Wo m e n ’s I m a g i n g • R ev i ew

Destounis et al.
Breast Density, Risk Estimation, and Supplemental Screening

Women’s Imaging
Review
Downloaded from www.ajronline.org by Hospital Italiano de Buenos Aires on 05/13/20 from IP address 132.174.251.183. Copyright ARRS. For personal use only; all rights reserved

Update on Breast Density,

FOCUS ON:

Risk Estimation, and
Supplemental Screening
Stamatia V. Destounis1 OBJECTIVE. Dense breast tissue is an established risk factor for the development of
Amanda Santacroce breast cancer. Methods for reliable and reproducible identification of breast density have been
Andrea Arieno developed and are increasingly being adopted into clinical practice, allowing enhanced iden-
tification of patients who will benefit from supplemental screening. Breast density is being
Destounis SV, Santacroce A, Arieno A used for patient risk stratification through incorporation into risk models, leading to more pre-
cise management and improved decision making regarding personalized screening strategies.
CONCLUSION. This review provides an update on breast density assessment, evalua-
tion of patient’s risk status, and the use of supplemental screening.

reast density notification legisla- ogy (ACR) BI-RADS [6]. Other qualitative

B tion has been adopted in more

Keywords: breast density; breast imaging;
risk ­assessment; supplemental screening
doi.org/10.2214/AJR.19.21994
Received July 10, 2019; accepted after revision
September 5, 2019.
1
All authors: Elizabeth Wende Breast Care, LLC,
170 Sawgrass Dr, Rochester, NY 14620. Address
­correspondence to S. V. Destounis
(sdestounis@ewbc.com).
AJR 2020; 214:296–305
0361–803X/20/2142–296
© American Roentgen Ray Society
than half of the states of the
United States. Increased breast
density is an independent risk factor for the
development of breast cancer; women in the
highest density category, classified as ex-
tremely dense (d), are four to six times more
likely than women with fatty tissue to devel-
op breast cancer [1, 2]. Further, the presence
of dense breast tissue limits the sensitivity of
mammography because of the masking ef-
fect [3]. Legislation varies from state to state,
ranging from only requiring reporting of
breast density to the patient to reporting den-
sity as well as describing the associated risks
of having increased breast density and the
potential benefit of integrating additional
screening into the breast care plan. The risk
stratification based on breast density that is
occurring is guiding referral to supplemental
screening [4, 5]. Simultaneously, the need for
accurate and reproducible measures of breast
density has increased because no recommen-
dations for standardized breast density as-
sessment are currently available.
This review provides an update on breast
density assessment, evaluation of patient’s risk
status, and the use of supplemental screening.
Breast Density Assessment
Visual Density Assessment
The most widely used method to assess
breast density has been visual assessment
guided by the American College of Radiol-
measures of breast density include the orig-
inal Wolfe classification [7] and the Tabar
patterns [8]. The Wolfe classification, as de-
scribed first in 1976, classified women into
four categories of parenchymal patterns
based on the relative amounts of fat, epitheli-
al and connective tissue densities, and prom-
inent ducts seen on mammography [7]. The
Tabár patterns, from 1997, went beyond clas-
sifying on the basis of simple tissue patterns
and instead is based on anatomic-mammo-
graphic correlation using a 3D subgross tech-
nique [8]. Table 1 compares these two meth-
ods of categorizing breast density. Use of the
visual BI-RADS method has been criticized
because of high rates of both intra- and in-
terreader variability [9–13]. Further incon-
sistency came to light with changes from the
4th edition to the 5th edition of BI-RADS [4,
14] (Table 2). Assessment of breast density
changed from a percentage value of the fi-
broglandular tissue in relation to the whole
breast area to a general visual impression by
the image interpreter, putting more weight
on the masking effect of dense tissue and al-
lowing the reader to categorize the breast as
dense when only a focal area of dense tis-
sue is present [6]. The impact of this change
in practice is not fully defined, though a few
small-scale studies have found that the new
guidelines lead to an increase in dense as-
sessments [15, 16]. One such investigation
found an overall decrease in fatty assess-
ments of 5.0%, 2.8% increase in scattered,

296 AJR:214, February 2020

 Breast Density, Risk Estimation, and Supplemental Screening

TABLE 1: Comparison of Wolfe Classifications and Tabár Patterns

Categorization Description Risk Level
Downloaded from www.ajronline.org by Hospital Italiano de Buenos Aires on 05/13/20 from IP address 132.174.251.183. Copyright ARRS. For personal use only; all rights reserved

Wolfe classification
N1 Normal Lower
P1 Composed mostly of fat, displaying prominent ducts behind the areola or in the upper axillary quadrant occupying no Lower
more than 25% of the breast
P2 A more prominent duct pattern than P1, a quarter or more of the breast occupied Higher
DY General increase in breast density with possible minor involvement of prominent ducts Higher
Tabár pattern
I Predominantly dense tissue with nodular densities, regions of fatty tissue Lower
II Completely fatty breasts Lower
III Mostly fatty breast with visible ducts behind areola Lower
IV Predominantly dense breasts with linear and nodular densities Higher
V High levels of homogeneous density Higher

2.6% increase in heterogeneously dense,
and 0.4% decrease in extremely dense as-
sessments [17]. When categorizing the four
densities into two categories (dense and non-
dense), there was an increase in dense assess-
ments. Adaptation to the new guidelines has
varied from radiologist to radiologist.
Further discrepancies in density assess-
ment have been noticed with the widespread
adoption of digital breast tomosynthesis
(DBT), with or without the synthetic view,
leading to the recent incorporation of a new
section to the BI-RADS atlas [18]. This shift
has had implications for density assessment,
particularly when a facility is using the syn-
thetic view in place of full-field digital mam-
mography (FFDM), because the synthetic
view can look very different from traditional
FFDM. Just how this impacts density assess-
ment is not completely understood, though
Zuckerman et al. [19] and Aujero et al. [20]
reported that more breasts are categorized
as nondense than dense when using the syn-
thetic image. Gastounioti et al. [21] report-
ed density differed with imaging modali-
ty, with more breasts classified as nondense
with DBT and synthetic mammography.
That study evaluated three different time pe-
riods, using three different mammographic
screening modalities: FFDM alone, FFDM
with DBT, and synthetic mammography with
DBT. Readers visually assessed breast den-
sity in a dichotomized fashion (nondense or
dense). A transition to more nondense assess-
ments is a significant finding that would ben-
efit from large-scale investigation, because
the impact of fewer women being classified
as having dense breasts would lead to fewer
recommendations for supplemental screen-
ing based solely on breast density. However,
Gastounioti et al. performed density assess-
ment visually, and this method comes with
known limitations.
Increased awareness of breast density
has been accompanied by growing criticism
about making screening recommendations
based on the subjective visual BI-RADS as-
sessment. This controversy has been a driv-
ing force behind the growth of automated
methods of density assessment.
Semiautomated and Fully Automated
Density Assessment
Automated density software has been in-
troduced to address the subjective nature of
visual assessment. Conant and colleagues
[22] posited that adopting automated meth-
ods will greatly reduce the variability of den-
sity assessments, help standardize density
thresholds for supplemental screening, and
better refine risk assessment and personal-
ized screening. Semiautomated and fully au-
tomated methods take a variety of approach-
es to density measurement; some are 2D
area-based, others use 3D volumetric-based
methods [23].
Cumulus (University of Toronto) and
Madena (Eye Physics) are two examples of
semiautomated interactive methods [24, 25].
These methods use segmentation and thresh-
olding performed by the image interpreter to
separate the breast edge and the areas of den-
sity on the mammogram; each pixel within
the breast area is segmented into either fat
or fibroglandular tissue. Automated tech-
niques utilizing an area-based approach in-
clude ImageJ (National Institutes of Health),
MedDensity (Giulio Tagliafico), the STRA-
TUS algorithm, Libra (Computational Breast
Imaging Group), and PowerLook (iCAD),
which was formerly known as iReveal [26–
30]. Studies have found comparable perfor-
mance between some of these methods, as
well as in comparison with visual BI-RADS

TABLE 2: Comparison of the BI-RADS 4th Edition and 5th Edition Density Assessments
4th Edition 5th Edition
Assessment Breast Tissue Characteristics Assessment Breast Tissue Characteristics
1 Almost entirely fatty (< 25% glandular) a Almost entirely fatty
2 Scattered densities (approximately 25–50% glandular) b Scattered areas of fibroglandular density
3 Heterogeneously dense, which could obscure detection of c Heterogeneously dense, which may obscure detection of small
small masses (approximately 51–75% glandular) masses
4 Extremely dense, which may lower the sensitivity of d Extremely dense, which lowers the sensitivity of ­mammography
­mammography (> 75% glandular)

AJR:214, February 2020 297


assessment [27, 31–33]. Despite some posi-
tive results, limitations have been reported,
including being time-consuming, difficult,
and prone to inter- and intraobserver subjec-
Downloaded from www.ajronline.org by Hospital Italiano de Buenos Aires on 05/13/20 from IP address 132.174.251.183. Copyright ARRS. For personal use only; all rights reserved
tivity [34–36]. These limitations are largely
the reasons that such methods have not been
routinely incorporated in clinical practice.
Two of the most well-known fully auto-
mated volumetric-based methods are Volpa-
ra and Quantra [37, 38]. Both methods take a
volumetric quantitative density measurement
and have been shown to be reliable and re-
producible [39–41]. These methods has been
largely used with FFDM, but positive re-
sults have also been seen when using DBT,
which is necessary because DBT continues
to be adopted in clinical practices at a high
rate. Agreement between visual BI-RADS
and automated density grades by Volpara
have shown moderate agreement (weighted
κ = 0.512) [42]. Youk et al. [15] compared vi-
sual assessments by radiologists using both
the BI-RADS 4th and 5th editions; the re-
sults were then correlated with automated
assessment by Quantra. Interobserver agree-
ment on breast density category was moder-
ate to substantial (κ = 0.58–0.63) with the 4th
edition and substantial (κ = 0.63–0.66) with
the 5th edition, but there was not a significant
difference between the two. The proportion
of dense breast assignments increased, and
the proportion of fatty breast assignments
decreased with use of the 5th edition com-
pared with the 4th edition (p < 0.0001) when
assessing intraobserver agreement. Auto-
mated assessment had a significant correla-
tion with both editions of BI-RADS visual
assessment. Eom and colleagues [43] report-
ed similarly high agreement levels between
visual assessment and volumetric assess-
ment; in particular, the agreement between
nondense and dense categories was almost
perfect between readers and Volpara (κ =
0.83). Tromans and colleagues (presented
at the European College of Radiology 2014
annual meeting) evaluated density assess-
ment between FFDM and DBT and report-
ed Volpara had a strong positive agreement
with BI-RADS (κ  = 0.953) and a volumet-
ric breast density correlation between DBT
and FFDM (r = 0.903). Phantom work with
Quantra has found that breast density is 10%
higher with DBT than with FFDM [44]. Cu-
mulus has shown strong intra- and interuser
correlations and agreement with DBT [45].
MedDensity has shown moderately positive
correlation of BI-RADS with DBT, though
image noise limits its capabilities and reduc-
298 AJR:214, February 2020
Destounis et al.
es the reliability of the software [34]. Posi-
tive performance of some of these methods is
important, because it gives radiologists con-
fidence in taking an automated approach to
assessing breast density. However, the pur-
chase, use, and maintenance of these prod-
ucts can be associated with significant cost,
which may be a limiting factor to widespread
clinical adoption.
Role of Augmented Intelligence in
Density Assessment
Application of deep learning (DL) meth-
ods for density assessment is an expanding
area of research. Lehman et al. [46] devel-
oped a DL method to assess BI-RADS breast
density using the original interpretation by
an experienced radiologist. The algorithm
was developed and tested on randomly se-
lected digital mammograms, with BI-RADS
breast density recorded by one of 12 radi-
ologists specializing in breast imaging. The
model was trained to map images in a single
view to assess breast density. To combine the
density assessments from each view into an
assessment for the examination, researchers
used the consensus density across views. A
reader study compared agreement between
the DL model and the majority consensus of
five breast imagers, between the DL model
and the original interpreting radiologist, and
between the majority consensus and the orig-
inal interpreting radiologist. After that, the
algorithm was implemented clinically. Table
3 provides a summary of the study findings.
The DL model showed very good agreement
with radiologists in the clinical setting, with
94% of the binary dense versus nondense
DL assessments accepted by the interpreting
physician; 90% were accepted in the four-
category BI-RADS assessment. This is a
promising investigation with a new tool that
may be able to address concerns regarding
accurate density assessment to properly allo-
cate supplemental screening resources. Oth-
er DL methods have been investigated for
density assessment [47–49]; however, none
were included in clinical practice, leaving
TABLE 3: Summary of Findings From Lehman et al. [46]
Comparison
Deep learning model vs original interpretation (test set)
Deep learning model vs original interpretation (reader consensus setting)
Reader consensus vs original interpretation
Deep learning model vs reader consensus
Deep learning model vs final radiologist assessment (clinical implementation)
the door open for further work. Research is
ongoing to improve the accuracy and consis-
tency of density assessment.
Density Assessment and Risk Prediction
Automated density measures have also
been applied as a predictor of risk for the de-
velopment of breast cancer. The risk of ad-
vanced cancer has been reported to be four
times higher for women with extremely
dense breasts than for all other women when
using a fully automated breast density mea-
surement for predicting the risk of advanced-
stage diagnosis and the first negative screen-
ing round [50]. This finding is comparable
with that of a similar publication, which
found that the highest risk for developing
breast cancer was for women with breasts
in the highest density category [42]. In that
retrospective study, Destounis et al. [42]
found breast density was the only risk factor
significantly associated with the diagnosis of
interval cancer versus screen-detected can-
cer, for both visual BI-RADS assessment and
automated volumetric breast density (VBD).
Results from this study showed a strong lin-
ear relationship between sensitivity of mam-
mography and automated volumetric breast
density, with substantial decreases in sensi-
tivity for women in the two higher automated
density groups (the equivalent of BI-RADS c
and d). Visual BI-RADS assessment showed
women whose breasts were in the highest
density category were 3.6 times more like-
ly than women in the two lower categories
to have an interval cancer diagnosis. Ac-
cording to quantitative VBD results, wom-
en in the highest quartile were four times as
likely as those in the lower quartile to have
a diagnosis of interval versus screen-detect-
ed cancer, leading the authors to conclude
that VBD more precisely captures the poten-
tial masking risk of dense breasts. As part
of the ongoing Predicting Risk of Cancer
at Screening, or PROCAS, study, research-
ers compared density assessment by visu-
al analog scale (VAS), Cumulus, Densitas
(Densitas), Quantra (Hologic), and Volpara
κ
0.67
0.62
0.63
0.78
0.85
 Breast Density, Risk Estimation, and Supplemental Screening
(­Volpara ­Solutions) [51]. VAS was found to
be the strongest predictor of screen-detect-
ed cancer at study entry, after adjustment for
classic risk factors, in the highest versus low-
Downloaded from www.ajronline.org by Hospital Italiano de Buenos Aires on 05/13/20 from IP address 132.174.251.183. Copyright ARRS. For personal use only; all rights reserved
est percent density. Volpara and VAS showed
a significant trend with increasing density.
Densitas and Cumulus percent density mea-
sures were also statistically significant when
comparing the highest quintile to the lowest;
for Quantra there was no significant associ-
ation. Although VAS was found to predict
breast cancer risk significantly better than
all other density assessment methods, the au-
thors cautioned that use of this method is un-
likely for wide-scale stratified screening and
thus conclude that Volpara or Densitas pro-
vide the most practical solution. As breast
imaging moves closer to personalized risk-
based assessments, determining which den-
sity methods are the most appropriate will be
increasingly important. Automated assess-
ment tools will likely play a large role.
Risk Estimation
Individual risk for developing breast can-
cer varies between 11.6% for women of aver-
age risk and 85% for women with pathogenic
germline mutations in highly penetrant genes
(i.e., BRCA1, BRCA2, TP53, and PTEN) [52–
56]. Assessment of individual risk is critical
for tailoring screening and prevention strat-
egies appropriate to the distinct risk lev-
el. The determination of a patient’s risk in-
volves many factors, traditionally including
family history, hormonal factors, body mass
index (BMI), and hormone therapy use [53,
57–59]. Some of the most commonly used
risk assessment models in the clinical setting
are the Gail, Claus, and Tyrer-Cuzick (TC)
models. Each considers a different combina-
tion of the classic risk factors. The Gail mod-
el uses reproductive and biopsy information,
with limited family history [53]. The Claus
model includes greater family history (first-
and second-degree relatives) but does not in-
clude other factors such as hormonal factors
or biopsy history [57]. TC is the more com-
prehensive of these models, using reproduc-
tive history, biopsy history, extended family
history, and BMI [58]. Recent advancements
have led to the incorporation of polygenic
risk information and breast density with the
goal of increasing risk assessment accuracy.
Advancements in Risk Assessment Models
Identification of over 100 single nucleotide
polymorphisms (SNPs) associated with breast
cancer through genomewide association stud-
AJR:214, February 2020 299
ies has been a recent genetic advancement,
with this information allowing improved risk
assessment at the individual level [55]. A re-
cent study, OncoArray [60], reported that
18% of familial risk of breast cancer can be
explained by SNPs [61]. At least one com-
monly used risk assessment model, TC, now
gives the option to include SNP information,
if available. Polygenic risk scores (PRSs) have
been developed, which when combined with
other classic factors can be used to estimate
an individual’s risk. Research is continuing in
this area, evaluating the potential to ultimate-
ly stratify women according to PRS. PRS pro-
vides powerful risk discrimination; even bet-
ter risk discrimination will be obtained by
combining the PRS with family history and
other risk factors [62]. Continued studies to
validate risk models including genetic, hor-
monal, and lifestyle factors, will be needed.
The incorporation of this level of individual-
ized genomic information will lead to a new
level of personalized risk assessment, stratifi-
cation, and management.
The addition of mammographic density
to breast cancer risk models has shown im-
proved predictive power [63–66]. A study by
Brentnall et al. [63] incorporated mammo-
graphic breast density into the Gail and TC
models, resulting in improvement in AUCs
from 0.55 and 0.57 to 0.59 and 0.61, respec-
tively. A more recent study by Brentnall and
colleagues [64] found that the addition of
volumetric and visual density assessment
to traditional risk factors can improve risk
stratification. When mammographic density
was added to the TC model, both volumet-
ric and visual assessment increased the ac-
curacy of risk prediction, with odds ratios of
1.55 and 1.40, respectively. The study also
found that adding mammographic density
affected the number of women assessed as
having high risk. When the TC model was
used without density, 4.8% of the population
was found to be at high risk; this increased to
7.1% with incorporation of BI-RADS densi-
ty and 6.8% when combined with volumetric
density. Combining breast density with clas-
sic risk factors almost doubled the number of
patients identified as being at high risk.
Because of efforts to provide more inclu-
sive breast cancer risk assessment models for
clinical use, DL methods are taking develop-
ment further. Three models use risk factor in-
formation from the patient’s medical record
and provide risk within 5 years: a risk fac-
tor–based logistic regression model using tra-
ditional risk factors, a DL model (image-only
DL) using mammograms alone, and a hybrid
DL model using both traditional risk factors
and mammography images [67]. Comparisons
were made with the TC version 8 model (TC
8). When the image-only DL model was used,
31% of women were identified as having high
risk, compared with 18% when the TC 8 mod-
el was used. The hybrid DL model was found
to be significantly more accurate than TC 8
(AUC of 0.70 vs 0.62, respectively). Interest-
ingly, the image-only DL model outperformed
TC 8; in particular, when traditional risk factor
information was unavailable, the image-only
DL model was able to provide more accurate
risk assessment. This difference can have im-
portance in clinical practice because of limi-
tations of patient-reported family history. The
incorporation of images is a common trend
in the new research occurring for risk assess-
ment. Harvard researchers collected screening
breast MR images and developed a DL mod-
el to predict 5-year breast cancer risk of a pa-
tient on the basis of a single breast MR image
from the patient’s screening MRI examina-
tion [68]. The single image used for this study
was a manipulated image, created by subtract-
ing the unenhanced 3D dataset from the con-
trast-enhanced 3D dataset, leaving a single 3D
volumetric image. Then, the axial view of the
maximum intensity projection was used to
convert this 3D volumetric image to a 2D im-
age. The model was trained to map a patient’s
risk factors at the time of an MRI examina-
tion to determine whether the patient had can-
cer develop within 5 years using the previously
described 2D projection image. The DL mod-
el’s performance was compared with a logis-
tic regression model based on traditional risk
factors in addition to personal history of breast
cancer and background parenchymal enhance-
ment on MRI and the TC 8 model. Table 4
provides a summary of the performance of the
three models. The image DL model showed
improved individual risk discrimination com-
pared with the TC model.
Impact of Risk Assessment on Clinical Practice
Finding a comprehensive model to deter-
mine the most accurate and individualized
TABLE 4: Summary of Findings From
Portnoi et al. [68]
Model Mean AUC ± SD
Image-based deep learning 0.638 ± 0.094
Risk factor logistic regression 0.558 ± 0.108
Tyrer-Cuzick 0.493 ± 0.092

lifetime risk score for patients is a large fo-
cus to allow accurate stratification of wom-
en into groups at different levels of risk,
ultimately allowing more informed deci-
Downloaded from www.ajronline.org by Hospital Italiano de Buenos Aires on 05/13/20 from IP address 132.174.251.183. Copyright ARRS. For personal use only; all rights reserved
sion-making regarding supplemental screen-
ing and prevention. Individualized risk as-
sessment is an important service to offer, yet
it is important to ensure that there is patient
access and understanding. A large, popula-
tion-based study found that most patients re-
ported wanting genetic testing, but only 29%
reported having it [69]. Only 52.9% of pa-
tients at high risk reported having genetic
testing. Patients described lack of a physi-
cian’s recommendation, not expense, as their
primary reason for not testing. The study au-
thors suggested improving physicians’ com-
munication skills with patients, along with
assessment of patients’ risk and desire for
testing, to better guide appropriate patients
toward risk assessment and testing. These
changes will ultimately lead the way to en-
suring that patients at higher risk are not
only identified but also understand the im-
portance of their risk level and can be pro-
vided the information they need to pursue
supplemental screening.
Breast Density Implications for
Supplemental Screening Practices
As risk assessments become more com-
prehensive, a large population of women
are being notified of their lifetime risk for
breast cancer for the first time [64]. Wom-
en who have significant factors that increase
their risk score above designated thresh-
olds (frequently  > 20% lifetime risk) are in
the higher-risk category, which has well-de-
fined screening guidelines. A larger num-
ber of women, however, are finding them-
selves in the vaguely defined moderate-risk
group, which is lacking consensus and clar-
ity on appropriate management. The incor-
poration of breast density into updated risk
assessment models has changed this land-
scape further by identifying a new subset of
women who are at increased risk because of
their breast density. Simultaneously, there
has been a nationwide movement to inform
women of their breast density, with the goal
of making those in the highest density cat-
egories aware and providing information on
the risks of dense tissue and potential bene-
fit of additional screening. The combination
of these factors have catapulted discussion of
best screening practices for this population,
but so far, there are no formal screening or
management recommendations.
300 AJR:214, February 2020
Destounis et al.
Patient and Physician Knowledge and
Understanding of Breast Density and
Supplemental Screening
Recently, the U. S. Food and Drug Admin-
istration acknowledged the importance of
women being informed of their own breast
anatomy to make informed health decisions
and proposed a rule to amend the reporting
requirements of mammography results to in-
clude a woman’s personal breast density [70].
This rule would impact the information giv-
en to women in 15 states because although
38 states have mandated Dense Breast No-
tification laws, three of those do not include
informing women of their breast density. A
mandate at the federal level would have pow-
erful implications for women’s autonomy
over their own breast health. Although the
movement for notification has been in place
for several years, studies are continuing to
find general confusion and lack of under-
standing concerning the meaning of dense
tissue and the implications for screening [71–
74]. Santiago-Rivas et al. [75], through use
of a survey, reported that most participants
had heard about breast density but less than
one-third knew their personal breast density.
Knowledge of the impact of breast density on
the accuracy of mammography was found to
be associated with the likelihood of complet-
ing supplemental ultrasound, highlighting
the importance of having an informed con-
versation with patients. Busch et al. [76] in-
vestigated the association of dense breast no-
tification on the utilization of supplemental
ultrasound and whether the type of informa-
tion in the notification had an influence. The
study included 1.2 million women who un-
derwent 1.4 million screening mammograms
from 34 states, nine of which had adopted
dense breast notification and 25 of which
with no dense breast notification. The nine
states selected had supplemental ultrasound
as a covered benefit and were included to de-
crease the likelihood that cost was a decid-
ing factor in pursuing supplemental screen-
ing. The results showed that in the population
of women who received notification that they
had dense breasts, an additional 10.5 individ-
uals per 1000 followed the screening mam-
mogram with screening ultrasound, result-
ing in a statistically significant increase:
0.37 more breast cancers detected per 1000
mammograms. The study further differenti-
ated the population who received the dense
breasts notification, distinguishing utiliza-
tion rates between two groups of states based
on the notification received: one group of
five states with notification of the presence
of dense tissue but no mention of potential
benefits and another group of four states with
notification of dense tissue and a brief expla-
nation of potential benefits of supplemen-
tal screening. Utilization was 1.3 per 1000
women higher in the group notified of po-
tential benefits, suggesting women may ben-
efit from a more detailed explanation along
with tissue type notification. This is impor-
tant information for providers, because sim-
ply informing women of their tissue type is
not enough to influence participation in addi-
tional screening.
Research has shown that once women are
informed of their breast density, the option
for supplemental screening, or both, many
reach out to their physicians to discuss [77].
However, recent studies have found that pri-
mary care physicians do not feel fully educat-
ed or prepared to answer all questions on this
topic [78, 79]. A recent survey of breast im-
aging radiologists questioned the perceived
adequacy of patient-provider conversations
regarding screening guidelines and found
that radiologists largely feel patient-provider
discussions are inadequate, specifically cit-
ing that discussions regarding supplemental
screening for increased breast density should
be standardized [80]. Most respondents re-
ported breast density information is includ-
ed in patient letters and radiology reports
yet feel further patient education regarding
breast density and supplemental screening
should be performed by radiologists.
Breast Density Is Shifting Screening
Recommendations
With more women being told they have
dense breasts, identification of best screening
practices for this population is needed [15, 81,
82]. Mammography is the reference standard
screening modality regardless of density,
with the proven ability to reduce breast can-
cer mortality [83]. Nevertheless, reduced per-
formance in certain populations of women,
primarily those with increased breast densi-
ty, has led to the use of other imaging mo-
dalities for supplemental screening, primar-
ily DBT, breast ultrasound, and breast MRI.
Organizations have issued position state-
ments on supplemental screening; however,
the messages are often ambiguous and non-
committal. The latest position statement by
the American Cancer Society acknowledg-
es that both ultrasound and MRI have higher
cancer detection rates in women with dense
breast tissue but also describes the low speci-
 Breast Density, Risk Estimation, and Supplemental Screening
ficity, resulting in increased rates of unneces-
sary tests and biopsies. The advice given is
to “talk with your healthcare provider about
whether you should have other tests” [84]. In
Downloaded from www.ajronline.org by Hospital Italiano de Buenos Aires on 05/13/20 from IP address 132.174.251.183. Copyright ARRS. For personal use only; all rights reserved
a similar vein, recent ACR Appropriateness
Criteria for breast cancer screening give sup-
plemental ultrasound for women with dense
breasts (of all risk levels) a “may be appropri-
ate” rating [85]. The ACR acknowledges that
dense breast tissue lowers mammograph-
ic sensitivity and that adding ultrasound in-
creases the cancer detection rate but at the
cost of a substantial increase in false-positive
rates. Ultimately, the criteria state that add-
ing ultrasound may be useful, but the balance
of benefits and harms should be considered
when making the decision to use supplemen-
tal ultrasound. The suggestion for patients to
balance the benefits and harms and have in-
formed conversations with healthcare pro-
viders follows an increasing trend toward
personalized screening with the intent of al-
lowing women to make decisions regarding
their healthcare on the basis of informed con-
versations and individual risk level.
Current and Future Use of Supplemental
Screening Modalities
A recent study by Liao and colleagues
[86] investigated physician ordering levels
of screening ultrasound examinations. The
study used the National Ambulatory Medi-
cal Care Survey data to analyze screening
ultrasound ordering rates before and after
mandated dense breast notification. The phy-
sicians included were primarily from prima-
ry care, family practice, internal medicine,
and gynecology and encountered patients
at preventive services wellness visits. Of
the 12,787 visits that met inclusion criteria,
22.1% received mammography referrals and
3.3% received screening ultrasound referrals.
Referral rates did not change significantly af-
ter legislation took effect (3.9% before and
4.2% after legislation). These low rates show
that physicians are not ordering supplemen-
tal tests but could also indicate that women
are not asking for them. A recent survey by
the Society of Breast Imaging sought to dis-
cover what supplemental screening practic-
es and recommendations are occurring in
clinical practice [87]. The survey results re-
vealed DBT is recommended at the highest
rate, with radiologists stating they are “like-
ly” and “very likely” to recommend DBT,
regardless of patient risk level. The level of
endorsement for ultrasound was not as high,
with the respondents stating they were only
AJR:214, February 2020 301
“somewhat likely” to recommend supple-
mental ultrasound. Patients highly value the
recommendation of radiologists; higher rates
of referrals and utilization could occur if ra-
diologists were more likely to recommend
ultrasound screening, as a recent study in
the AJR found [88]. Of 751 women with nor-
mal mammograms and breast density of het-
erogeneously or extremely dense breasts, the
study examined the return rate for a screen-
ing ultrasound on the basis of the type of fol-
low-up communication the patient received.
One-third of the women received a letter
stating mammography was normal, with no
mention of density or supplemental screen-
ing benefits. Another one-third received a
letter indicating a normal mammogram and
included the density category. When appli-
cable, an explanation of how supplemental
screening may be beneficial was included.
The remaining one-third received the same
letter as the second group and received a fol-
low-up telephone call from the radiology of-
fice reiterating the mammography results,
presence of dense tissue, and possible ben-
efit of supplemental screening. The group
of women receiving the letter with densi-
ty information and benefits of supplemental
screening had a return rate for supplemental
ultrasound of 48.8%, and the group who re-
ceived the letter and a follow-up telephone
call had a return rate of 86.9%. In compari-
son, women who received no information re-
garding density, supplemental screening, or
a follow-up call had a 9.9% return rate. Such
results illustrate the important influence a ra-
diologist’s advice can have on patients.
Digital Breast Tomosynthesis
DBT use in the United States has increased
exponentially since 2011 when it received ap-
proval from the Food and Drug Administra-
tion. Value has been shown in utilizing DBT
as a supplement to FFDM, with large retro-
spective and prospective studies consistent-
ly showing increased cancer detection rates,
reduced recall rates, and increased sensi-
tivity [89–92]. Since 2011, DBT has proven
more effective not only as a supplemental
tool but also as a primary screening device
for all breast types [93]. DBT has also been
shown to perform well in imaging women
with dense breast tissue [94]. However, many
practices have not been able to make a com-
plete transition, working with a limited num-
ber of units or no units at all. In these hybrid
scenarios, practices frequently use DBT as a
supplement to FFDM [95].
Studies have found that some cancers
missed by DBT can be detected on supple-
mental ultrasound or MRI. The ability of ul-
trasound and MRI to find additional mam-
mographically occult cancers is broadly
acknowledged, but there are known draw-
backs to these technologies that prevent
widespread endorsement of their routine
use. Although a complete enumeration of the
benefits and drawbacks are outside the scope
of this article, we briefly highlight the most
common advantages and disadvantages of
these supplemental screening modalities and
indicate areas of current research seeking to
improve on the limitations.
Screening Ultrasound
Screening breast handheld ultrasound
(HHUS) has been shown in several single-
and multiple-institution studies to detect
breast cancers otherwise missed by mam-
mography, including DBT [96–98]. Addi-
tional benefits aside from increased cancer
detection include no ionizing radiation and
no need for contrast agents. The increased
cancer detection rate with HHUS combined
with mammography is reportedly up to 4.3
cancers per 1000 women screened, and most
of these cancers are stage 0 or 1 [99–102].
However, HHUS has drawbacks that prove to
be limiting factors for its widespread use in
a screening setting, including that it is oper-
ator-dependent, lacks reproducibility, is time
intensive, and requires specially trained staff
[103]. Automated systems (i.e., automated
breast ultrasound [ABUS]) have been devel-
oped to improve on the limitations of HHUS.
ABUS removes the dependence on a skilled
operator to perform the examination, utiliz-
ing an automated scanner. ABUS has been
shown to provide reproducible, high-resolu-
tion images. Results from several prospec-
tive studies have shown that ABUS increases
cancer detection rates and has specificity and
sensitivity comparable with those of HHUS
[101, 104, 105], showing that ABUS is a fea-
sible alternative to HHUS for screening pur-
poses. A commonly cited criticism of both
of these methods is the false-positive rate,
which has been shown to be substantially
more than what is seen with mammography
screening. Recent investigations have exam-
ined the utility of additional automated ultra-
sound applications with the goal of decreas-
ing the number of false-positives, including
optoacoustic breast imaging, contrast-en-
hanced ultrasound, and elastography. Opto-
acoustic imaging is a novel ultrasound ap-

plication that fuses anatomic and functional
diagnostic imaging through use of laser op-
tics and sound. The fusion of laser optic im-
aging and gray-scale ultrasound gives this
Downloaded from www.ajronline.org by Hospital Italiano de Buenos Aires on 05/13/20 from IP address 132.174.251.183. Copyright ARRS. For personal use only; all rights reserved
technology the ability to depict structure and
hemoglobin as well as relative oxygenation
within and around breast masses. Results of
a prospective multicenter trial found that op-
toacoustic ultrasound had better specificity
than the internal gray-scale ultrasound of the
device in breast mass assessment [106].
Contrast-enhanced ultrasound (CEUS) has
shown potential value in predicting benig-
nity when evaluating breast masses. A pilot
study evaluating CEUS to reduce the num-
ber of benign breast masses recommended
for biopsy used prediction models and found
that CEUS may reduce 31% of benign biop-
sies for masses that are nonenhancing with
circumscribed margins or enhancing with an
oval shape and homogeneous enhancement
[107]. A meta-analysis similarly concluded
that CEUS has good sensitivity and specific-
ity for the characterization of breast lesions,
potentially being able to help reduce unnec-
essary benign biopsies [108].
Ultrasound elastography has been avail-
able for over 15 years, though use in clini-
cal practice remains relatively infrequent be-
cause it has not been incorporated as standard
care. Recent advancements in elastography
technology include shear wave techniques.
Shear wave elastography was investigated in
a large multinational trial and was found to
improve specificity of breast ultrasound mass
assessment without a loss of sensitivity [109].
Acoustic radiation force impulse has been
introduced, which has two different modes:
virtual touch tissue quantification and vir-
tual touch tissue imaging. Researchers have
found potential with these techniques [110,
111]. Many of these advancements seek to
improve on limitations of traditional ultra-
sound, but further work is needed for them to
gain widespread acceptance.
MRI and Abbreviated MRI
Traditionally, screening MRI has not been
recommended to any group of patients out-
side of those with higher (>  20%) lifetime
risk, primarily because of the time the pro-
cedure takes for the patient, the reading time
for the radiologist, the unknown effects of
long-term gadolinium exposure, the rate of
false-positives, and the high cost of the pro-
cedure. Because women with dense tissue do
not fall into the higher-risk category on the
basis of density alone, MRI has not been in-
302 AJR:214, February 2020
Destounis et al.
cluded in any screening guidelines for this
group. The DENSE trial evaluated the effect
of supplemental MRI for women with ex-
tremely dense breasts within a population-
based screening program (Bakker MFLS,
et al., presented at the European Congress
of Radiology 2019 annual meeting). The re-
sults showed excellent performance in this
population, with a cancer detection rate
of 16.5/1000 and positive predictive val-
ue for biopsy of 26.3%. This high detection
rate and positive predictive value for biopsy
show MRI can be a useful tool for decreas-
ing false-positives. Despite the evidence of
greatly increased benefit to women in this
population, the deterrents of traditional MRI
still pose a problem for mainstream utiliza-
tion, which has led the way for abbreviated
breast MRI protocols to be developed. Re-
duced magnet time, shown to be as little as
3 minutes, combined with reduced image in-
terpretation time, can significantly reduce the
cost of MRI and thus significantly increase
the availability of screening MRI. Studies
have shown that abbreviated MRI maintains
the high level of cancer detection, sensitivity,
and diagnostic accuracy of traditional MRI
protocols [112–115]. By addressing the short-
comings of MRI while maintaining levels of
diagnostic integrity, access can be increased
to groups of women outside of the higher-
risk classification, such as women with dense
breast tissue. In the ongoing EA1141 trial,
women without symptoms who are not de-
fined as high risk (lifetime risk < 20%) with
dense breasts undergo DBT and abbreviated
breast MRI in randomized order for 2 con-
secutive years [116]. Participants then return
to regular screening and are followed for an-
other 3 years. Cancer detection rates of DBT
compared with abbreviated MRI in the first
(prevalence) and second (incidence) screen-
ing rounds, along with positive predictive
values and types of cancers found are the ob-
jectives for comparison and will provide in-
sight into the potential for abbreviated MRI
in clinical practice for screening.
Conclusion
Dense breast tissue remains a significant
topic in breast imaging. The acknowledg-
ment of breast density as a risk factor has
led to improvements in screening technolo-
gies as well as a grassroots movement to in-
form women of their breast density. Efforts
to standardize density assessment are neces-
sary, with widespread adoption of automated
measures likely. The use of automated densi-
ty assessment will help to streamline the pro-
cess of dense tissue identification in a way
that is reproducible and reliable and allow
incorporation into risk assessment models,
to permit the most accurate identification of
women at higher than average risk. The hope
is that this will lead to refinement in supple-
mental screening guidelines as well as tai-
lored, personalized screening.
References
1. McCormack VA, dos Santos Silva I. Breast den-
sity and parenchymal patterns as markers of
breast cancer risk: a meta-analysis. Cancer
­Epidemiol Biomarkers Prev 2006; 15:1159–1169
2. Boyd NF, Martin LJ, Bronskill M, Yaffe MJ, Du-
ric N, Minkin S. Breast tissue composition and
susceptibility to breast cancer. J Natl Cancer Inst
2010; 102:1224–1237
3. Boyd NF, Guo H, Martin LJ, et al. Mammo-
graphic density and the risk and detection of
breast cancer. N Engl J Med 2007; 356:227–236
4. Kerlikowske K, Sprague BL, Tosteson ANA, et
al. Strategies to identify women at high risk of
advanced breast cancer during routine screening
for discussion of supplemental imaging. JAMA
Intern Med 2019 Jul 1 [Epub ahead of print]
5. Vourtsis A, Berg WA. Breast density implica-
tions and supplemental screening. Eur Radiol
2019; 29:1762–1777
6. D’Orsi CJ, Sickles EA, Mendelson EB, et al. ACR
BI-RADS Atlas, Breast Imaging Reporting and
Data System. Reston, VA: American College of
Radiology, 2013
7. Wolfe JN. Breast patterns as an index of risk for de-
veloping breast cancer. AJR 1976; 126:1130–1137
8. Gram IT, Funkhouser E, Tabár L. The Tabar
classification of mammographic parenchymal
patterns. Eur J Radiol 1997; 24:131–136
9. Sprague BL, Conant EF, Onega T, et al. Variation
in mammographic breast density assessments
among radiologists in clinical practice: a multi-
center observational study. Ann Intern Med 2016;
165:457–464
10. Kerlikowske K, Grady D, Barclay J, et al. Vari-
ability and accuracy in mammographic interpre-
tation using the American College of Radiology
Breast Imaging Reporting and Data System.
J Natl Cancer Inst 1998; 90:1801–1809
11. Ciatto S, Houssami N, Apruzzese A, et al. Cate-
gorizing breast mammographic density: intra-
and interobserver reproducibility of BI-RADS
density categories. Breast 2005; 14:269–275
12. Ekpo EU, Ujong UP, Mello-Thoms C, McEntee
MF. Assessment of interradiologist agreement
regarding mammographic breast density classifi-
cation using the fifth edition of the BI-RADS
Atlas. AJR 2016; 206:1119–1123
 Breast Density, Risk Estimation, and Supplemental Screening
13. Spayne MC, Gard CC, Skelly J, Miglioretti DL,
Vacek PM, Geller BM. Reproducibility of
BI-RADS breast density measures among com-
Downloaded from www.ajronline.org by Hospital Italiano de Buenos Aires on 05/13/20 from IP address 132.174.251.183. Copyright ARRS. For personal use only; all rights reserved
munity radiologists: a prospective cohort study.
Breast J 2012; 18:326–333
14. D’Orsi CJ, Mendelson EB, Ikeda DM, et al.
Breast Imaging Reporting and Data System:
ACR BI-RADS—breast imaging atlas. Reston,
VA: American College of Radiology, 2003
15. Youk JH, Kim SJ, Son EJ, Gweon HM, Kim JA.
Comparison of visual assessment of breast density
in BI-RADS 4th and 5th editions with automated
volumetric measurement. AJR 2017; 209:703–708
16. Alikhassi A, Gourabi HE, Baikpour M. Com-
parison of inter- and intra-observer variability of
breast density assessments using the fourth and
fifth editions of Breast Imaging Reporting and
Data System. Eur J Radiol Open 2018; 5:67–72
17. Irshad A, Leddy R, Lewis M, et al. Changes in
breast density reporting patterns of radiologists
after publication of the 5th edition BI-RADS
guidelines: a single institution experience. AJR
2017; 209:943–948
18. Lee CH, Destounis SV, Friedewald SM, Newell
MS. Digital breast tomosynthesis (DBT) guid-
ance (a supplement to ACR BI-RADS Mammog-
raphy 2013). Reston, VA: American College of
Radiology, 2013
19. Zuckerman SP, Conant EF, Keller BM, et al. Imple-
mentation of synthesized two-dimensional mam-
mography in a population-based digital breast to-
mosynthesis screening program. R ­ adiology 2016;
281:730–736
20. Aujero MP, Gavenonis SC, Benjamin R, Zhang
Z, Holt JS. Clinical performance of synthesized
two-dimensional mammography combined with
tomosynthesis in a large screening population.
Radiology 2017; 283:70–76
21. Gastounioti A, McCarthy AM, Pantalone L,
Synnestvedt M, Kontos D, Conant EF. Effect of
mammographic screening modality on breast
density assessment: digital mammography ver-
sus digital breast tomosynthesis. Radiology
2019; 291:320–327
22. Conant EF, Sprague BL, Kontos D. Beyond
BI-RADS density: a call for quantification in the
breast imaging clinic. Radiology 2018; 286:401–
404
23. Destounis S, Arieno A, Morgan R, Roberts C, Chan
A. Qualitative versus quantitative mammographic
breast density assessment: applications for the US
and abroad. Diagnostics (Basel) 2017; 7:E30
24. Byng JW, Boyd NF, Fishell E, Jong RA, Yaffe
MJ. The quantitative analysis of mammographic
densities. Phys Med Biol 1994; 39:1629–1638
25. Ursin G, Astrahan MA, Salane M, et al. The detec-
tion of changes in mammographic densities.
­Cancer Epidemiol Biomarkers Prev 1998; 7:43–47
AJR:214, February 2020 303
26. Li J, Szekely L, Eriksson L, et al. High-through-
put mammographic-density measurement: a tool
for risk prediction of breast cancer. Breast
­Cancer Res 2012; 14:R114
27. Tagliafico A, Tagliafico G, Tosto S, et al. Mam-
mographic density estimation: comparison
among BI-RADS categories, a semi-automated
software and a fully automated one. Breast 2009;
18:35–40
28. Eriksson M, Czene K, Pawitan Y, Leifland K,
Darabi H, Hall P. A clinical model for identifying
the short-term risk of breast cancer. Breast
­Cancer Res 2017; 19:29
29. Keller BM, Chen J, Daye D, Conant EF, Kontos
D. Preliminary evaluation of the publicly avail-
able Laboratory for Breast Radiodensity Assess-
ment (LIBRA) software tool: comparison of ful-
ly automated area and volumetric density
measures in a case-control study with digital
mammography. Breast Cancer Res 2015; 17:117
30. iCad website. Powerlook Density Assessment.
www.icadmed.com/assets/dmm211_powerlook_
density_assessment_revg.pdf. Accessed October
22, 2019
31. Tagliafico A, Tagliafico G, Astengo D, Airaldi S,
Calabrese M, Houssami N. Comparative estima-
tion of percentage breast tissue density for digital
mammography, digital breast tomosynthesis, and
magnetic resonance imaging. Breast Cancer Res
Treat 2013; 138:311–317
32. Tagliafico A, Tagliafico G, Astengo D, et al.
Mammographic density estimation: one-to-one
comparison of digital mammography and digital
breast tomosynthesis using fully automated soft-
ware. Eur Radiol 2012; 22:1265–1270
33. Couwenberg AM, Verkooijen HM, Li J, et al. As-
sessment of a fully automated, high-throughput
mammographic density measurement tool for
use with processed digital mammograms. Can-
cer Causes Control 2014; 25:1037–1043
34. Bakic PR, Carton AK, Kontos D, Zhang C,
­Troxel AB, Maidment AD. Breast percent densi-
ty: estimation on digital mammograms and cen-
tral tomosynthesis projections. Radiology 2009;
252:40–49
35. Yaffe MJ. Mammographic density: measurement
of mammographic density. Breast Cancer Res
2008; 10:209
36. Oliver A, Tortajada M, Lladó X, et al. Breast den-
sity analysis using an automatic density segmenta-
tion algorithm. J Digit Imaging 2015; 28:604–612
37. Highnam R, Brady M, Yaffe MJ, Karssemeijer N,
Harvey J. Robust breast composition measurement:
Volpara. In: Martí J, Oliver A, Freixenet J, Martí R,
eds. Proceedings of the Digital Mammography:
10th International Workshop—IWDM 2010. Ber-
lin/Heidelberg, Germany: Springer, 2010:342–349
38. [No authors listed]. Understanding Quantra 2.0:
user manual. Bedford, MA: Hologic, 2012
39. Wang J, Azziz A, Fan B, et al. Agreement of
mammographic measures of volumetric breast
density to MRI. PLoS One 2013; 8:e81653
40. Alonzo-Proulx O, Mawdsley GE, Patrie JT,
Yaffe MJ, Harvey JA. Reliability of automated
breast density measurements. Radiology 2015;
275:366–376
41. Engelken F, Singh JM, Fallenberg EM, Bick U,
Bottcher J, Renz DM. Volumetric breast compo-
sition analysis: reproducibility of breast percent
density and fibroglandular tissue volume mea-
surements in serial mammograms. Acta Radiol
2014; 55:32–38
42. Destounis S, Johnston L, Highnam R, Arieno A,
Morgan R, Chan A. Using volumetric breast den-
sity to quantify the potential masking risk of
mammographic density. AJR 2017; 208:222–227
43. Eom HJ, Cha JH, Kang JW, Choi WJ, Kim HJ,
Go E. Comparison of variability in breast density
assessment by BI-RADS category according to
the level of experience. Acta Radiol 2018;
59:527–532
44. Ren BR, Smith A, Jing ZX. Measurement of
breast density with digital breast tomosynthesis.
In: Pelc NJ, Nishikawa RM, Whiting BR, eds.
Medical imaging: physics of medical imaging—
proceedings of SPIE, vol. 8313. Bellingham, WA:
SPIE, 2012:83134Q
45. Ekpo EU, McEntee MF. Measurement of breast
density with digital breast tomosynthesis: a sys-
tematic review. Br J Radiol 2014; 87:20140460
46. Lehman CD, Yala A, Schuster T, et al. Mammo-
graphic breast density assessment using deep
learning: clinical implementation. Radiology
2019; 290:52–58
47. Wu N, Geras KJ, Shen Y, et al. Breast density
classification with deep convolutional neural net-
works. arXiv website. arxiv.org/pdf/1711.03674.
Published November 10, 2017. Accessed October
23, 2019
48. Kallenberg M, Petersen K, Nielsen M, et al. Unsu-
pervised deep learning applied to breast density
segmentation and mammographic risk scoring.
IEEE Trans Med Imaging 2016; 35:1322–1331
49. Mohamed AA, Berg WA, Peng H, Luo Y,
Jankowitz RC, Wu S. A deep learning method for
classifying mammographic breast density cate-
gories. Med Phys 2018; 45:314–321
50. Puliti D, Zappa M, Giorgi Rossi P, et al.;
­DENSITY Working Group. Volumetric breast
density and risk of advanced cancers after a neg-
ative screening episode: a cohort study. Breast
Cancer Res 2018; 20:95
51. Astley SM, Harkness EF, Sergeant JC, et al. A
comparison of five methods of measuring mam-
mographic density: a case-control study. Breast
Cancer Res 2018; 20:10

52. Kuchenbaecker KB, Hopper JL, Barnes DR, et
al.; BRCA1 and BRCA2 Cohort Consortium.
Risks of breast, ovarian, and contralateral breast
Downloaded from www.ajronline.org by Hospital Italiano de Buenos Aires on 05/13/20 from IP address 132.174.251.183. Copyright ARRS. For personal use only; all rights reserved
cancer for BRCA1 and BRCA2 mutation carriers.
JAMA 2017; 317:2402–2416
53. Costantino JP, Gail MH, Pee D, et al. Validation
studies for models projecting the risk of invasive
and total breast cancer incidence. J Natl Cancer
Inst 1999; 91:1541–1548
54. Tan MH, Mester JL, Ngeow J, Rybicki LA,
­Orloff MS, Eng C. Lifetime cancer risks in indi-
viduals with germline PTEN mutations. Clin
Cancer Res 2012; 18:400–407
55. Wood ME, Farina NH, Ahern TP, et al. Towards
a more precise and individualized assessment of
breast cancer risk. Aging (Albany NY) 2019;
11:1305–1316
56. Bray F, Ferlay J, Soerjomataram I, Siegel RL,
Torre LA, Jemal A. Global cancer statistics 2018:
GLOBOCAN estimates of incidence and mortal-
ity worldwide for 36 cancers in 185 countries. CA
Cancer J Clin 2018; 68:394–424
57. Claus EB, Risch N, Thompson WD. Autosomal
dominant inheritance of early-onset breast can-
cer: implications for risk prediction. Cancer
1994; 73:643–651
58. Tyrer J, Duffy SW, Cuzick J. A breast cancer pre-
diction model incorporating familial and per-
sonal risk factors. Stat Med 2004; 23:1111–1130
59. Parmigiani G, Berry DA, Aquilar O. Determin-
ing carrier probabilities for breast cancer suscep-
tibility genes BRCA1 and BRCA2. Am J Hum
Genet 1998; 62:145–148
60. Michailidou K, Lindstrom S, Dennis J, et al. As-
sociation analysis identifies 65 new breast cancer
risk loci. Nature 2017; 551:92–94
61. Lilyquist J, Ruddy KJ, Vachon CM, Couch FJ.
Common genetic variation and breast cancer
risk: past, present, future. Cancer Epidemiol
Biomarkers Prev 2018; 27:380–394
62. Rudolph A, Song M, Brook MN, et al. Joint as-
sociations of a polygenic risk score and environ-
mental risk factors for breast cancer in the Breast
Cancer Association Consortium. Int J Epidemiol
2018; 47:526–536
63. Brentnall AR, Harkness EF, Astley SM, et al.
Mammographic density adds accuracy to both
the Tyrer-Cuzick and Gail breast cancer risk
models in a prospective UK screening cohort.
Breast Cancer Res 2015; 17:147
64. Brentnall AR, Cohn WF, Knaus WA, et al. A
case-control study to add volumetric or clinical
mammographic density into the Tyrer-Cuzick
breast cancer risk model. J Breast Imaging 2019;
1:99–106
65. Chen J, Pee D, Ayyagari R, et al. Projecting abso-
lute invasive breast cancer risk in white women
with a model that includes mammographic den-
304 AJR:214, February 2020
Destounis et al.
sity. J Natl Cancer Inst 2006; 98:1215–1226
66. Tice JA, Cummings SR, Ziv E, Kerlikowske K.
Mammographic breast density and the Gail mod-
el for breast cancer risk prediction in a screening
population. Breast Cancer Res Treat 2005;
94:115–122
67. Yala A, Lehman C, Schuster T, Portnoi T,
Barzilay R. A deep learning mammography-
­ Imaging 2019; 1:109–114
based model for improved breast cancer risk pre-
diction. Radiology 2019; 292:60–66
68. Portnoi T, Yala A, Schuster T, et al. Deep learn-
ing model to assess cancer risk on the basis of a
breast MR image alone. AJR 2019; 213:227–233
69. Kurian AW, Griffith KA, Hamilton AS, et al. Ge-
netic testing and counseling among patients with
newly diagnosed breast cancer. JAMA 2017;
317:531–534
70. Mammography Quality Standards Act: proposed
rule. Fed Regist 2019; 84:11669–11686
71. Pacsi-Sepulveda AL, Shelton RC, Rodriguez CB,
Coq AT, Tehranifar P. “You probably can’t feel as
safe as normal women”: Hispanic women’s reac-
tions to breast density notification. Cancer 2019;
125:2049–2056
72. Miles RC, Lehman C, Warner E, Tuttle A, ­Saksena
M. Patient-reported breast density awareness and
knowledge after breast density legislation passage.
Acad Radiol 2019; 26:726–731
73. Gunn CM, Battaglia TA, Paasche-Orlow MK,
West AK, Kressin NR. Women’s perceptions of
dense breast notifications in a Massachusetts
safety net hospital: “So what is that supposed to
mean?” Patient Educ Couns 2018; 101:1123–1129
74. Haas JS, Giess CS, Harris KA, et al. Randomized
trial of personalized breast density and breast
cancer risk notification. J Gen Intern Med 2019;
34:591–597
75. Santiago-Rivas M, Benjamin S, Andrews JZ,
Jandorf L. Breast density awareness and knowl-
edge, and intentions for breast cancer screening
in a diverse sample of women age eligible for
mammography. J Cancer Educ 2019; 34:90–97
76. Busch SH, Hoag JR, Aminawung JA, et al. As-
sociation of state dense breast notification laws
with supplemental testing and cancer detection
after screening mammography. Am J Public
Health 2019; 109:762–767
77. Cappello NM, Richetelli D, Lee CI. The impact
of breast density reporting laws on women’s
awareness of density-associated risks and conver-
sations regarding supplemental screening with
providers. J Am Coll Radiol 2019; 16:139–146
78. Gunn CM, Kressin NR, Cooper K, Marturano C,
Freund KM, Battaglia TA. Primary care provider
experience with breast density legislation in
Massachusetts. J Womens Health (Larchmt)
2018; 27:615–622
79. Brown J, Soukas C, Lin JJ, Margolies L,
­ antiago-Rivas M, Jandorf L. Physician knowledge,
S
attitudes, and practices regarding breast density.
J Womens Health (Larchmt) 2019; 28:1193–1199
80. Aminololama-Shakeri S, Soo MS, Grimm LJ,
Destounis S. Screening guidelines and supple-
mental screening tools: assessment of the ade-
quacy of patient-provider discussions. J Breast
81. Irshad A, Leddy R, Ackerman S, et al. Effects of
changes in BI-RADS density assessment guide-
lines (fourth versus fifth edition) on breast den-
sity assessment: intra- and interreader agree-
ments and density distribution. AJR 2016;
207:1366–1371
82. Youk JH, Gweon HM, Son EJ, Kim JA. Auto-
mated volumetric breast density measurements
in the era of the BI-RADS fifth edition: a com-
parison with visual assessment. AJR 2016;
206:1056–1062
83. Tabár L, Vitak B, Chen TH, et al. Swedish two-
county trial: impact of mammographic screening
on breast cancer mortality during 3 decades.
­Radiology 2011; 260:658–663
84. Oeffinger KC, Fontham ETH, Etzioni R, et al.
Breast cancer screening for women at average
risk: 2015 guideline update from the American
Cancer Society. JAMA 2015; 314:1599–1614
85. Mainiero MB, Moy L, Baron P, et al. American
College of Radiology appropriateness criteria
breast cancer screening. American College of
Radiology website. acsearch.acr.org/docs/70910/
Narrative/. Revised 2017. Accessed June 28, 2019
86. Liao GJ, Hippe DS, Chen LE, et al. Physician or-
dering of screening ultrasound: national rates
and association with state-level breast density
reporting laws. J Am Coll Radiol 2019 Jul 18
[Epub ahead of print]
87. Singer T, Lourenco AP, Baird GL, Mainiero MB.
Supplemental screening for women with dense
breasts: what do practicing radiologists recom-
mend? J Breast Imaging 2019; 1:32–36
88. Aripoli A, Fountain K, Winblad O, et al. Supple-
mental screening with automated breast ultra-
sound in women with dense breasts: comparing
notification methods and screening behaviors.
AJR 2018; 210:[web]W22–W28
89. Tagliafico AS, Mariscotti G, Valdora F, et al. A
prospective comparative trial of adjunct screen-
ing with tomosynthesis or ultrasound in women
with mammography-negative dense breasts
(­ASTOUND-2). Eur J Cancer 2018; 104:39–46
90. Skaane P, Sebuødegård S, Bandos AI, et al. Per-
formance of breast cancer screening using digital
breast tomosynthesis: results from the prospec-
tive population-based Oslo Tomosynthesis
Screening Trial. Breast Cancer Res Treat 2018;
169:489–496
91. Conant EF, Beaber EF, Sprague BL, et al. Breast
 Breast Density, Risk Estimation, and Supplemental Screening
cancer screening using tomosynthesis in combi-
nation with digital mammography compared to
digital mammography alone: a cohort study
Downloaded from www.ajronline.org by Hospital Italiano de Buenos Aires on 05/13/20 from IP address 132.174.251.183. Copyright ARRS. For personal use only; all rights reserved
within the PROSPR consortium. Breast Cancer
Res Treat 2016; 156:109–116
92. Ciatto S, Houssami N, Bernardi D, et al. Integra-
tion of 3D digital mammography with tomosyn-
thesis for population breast-cancer screening
(STORM): a prospective comparison study.
­L ancet Oncol 2016; 14:583–589
93. Caumo F, Zorzi M, Brunelli S, et al. Digital
breast tomosynthesis with synthesized two-­
dimensional images versus full-field digital
mammography for population screening: out-
comes from the Verona screening program. Ra-
diology 2017; 287:37–46
94. Destounis SV, Morgan R, Arieno A. Screening
for dense breasts: digital breast tomosynthesis.
AJR 2015; 204:261–264
95. Gao Y, Babb JS, Toth HK, Moy L, Heller SK. Dig-
ital breast tomosynthesis practice patterns follow-
ing 2011 FDA approval: a survey of breast imaging
radiologists. Acad Radiol 2017; 24:947–953
96. Ohuchi N, Suzuki A, Sobue T, et al.; J-START In-
vestigator Groups. Sensitivity and specificity of
mammography and adjunctive ultrasonography to
screen for breast cancer in the Japan strategic anti-
cancer randomized trial (J-START): a randomised
controlled trial. Lancet 2016; 387:341–348
97. Destounis S, Arieno A, Morgan R. New York
State breast density mandate: follow-up data with
screening sonography. J Ultrasound Med 2017;
36:2511–2517
98. Vourtsis A, Kachulis A. The performance of 3D
ABUS versus HHUS in the visualisation and
BI-RADS characterisation of breast lesions in a
large cohort of 1,886 women. Eur Radiol 2018;
28:592–601
99. Berg WA, Blume JD, Cormack JB, et al. Com-
bined screening with ultrasound and mammog-
raphy vs mammography alone in women at ele-
AJR:214, February 2020 305
vated risk of breast cancer. JAMA 2008;
299:2151–2163
100. Weigert J, Steenergen S. The Connecticut experi-
ment: the role of ultrasound in the screening of
women with dense breasts. Breast J 2012;
18:517–522
101. Hooley RJ, Greenberg KL, Stackhouse RM, et al.
Screening US in patients with mammographi-
cally dense breasts: initial experience with Con-
necticut Public Act 09-41. Radiology 2012;
265:59–69
102. Destounis S, Arieno A, Morgan R. Initial experi-
ence with the New York State breast density in-
form law at a community-based breast cen-
ter. J Ultrasound Med 2015; 34:993–1000
103. Maimone S, McDonough M. Dense breast notifi-
cation and supplemental screening: a survey of
current strategies and sentiments. Breast J 2017;
23:193–199
104. Wilczek B, Wilczek HE, Rasouliyan L, Leifland
K. Adding 3D automated breast ultrasound to
mammography screening in women with hetero-
geneously and extremely dense breasts: report
from a hospital-based, high-volume, single-cen-
ter breast cancer screening program. Eur J
­Radiol 2016; 85:1554–1563
105. Giger ML, Inciardi MF, Edwards A, et al. Auto-
mated breast ultrasound in breast cancer screen-
ing of women with dense breasts: reader study of
mammography-negative and mammography-
positive cancers. AJR 2016; 206:1341–1350
106. Neuschler EI, Butler R, Young CA, et al. A piv-
otal study of optoacoustic imaging to diagnose
benign and malignant breast masses: a new eval-
uation tool for radiologists. Radiology 2018;
287:398–412
107. Lee SC, Tchelepi H, Grant E, et al. Contrast-­
enhanced ultrasound imaging of breast masses:
adjunct tool to decrease the number of false-pos-
itive biopsy results. J Ultrasound Med 2019;
38:2259–2273
108. Li Q, Hu M, Chen Z, et al. Meta-analysis: con-
trast-enhanced ultrasound versus conventional
ultrasound for differentiation of benign and ma-
lignant breast lesions. Ultrasound Med Biol
2018; 44:919–929
109. Berg WA, Cosgrove DO, Dore CJ, et al. Shear-
wave elastography improves the specificity of
breast US: the BE1 multinational study of 939
masses. Radiology 2012; 262:435–449
110. Kapetas P, Pinker-Domenig K, Woitek R, et al.
Clinical application of acoustic radiation force
impulse imaging with Virtual Touch IQ in breast
ultrasound: diagnostic performance and repro-
ducibility of a new technique. Acta Radiol 2017;
58:140–147
111. Jayaraman J, Indiran V, Kannan K, ­Maduraimuthu
P. Acoustic radiation force impulse imaging in
benign and malignant breast lesions. C ­ureus
2017; 9:e1301
112. Panigrahi B, Mullen L, Falomo E, et al. An ab-
breviated protocol for high-risk screening breast
magnetic resonance imaging: impact on perfor-
mance metrics and BI-RADS assessment. Acad
Radiol 2017; 24:1132–1138
113. Strahle DA, Pathak DR, Sierra A, et al. System-
atic development of an abbreviated protocol for
screening breast magnetic resonance imaging.
Breast Cancer Res Treat 2017; 162:283–295
114. Kuhl CK, Schrading S, Strobel K, et al. Abbrevi-
ated breast magnetic resonance imaging (MRI):
first post-contrast subtracted images and maxi-
mum-intensity projection—a novel approach to
breast cancer screening with MRI. J Clin Oncol
2014; 32:2304–2310
115. Mango VL, Morris EA, David Dershaw D, et al.
Abbreviated protocol for breast MRI: are multi-
ple sequences needed for cancer detection? Eur J
Radiol 2015; 84:65–70
116. Kuhl CK. Abbreviated breast MRI for screening
women with dense breast: the EA1141 trial. Br J
Radiol 2018; 91:20170441