Assessment of Periodic Screening of Women With Denser Breast Using WBUS and DBT (Also Known as "DBTUST-Dense Breast Tomosynthesis / Ultrasound Screening Trial")
Phase: NA
Conditions: Breast Cancer
Sponsor: Wendie Berg

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Study Protocol  
 
 
 
 
 
 
Official Title:  Assessment of Periodic Screening of Women With Denser 
Breast Using WBUS and DBT (Also Known as "DBTUST-Dense Breast 
Tomosynthesis / Ultrasound Screening Trial") 
  
 
 
ClinicalTrials.gov ID (NCT number): NCT02643966 
 
 
 
Protocol Date: 5/11/2022 
 
 
 
 

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Scientific Background 
 
Despite significant advancements in detection, diagnosis, and treatment, breast cancer remains one 
of the leading causes of death in women over the age of 40 [1, 2]. Across multiple randomized 
controlled trials (RCTs), mammography has been shown to reduce deaths due to breast cancer in 
women aged 40 to 74 [3]. There are subsets of women, however, where mammography is less 
effective. Invasive breast cancers are recognizable primarily as masses, areas of architectural 
distortion, and/or calcifications. Because masses are often similar in density to the breast 
parenchyma itself, dense breast tissue can mask cancer detection, with mammographic sensitivity 
of only approximately 50% in dense breasts [4-6]. Periodic mammography screening results in 
earlier detection of breast cancers and in the last two decades both mortality and, for many reasons 
including but not limited to earlier detection, morbidity of breast cancer has been steadily declining 
[7 -10]. However, there remains a serious and credible controversy as to the attributable benefit 
from mammography screening to this overall decline [11, 12]. Visually searching for and detecting 
breast abnormalities on any modality, but in mammography in particular, is difficult and time-
consuming for radiologists due to the large volume of examinations and the low yield of detected 
cancers in the screening environment, in particular as related to mammograms of younger women 
with dense breasts. Therefore, a substantial fraction (>30%) of “detectable” breast abnormalities, 
including cancers that are retrospectively judged to be “visible” on mammograms, are initially 
completely missed (omission) or actually detected but unreported (commission) by radiologists 
[13-15]. The specificity of mammography is also relatively low for screening in that approximately 
10% of women are recalled for additional imaging procedures and only a small fraction (15%-
30%) of biopsies proves to be positive [16; 17]. Recall rates are even higher among younger 
women with dense breast tissue and for those women receiving their initial screening examination 
before a comparison to prior findings can be made [4; 5; 18-22]. To address reduced 
mammographic sensitivity in dense breasts, several imaging tests have been proposed as a 
replacement and/or for supplemental screening. Magnetic resonance imaging (MRI) has been 
recommended for supplemental screening in women at high risk because of genetic or familial 
history or prior radiation therapy to the chest before age 30 [23]. While MRI detects more cancers 
than even the combination of mammography plus ultrasound [6; 24-26], MRI is not well tolerated 
[27] or cost effective in broader populations [28], and there is currently “insufficient evidence” for 
or against its use in women at intermediate risk for reasons including breast density [23]. 
Large area size full-field digital detectors with high-resolution and wide latitude [29] enabled the 
development of advanced digital imaging techniques, such as digital breast tomosynthesis (DBT) 
[30] and breast computed tomography (CT) [31], that improve conspicuity of breast lesions by 
enabling the enhancement of lesion contrast and/or the provision of 3D non-overlapped tissue 
information at comparable radiation dose levels. Currently, several leading manufacturers are 
marketing and/or testing DBT systems. The DBT systems available to us are manufactured by 
Hologic Inc (Bedford, MA). The system acquires initially 15 low dose projection images (frames) 
and generates mathematically / reconstructs between 50 and 120 tomographic type slices with a 
non-isotropic voxel size of 125µm × 125µm × 1mm depending on the breast thickness during 
compression. DBT has been shown to improve performance substantially over FFDM in all breast 
densities, but, in particular, in women with density BIRADS 2 and 3 [32]. Interestingly, the vast 
majority of these improvements are in reducing recall rates while increasing the detection of 
invasive cancers [33-37]. With recent investigations on and approval of synthesized 2D 
reconstruction (C-View), the issue of added radiation dose when implementing a FFDM+DBT 

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screening practice is largely eliminated as the resulting procedure uses radiation exposure that is 
like that used in conventional FFDM. Hence, DBT is clearly a candidate for both baseline 
screening procedures, as well as for supplementary imaging, in particular as operationally the 
procedure is virtually identical to FFDM from a technologist’s and a woman’s perspective. The 
only meaningful operational difference is the increased time to interpretation (as compared with 
conventional FFDM based practice), which can be expected because of the large number of 
additional images generated by the procedure [38; 39]; however, it decreases substantially with 
experience [40]. Recent data on the performance of C-View alone has been published 
demonstrating comparable diagnostic performance to FFDM alone, as well as in conjunction with 
DBT [135, 136]. This comparable performance results in reducing radiation exposure to the 
screening population by approximately 45%, and allows for a DBT practice to be performed at 
comparable radiation dose to a conventional FFDM based practice. 
Ultrasound is another test which has been considered for supplemental screening to FFDM of 
women with dense breasts [41]. Across eight single-center studies [5; 42-48] and three prospective 
multicenter trials [6; 49; 50], encompassing over 64,000 examinations, the supplemental cancer 
detection rate of ultrasound has consistently been approximately 2 to 4 per 1000. Across those 
series, over 90% of cancers seen only on ultrasound were invasive, with median size of ~10 mm. 
Among invasive cancers, where detailed [5; 6; 42; 43; 46; 49; 50], over 85% of invasive cancers 
seen only on ultrasound were node negative. While MRI will detect more cancers than ultrasound, 
the interval cancer rate with mammography plus ultrasound was only 8% after three years of 
screening mammography and ultrasound in the ACRIN 6666 study [6]; this rate compares 
favorably to those observed with mammography alone in fatty breasts [4; 51], where 
mammographic performance is close to being optimal. This suggests that, while additional cancers 
could be detected using MRI, the combination of ultrasound and mammography is sufficient. 
Importantly, 94% of cancers detected only with ultrasound were invasive,(96% of those were node 
negative, with a median size of ~10 mm [6]). The primary issues related to WBUS in large volumes 
are the needed professional resources (i.e., ,training, cost and practice complexity) and increasing 
recall rates [6; 22; 52]. In support of the aims of this proposal, at the recent Radiological Society 
of North America (RSNA) meeting a very preliminary report on the analysis of DBT supplemented 
by WBUS in the first cycle of WBUS was presented [139] and the results from 1039 examinations 
in a non-controlled environment confirmed that, as expected, WBUS detected approximately two 
additional cancers per 1000 examinations during this first WBUS cycle. There are no data available 
on repeat screening of this type of practice. Although there are little data on the performance of 
using WBUS alone for primary screening, this approach is being explored (primarily abroad) and 
is being assessed very preliminarily in this country as well [140]. Other recent published reports 
focus on comparing classification performance of DBT versus US of known abnormalities and/or 
include a very small number of cases [141-143]. Additional important supporting data are provided 
in the Preliminary Studies section later in the proposal. 
There is currently a great interest in exploring practices that would increase screening efficacy in 
women with denser breasts who constitute a very large fraction of the screening population. WBUS 
and DBT are likely the most feasible approaches to replace and/or supplement screening in a large 
volume of women with denser breasts, because these approaches do not require injection of 
contrast and/or radioactive material. The objective is to demonstrate that using these technologies 
will increase screening efficacy in these women either by reducing recall rates or by improving 
cancer detection rates. Most important for future screening practices which are criticized for over-
diagnosis is to increase the detection of those cancers who left alone would impact life expectancy 

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of the woman (as well as lifetime management cost). In this regard ultrasound seems to be doing 
significantly better than DBT, therefore, despite its higher recall rate, it may eventually prove to 
be either, as if not more efficacious than DBT as the primary screening modality in these women 
constituting approximately 45-50 percent of all screened women. Hence, assessing clinical utility 
of WBUS as either a supplementary modality or a primary screening modality is of utmost 
importance. 
 
 
 
Study Objectives 
 
The overriding objective is to perform a clinical study that would allow for assessing the 
performance of DBT alone versus DBT plus WBUS, and potentially WBUS serving as a primary 
screening modality. 
 
 
 
Study Design & Methods 
 
1) We will recruit sequentially approximately 6,200 women with known heterogeneously dense 
and/or primarily dense breast tissue (from a prior mammogram) who are scheduled to undergo 
routine mammography screening that includes a DBT examination. 
2) Consenting women will undergo a DBT examination as part of their clinical exam and a WBUS 
examination. 
3) DBT, WBUS, and a combination of both, will be independently reviewed and interpreted 
(Breast Imaging, Reporting and Data System rated) by experienced and specifically trained 
radiologists in a cross balanced (cases by mode and by reader) study design. 
4) Using the results of the interpretations in a slightly modified “LOGICAL OR” mode, namely, 
the highest rating determines the recommendation/need for follow up, we will perform diagnostic 
work ups as needed (i.e., resulting from the “arbitration step”). 
5) We will compare cancers and other benign abnormalities detected with DBT only to those 
detected with WBUS. We will compare rates of false positives as a result of interpreting DBT vs. 
WBUS vs. a combination of both, including recall for additional testing, short-interval follow-up 
rates and biopsy rates. We will assess positive predictive values (PPVs) and negative predictive 
values (NPVs). For marginal value assessment when utilizing both modalities, we will also assess 
the type of abnormalities detected by each modality, assuming that a larger study will be required 
to assess cancer detection rates by specific types. 
6) We will analyze the impact of double reading DBT on cancer detection and false positive rates. 
We expect to show that double reading DBT+synthetic 2D will significantly improve cancer 
detection compared to single reading. We hope to show that this can be achieved with minimal 
increase in false positives. 
 

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Eligibility Criteria  
 
Women aged 40 to 75 years of age with heterogeneously dense or extremely dense parenchyma 
by prior digital mammography report (i.e., “dense breasts”), presenting for routine annual 
mammography with digital breast tomosynthesis. For women who have not had any prior 
mammography (i.e. this is their first, baseline, mammogram), the breast tissue must be dense 
(heterogeneously dense or extremely dense) on the current mammogram. 
 
 
 
Statistical Considerations 
 
We will primarily compare rates of true positive and false positives findings induced by DBT vs. 
ABUS, including recall for additional testing, short-interval follow-up rates, biopsy rates. For 
marginal value assessment when utilizing both modalities, we will also assess the type of 
abnormalities detected by each modality, assuming that a larger study will be required to assess 
cancer detection rates by specific types. 
 
Our secondary analysis will compare cancer detection and recall rates from single reading DBT 
vs. optimal double reading DBT (best pairs). We will compare the added cancer detection from 
double reading to that achieved with addition of screening ultrasound. 
 
With over 12,000 examinations that had been double read and an expected yield of approximately 
80 cancers, the limiting factor will be the assessment of cancer detection as a result of the double 
reading with arbitration. With an expected agreement rate of 50% we estimate that we will have a 
power of 78% to detect an increase of 15% or more in cancer detection rate in the experimental 
(double reading set) as compared with single readings.The analysis for changes in recall rates will 
have higher power because of the substantially larger number of cases being recalled (~1200). 
 
 
 
 
 
 
 
 
 
 
 
 

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