REVIEWS AND COMMENTARY • REVIEW

Novel Approaches to Screening for Breast Cancer

Ritse M. Mann, MD, PhD • Regina Hooley, MD • Richard G. Barr, MD, PhD • Linda Moy, MD
From the Department of Radiology, Nuclear Medicine and Anatomy, Radboud University Medical Center, Geert Grooteplein 10, PO Box 9101, 6500 HB, Nijmegen, the
Netherlands (R.M.M.); Department of Radiology, the Netherlands Cancer Institute, Amsterdam, the Netherlands (R.M.M.); Department of Radiology and Biomedical
Imaging, Yale School of Medicine, New Haven, Conn (R.H.); Department of Radiology, Northeastern Ohio Medical University, Rootstown, Ohio (R.G.B.); Southwoods
Imaging, Youngstown, Ohio (R.G.B.); Department of Radiology, New York University Langone School of Medicine, New York, NY (L.M.); and Department of Radiol-
ogy, New York University Grossman School of Medicine, Center for Advanced Imaging Innovation and Research, Laura and Isaac Perlmutter Cancer Center, New York,
NY (L.M.). Received January 24, 2020; revision requested March 16; revision received June 24; accepted June 30. Address correspondence to R.M.M. (e-mail: Ritse.
mann@radboudumc.nl).

Conflicts of interest are listed at the end of this article.

Radiology 2020; 00:1–20 • https://doi.org/10.1148/radiol.2020200172 • Content code:

Screening for breast cancer reduces breast cancer–related mortality and earlier detection facilitates less aggressive treatment.
Unfortunately, current screening modalities are imperfect, suffering from limited sensitivity and high false-positive rates. Novel
techniques in the field of breast imaging may soon play a role in breast cancer screening: digital breast tomosynthesis, contrast
material–enhanced spectral mammography, US (automated three-dimensional breast US, transmission tomography, elastography,
optoacoustic imaging), MRI (abbreviated and ultrafast, diffusion-weighted imaging), and molecular breast imaging. Artificial intel-
ligence and radiomics have the potential to further improve screening strategies. Furthermore, nonimaging-based screening tests
such as liquid biopsy and breathing tests may transform the screening landscape.
© RSNA, 2020

Online supplemental material is available for this article.

B reast cancer is the most common cancer in women
worldwide, with approximately 2 million women diag-
nosed each year (1). It is the second leading cause of can-
cer-related mortality in the United States (2). The rate is
rising at 0.4% per year, with 1 million more cases estimat-
ed for diagnosis worldwide by 2040 (1). Many randomized
controlled trials and observational studies have shown that
regular screening mammography can reduce breast cancer
mortality substantially (3,4).
Beyond traditional screen-film mammography, breast
cancer screening and diagnosis has evolved during
the past 20 years. Full-field digital mammography re-
placed analog film mammography in the early 2000s
(5), and digital breast tomosynthesis is emerging as
the new standard of care in screening mammography
(6). Breast US also progressed beyond its initial role in
the differentiation of cysts versus solid masses detected
at mammography or physical examination (7). Breast
MRI, first thought to be useful as a problem-solving
tool, is now the standard supplemental screening tool
available for both high- and intermediate-risk women
(8).
With ongoing, rapid advances in technology ex-
pected in the next decade, it is likely that breast can-
cer screening will be very different from our current
standards. The new technology introduced into clini-
cal practice is often first evaluated in the diagnostic
setting for ease of measuring initial cancer specificity
and sensitivity. In this review, we explore state-of-the-
art, emerging techniques for breast cancer screening
in mammography, US, MRI, and nuclear medicine
(Tables 1, 2); summarize the automated analysis of ra-
diologic images; and introduce modern non-imaging
screening techniques.
This copy is for personal use only. To order printed copies, contact reprints@rsna.org
Mammography
Digital Breast Tomosynthesis
Since gaining U.S. Food and Drug Administration ap-
proval in 2011, digital breast tomosynthesis (DBT),
typically combined with two-dimensional (2D) full-
field digital mammography (DM) is now widely used
in the screening and diagnostic mammography setting.
The image stack, comprised of thin slices of breast
tissue, decreases tissue overlap, producing a “quasi
three-dimensional” mammogram. This allows for both
improved sensitivity and specificity. Multiple stud-
ies show that screening DBT plus DM increases the
incremental cancer detection rate, reduces the recall
rate, and can improve cancer detection rates (Table 3)
(9–14).
Although DBT may increase the cancer detection
rate, some studies show most DBT-detected cancers
tend to be less aggressive (15,16), raising concerns re-
garding overdiagnosis (17). Currently available data do
not show a significant reduction in interval cancers in
women screened with DBT compared with DM (18).
However, a recent large single-institution study demon-
strated that more invasive cancers with poor prognoses
were detected with DBT at both the first and subse-
quent screening rounds compared with conventional
DM (19). Despite the abundance of published clinical
data and widespread clinical use, it is thus still uncer-
tain whether DBT also improves short- and long-term
outcomes for patients with breast cancer compared with
DM. The multicenter randomized controlled Tomo-
synthesis Mammography Imaging Screening Trial and
several similar trials are ongoing and designed to answer
these questions (20).
Novel Approaches to Screening for Breast Cancer
Abbreviations
AI = artificial intelligence, BI-RADS = Breast Imaging Reporting and
Data System, DBT = digital breast tomosynthesis, DM = digital mam-
mography, MBI = molecular breast imaging, 2D = two-dimensional
Summary
This review explores state-of-the-art techniques in mammography,
US, MRI, and automation for breast cancer screening.
Essentials
n Many potential alternative screening modalities for breast cancer
are in various states of clinical development, either as stand-alone
techniques or supplemental to mammography, each with potential
advantages and disadvantages.
n Machine learning algorithms will soon play a major role in breast
cancer screening, both in improving the quality of the screening
programs and assisting with increasing workload due to expanding
screening indications.
n Adopting new screening tools requires careful investigation to
determine true examination-specific benefits and improvements in
breast cancer morbidity and mortality.
n In the next decade, breast cancer screening will move beyond tra-
ditional tools such as mammography, US, and MRI.
The synthetic 2D mammogram, derived from the DBT data
set, permits a standard DBT screening examination to have a
radiation dose comparable to that with DM with similar diag-
nostic performance (21,22). The synthetic view has a different
“look” compared with DM as the algorithms enhance bright
spots such as calcifications and linear structures (22).
Ongoing technologic advances in DBT algorithms, such as
deep learning–based reconstruction, will provide high-spatial-
resolution (synthetic) images with less image noise and fewer
artifacts. These advances, combined with new postprocess-
ing enhancements such as the generation of thick slices and/
or slabs, should allow the radiologist to manipulate the im-
ages at the clinical workstation and improve DBT accuracy
(Fig 1). Thicker slices with improved resolution could also
potentially decrease the interpretation time of 2D plus DBT
mammography.
Contrast Material–enhanced Spectral Mammography
Contrast-enhanced spectral mammography, or contrast mam-
mography, adds functional information to the anatomic and
morphologic information provided with conventional (stan-
dard) mammography and DBT. Like breast MRI, contrast-
enhanced spectral mammography depicts (neo)vasculature
associated with breast lesions and is largely independent of
breast density.
Contrast-enhanced spectral mammography requires a dual-
energy mammography system (added to several current mam-
mography units) and intravenous injection of iodinated contrast
material (dose, 1.5 mL/kg), followed by standard craniocaudal
and mediolateral mammographic views. Each image consists of
a “low-energy” acquisition, resembling a normal mammogram,
and a “high-energy” image, obtained by using a kiloelectron
volt above the k-edge of iodine to enhance the contrast material
signal. The low-energy image is equivalent to a standard mam-
mogram for the detection of masses and calcifications, replacing
2 radiology.rsna.org n Radiology: Volume 00: Number 0— 2020
the conventional mammogram (23–25). Postprocessing the
low- and high-energy image removes background signal, and the
recombined iodine-only image helps identify enhancing lesions.
Contrast-enhanced spectral mammography is safe, and serious
adverse contrast material reactions are rare (26). The radiation
dose for contrast-enhanced spectral mammography is higher
than that for conventional mammography (27,28) but below
the U.S. Food and Drug Administration mammography safety
limits (29). The lack of a contrast-enhanced spectral mammog-
raphy biopsy device for lesions seen only at contrast-enhanced
spectral mammography is a disadvantage, and prototypes are
under evaluation.
Studies show that contrast-enhanced spectral mammogra-
phy outperforms combined mammography and US for lesion
detection (Table E1 [online]) as well as for assessment of size
and disease extent (30–33). In comparison with MRI, most
contrast-enhanced spectral mammography studies show only a
small reduction of sensitivity while providing a higher specificity
(34,35).
Although contrast-enhanced spectral mammography com-
bines the disadvantages of mammography (x-ray dose and com-
pression) and breast MRI (the need for intravenous contrast
material), studies report its potential as a screening tool. Sorin
et al (36) reported an additional cancer detection rate of 13.1
per 1000 screens over conventional mammography in a series
of 611 women with intermediate breast cancer risk and dense
breasts. More recently, Sung et al (37) reported an additional
six cancers detected in 904 patients at contrast-enhanced spectral
mammography compared with low-energy images, for a supple-
mental detection rate of 6.6 per 1000. The lower additional detec-
tion rate is likely explained by 75% of patients having previously
undergone contrast-enhanced breast MRI (37). In a previously
reported subset of this cohort (n = 307), contrast-enhanced spec-
tral mammography compared with MRI for screening showed
two of three MRI-detected cancers (in three women) at compa-
rable specificity (94.7% vs 94.1%) and positive predictive value
for biopsy (15% vs 14%) (38).
Contrast-enhanced spectral mammography may provide
an advantage over breast MRI—particularly for women at
moderately increased risk—due to its potential easier clinical
implementation and greater accessibility for screening large pop-
ulations. A multicenter trial supported by the American College
of Radiology, the Contrast-enhanced Mammography Imaging
Screening Trial, will compare the performance of contrast-
enhanced spectral mammography with that of DBT by screen-
ing U.S. women with average-to-intermediate risk for breast
cancer (39).
US Examination
US is commonly regarded as supplemental screening technique,
particularly for women with dense breasts in whom mammogra-
phy and DBT have a lower sensitivity. A major advantage of US
is that it does not use ionizing radiation. Supplemental cancer
detection rates of around four per 1000 screens have consistently
been reported, and it was shown that US may decrease the in-
terval cancer rate (40). However, US is criticized for its relatively
low specificity, leading to many recalls and biopsies for benign
 Mann et al

Table 1: Novel Imaging-based Screening Techniques in Mammography and US

Technique Current Status Role in Diagnostics Role in Screening Advantages Disadvantages

Mammography
DBT Can be clinically Reduces masking Improves sensitiv- Widely available; further Small increase in radiation
used of fibroglandular ity by 40%, increases in resolution and dose; no evidence on re-
tissue improves specific- viewing enhancements duction in interval cancers
ity in screen­ing may improve specificity
programs with
high recall rates
Contrast- Can be clinically Shows enhancing Currently mainly Strong improvement of Need for intravenous canula
   enhanced spectral used lesions on experimental, sensitivity compared with and intravenous contrast
mammography recombined published series mammography (100%– material administration,
images are small; avail- 200%), only slightly below small increase in radiation
able for DBT sensitivity of breast MRI; dose
can be added to existing
mammography units
US
Microvascular Can be clinically Improves the May reduce the Available on most modern Cannot be used as a stand-
   imaging and/or used specificity of biopsy rate for US units alone technique (only
elastography B-mode US by benign lesions concurrently with B-mode
showing the US); learning curve and
stiffness of relatively high interreader
lesions variability
Automated Can be clinically Is an alternative to Detects cancer in Allows standardized imaging Artifacts may make image
  breast US used handheld whole 2–7 per 1000 of the whole breast; can be interpretation difficult, es-
breast US supplemental performed by technician pecially behind the nipple;
screens after and read in batches; theo- relatively long reading
negative mam- retically may be combined times; high false-positive
mography with US contrast agents rate
US transmission Experimental May be used for None; clinical data Potentially allows whole Requires imaging of the
  tomography only density estima- are too limited breast 3D imaging breast in a water bath for
tion and risk pre- without ionizing radia- coupling
diction; potential tion, contrast material, or
for noninvasive compression
lesion character-
ization
Targeted OA Can be clinically Improves the May reduce the Noninvasive assessment of Cannot be used as a stand-
  imaging used specificity of biopsy rate for vascularity and oxygen- alone technique (only
B-mode US by benign lesions ation of breast lesions concurrently with B-mode
showing the US), and SNR is limited;
microvasculature uses laser, for which pre-
of breast lesions, cautions are mandatory
including (goggles, signaling); gener-
oxygenation ates a lot of heat, cooling
status of the imaging room is
essential
Whole-breast Experimental Potential for None; clinical data Potentially allows whole Low SNR and long acquisi-
  OA imaging only noninvasive are too limited breast 3D imaging with- tion times
assessment out ionizing radiation or
of lesions in the contrast material; may be
breast combined with US (reflec-
tion and/or transmission)
Fusion imaging Experimental Potentially allows None; clinical data US scan and mammogram Lower resolution US image
only for spatially are too limited obtained in same compres- quality; US may miss
matched sion, and patient examina- posterior lesions
mammography tion time is decreased;
and US accurate lesion coregistra-
acquisitions tion
Note.—DBT = digital breast tomosynthesis, OA = optoacoustic, SNR = signal-to-noise ratio, 3D = three-dimensional.

Radiology: Volume 00: Number 0— 2020 n radiology.rsna.org 3

Novel Approaches to Screening for Breast Cancer

Table 2: Novel Imaging-based Screening Techniques in MRI and Nuclear Medicine

Technique Current Status Role in Diagnostics Role in Screening Advantages Disadvantages

MRI
Abbreviated Can be clinically Shortens the duration May reduce the costs Retains high sensitivity of Intravenous contrast
  breast MRI used of breast MRI of breast MRI and breast MRI material administra-
acquisition and increase availability tion; may slightly
decreases reading reduce the specific-
time ity of breast MRI
Ultrafast Can be clinically Provides dynamic May enable preserva- Provides dynamic parameters Requires very short
  breast MRI used information on breast tion of sensitivity and with high discriminative acquisition times,
lesions without specificity of abbrevi- power between benign and which reduces the
increasing acquisition ated MRI malignant findings spatial resolution
time and may introduce
artifacts
DWI Can be clinically Shows hindered Currently as supple- Does not require intravenous Has lower sensitiv-
used diffusion of water mental technique to contrast material; improves ity than contrast-
molecules in tissue, improve specificity; as specificity of contrast- enhanced MRI;
which is indicative of stand-alone screening enhanced MRI; may have has limited value in
malignancy modality experimental higher sensitivity than small and diffuse
only mammography and/or lesions
DBT
Nuclear medicine
MBI Can be clinically Shows lesions with Improves the sensitivity Rapid interpretation and Long acquisition
used uptake of a radio- of mammography by detection of subcentimeter times; radiotracer
active technetium 100%–200% breast cancers tracer intravenous
tracer contrast material;
radiation dose 2–5
times higher than
that of mammog-
raphy
PET and/or Can be clinically Shows lesions with None; investigational High sensitivity, potential to Long acquisition
  PEM used uptake of fluorine only, limited clinical integrate screening with times; radiotracer
18 fluorodeoxyglucose data targeted drug therapy (ther- intravenous contrast
anostics) material; radia-
tion dose 10 times
higher than that of
mammography
Note.—DBT = digital breast tomosynthesis, DWI = diffusion-weighted imaging, MBI = molecular breast imaging, PEM = positron emis-
sion mammography.

lesions. Although studies on US have shown decreasing recall
and increasing positive predictive values of US screening (41),
many developments are still primarily aimed at increasing the
specificity of US to improve its value as a screening modality.
Microvascular Imaging
The use of color Doppler is one of the oldest techniques to in-
crease the specificity of US. Doppler color codes motion of re-
flectors by analyzing the frequency shift of the returning ultra-
sound signal. Consequently, Doppler US may be used to show
flow in lesions. However, the spatial resolution and flow sensi-
tivity of standard Doppler US only allows for the visualization
of large vessels, which are not typically present in breast lesions.
With use of very low flow velocity scales and vendor-specific
algorithms to separate flow signals from artifacts caused by mo-
tion (eg, superb microvascular imaging [SMI, Canon Medical
Systems, Ota, Japan], microflow imaging [Philips, Eindhoven,
the Netherlands], AngioPLUS [SuperSonic Imaging, Aix-en-
Provence, France], and microvascular flow imaging [MV-Flow;
Samsung, Seoul, Korea]), it is now possible to better document
the microvascular distribution of vessels within lesions. Early
investigations show that this leads to better depiction of pen-
etrating vessels and a clearer view of the internal microvascular
distribution (42,43). This, in turn, can be used to improve le-
sion classification and thus improve the specificity of US (44–
46). For example, Zhu et al (46) reported an increase in area
under the curve from 0.70 to 0.85 when superb microvascular
flow imaging was added to gray-scale US in the classification
of Breast Imaging Reporting and Data System (BI-RADS) cat-
egory 4 breast lesions.
Elastography
Elastography measures the stiffness of lesions and has been
clinically available for more than 15 years. Stiffness of malig-

4 radiology.rsna.org n Radiology: Volume 00: Number 0— 2020

 Mann et al

Table 3: Recent Large-Scale Tomosynthesis Screening Studies

Recall Rate CDR per PPV1 (%): Sensitivity Specificity

Study and No. of (%): DM vs 1000: DM vs DM vs 2D (%): DM vs (%): DM vs
Year Type of Study Women 2D + DBT 2D + DBT + DBT 2D + DBT 2D + DBT Other Findings
Marinovich Meta-analysis of 1 009 790 3.5–11.3 vs 4.5–6.4 vs NA NA NA Results varied by screen-
et al, 2018 17 studies and 4.1–8.0 5.7–8.8 ing setting; greater
(9) 413 citations improvement in DBT
(United States and CDR seen in European
Europe), includes studies (biennial screen-
paired and un- ing); greater reduction
paired studies* of absolute DBT recall
rates seen in U.S. stud-
ies (high baseline recall)
Pattacini Prospective unpaired 19 560 3.5 vs 3.5 4.5 vs 8.6 13 vs 24† NA NA DBT increased CDR of
et al, 2018 randomized trial DCIS and grade 1–2
(10) (Italy) invasive cancers smaller
than 20 mm
Zackrisson Prospective paired 14 848 2.5 vs 3.6† 6.5 vs 8.7† 25.9 vs 24.1 60.4 vs 81.1 98.1 vs 97.2 One-view DBT with re-
et al, 2018 study (Sweden); duced compression may
(11) only one-view reduce radiation dose
DBT (MLO) and screening burden;
additional cancers de-
tected with DBT only
were predominantly
invasive, but otherwise
similar to mammogra-
phy-detected cancers
Skaane Prospective paired 24 301 NA 6.3 vs 8.1 NA 54.1 vs 70.5† 94.2 vs 95.0† Additional analysis of
et al, 2019 study (Norway) synthetic 2D mam-
(12) mography plus DBT
showed no substantial
difference in sensitivity
or specificity compared
with DM plus DBT;
cancers seen only with
DBT were mostly
small, low grade, and
node negative
Hofvind Prospective unpaired 28 749 4.0 vs 3.1† 6.1 vs 6.6 15.2 vs NA NA Distribution of tumor
et al, 2019 randomized trial 21.4† characteristics did not
(13) (Norway), DBT differ significantly be-
performed only tween DM and 2D syn-
with 2D synthetic thetic mammography
mammography plus DBT for invasive
cancer or DCIS
Conant Retrospective analysis 96 269 11.2 vs 8.7† 4.4 vs 5.8† 3.9 vs 6.3† 91.5 vs 90.6 88.9 vs 91.3† Study includes age and
et al, 2019 of prospective density subgroup
(14) cohort data; multi- analysis; DBT helped
institutional study detect more smaller
(United States) node-negative invasive
cancer, especially
among women aged
40–49 years
Note.—CDR = cancer detection rate, DBT = digital breast tomosynthesis, DCIS = ductal carcinoma in situ, DM = digital mammography,
MLO = mediolateral oblique, PPV1 = positive predictive value of recall, 2D = two-dimensional.
* Unpaired study indicates that patients underwent either DBT plus DM or DM only. Paired studies indicate that patients underwent only
DBT plus DM (DM only results recorded separately).
†
P  .05.

Radiology: Volume 00: Number 0— 2020 n radiology.rsna.org 5

Novel Approaches to Screening for Breast Cancer
Figure 1: Mediolateral oblique digital breast tomosynthesis (DBT) images from a screening
examination in a 53-year-old woman. (a) A spiculated mass is seen in the right posterior breast
(arrow) on a routine 1-mm-thick DBT slice. (b) A high-resolution 6-mm-thick slice shows better
detail and sharpness of the mass (arrow) and surrounding fibroglandular tissue. Biopsy showed a
grade 1 infiltrating ductal carcinoma. The 6-mm-thick slice is enhanced by using machine learning
algorithms targeting calcifications, spiculations, and masses. Thicker slices also allow fewer images
to review and may reduce radiologist reading time. (Images courtesy of Washington Radiology
Associates, Fairfax, Va.)
nant breast lesions in vitro is greater than that in benign le-
sions, with little overlap (47). Elastography supplements rou-
tine US screening in women with dense breasts to characterize
lesions as benign or malignant, improving specificity (Fig 2).
It also improves sensitivity by depicting isoechoic lesions (48).
Strain elastography compares the relative stiffness of a lesion
with other tissues in the field of view (48), so a specific numeric
value of lesion stiffness is not measured. The technique for opti-
mal images varies by vendor (48). Two-dimensional shear-wave
elastography provides a quantitative estimate of the lesion stiff-
ness based on the speed of shear waves generated by applying
an acoustic radiation force impulse push pulse (49). A unique
feature of breast elastography for both strain elastography and
shear-wave elastography is that malignant breast lesions appear
larger on elastographic images than on B-mode US images,
whereas benign breast lesions appear smaller (48).
Numerous studies have shown that both strain elastogra-
phy and 2D shear-wave elastography can help evaluate breast
lesions and improve lesion characterization to various degrees
(49–51). A meta-analysis of strain elastography reported
that use of the elastography-to–B-mode ratio has a negative
predictive value of 0.03, downgrading a lesion with pretest
probability of 50% malignancy to 2% (52). The addition
of elastography and Doppler to B-mode US improved the
positive predictive value of screening US while reducing the
number of false-positive findings without missing cancers (53).
Recent studies suggest that the combination of strain elastogra-
phy and shear-wave elastography can further increase sensitiv-
ity and specificity (54,55).
Despite being available, elastography has not been widely
implemented due to a high learning curve for performing and
interpreting examinations. The recent improvements in both
strain and shear-wave technology with the addition of quality
maps are aimed at overcoming these problems and enabling the
incorporation of elastography in “best-practice” algorithms (56).
6 radiology.rsna.org n Radiology: Volume 00: Number 0— 2020
Automated Breast US
In automated breast US, a wide transducer scans
the entire breast, which is imaged in two to five
overlapping views (anteroposterior, lateral, and
medial). Continuous scanning allows reconstruc-
tion of acquisition views into coronal and sagittal
planes displayed alongside the original acquisi-
tion planes (Fig 2) (57). The technique captures
images of the entire breast, eliminating the need
for technologists to assess specific findings in real
time, enabling remote (batch) reading by radiolo-
gists, and facilitating comparison of current and
previously obtained images, which is important
for screening.
The diagnostic quality of automated breast US
is comparable to that of handheld US. Several
studies show supplemental cancer detection rates
after digital mammography ranging from 1.9 to
7.7 per 1000 screens (58,59). However, reported
high false-positive rates (up to 13%) and long
reading times have tempered the enthusiasm for
automated breast US as a supplemental screening
modality (60). Nonetheless, automated breast US is a viable
alternative for screening handheld US in women with dense
breasts at mammography or for high-risk women who cannot
tolerate MRI. Future developments, including incorporation
of whole-breast Doppler US or elastography, may reduce the
false-positive rate and improve the value of the technique for
screening (61).
US Transmission Tomography
US transmission tomography is a currently experimental,
prone scanning technique that uses water as the coupling
agent combined with low-frequency ultrasound waves (1–7
MHz) emitted by a ring-like transducer surrounding the
breast. Ultrasound waves travel through water at a speed of
approximately 1.5 km/sec. The time required to traverse the
breast is dependent on the tissue type encountered by ultra-
sound waves, so the generated speed of sound map provides
classifying information of underlying tissue (62,63). The
speed of sound is somewhat lower in fibroglandular tissue,
whereas it is higher in solid masses. Speed of sound is also
higher in malignant compared with benign lesions and may
help differentiate lesions (63,64). Ultrasound waves also lose
power while traversing the breast, so attenuation can help
classify breast parenchymal patterns.
Although in early development, US transmission tomogra-
phy holds promise for efficacy in screening. Studies on lesion
detection and classification are currently limited. An early study
of 71 BI-RADS category 4 lesions showed that a composite score
based on speed of sound and attenuation could help differenti-
ate benign from malignant lesions (Fig 3) (65). US transmission
tomography may also use standard reflection images showing
underlying anatomy. This combination yields a technique that
provides a three-dimensional breast image resembling a breast
MRI scan (Fig 4) (64). Several studies demonstrate the possibil-
ity of estimating breast density with these acquisitions (66–68),
 Mann et al

Figure 2: Images in a 61-year-old woman with a density C breast. (a) Screening mammogram shows a Breast Imaging Reporting and Data
System category 2 lesion. Patient has a history of previous remote benign biopsy of the left breast with clip placement. (b, c) Axial (b) and coronal
(c) supplemental screening US scans obtained with an automated breast scanner show a 2-cm hypoechoic mass in the left breast at 4 o’clock. (d)
Image obtained with hand-held US shows an irregular hypoechoic mass. (e) Image obtained at strain elastography shows that the mass has an
elastography–B-mode distance ratio of 1.5, which is suggestive of a malignant lesion. (f) Image obtained with two-dimensional shear-wave elastog-
raphy shows that the lesion has a maximum stiffness of more than 9.0 m/sec, which is also consistent with a malignant lesion. At biopsy, the lesion was
an invasive moderately differentiated ductal carcinoma that was estrogen receptor positive, progesterone receptor negative, and human epidermal
growth factor receptor 2 negative.

which may assist in breast cancer risk estimation. Larger studies transmission tomography with other nonionizing techniques,
are mandatory, with a particular focus on investigating specific- such as optoacoustic imaging or microwave imaging, to further
ity. Future developments include a possible combination of US increase performance.

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Novel Approaches to Screening for Breast Cancer
Optoacoustic US
Optoacoustic imaging has advanced over the past 2 decades and
is now poised for clinical use. Optoacoustic US, also known as
optoacoustic tomography and photoacoustic imaging, can help
visualize blood vessels and detect tumor-driven angiogenesis by
using laser light pulses, while monitoring returning acoustic
stress waves, to generate the photoacoustic signal (69). Cancers
are active compared with benign lesions, extracting more oxy-
gen and resulting in more deoxygenated hemoglobin. The use
of different wavelengths for the laser pulses allows optoacoustic
US to enable the differentiation of deoxygenated hemoglobin
from oxygenated hemoglobin, which may then be color-coded.
The angiogenesis visible on optoacoustic US images can be cor-
related with pathologic and molecular subtypes (70).
State-of-the-art optoacoustic US systems combine tradi-
tional gray-scale US with functional optoacoustic US data
during real-time display (Fig 5) (71). Current clinical opto-
acoustic US systems use a handheld probe similar to that used
with conventional US units. The main goal of optoacoustic
US systems is to increase the specificity of US screening. Prone
systems in early development can image the entire breast and
have promise as a stand-alone screening tool (Fig 6) (72,73).
8 radiology.rsna.org n Radiology: Volume 00: Number 0— 2020
Figure 3: (a–c) US transmission images in a
69-year-old woman with an 8-mm invasive breast
cancer at 11 o’clock in the left breast (arrow).
Speed of sound image (a) and attenuation image
(b) are combined in a composite image (c), where
values higher than 1 are indicative of malignancy
(red). (d) Three-dimensional rendering of the entire
breast shows all red voxels against a background
of voxels with a very low composite index. (Im-
ages courtesy of Vasilis Marmarelis, PhD, University
of Southern California, Dr Allen and Charlotte
Ginsburg Institute for Biomedical Therapeutics, Los
Angeles, Calif, and Transonic Imaging, Los Angeles,
Calif.)
Recent multi-institutional studies showed that optoacoustic
US improves specificity for BI-RADS category 3, 4, and 5
masses compared with gray-scale US alone, whereas the sensi-
tivity of optoacoustic US was noninferior to that of gray-scale
US (71,74). Future technical advances coupled with clinical
trials are required to determine clinical implementation and
the role of optoacoustic US in the screening setting.
Fusion Imaging
Breast imaging often involves cross-correlation between
multiple modalities. Fusion imaging facilitates this by ac-
quiring multimodality information with a single device. In
the screening setting, the cross-correlation between screen-
ing US and mammographic findings may be challenging.
There is, consequently, ongoing interest in the fusion of
mammography and US imaging. Early prototypes demon-
strate the possibility of a dual-modality system that com-
bines full-field DM or DBT with automated breast US
(75,76). With this technology, the US probe is built into
the compression paddle or located on the detector side
(75,76). The probe scans the compressed breast, acquiring
US images simultaneously with mammography, simplifying
 Mann et al

Figure 4: US transmission and reflection images in a 67-year-old woman who presented with a 2.1-cm grade 3 estrogen receptor–negative, progester-
one receptor–negative, and human epidermal growth factor receptor 2–positive cancer in the lower medial quadrant of the left breast (arrows). The speed
of sound image (top right) and the reflection image (bottom left) were directly obtained from the scan. These are combined to produce a so-called wafer
image (top left), or waveform-enhanced reflection. The speed of sound image is combined with the attenuation map (not shown) to create a relative tissue
stiffness map that is projected on top of the reflection image in the stiffness fusion image (bottom right). (Images courtesy of Corinne Duluk, Delphinus Medical
Technologies, Novi, Mich.)

co-registration. Although some units fail to adequately im-
age the posterior breast, early small studies show potential
in this developing technology (75,77).
MRI Examination
Breast MRI offers the highest sensitivity for the detection of
occult cancer, regardless of breast density (8). A review on
state-of-art breast MRI was recently published in Radiology
(8). Breast MRI offers superior tissue contrast due to uptake
of gadolinium secondary to neoangiogenesis and increased
permeability of malignancies (78). Studies show MRI is bet-
ter than mammography and US in the detection of high-
grade invasive cancers (79). A recent multicenter randomized
clinical trial from the Netherlands, where screening MRI was
performed in women with extremely dense breasts, found sig-
nificantly fewer interval cancers in women who underwent
supplemental MRI compared with mammography alone (0.8
per 1000 screenings vs 5.1 per 1000 screenings, respectively;
P , .001) (80). But high costs as well as the limited toler-
ability and availability of MRI scanners preclude population-
wide screening with breast MRI.
Abbreviated Breast MRI
Abbreviated MRI has shorter image acquisition and interpreta-
tion times, which may increase the availability of breast MRI
and reduce the costs.
The American College of Radiology accreditation require-
ments for breast MRI include a T2-weighted sequence and
precontrast, early postcontrast, and delayed postcontrast T1-
weighted images (81). In contradistinction, the abbreviated
protocol includes a precontrast examination and one postcon-
trast T1-weighted examination, along with subtraction images
and maximum intensity projection images (Fig 7). In a seminal
study, Kuhl et al (82) found equivalent diagnostic accuracy for
the abbreviated and full protocols among 443 women and 606
MRI studies. Both protocols enabled identification of all 11
breast cancers. In addition, the authors found similar diagnostic
accuracies: Specificity was 94.5% for the abbreviated protocol
and 93.9% for the full diagnostic protocol, and positive predic-
tive value was 24.4% for the abbreviated protocol and 23.4% for
the full diagnostic protocol. Furthermore, there was a vast reduc-
tion in time for image acquisition (17 minutes vs 3 minutes) and
radiologist interpretation (28 seconds for the first postcontrast
images and 2.8 seconds for the maximum intensity projection
image alone) (82).
The basic abbreviated protocol described earlier has many
variations. A recent review of 21 studies on various abbreviated
breast MRI protocols performed in eight different countries
and in more than 4500 women confirmed that the diagnostic
accuracy was similar to that of the full breast MRI protocol
(83). These protocols exploit the high sensitivity of MRI while
reducing acquisition and interpretation times (Table E2 [on-
line]). Recently, a multicenter randomized trial that compared
the screening performance of abbreviated breast MRI and
DBT in women with dense breasts found the invasive cancer
detection rate was 11.8 per 1000 women for abbreviated breast

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Novel Approaches to Screening for Breast Cancer

Figure 5: Optoacoustic images in two patients. (a) Conventional B-mode image in a 44-year-old woman shows an oval mass with indistinct margins
and parallel orientation (arrow) consistent with a Breast Imaging Reporting and Data System (BI-RADS) category 4a lesion. This mass could be misinterpreted
as a BI-RADS category 3 lesion. (b) Simultaneously obtained optoacoustic map demonstrates absence of internal vascularity or deoxygenation. Vessels are
parallel to capsule, not perpendicular, and are gently curved and gradually tapered. These findings are consistent with benign findings. Core needle biopsy
showed a fibroadenoma. (Images courtesy of Tchaiko Parris, MD, RadNet, Long Beach, Calif.) (c) Conventional B-mode US scan in a 56-year-old woman
shows an oval mass with partially circumscribed margins and a parallel orientation and mixed posterior acoustic enhancement (arrow). (d) Optoacoustic
map in same patient shows internal vascularity with mostly deoxygenated signal (red), consistent with a hypervascular BI-RADS category 4 mass. Core
needle biopsy showed a human epidermal growth factor receptor 2–enriched infiltrating ductal carcinoma. (Images courtesy of Minh Nguyen, MD, Solis
Women's Health, Plano, Tex.)

issues must be addressed supporting implementa-

tion of this examination into clinical workflow. In
the United States, there is no Current Procedural
Terminology code for an abbreviated MRI exami-
nation. In addition, Borthakur et al (85) analyzed
the activity times from 70 abbreviated breast MRI
studies and 736 full MRI screening studies, con-
cluding that the realized gains in patient flow rate
were lower than expected for an abbreviated MRI
examination. These results are not entirely unex-
pected because of workflow considerations includ-
ing setup, patient positioning, and room turnover.
Figure 6: Images in a 44-year-old woman who presented with a 19-mm invasive ductal car-
cinoma grade 3 in the right breast (arrow). (a) Maximum intensity projection image of the contrast Ultrafast Breast MRI
material–enhanced MRI scan with a color overlay of average enhancement intensity. (b) Large field- An ultrafast sequence can help document fast ar-
of-view (approximately 35 cm2) optoacoustic image obtained with a photoacoustic mammoscope by terial enhancement and fast venous drainage of
using a 1064-nm yttrium-aluminum-garnet laser of the area within the dashed box in a. Tumor is well
visible and of similar size and shape as in the MRI scan. (Images courtesy of Srirang Manohar, PhD,
breast cancers. The temporal resolution of an ul-
University of Twente, Enschede, the Netherlands; adapted with permission from reference 73.) trafast protocol is typically less than 10 seconds
per frame and may be incorporated into abbrevi-
ated or full breast MRI protocols. These sequences
MRI versus 4.8 per 1000 women for DBT, a difference of seven often use various k-space view sharing and compressed sensing
per 1000 women (P = .002) (84). Abbreviated breast MRI will techniques where the central region of k-space is sampled con-
likely be increasingly used as a screening tool, but operational tinuously. However, the outer region is only partially sampled,

10 radiology.rsna.org n Radiology: Volume 00: Number 0— 2020


Figure 7: Images in a 44-year-old woman with BRCA1 gene mutation
and history of left breast cancer. The patient had undergone lumpectomy
and radiation therapy in 2008 and presented for high-risk surveillance.
(a) Precontrast axial MRI scan demonstrates no abnormalities. (b) First
contrast-enhanced axial MRI scan and (c) first subtraction postcontrast
MRI scan demonstrate an irregular heterogeneously enhancing mass (ar-
row) in right breast. Biopsy yielded a moderately differentiated estrogen
receptor–positive, progesterone receptor–positive, human epidermal
growth factor receptor 2–negative invasive carcinoma that is well seen
with an abbreviated breast MRI protocol.
allowing for simultaneous high temporal resolution with a
minimal decrease in spatial resolution (Fig 8) (86–88). Mann
et al (87) found that the maximum slope of malignancy in early
Radiology: Volume 00: Number 0— 2020 n radiology.rsna.org
Mann et al
enhancement outperformed the BI-RADS wash-out evaluation
(area under the curve, 0.829 vs 0.692). Abe et al (88) found the
initial enhancement rate and signal enhancement ratio af-
ter aortic enhancement was higher for malignant than benign
lesions. Additional studies using various ultrafast techniques
showed high reproducibility of early wash-in temporal kinetic
parameters. Hence, ultrafast breast MRI allows for increasing
the specificity of (abbreviated) breast MRI, without increasing
the scanning time. The most modern sequences even obtain a
diagnostic spatial resolution with the potential as a stand-alone
screening technique. van Zelst et al (89) showed similar sensi-
tivity and increased specificity by reading only ultrafast images
compared with a full diagnostic MRI protocol.
Diffusion-weighted Imaging
Diffusion-weighted imaging can help visualize and quantify
random movement of water molecules in tissue, influenced by
tissue microstructure and cell density. It does not require the
use of an intravenous contrast agent. Breast cancers show de-
creased water diffusion due to increased cell density, leading to
higher signal intensity on diffusion-weighted images. Multiple
studies show that diffusion-weighted imaging can improve the
differentiation between benign and malignant lesions (90,91).
Given the concerns of gadolinium deposition in the brain and
the general burden of the need for intravenous access (92),
there is growing interest to develop a screening noncontrast
MRI examination. The use of high b values with background
suppression seems to be a viable screening technique (93).
Preliminary studies suggest unenhanced MRI with diffusion-
weighted MRI may provide higher sensitivity than screening
mammography for the detection of breast malignancies (94).
However, current diffusion-weighted imaging techniques are
not sensitive enough to replace contrast-enhanced breast MRI
(95,96), particularly because the sensitivity for subcentimeter
and nonmass lesions is limited.
Nuclear Medicine Techniques
Advances in nuclear medicine, using dedicated gamma or PET
breast scanners, provide functional breast imaging techniques
that, in turn, may allow the use of specific cellular information
to assist in the diagnosis, staging, and treatment of breast can-
cer. Although current American College of Radiology practice
guidelines do not recommend use of molecular breast imaging
(MBI) or PET for routine screening (97), further technologic
advances may enhance these techniques to allow a role in breast
cancer screening.
MBI Examination
MBI, which includes gamma-specific breast imaging, uses dedi-
cated breast-specific high-spatial-resolution gamma camera sys-
tems combined with intravenous technetium 99m (99mTc) sesta-
mibi to image subcentimeter cancers in projections comparable
to mammography (98,99). Dual-panel MBI systems that use
cadmium zinc telluride detectors demonstrate improved sensi-
tivity, energy resolution, spatial resolution, and lesion detection
compared with the single-panel breast-specific gamma imaging
systems with sodium or cesium iodide crystals (99,100).
11
Novel Approaches to Screening for Breast Cancer
Figure 8: Images in a 41-year-old woman who is a carrier for the
ataxia-telangiesctasia mutated gene, ATM, and who presented for high-
risk screening MRI. (a) Ultrafast time-resolved angiography with stochastic
trajectories, or TWIST, axial MRI scan with 4-second temporal resolution
after contrast material injection demonstrates early wash-in of contrast ma-
terial in a mass in the right breast (thin arrow) at first time frame (4 seconds
after aortic enhancement). Note the contrast material in the thoracic aorta
(thick arrow). (b) Second frame (8 seconds after aortic enhancement)
shows marked enhancement of the mass (arrow). (c) Routine postcontrast
axial MRI scan shows an irregular heterogeneous mass (arrow) within
marked background parenchymal enhancement.
A complete MBI study consists of standard craniocaudal and
mediolateral oblique views of the breast, with acquisition times
of 7–10 minutes for each projection (Fig 9) (99,101). 99mTc
sestamibi is sequestered by mitochondria (increased in cancer
cells) and influenced by blood flow and angiogenesis (102). Pa-
tients are imaged approximately 5–10 minutes after injection.
MBI has a long patient safety history and only rare mild adverse
12
reactions (metallic taste, rash, flushing), making it a good sup-
plemental screening examination for women with elevated risk
and those with dense breasts. The incremental cancer detection
rate across multiple studies in asymptomatic women is 8–16 per
1000 women screened, with most cancers being invasive and tu-
mor size ranging from 2 mm to 5 cm (99–101). The high cancer
detection rate of MBI is in range of those of other vascular imag-
ing techniques (Table 4).
Despite being available for at least 15 years, MBI has not
gained widespread adoption primarily due to concerns regard-
ing whole-body radiation dose. With technical improvements,
radiation dose has decreased over time. The effective dose of 8
mCi of 99MTc sestambi is approximately 2.4 mSv, compared
with 0.5–1.2 mSv for mammography and DBT (100). Al-
though MBI dose is thus still two- to fivefold that with mam-
mography, it has a much higher cancer yield (99,100). Current
dosage for breast-specific gamma imaging studies are higher
than MBI requirements (103). Novel image processing tech-
niques may allow further decrease in both radiation dose and
scanning time (104). MBI-directed biopsy is also available for
lesions occult with other modalities. Beyond the high supple-
mental cancer detection rate, MBI also has the advantage of
being cost-effective and well-tolerated by patients, as it requires
minimal breast compression.
Breast PET Imaging
Breast PET employs detectors positioned close to the breast
and measures fluorine 18 (18F) fluorodeoxyglucose uptake.
18
F fluorodeoxyglucose is a positron-emitting glucose analog
that accumulates in metabolically active cells, which is usually
the case for cancer cells. Patients must fast 4–6 hours as blood
glucose should be within normal limits before 18F fluorode-
oxyglucose injection. Patients must also wait 60–90 minutes
after the injection to allow for optimal tracer uptake before
imaging. Breast PET systems use detectors so that patients may
be imaged in the upright position with minimal compression
(similar to mammography and often referred to as positron
emission mammography or PEM) or the prone position with
no compression (100).
Breast PET systems are primarily used for the evaluation of
patients with newly diagnosed breast cancer and for treatment
planning. However, an early study published by Yamamoto
et al (105) in 2016 showed that positron emission mammog-
raphy may have a potential role in breast cancer screening. In
that study, which comprised 265 asymptomatic and symptom-
atic patients, the overall recall rate, positive predictive value, and
cancer detection rate were 8.3%, 27.3%, and 2.3%, respectively.
Although the spatial resolution was only 2.4 mm, the smallest
cancer reported in that study measured 7 mm.
Despite techniques used to lower 18F fluorodeoxyglucose
dose, the radiation exposure, costs, and patient time to prepare
for the examination currently limit the utility of breast PET im-
aging for widespread screening. Ongoing investigation of novel
PET tracers with improved dosimetry and pharmacologic safety
plus development of new imaging techniques may allow this
technology to be more widely used in clinical practice for diag-
nosis as well as treatment selection (106).
radiology.rsna.org n Radiology: Volume 00: Number 0— 2020
 Mann et al

Figure 9: Images in a 45-year-old woman with bilateral saline implants who presented for breast screening. Molecular breast imaging (MBI) was recommended
for supplemental screening on the basis of breast density and family history of breast cancer. (a, b) Left mediolateral oblique image (a) with implant displacement
view (b) from screening tomosynthesis examination were interpreted as negative (the biopsy clip is from a previously biopsied fibroadenoma). (c, d) Left mediolateral
oblique (c) and craniocaudal (d) views from screening MBI performed the same day as mammography demonstrate focal uptake in the upper posterior left breast (ar-
row). Pathologic examination confirmed invasive ductal carcinoma, grade 2, with an extensive 19-mm ductal carcinoma in situ component. (Images courtesy of Carrie
Hruska, PhD, May Clinic, Rochester, Minn.)

Table 4: Comparison of Vascular-based Screening Techniques

Parameter Abbreviated MRI Contrast-enhanced SM MBI PET and/or PEM Optoacoustic US

Indication Elevated risk, dense Elevated risk, dense Elevated risk, dense Potential for screening Potential to enhance
Breasts breasts breasts handheld or
automated US
Intravenous contrast Gadolinium-based Standard iodinated Technetium 99 Fluorine 18 None
material agent contrast material sestamibi fluorodeoxyglucose
FDA approved Yes Yes Yes Yes No
Clinical use Yes Yes, but investigational Yes, but investigational Yes, but investigational Investigational, not
for screening for screening for screening FDA approved
Supplemental CDR 19 per 1000 13 per 1000 screened 8–16 per 1000 23 per 1000 Unknown
screened, range: screened (single study)
9–36 prevalence
screening
Other considerations No CPT code (full Potential to be easily Dedicated equipment Dedicated equipment, Laser light
protocol only) accessible and radiation dose radiation dose, and technology
potential use of other
breast-specific tracers
Note.—CDR = cancer detection rate, CPT = current procedural terminology, FDA = U.S. Food and Drug Administration, MBI = molecu-
lar breast imaging, PEM = positron emission mammography, SM = spectral mammography.

Radiology: Volume 00: Number 0— 2020 n radiology.rsna.org 13

Novel Approaches to Screening for Breast Cancer

Table 5: Status of Current AI Algorithms

AI Use Current Performance Clinical Role Experimental Strategies

Mammography On par with human readers for In use as an aid for concurrent reading Preselection of normal mammograms;
lesion detection and of mammograms to improve human independent second reader of screening
classification performance mammograms; risk prediction for the
development of breast cancer
DBT On par with human readers for In use as an aid for concurrent reading Independent reading of DBT examina-
lesion detection and of mammograms to improve human tions; creation of “intelligent” synthetic
classification performance and decrease reading mammograms that highlight potential
time abnormalities
Handheld US On par with human readers for In use to aid in lesion classification Incorporation of multiparametric data,
lesion classification detected by human readers including Doppler and elastography;
extraction of quantitative data for lesion
classification
Automated breast Below human performance for In use to prevent overlook errors and Improvement of detection and classification
US lesion detection and decrease reading time algorithms; creation of intelligent sum-
classification mary images
MRI Below human performance for Experimental only Incorporation of multiparametric data, in-
lesion detection and cluding dynamics, T2-weighted imaging,
classification and DWI; improvement of detection and
classification algorithms; enhanced image
reconstruction; creation of intelligent
summary images
Note.—AI = artificial intelligence, DBT = digital breast tomosynthesis, DWI = diffusion-weighted imaging.

Artificial Intelligence and Machine Learning
The application of machine learning to medical images has
been performed for decades. Until recently, however, the per-
formance of these algorithms for lesion detection and classi-
fication (commonly referred to as computer-aided diagnosis)
has been below human standards. In recent years, increased
computer power, along with mathematical advances, has en-
abled the use of complex multilayered (deep) neural networks,
leading to a markedly improved performance of machine in-
terpretation of highly standardized imaging tasks (Table 5). It
is widely believed that these deep learning algorithms will soon
play a major role in screening, both to improve the quality of
the screening programs and to assist with the increasing work-
load that originates from ever-expanding screening indications.
Research using deep learning algorithms has focused on
screening mammography because there is a simple binary out-
come (cancer vs not cancer) and the large number of screening
mammograms permits leverage of big data sets as well as the
potential for important clinical impact (improved mortality)
(107). Several studies show that diagnostic accuracies of cur-
rent algorithms for mammography approach that of radiologists
(Fig 10) (108–110). DBT studies report similar performance
(Fig 11) (111). Furthermore, early studies suggest that when
artificial intelligence (AI) models predict a very low likelihood
of malignancy, the algorithms can triage and interpret these
mammograms (112,113) to save time and resources. Beyond
lesion detection and classification, other potential applications
for deep learning models include assessment of mammographic
breast density (114) and prediction of breast cancer risk by in-
corporating the normal mammographic parenchymal pattern
(density, texture, etc) (115,116). Risk assessment may be further
personalized when deep learning risk models include electronic
health records (117).
Although breast US is often used as a supplemental screening
technique, image acquisition is not standardized compared with
mammography and MRI. Typically, operators store static images
of lesions deemed relevant, and the assessment of the remaining
breast (when performed) is usually not captured. The result is
that the sensitivity of AI for US is much more operator depen-
dent than for mammography. Current algorithms mainly focus
on the classification of lesions pointed out by the operator, where
AI achieves human-like performance (118,119), and may aid in
radiologist decision support to improve reader performance and
decrease interreader variability (Fig 12) (120). The use of such
an algorithm (S-detect; Samsung, Seoul, Korea) in real time
may improve the performance of practicing breast radiologists,
leading to an improvement in specificity and reduction in false-
positive assessments (121).
Because the performance of automated breast US is stan-
dardized, it is possible to use AI not only for lesion classifi-
cation but also for lesion detection. One commercial applica-
tion developed for this purpose (QVCAD; Qview, Los Altos,
Calif ) generates a composite image of each automated breast
US view, with potential lesions displayed as dark areas. This
system allows for reduced reading time while also providing
potential for improved performance, particularly for less expe-
rienced readers (122,123). Underlying AI algorithms for breast
US require further improvements to increase their value and
accuracy in screening.
Like mammography, breast MRI is a standardized technique
well suited for automated analysis and often used for staging
in patients with newly diagnosed breast cancer. There is active

14 radiology.rsna.org n Radiology: Volume 00: Number 0— 2020

 Mann et al

Figure 10: Screening mammograms in a 72-year-old asymptomatic woman. (a) Mediolateral view of the right breast dem-
onstrates multiple masses (black arrows), with the largest mass (white arrow) located in the superior breast. (b) The deep learning
model identified the superior mass as suspicious (color overlay in red). There was no heat map overlying the other masses (c–e).
(d, e) Patch-wise attention scores are highly concentrated on the two region-of-interest patches (0.6 and 0.38) that contain the
superior mass. The deep learning model predicted this mass was highly suspicious for carcinoma. Pathologic examination yielded
poorly differentiated invasive ductal carcinoma.

interest in MRI radiomics, using quantified characteristics of the
gray-scale distribution in cancers and the surrounding tissue for
classification and to predict eventual response to therapy as well
as to provide a short- and long-term prognosis (124,125). To en-
hance specificity of automated lesion classification, deep learn-
ing algorithms can differentiate between benign and malignant
breast lesions with acceptable accuracy (126,127). Although per-
formance is still below human standards, concurrent use of such
algorithms may prevent false-positive recalls and may someday
improve the accuracy of MRI screening.
Preliminary studies also report on deep learning–based au-
tomated detection algorithms for breast cancer at screening
MRI (128–130). Although these systems improve upon pre-
viously reported machine learning approaches, an acceptable
sensitivity is only achieved at high false-positive rates (currently
more than one per MRI), which reduces their use in clinical
practice. However, current studies are conducted by using
relatively small data sets. Once much larger case sets become
available, AI algorithms should achieve human-like perfor-
mance for breast lesion detection and classification.
For further reference, interested readers are referred to more
extensive reviews on AI for breast imaging that have recently
been published (107,131).
Most studies on AI and breast imaging are retrospective. In-
creasing the generalizability of the results requires prospective
studies in different patient populations. Investigators should fol-
low guidelines to increase the reproducibility of their results (132).
Non-Imaging Novel Screening Techniques
A liquid biopsy helps detect circulating tumor components in
blood or plasma (133). Growing cancers actively or passively
shed debris into the bloodstream, including cell-free RNA,
tumor DNA, and dead and living cancer cells. Although con-
centrations are usually low, modern amplification techniques

Radiology: Volume 00: Number 0— 2020 n radiology.rsna.org 15

Novel Approaches to Screening for Breast Cancer

Figure 11: Images from digital breast tomosynthesis of the right breast. Images in top row are mediolateral oblique views, images in bottom row are craniocaudal
views. The tomosynthesis stack is summarized in synthetic mammograms in a, b, e, and f. Original tomosynthesis slices are shown in c, d, g, and h. There is a subtle irregular
mass (red circle), which was sampled for biopsy and proven to be a 13-mm invasive cancer not otherwise specified (estrogen receptor positive, progesterone receptor
positive, human epidermal growth factor receptor 2 negative) present in the upper outer quadrant. This was detected by an artificial intelligence system that marks the find-
ing on the synthetic images and on the tomosynthesis slices (b, c, f, and g). Clicking on the mark in the synthetic image will take the reader immediately to the most suspi-
cious slice in the tomosynthesis stack. (Images courtesy of Nico Karssemeijer, PhD, Radboud University Medical Center, Nijmegen, the Netherlands, Screenpoint Medical,
Nijmegen, the Netherlands.)

permit detection of RNA and DNA remnants, which may
contain carcinogenic mutations. Molecular profiling may al-
low assessment of tumor heterogeneity in patients with breast
cancer (134). Circulating tumor DNA can also help predict
therapy response and prognosis (135). A major advantage is
that liquid biopsy is repeatable and used for the evaluation of
changes over time.
Screening with liquid biopsy is more challenging. In one study
of patients with stage I and II breast cancer, somatic mutations
were detected in only 59% of patients (136). Another study tar-
geting multiple tumors showed a median sensitivity of 70% using
a combination of circulating tumor DNA and cancer-associated
proteins. Unfortunately, only 33% of asymptomatic breast cancers
were found (137), requiring more sensitive tests. More frequent
somatic mutations occur with advancing age, and these mutations
do not necessarily all cause cancer (138). Consequently, the risk of
false-positive results requires mitigation before the liquid biopsy
technique has real merit for screening. Further advancements and

16 radiology.rsna.org n Radiology: Volume 00: Number 0— 2020

 Mann et al

Figure 12: Images in a 59-year-old woman who presented with a mass detected at screening mammography. Pathologic examination
showed infiltrating ductal carcinoma, grade 2. A, Gray-scale US scan in the radial plane demonstrates an oval heterogeneous, but pre-
dominately hyperechoic, mass in the posterior right upper outer breast (arrow). B, Artificial intelligence decision support software graded this
lesion as suspicious (risk alignment: Breast Imaging Reporting and Data System [BI-RADS] category 4A–4B). C, Diagram shows results of an
independent reader evaluation. Three of 15 readers (20%) initially classified this lesion as BI-RADS category 2 or 3; all readers classified this
lesion as BI-RADS category 4 or higher after being shown the decision support (DS) result.

more clinical data are needed to provide more extensive tumor
analysis for liquid biopsy to become a reliable and cost-effective
means of screening and diagnosis (139).
Conclusion
Breast cancer screening in the next decade will move beyond
the traditional familiar tools including mammography, US,
and MRI. Ideally, the variety of new imaging options, com-
bined with artificial intelligence and/or neural networks, will
be enhanced by the integration of new screening protocols di-
rected toward more personalized and precision medicine. The
“one size fits all” approach of past decades may no longer be
relevant. Primary and supplemental screening tools will likely
progress beyond screening mammography plus US or MRI for
women with dense breasts and/or elevated breast cancer risk.
New screening benchmarks and development of efficient can-
cer registries are crucial to enhance our ability to track efficacy
and performance of new screening tools and treatments in a
timely and relevant manner.
Disclosures of Conflicts of Interest: R.M.M. Activities related to the present ar-
ticle: disclosed no relevant relationships. Activities not related to the present article:
is a paid consultant for Screenpoint Medical and Transonic Imaging; institution
has grants/grants pending with Siemens Healthineers, Bayer Healthcare, Medtronic,
BD, Seno Medical, Screenpoint Medical, Identification Solutions, and Elswood;
receives payment for lectures including service on speakers bureaus from Bayer
Healthcare. Other relationships: disclosed no relevant relationships. R.H. Activities
related to the present article: receives support for travel or speaking engagements
from Hologic. Activities not related to the present article: receives honorarium for
consulting from Hologic; receives honoraria and travel expenses for speaking en-
gagements from Holigic. Other relationships: disclosed no relevant relationships.
R.G.B. Activities related to the present article: disclosed no relevant relationships.
Activities not related to the present article: institution received equipment grants
from Philips Ultrasound, Siemens Healthineers, Mindray, and Samsung Ultra-
sound; receives payment for lectures including service on speakers bureaus from
Philips Ultrasound, Mindray, and Siemens Healthineers; receives royalties from
Thieme Publishers; receives travel/accommodations/meeting expenses unrelated to
activities listed from Philips Ultrasound and Mindray. Other relationships: disclosed
no relevant relationships. L.M. Activities related to the present article: disclosed no
relevant relationships. Activities not related to the present article: is paid to be on
advisory boards at Lunit and iCAD; has grants/grants pending from Siemens. Other
relationships: disclosed no relevant relationships.
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