologies). Women were randomized to the intervention arm (invitation to undergo supplemental MRI screening, n = 8061) or to the control arm (biennial mammographic screening only, n = 32 312).
The trial has been designed to consist of three consecutive screening rounds. Between December 2011 and January 2016, 4783 women in the intervention arm participated in the first screening round of the trial and underwent the first screening MRI examination. Women who completed the first screening MRI were eligible for a second MRI round if they had responded to their next invitation from the regular mammography screening program and had a negative screening result. Eligibility for a second MRI round was independent of any change in breast density since the first round.
The DENSE trial has been approved by the Dutch Minister of Health, Welfare and Sport, who was advised by the Health Council (2011/2019 Population Screening Act, The Hague, the Netherlands). Ethical approval was obtained on November 11, 2011. All participants provided informed written consent.
Breast MRI
MRI scans were read by the same group of radiologists (including W.B.V., R.M.P., R.M.M., P.K.d.K.D., R.H.C.B., M.B.I.L., M.D.F.d.J., K.M.D., J.V., and 12 other radiologists who had also been part of the DENSE trial study group) in the prevalence round and classified according to the BI-RADS MRI lexicon (7,8). Their experience with reading breast MRI scans is summarized in Table E1 (online). All had access and were not blinded to the current or previous MRI or mammographic examinations in accordance with clinical and screening practice. Women with a BI-RADS 4 or 5 score were recalled for additional diagnostic work-up. In case of a BI-RADS 3 score, mandatory independent double reading was performed. If there was consensus on a score of 3, then a follow-up MRI after 6 months was planned. The follow-up MRI had to be reported as either negative (BI-RADS 1 or 2, with return to the regular mammography screening program) or positive (BI-RADS 4 or 5), after which women were recalled for additional work-up.
All MRI examinations were performed with 3.0-T MRI systems, and the macrocyclic gadolinium-based contrast agent gadobutrol (0.1 mmol per kilogram body weight) (Gadovist, Bayer) was used in all examinations. The full screening MRI protocol has been described in detail in dedicated articles (5,6).
Statistical Analysis
The primary outcomes in this article are the recall rate, CDR, FPR, positive predictive values, and tumor characteristics in the second round of MRI screening. The interval cancer rate, another important outcome of interest, is not included in this report because data collection for this end point is still ongoing. Calculations of all outcomes have been described in a previous article and are referred to in Tables 1 and 2 (5).
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We described the following tumor characteristics of MRI-detected cancers: histologic type, TNM stage, grade, and receptor status. In women with more than one tumor, we described the tumor with the highest TNM stage. All rates are presented per 1000 screening examinations. A comparison was made with the previously published results of the first round (5). Differences in distributions of tumor characteristics between the first and second rounds were tested using the χ2 test or Fisher exact test in the case of low counts.
Adverse events and serious adverse events were recorded during or immediately after the MRI examination in the trial center or reported by the women within 30 days. A serious adverse event was defined as an adverse event that required an emergency department visit or unplanned hospital admission.
All analyses were performed with use of RStudio software (version 1.1.456, RStudio), and P < .05 was indicative of a statistically significant difference.
Results
Participant Characteristics
The median age at recruitment for the trial was 54 years (interquartile range, 51–59 years). Of the 3436 participants, 1388 (40%) had completed higher vocational education or university education, 2141 (62%) had given birth to two or more children, and 1963 (57%) were postmenopausal at recruitment (Table 3).
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Of the 4783 women who participated in the first round of the DENSE trial, 3436 (72%) also participated in the second MRI screening round (Fig 1). Women who were diagnosed with breast cancer after the first MRI examination or with an interval cancer received clinical follow-up and were therefore no longer invited for the DENSE trial (n = 83). Women who were not invited for a subsequent mammography screening round because of age (>75 years), emigration, or death; those who declined the invitation for mammography screening; or those who actively withdrew from the DENSE trial before repeat invitation were not re-invited for the second MRI round of the DENSE trial (n = 319). Women who were referred based on the results of the second mammographic examination were not eligible for the second MRI examination and were therefore also not invited (n = 71). Twenty-nine women dropped out before the second MRI examination, and another 29 women were, due to logistic reasons, not invited for MRI after their second mammographic examination and invited for the third round instead. The succesful MRI participation rate among those who were re-invited was 81% (3436 of 4252 women). For those who participated in the second MRI screening round, the median time between the first and second MRI examination was 103 weeks (interquartile range, 92–114 weeks), and between the second mammography and second MRI examination, 8 weeks (interquartile range, 3–13 weeks).
Figure 1: Chart shows participation in the second MRI screening round. BI-RADS = Breast Imaging Reporting and Data System, DENSE = Dense Tissue and Early Breast Neoplasm Screening trial, NA = not available. * = Two women underwent biopsy after a BI-RADS 4 result at follow-up, ** = one woman dropped out before the follow-up MRI was performed.
Recall and Biopsy Rates
Of the 3436 participants in the second MRI screening round, 110 were recalled because of a finding classified as BI-RADS 3 (n = 20), BI-RADS 4 (n = 87), or BI-RADS 5 (n = 3) (Fig 1,Table 1). This resulted in a recall rate of 32.0 per 1000 screening examinations (95% CI: 26.6, 38.4). Figure 2 shows example MRI scans in a participant in the second round in whom the availability of a prior prevalent MRI scan prevented recall for an otherwise suspicious lesion. Figure 3 shows example MRI scans in a participant who was recalled in the second round because comparison to her prior MRI scan revealed a small focus to be a new lesion.
Figure 2a: (a–c) MRI scans in a 55-year-old participant in the second round compared with (d) the MRI scan from the first round (prevalence round). Her current axial post-contrast T1-weighted MRI scan (a) shows an oval lesion with irregular margin in the right lower inner quadrant (arrow), with type 3 enhancement kinetics (kinetic overlay not shown). The lesion is hypo- to isointense on the axial T2-weighted MRI scan (b) and shows dubious diffusion restriction on the axial apparent diffusion coefficient map (c), consistent with a moderately suspicious lesion that should be recalled for biopsy. The availability of her MRI scan from the first round allowed for a Breast Imaging Reporting and Data System 2 (benign) classification. The lesion is completely unchanged compared with the prior axial post-contrast T1-weighted MRI scan (d). Four years after the second MRI examination, the participant is still free of cancer.
Figure 2b: (a–c) MRI scans in a 55-year-old participant in the second round compared with (d) the MRI scan from the first round (prevalence round). Her current axial post-contrast T1-weighted MRI scan (a) shows an oval lesion with irregular margin in the right lower inner quadrant (arrow), with type 3 enhancement kinetics (kinetic overlay not shown). The lesion is hypo- to isointense on the axial T2-weighted MRI scan (b) and shows dubious diffusion restriction on the axial apparent diffusion coefficient map (c), consistent with a moderately suspicious lesion that should be recalled for biopsy. The availability of her MRI scan from the first round allowed for a Breast Imaging Reporting and Data System 2 (benign) classification. The lesion is completely unchanged compared with the prior axial post-contrast T1-weighted MRI scan (d). Four years after the second MRI examination, the participant is still free of cancer.
Figure 2c: (a–c) MRI scans in a 55-year-old participant in the second round compared with (d) the MRI scan from the first round (prevalence round). Her current axial post-contrast T1-weighted MRI scan (a) shows an oval lesion with irregular margin in the right lower inner quadrant (arrow), with type 3 enhancement kinetics (kinetic overlay not shown). The lesion is hypo- to isointense on the axial T2-weighted MRI scan (b) and shows dubious diffusion restriction on the axial apparent diffusion coefficient map (c), consistent with a moderately suspicious lesion that should be recalled for biopsy. The availability of her MRI scan from the first round allowed for a Breast Imaging Reporting and Data System 2 (benign) classification. The lesion is completely unchanged compared with the prior axial post-contrast T1-weighted MRI scan (d). Four years after the second MRI examination, the participant is still free of cancer.
Figure 2d: (a–c) MRI scans in a 55-year-old participant in the second round compared with (d) the MRI scan from the first round (prevalence round). Her current axial post-contrast T1-weighted MRI scan (a) shows an oval lesion with irregular margin in the right lower inner quadrant (arrow), with type 3 enhancement kinetics (kinetic overlay not shown). The lesion is hypo- to isointense on the axial T2-weighted MRI scan (b) and shows dubious diffusion restriction on the axial apparent diffusion coefficient map (c), consistent with a moderately suspicious lesion that should be recalled for biopsy. The availability of her MRI scan from the first round allowed for a Breast Imaging Reporting and Data System 2 (benign) classification. The lesion is completely unchanged compared with the prior axial post-contrast T1-weighted MRI scan (d). Four years after the second MRI examination, the participant is still free of cancer.
Figure 3a: (a, b) MRI scans in a 54-year-old participant in the second round compared with (c) the MRI scan from the first round (prevalence round). Her current axial post-contrast T1-weighted MRI scan (a) shows a sharply demarcated 3-mm lesion in the left upper outer quadrant (arrow). The lesion shows type 2 kinetics (kinetic overlay not shown) and no diffusion restriction (circled area on b) on the axial apparent diffusion coefficient map (b). In a non–high-risk screening examination, this indifferent focus would normally not be recalled. In this case, the participant was recalled because comparison with her prior axial post-contrast T1-weighted MRI scan (c) revealed that this focus was new (circled area on c). Biopsy showed an infiltrating lobular carcinoma.
Figure 3b: (a, b) MRI scans in a 54-year-old participant in the second round compared with (c) the MRI scan from the first round (prevalence round). Her current axial post-contrast T1-weighted MRI scan (a) shows a sharply demarcated 3-mm lesion in the left upper outer quadrant (arrow). The lesion shows type 2 kinetics (kinetic overlay not shown) and no diffusion restriction (circled area on b) on the axial apparent diffusion coefficient map (b). In a non–high-risk screening examination, this indifferent focus would normally not be recalled. In this case, the participant was recalled because comparison with her prior axial post-contrast T1-weighted MRI scan (c) revealed that this focus was new (circled area on c). Biopsy showed an infiltrating lobular carcinoma.
Figure 3c: (a, b) MRI scans in a 54-year-old participant in the second round compared with (c) the MRI scan from the first round (prevalence round). Her current axial post-contrast T1-weighted MRI scan (a) shows a sharply demarcated 3-mm lesion in the left upper outer quadrant (arrow). The lesion shows type 2 kinetics (kinetic overlay not shown) and no diffusion restriction (circled area on b) on the axial apparent diffusion coefficient map (b). In a non–high-risk screening examination, this indifferent focus would normally not be recalled. In this case, the participant was recalled because comparison with her prior axial post-contrast T1-weighted MRI scan (c) revealed that this focus was new (circled area on c). Biopsy showed an infiltrating lobular carcinoma.
Of the recalled women, 92 had an indication for additional work-up (BI-RADS 4 or 5). In two women, this indication was based on a BI-RADS 4 or 5 score at the 6-month follow-up MRI after a BI-RADS 3 score at the initial second screening round MRI. Eighty-four of these women underwent a breast biopsy, which resulted in a biopsy rate of 24.4 per 1000 screening examinations (95% CI: 19.8, 30.2).
Cancer Detection Rate
The CDR of the second round was 5.8 per 1000 screening examinations (95% CI: 3.8, 9.0), compared with a CDR of 16.5 per 1000 screening examinations in the first round (95% CI: 13.3, 20.5). The CIs of the first and second round were not overlapping.
False-Positive Rate
The FPR in the second round was 26.3 per 1000 screening examinations (95% CI: 21.5, 32.3) (specificity, 97%), compared with an FPR of 79.8 per 1000 screening examinations in the first round (95% CI: 72.4, 87.9). The FPR due to BI-RADS 3 scores was 5.2 per 1000 screening examinations (95% CI: 3.3, 8.3) in the second round versus 31.1 per 1000 screening examinations (95% CI: 26.5, 36.4) in the first round. The FPR due to BI-RADS 4 and 5 scores was 21.1 per 1000 screening examinations (95% CI: 16.8, 26.5) in the second round versus 48.7 per 1000 screening examinations (95% CI: 42.9, 55.3) in the first round (Table 2). There was no overlap in CIs from the first and second round in any of these comparisons.
Positive Predictive Value
The positive predictive value of recall (BI-RADS 3, 4, or 5) was 18.2% (95% CI: 12.1, 26.4) in the second round, compared with 17.4% (95% CI: 14.2, 21.2) in the first round. The positive predictive value of a BI-RADS 4 or 5 classification was 21.7% (95% CI: 14.5, 31.2) in the second round, compared with 23.9% (95% CI: 19.6, 28.8) in the first round, and the positive predictive value of biopsy was 23.8% (95% CI: 16.0, 33.9) in the second round, compared with 26.3% (95% CI: 21.7, 31.6) in the first round (Table 2).
Tumor Characteristics
In the second MRI round, 20 women were diagnosed with an MRI screening–detected breast cancer, of which six were ductal carcinoma in situ (DCIS) and 14 were invasive cancers (Tables 1–2). For comparison we included the findings from the first round in Table 2 (5). The detection rate of DCIS was 1.7 per 1000 screening examinations (95% CI: 0.8, 3.8) in the second round, compared with 3.1 per 1000 screening examinations (95% CI: 1.9, 5.2) in the first round. The percentage of DCIS among all cancers detected in the second round was 30% (six of 20), compared with 19% (15 of 79) in the first round (P = .36, Fisher exact test). All detected cases of DCIS were intermediate or high grade (Table 4).
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In the second round, none of the MRI-detected cancers were node positive (0 per 1000 screening examinations; 95% CI: 0, 16.1) or late stage (stage II–IV) (0 per 1000 screening examinations; 95% CI: 0, 16.1) at diagnosis, compared with 1.9 per 1000 screening examinations (95% CI: 1.0, 3.6) and 1.5 per 1000 screening examinations (95% CI: 0.8, 3.0), respectively, in the prevalence round.
The proportion of high-grade (grade III) invasive cancers was comparable in the first and second screening rounds (6.8% and 6.7%, respectively; P > .99, Fisher exact test) (Table 4). In the second screening round, all 14 invasive cancers were positive for estrogen and/or progesterone receptors, compared with 56 of 64 invasive cancers in the first screening round (P = .34, Fisher exact test).
Serious Adverse Events
During the second round of MRI screening, one vasovagal reaction led to an emergency department visit and thus was classified as a serious adverse event. Additionally, two adverse events were registered during or immediately after the screening MRI, both caused by extravasation of the contrast agent.
Discussion
In the Dense Tissue and Early Breast Neoplasm Screening trial, women with extremely dense breasts, who have increased breast cancer risk and in whom mammographic screening has limited sensitivity, are screened biennially with supplemental breast MRI. Compared with the first round, the additional cancer detection rate of the second round was lower (5.8 per 1000 screening examinations vs 16.5 per 1000 screening examinations), and the false-positive rate showed a sharp reduction (26.3 per 1000 screening examinations vs 79.8 per 1000 screening examinations). For both measures, the 95% CIs of the first and second round did not overlap. All tumors detected in the second round were early stage (stage 0–I). The proportion of ductal carcinoma in situ (DCIS) was higher in the second round than in the prevalence round, although the difference was not statistically significant (30% vs 19%, P = .36). In the second round, all cases of DCIS were intermediate or high grade.
The reduction in CDR was anticipated because a larger pool of prevalent breast cancers is expected in the prevalence round that cannot be detected with mammography only (5). This has also been observed in other prospective MRI screening studies. Of these, only Kuhl et al (9) studied women at average risk of breast cancer. Other studies relate to high-risk populations. Their results are summarized in Table E2 (online) (9–13). The participants in the study by Kuhl et al were between 40 and 70 years old, and approximately 20% had extremely dense breasts. Screening intervals ranged between 12 and 36 months. The average CDR was lower in incidence rounds than in the prevalence round (6.9 per 1000 screening examinations vs 22.6 per 1000 screening examinations), and the first incident cancer was detected on an MRI scan almost 3 years after a previous screening examination. These results suggest that for MRI screening in an average-risk population, an interval exceeding 2 years could be considered; however, this needs further investigation.
Kuhl et al observed a lower proportion of DCIS in their incidence rounds compared with their prevalence round (15% vs 38%) (9). We observed a lower proportion of DCIS in the prevalence round instead, although it was not statistically significant. This apparent discrepancy may have been caused by chance due to the low absolute numbers of cancers. Another possible explanation is the strong focus on prevention of overcalling nonmass enhancement lesions. During the 1st years, all readers convened twice a year to discuss their recall rates, with special attention for nonmass enhancement lesions. In addition, the availability of prior MRI scans for comparison in the second round may have increased the readers’ confidence in recalling small nonmass enhancement lesions they would not have recalled in the prevalent round.
The observed reduction in the FPR was expected and can partly be explained by the availability of prior MRI examinations, which facilitated the reading by serving as comparison. In addition, the radiologists, although experienced in breast MRI screening of high-risk populations, went through a learning curve in reading MRI scans from the average-risk DENSE population. Kuhl et al too observed a lower FPR in incidence than in prevalence screenings (47.0 per 1000 screening examinations vs 99.0 per 1000 screening examinations) (9).
A limitation of our study is that the interval cancer rates after the second round are not yet available, as this requires longer follow-up and linkage with the cancer registry. They will be reported in subsequent articles as an indicative measure of breast cancer mortality. Our trial is not large enough to look at the effect of MRI screening on breast cancer–specific or overall mortality, but a modeled analysis of the impact of MRI screening on mortality based on the trial data will be published separately.
Generalizability of results may be reduced, as the women in our study are predominantly White and they take part in biennial as opposed to the annual screening that is more common in several other countries. The fact that these women are recurrent participants in an MRI screening study may have caused further selection.
Because of shorter MRI acquisition and reading times, abbreviated MRI is considered a more feasible and probably more cost-effective option for screening than the full diagnostic protocol used in the DENSE trial. The DENSE protocol, however, allows for post hoc assessment of the performance of such a short acquisition protocol in future research, as from the start in 2011, it has been 3-T only and included the hybrid bitemporal dynamic acquisition now considered the standard for abbreviated MRI.
In conclusion, this study provides results on an incidence MRI screening round in women with extremely dense breasts and at average risk of breast cancer. Incidence studies of supplemental screening are needed to adequately measure the performance of an ongoing, as opposed to a one-time-only, intervention. The sharp reduction in false-positive results in the second round is reassuring and may be even further reduced with use of computer-aided diagnosis (14). The next step, after longer follow-up and linkage with the cancer registry, is to compare the two DENSE trial arms and study the effect of multiple supplemental MRI screening rounds on rates of interval and late-stage cancers.
Acknowledgment
For research purposes, Volpara Health Technologies provided Volpara imaging software version 1.5 for installation on servers in the screening units of the Dutch screening program.
Author Contributions
Author contributions: Guarantors of integrity of entire study, K.M.D., C.H.v.G., W.B.V.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; agrees to ensure any questions related to the work are appropriately resolved, all authors; literature research, S.G.A.V., M.F.B., R.M.M., M.D.F.d.J., C.H.v.G., W.B.V.; clinical studies, S.V.d.L., M.F.B., R.M.P., R.M.M., E.M.M., P.K.d.K.D., R.H.C.B., M.B.I.L., M.D.F.d.J., K.M.D., J.V., W.P.T.M.M., M.A.A.J.v.d.B., C.H.v.G., W.B.V.; experimental studies, M.D.F.d.J., N.K., P.J.v.D.; statistical analysis, S.G.A.V., S.V.d.L., M.F.B., M.D.F.d.J., C.H.v.G.; and manuscript editing, S.G.A.V., S.V.d.L., M.F.B., R.M.P., R.M.M., E.M.M., M.J.E., P.K.d.K.D., M.B.I.L., M.D.F.d.J., K.M.D., J.V., P.J.v.D., W.P.T.M.M., M.A.A.J.v.d.B., C.H.v.G., W.B.V.
The DENSE trial is financially supported by the University Medical Center Utrecht (Universitair Medisch Centrum Utrecht, project number UMCU DENSE), the Netherlands Organization for Health Research and Development (ZonMw, project numbers ZONMW-200320002-UMCU and ZonMW Preventie 50-53125-98-014), the Dutch Cancer Society (KWF Kankerbestrijding; project numbers DCS-UU-2009-4348, UU-2014-6859, and UU2014-7151), Dutch Pink Ribbon/A Sister’s Hope Organization (project number Pink Ribbon-10074), Bayer AG Pharmaceuticals, Radiology (project number BSP-DENSE), and Stichting Kankerpreventie Midden-West.
* Members of the DENSE trial study group are listed at the end of this article.
Members of the DENSE trial study group: University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands: C. H. van Gils, PhD; M. F. Bakker, PhD; S. V. de Lange, MD; S. G. A. Veenhuizen, MSc; W. B. Veldhuis, MD, PhD; R. M. Pijnappel, MD, PhD; M. J. Emaus, PhD; P. H. M. Peeters, MD, PhD; E. M. Monninkhof, PhD; M. A. Fernandez-Gallardo, MD; W. P. T. M. Mali, MD, PhD; M. A. A. J. van den Bosch, MD, PhD; and P. J. van Diest, MD, PhD. Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands: R. M. Mann, MD, PhD; R. Mus, MD; M. Imhof-Tas, MD; and N. Karssemeijer, PhD. The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands: C. E. Loo, MD, PhD; P. K. de Koekkoek-Doll, MD; and H. A. O. Winter-Warnars, MD, PhD. Albert Schweitzer Hospital, Dordrecht, the Netherlands: R. H. C. Bisschops, MD, PhD; M. C. J. M. Kock, MD, PhD; R. K. Storm, MD; and P. H. M. van der Valk, MD. Maastricht University Medical Centre, Maastricht, the Netherlands: M. B. I. Lobbes, MD, PhD, and S. Gommers, MD. Zuyderland Medical Centre: M. B. I. Lobbes, MD, PhD. Jeroen Bosch Hospital, ’s-Hertogenbosch, the Netherlands: M. D. F. de Jong, MD, and M. J. C. M. Rutten, MD, PhD. Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands: K. M. Duvivier, MD, and P. de Graaf, MD, PhD. Hospital Group Twente (ZGT), Almelo, the Netherlands: J. Veltman, MD, PhD, and R. L. J. H. Bourez, MD. Erasmus Medical Center, Rotterdam, the Netherlands: H. J. de Koning, MD, PhD.
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Article History
Received: Sept 8 2020Revision requested: Oct 23 2020
Revision received: Dec 22 2020
Accepted: Jan 12 2021
Published online: Mar 16 2021
Published in print: May 2021
