Combined Screening With Ultrasound and Mammography vs Mammography Alone in Women With Elevated Risk of Breast Cancer (vol 299, pg 2151, 2008)

ArticleinJAMA The Journal of the American Medical Association 299(18):2151-63 · June 2008with163 Reads
Impact Factor: 35.29 · DOI: 10.1001/jama.299.18.2151 · Source: PubMed
Abstract

Screening ultrasound may depict small, node-negative breast cancers not seen on mammography. To compare the diagnostic yield, defined as the proportion of women with positive screen test results and positive reference standard, and performance of screening with ultrasound plus mammography vs mammography alone in women at elevated risk of breast cancer. From April 2004 to February 2006, 2809 women, with at least heterogeneously dense breast tissue in at least 1 quadrant, were recruited from 21 sites to undergo mammographic and physician-performed ultrasonographic examinations in randomized order by a radiologist masked to the other examination results. Reference standard was defined as a combination of pathology and 12-month follow-up and was available for 2637 (96.8%) of the 2725 eligible participants. Diagnostic yield, sensitivity, specificity, and diagnostic accuracy (assessed by the area under the receiver operating characteristic curve) of combined mammography plus ultrasound vs mammography alone and the positive predictive value of biopsy recommendations for mammography plus ultrasound vs mammography alone. Forty participants (41 breasts) were diagnosed with cancer: 8 suspicious on both ultrasound and mammography, 12 on ultrasound alone, 12 on mammography alone, and 8 participants (9 breasts) on neither. The diagnostic yield for mammography was 7.6 per 1000 women screened (20 of 2637) and increased to 11.8 per 1000 (31 of 2637) for combined mammography plus ultrasound; the supplemental yield was 4.2 per 1000 women screened (95% confidence interval [CI], 1.1-7.2 per 1000; P = .003 that supplemental yield is 0). The diagnostic accuracy for mammography was 0.78 (95% CI, 0.67-0.87) and increased to 0.91 (95% CI, 0.84-0.96) for mammography plus ultrasound (P = .003 that difference is 0). Of 12 supplemental cancers detected by ultrasound alone, 11 (92%) were invasive with a median size of 10 mm (range, 5-40 mm; mean [SE], 12.6 [3.0] mm) and 8 of the 9 lesions (89%) reported had negative nodes. The positive predictive value of biopsy recommendation after full diagnostic workup was 19 of 84 for mammography (22.6%; 95% CI, 14.2%-33%), 21 of 235 for ultrasound (8.9%, 95% CI, 5.6%-13.3%), and 31 of 276 for combined mammography plus ultrasound (11.2%; 95% CI. 7.8%-15.6%). Adding a single screening ultrasound to mammography will yield an additional 1.1 to 7.2 cancers per 1000 high-risk women, but it will also substantially increase the number of false positives. clinicaltrials.gov Identifier: NCT00072501.

Full-text

Available from: Richard G Barr
ORIGINAL CONTRIBUTION
Combined Screening With Ultraso und
and Mammography vs Mammography Alone
in W omen at Elevated Risk of B reast Cancer
Wendie A. Berg, MD, PhD
Jeffrey D. Blume, PhD
Jean B. Cormack, PhD
Ellen B. Mendelson, MD
Daniel Lehrer, MD
Marcela Bo¨hm-Ve´lez, MD
Etta D. Pisano, MD
Roberta A. Jong, MD
W. Phil Evans, MD
Marilyn J. Morton, DO
Mary C. Mahoney, MD
Linda Hovanessian Larsen, MD
Richard G. Barr, MD, PhD
Dione M. Farria, MD, MPH
Helga S. Marques, MS
Karan Boparai, RT
for the ACRIN 6666 Investigators
E
ARLY DETECTION REDUCES DEATHS
due to breast cancer. The US Pre-
ventive Services Task Force
analysis of 7 randomized trials of
mammographic screening found that the
point estimate of the reduction in mor-
tality from screening mammography was
22% in women aged 50 years or older and
15% among women between 40 and 49
years,
1
with some individual trials show-
ing far greater benefits in both age groups
and with any specific age distinction arbi-
trary. The magnitude of reduction in
mortality seen in individual trials paral-
lels reductions in size distribution
2
and
rates of node-positive breast cancer.
3
Mammography can depict calcifica-
tions due to malignancy, including duc-
tal carcinoma in situ (DCIS). Invasive
cancers, which can spread to lymph
nodes and cause systemic metastases,
are most often manifest as noncalci-
fied masses
4
and can be mammographi-
cally subtle or occult, particularly when
the parenchyma is dense. Dense breast
tissue is common. More than half of
women younger than 50 years
5
have
either heterogeneously dense, visually es-
timated as 51% to 75% glandular,
6
or
For editorial comment see p 2203.
Context Screening ultrasound may depict small, node-negative breast cancers not
seen on mammography.
Objective To compare the diagnostic yield, defined as the proportion of women with
positive screen test results and positive reference standard, and performance of screen-
ing with ultrasound plus mammography vs mammography alone in women at el-
evated risk of breast cancer.
Design, Setting, and Participants From April 2004 to February 2006, 2809 women,
with at least heterogeneously dense breast tissue in at least 1 quadrant, were recruited
from 21 sites to undergo mammographic and physician-performed ultrasonographic ex-
aminations in randomized order by a radiologist masked to the other examination re-
sults. Reference standard was defined as a combination of pathology and 12-month fol-
low-up and was available for 2637 (96.8%) of the 2725 eligible participants.
Main Outcome Measures Diagnostic yield, sensitivity, specificity, and diagnostic accu-
racy (assessed by the area under the receiver operating characteristic curve) of combined
mammography plus ultrasound vs mammography alone and the positive predictive value
of biopsy recommendations for mammography plus ultrasound vs mammography alone.
Results Forty participants (41 breasts) were diagnosed with cancer: 8 suspicious on
both ultrasound and mammography, 12 on ultrasound alone, 12 on mammography
alone, and 8 participants (9 breasts) on neither. The diagnostic yield for mammogra-
phy was 7.6 per 1000 women screened (20 of 2637) and increased to 11.8 per 1000
(31 of 2637) for combined mammography plus ultrasound; the supplemental yield
was 4.2 per 1000 women screened (95% confidence interval [CI], 1.1-7.2 per 1000;
P=.003 that supplemental yield is 0). The diagnostic accuracy for mammography was
0.78 (95% CI, 0.67-0.87) and increased to 0.91 (95% CI, 0.84-0.96) for mammog-
raphy plus ultrasound (P=.003 that difference is 0). Of 12 supplemental cancers de-
tected by ultrasound alone, 11 (92%) were invasive with a median size of 10 mm (range,
5-40 mm; mean [SE], 12.6 [3.0] mm) and 8 of the 9 lesions (89%) reported had nega-
tive nodes. The positive predictive value of biopsy recommendation after full diag-
nostic workup was 19 of 84 for mammography (22.6%; 95% CI, 14.2%-33%), 21 of
235 for ultrasound (8.9%, 95% CI, 5.6%-13.3%), and 31 of 276 for combined mam-
mography plus ultrasound (11.2%; 95% CI. 7.8%-15.6%).
Conclusions Adding a single screening ultrasound to mammography will yield an
additional 1.1 to 7.2 cancers per 1000 high-risk women, but it will also substantially
increase the number of false positives.
Trial Registration clinicaltrials.gov Identifier: NCT00072501
JAMA. 2008;299(18):2151-2163 www.jama.com
Author Affiliations are listed at the end of this article.
Corresponding Author: Wendie A. Berg, MD, PhD,
10755 Falls Rd, Suite 440, Lutherville, MD 21093
(wendieberg@gmail.com).
©2008 American Medical Association. All rights reserved. (Reprinted with Corrections) JAMA, May 14, 2008—Vol 299, No. 18 2151
Downloaded From: http://jama.jamanetwork.com/ on 02/25/2013
Page 1
extremely dense, visually estimated as
more than 75% glandular
6
breasts, as
do at least one-third of women older
than 50 years.
5
In women with dense
breasts, mammographic sensitivity may
be as low as 30% to 48%,
7,8
with much
higher interval cancer rates
7,9
and worse
prognosis for resulting clinically de-
tected cancers. Furthermore, dense
breast tissue is itself a marker of in-
creased risk of breast cancer on the or-
der of 4- to 6-fold.
10
In dense breasts,
digital mammography has improved
performance, with sensitivity increas-
ing from 55% with screen film to 70%
with digital in 1 large series using mam-
mographic and clinical follow-up as a
gold standard.
11
Digital mammogra-
phy does not, however, eliminate the
fundamental limitation that noncalci-
fied breast cancers are often obscured
by surrounding and overlying dense pa-
renchyma.
In women younger than 50 years, the
reduced benefit of mammographic
screening is attributed to increased breast
density, biologically more aggressive can-
cers, and reduced prevalence of dis-
ease. Using a screening interval of 12
months, rather than 24 months, should
improve results with rapidly growing ma-
lignancies, even though dense tissue re-
mains a major limitation to improving
outcomes.
12
Methods to address improv-
ing detection despite dense breast tis-
sue are needed.
Supplemental screening ultrasound
has the potential of depicting small, node-
negative breast cancers not seen on mam-
mography,
8,13-17
and its performance is
improved in dense parenchyma.
8
It is
natural to expect that methods that im-
prove the detection of small, node-
negative cancers would further reduce
mortality when performed in addition to
screening mammography. However, di-
rect evidence of a mortality reduction due
to screening can only be generated in a
large prospective randomized screen-
ing trial with mortality as an end point.
Such trials are costly, require extensive
infrastructure and resources, and are not
practical under all contexts. Surrogate
aims and end points, such as the diag-
nostic performance for the screening mo-
dality or the size and stage of breast can-
cers depicted, have been correlated with
mortality outcomes,
18,19
and can be used
to project the mortality reduction if the
screening modality were implemented.
Across 42 838 examinations from the
6 published single-center studies of
screening ultrasound to date,
8,13-17
126
women (0.29%) were shown to have
150 cancers identified only on supple-
mental ultrasound.
20
Of 141 invasive
cancers detected only on ultrasound, 99
(70%) were 1 cm or smaller in size.
20
In studies for which staging was de-
tailed, 36 of 40 cancers (90%) de-
picted by ultrasonography alone were
categorized as stage 0 or I.
20
Concerns remain, however, over the
generalizability of such favorable re-
sults with screening ultrasound. In par-
ticular, there is concern for the opera-
tor dependence of freehand screening
breast ultrasound because an abnor-
mality must be perceived while scan-
ning for it to be documented. Impor-
tantly, recent reports have shown that
consistent breast ultrasound examina-
tion performance and interpretation is
possible with minimal training.
21,22
Other limitations to implementing
widespread screening ultrasound in-
clude a shortage of qualified person-
nel to perform and interpret the exami-
nation and lack of standardized
scanning protocols. These concerns
have hampered use of screening ultra-
sound; 35% of surveyed facilities spe-
cializing in breast imaging offered it in
2005,
23
even though most facilities of-
fering screening ultrasound will do so
only on a limited basis.
In this study, we report a prospec-
tive, multicenter trial, randomized to se-
quence of performance of mammogra-
phy and ultrasound, designed to
investigate and validate the perfor-
mance of screening ultrasound in con-
junction with mammography, using a
standardized protocol and interpretive
criteria. This trial was designed to com-
pare the diagnostic yield of screening
breast mammography plus ultrasound
with mammography alone in women at
increased risk of breast cancer. Since be-
ginning this trial, a multicenter study was
published from Italy in which 6449
women with dense breasts and negative
mammogram results underwent screen-
ing ultrasound, with 29 cancers de-
picted by ultrasound (cancer detection
rate, 0.45%).
24
The American College of
Radiology Imaging Network (ACRIN)
6666 is the largest trial of screening ul-
trasound in which mammography and
ultrasound have been performed and
read independently, allowing detailed
analysis of the performance of each mo-
dality separately and in combination and
reducing potential biases in patient re-
cruitment and interpretation of both
mammography and ultrasound. Further-
more, we used standardized scanning
and interpretive criteria (http://www
.acrin.org/TabID/153/Default.aspx),
which should facilitate generalizability
of our results.
Unlike previous reports evaluating
screening ultrasound, we chose to study
a population at elevated risk of breast
cancer. Supplemental screening in ad-
dition to mammography may be more
cost-effective in such populations be-
cause the expected prevalence of dis-
ease is higher than it is for popula-
tions with no risk factors. Furthermore,
patients at higher risk may be encour-
aged to begin screening at an earlier
age when the tissue is denser and
mammography is more limited in its
benefits. Indeed, annual magnetic reso-
nance imaging (MRI) is now recom-
mended in addition to mammography
for women at very high risk of breast
cancer,
25
but it remains limited by high
cost, required injection of contrast, re-
duced patient tolerance, and limited
availability and expertise. Ultrasound
is relatively inexpensive, requires no
contrast, is well tolerated, and is widely
available.
METHODS
Study Design
Participants were women at elevated risk
of breast cancer (T
ABLE 1) who pre-
sented for routine annual mammogra-
phy and provided written informed con-
sent. Each participant underwent
mammographic and ultrasonographic
screening examinations in randomized
ULTRASOUND PLUS MAMMOGRAPHY SCREENING
2152 JAMA, May 14, 2008—Vol 299, No. 18 (Reprinted with Corrections) ©2008 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ on 02/25/2013
Page 2
of ultrasound-only cancers of 2.7 to
4.6 cancers per 1000 women screened
in other series.
8,13-17,24
As in prior stud-
ies, the vast majority of cancers seen
only on ultrasound were invasive be-
cause DCIS is difficult to see on ultra-
sound. All but 1 cancer seen only on ul-
trasound was node negative. Invasive
cancers not seen on mammography can
be expected to present as interval can-
cers with a worse prognosis: detection
of asymptomatic, mammographically oc-
cult, node-negative invasive carcino-
mas with ultrasound should reduce mor-
tality from breast cancer, although
mortality was not an end point of this
study.
Strengths of our study include its
matching within a participant, and
examinations performed by radiolo-
gists who were masked to results
of the other examination. Random-
ized order of these tests helped con-
trol biases of recruiting women with
vague mammographic abnormalities.
Furthermore, these results were
consistent and generalizable across
21 international centers. The ra-
diologist investigators in this trial
were all specialists in breast imaging
who met experience requirements
and completed qualification tasks.
As such, our results may vary slightly
from those observed in general prac-
tice, even though similar results were
observed by Kaplan
16
for which study
technologists performed screening
ultrasound. Educational materials
used for radiologist investigator
training in ultrasound lesion detec-
tion and characterization are ar-
chived by ACRIN.
The use of the Gail and Claus
models to calculate risk may have
affected the racial distribution of par-
ticipants, for the Gail model is
known to underestimate risk in Afri-
can Americans.
34
Neither model has
been validated in other races other
than whites,
34,35
although Gail et al
36
have recently validated a new risk
assessment tool based on data from
the Contraceptives and Reproductive
Experiences (CARE) Study, which
involved African American women
(which was not available for use in
this protocol).
In our elevated-risk study popula-
tion, enriched in women with dense
breasts, mammographic sensitivity was
only 50% (95% CI, 33.8%-66.2%) and
the sensitivity of mammography plus
ultrasound was 77.5% (95% CI, 61.6%-
Table 5. Summary of Cancers Identified by Participant as a Function of Breast Density, Mammogram Type, and Eligibility Risk Factor
No. (%) of
Participants
in the
Analysis Set
(n = 2637)
No. of Cancers (No. Invasive)
All Cancers
BI-RADS Score 3
BI-RADS Score 3,
Mammography
Plus Ultrasound
b
Mammography
Alone
a
Ultrasound
Alone
Mammography
Plus
Ultrasound
Total 2637 (100.0) 40 (34) 12 (7) 12 (11) 8 (8) 8 (8)
Breast density, %
c
25 53 (2.0)
26-40 297 (11.3) 6 (4) 3 (2) 3 (2)
41-60 811 (30.7) 14 (13) 4 (3) 4 (4) 3 (3) 3 (3)
61-80 968 (36.7) 11 (9) 3 (1)
a
2 (2) 4 (4) 2 (2)
80 506 (19.2) 9 (8) 2 (1) 3 (3) 1 (1) 3 (3)
b
Missing 2 (0.1)
Total 2637 (100.0) 40 (34) 12 (7) 12 (11) 8 (8) 8 (8)
Mammogram type
Digital 923 (35.0) 14 (14) 3 (3) 4 (4) 3 (3) 4 (4)
Film-screen 1714 (64.9) 26 (20) 9 (4)
a
8 (7) 5 (5) 4 (4)
b
Total 2637 (100.0) 40 (34) 12 (7) 12 (11) 8 (8) 8 (8)
Eligibility risk factor
Personal history of breast cancer 1400 (53.1) 28 (25) 7 (5) 9 (8) 7 (7) 5 (5)
b
Lifetime risk 25% 497 (18.8) 5 (4) 3 (2)
a
1 (1) 1 (1)
5-y risk, Gail model
2.5% 403 (15.3) 4 (4) 2 (2) 1 (1) 1 (1)
1.7% and extremely dense breasts 223 (8.5) 2 (1) 1 (0) 1 (1)
ADH, ALH, LCIS, or atypical papilloma
d
83 (3.1) 1 (0) 1 (0)
Mutation in BRCA1 or BRCA2 genes 23 (0.9)
History of prior chest and/or mediastinal
and/or axillary irradiation
8 (0.3)
Total 2637 (100.0) 40 (34) 12 (7) 12 (11) 8 (8) 8 (8)
Abbreviations: ADH, atypical ductal hyperplasia, ALH, atypical lobular hyperplasia; LCIS, lobular carcinoma in situ.
a
One invasive ductal cancer seen on initial mammography was classified as probably benign (BI-RADS 3) after integrated interpretation with ultrasound and had breast density between
41% and 60%, mammographic type film-screen, and lifetime risk of 25% or higher.
b
Melanoma case had breast density of more than 80%, mammographic type film-screen, and personal history of breast cancer.
c
Breast density is overall visually estimated breast density. All participants were visually judged to have at least heterogeneously dense parenchyma in at least 1 quadrant of the breast(s)
on prior mammography, except for 43 participants who had no prior mammography.
d
A patient originally included in this group for the analysis set was receiving chemoprevention therapy. Her basis of eligibility is unknown as reported by the site, even though her reported
family history yields a lifetime Gail model risk exceeding 25%. She did not have cancer.
ULTRASOUND PLUS MAMMOGRAPHY SCREENING
2160 JAMA, May 14, 2008—Vol 299, No. 18 (Reprinted with Corrections) ©2008 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ on 02/25/2013
Page 3
ORIGINAL CONTRIBUTION
Combined Screening With Ultraso und
and Mammography vs Mammography Alone
in W omen at Elevated Risk of B reast Cancer
Wendie A. Berg, MD, PhD
Jeffrey D. Blume, PhD
Jean B. Cormack, PhD
Ellen B. Mendelson, MD
Daniel Lehrer, MD
Marcela Bo¨hm-Ve´lez, MD
Etta D. Pisano, MD
Roberta A. Jong, MD
W. Phil Evans, MD
Marilyn J. Morton, DO
Mary C. Mahoney, MD
Linda Hovanessian Larsen, MD
Richard G. Barr, MD, PhD
Dione M. Farria, MD, MPH
Helga S. Marques, MS
Karan Boparai, RT
for the ACRIN 6666 Investigators
E
ARLY DETECTION REDUCES DEATHS
due to breast cancer. The US Pre-
ventive Services Task Force
analysis of 7 randomized trials of
mammographic screening found that the
point estimate of the reduction in mor-
tality from screening mammography was
22% in women aged 50 years or older and
15% among women between 40 and 49
years,
1
with some individual trials show-
ing far greater benefits in both age groups
and with any specific age distinction arbi-
trary. The magnitude of reduction in
mortality seen in individual trials paral-
lels reductions in size distribution
2
and
rates of node-positive breast cancer.
3
Mammography can depict calcifica-
tions due to malignancy, including duc-
tal carcinoma in situ (DCIS). Invasive
cancers, which can spread to lymph
nodes and cause systemic metastases,
are most often manifest as noncalci-
fied masses
4
and can be mammographi-
cally subtle or occult, particularly when
the parenchyma is dense. Dense breast
tissue is common. More than half of
women younger than 50 years
5
have
either heterogeneously dense, visually es-
timated as 51% to 75% glandular,
6
or
For editorial comment see p 2203.
Context Screening ultrasound may depict small, node-negative breast cancers not
seen on mammography.
Objective To compare the diagnostic yield, defined as the proportion of women with
positive screen test results and positive reference standard, and performance of screen-
ing with ultrasound plus mammography vs mammography alone in women at el-
evated risk of breast cancer.
Design, Setting, and Participants From April 2004 to February 2006, 2809 women,
with at least heterogeneously dense breast tissue in at least 1 quadrant, were recruited
from 21 sites to undergo mammographic and physician-performed ultrasonographic ex-
aminations in randomized order by a radiologist masked to the other examination re-
sults. Reference standard was defined as a combination of pathology and 12-month fol-
low-up and was available for 2637 (96.8%) of the 2725 eligible participants.
Main Outcome Measures Diagnostic yield, sensitivity, specificity, and diagnostic accu-
racy (assessed by the area under the receiver operating characteristic curve) of combined
mammography plus ultrasound vs mammography alone and the positive predictive value
of biopsy recommendations for mammography plus ultrasound vs mammography alone.
Results Forty participants (41 breasts) were diagnosed with cancer: 8 suspicious on
both ultrasound and mammography, 12 on ultrasound alone, 12 on mammography
alone, and 8 participants (9 breasts) on neither. The diagnostic yield for mammogra-
phy was 7.6 per 1000 women screened (20 of 2637) and increased to 11.8 per 1000
(31 of 2637) for combined mammography plus ultrasound; the supplemental yield
was 4.2 per 1000 women screened (95% confidence interval [CI], 1.1-7.2 per 1000;
P=.003 that supplemental yield is 0). The diagnostic accuracy for mammography was
0.78 (95% CI, 0.67-0.87) and increased to 0.91 (95% CI, 0.84-0.96) for mammog-
raphy plus ultrasound (P=.003 that difference is 0). Of 12 supplemental cancers de-
tected by ultrasound alone, 11 (92%) were invasive with a median size of 10 mm (range,
5-40 mm; mean [SE], 12.6 [3.0] mm) and 8 of the 9 lesions (89%) reported had nega-
tive nodes. The positive predictive value of biopsy recommendation after full diag-
nostic workup was 19 of 84 for mammography (22.6%; 95% CI, 14.2%-33%), 21 of
235 for ultrasound (8.9%, 95% CI, 5.6%-13.3%), and 31 of 276 for combined mam-
mography plus ultrasound (11.2%; 95% CI. 7.8%-15.6%).
Conclusions Adding a single screening ultrasound to mammography will yield an
additional 1.1 to 7.2 cancers per 1000 high-risk women, but it will also substantially
increase the number of false positives.
Trial Registration clinicaltrials.gov Identifier: NCT00072501
JAMA. 2008;299(18):2151-2163 www.jama.com
Author Affiliations are listed at the end of this article.
Corresponding Author: Wendie A. Berg, MD, PhD,
10755 Falls Rd, Suite 440, Lutherville, MD 21093
(wendieberg@gmail.com).
©2008 American Medical Association. All rights reserved. (Reprinted with Corrections) JAMA, May 14, 2008—Vol 299, No. 18 2151
Downloaded From: http://jama.jamanetwork.com/ on 02/25/2013
Page 4
(Insightful Corp, Seattle, Washing-
ton), and ROCKIT, version 0.9.4 beta
(available from the Kurt Rossmann
Laboratories for Radiologic Image Re-
search, University of Chicago, Chi-
cago, Illinois). All P values were re-
ported as 2-sided. P.05 was set as the
threshold for significance. All confi-
dence intervals (CIs) are reported at the
95% level.
The primary unit of analysis is the par-
ticipant, with the most severe breast
imaging assessment on mammography
or on mammography plus ultrasound
used as the primary end point. A BI-
RADS assessment of 4a, 4b, 4c, or 5 was
considered positive (seen and suspi-
cious) for the mammographic or ultra-
sonographic imaging test or combina-
tion of tests, and an assessment of
BI-RADS 1, 2, or 3 was considered nega-
tive, as is standard in audits of mammo-
graphic outcomes.
6,29
We separately ana-
lyzed results based on recommendations,
with additional imaging or biopsy or both
considered positive and short interval or
routine follow-up considered negative.
Sample-size projections were designed
to achieve both the desired level of sta-
tistical precision for estimating the yields
and at least 80% power to detect a dif-
ference in the yields of at least 3 per 1000,
while allowing for 17% missing data.
The diagnostic yield (ie, the propor-
tion of women with a positive screen
test and positive reference standard),
sensitivity, specificity, positive predic-
tive value (PPV), and negative predic-
tive value (NPV) were estimated as
simple proportions with exact 95% CIs.
To account for the natural pairing of
assessments within a participant, the
McNemar test was used to compare
the diagnostic yields, sensitivity, and
specificity (T
ABLE 2) and the test was
inverted to provide a CI for their dif-
ference. Conditional logistic regres-
sion was used where appropriate. Com-
parison of PPVs and NPVs was done
according to Leisenring et al.
30
For sen-
sitivity at the lesion level, we ac-
counted for clustering by using a lo-
gistic regression with robust SEs.
Empirical and model-based ROC curves
were estimated from degree of suspi-
cion (BI-RADS) and quasi-continuous
probability scales pooled across the
study.
31
The areas under the curve
(AUCs) were compared under a bivar-
iate, binormal model that accounts for
the paired-test design (ie, every par-
Figure 1. Flowchart of Protocol
84 Excluded (not eligible)
38 Medical history ineligible
19 Risk assessment criteria not met
10 Duplicate registrations
8 Enrolled under expired IRB approval
7 Diagnostic cases
1 Metastatic disease at study entry
1 Had breast implants
75 Did not have reference standard
b
53 Both tests negative
17 Mammography negative, integrated
reading positive
3 Both tests positive
2 Mammography positive, integrated
reading negative (withdrawn)
24 Lost to follow-up
13 Withdrew
8 Cancer status unknown
8 Died
8 Lost to follow-up
7 Withdrawn
2 Cancer status unknown
1 Lost to follow-up
2 Withdrawn
13 Excluded
7 Withdrawn before imaging
4 Did not undergo any imaging
2 Did not undergo ultrasound examination
2725 Eligible
2637 Had reference standard (analysis set)
2712 Underwent imaging
1340 Mammography then ultrasound
1372 Ultrasound then mammography
Index test results
Integrated mammography plus
ultrasound test results
a
Mammography
test results
Total
+
+
110
216
326
31
2355
2386
Total
141
2571
2712
Negative reference
standard
Positive reference
standard
2809 Women enrolled and randomized
to order of imaging studies
Integrated test results
Mammography
test results
Total
+
+
19
12
31
Total
20
20
40
1
8
9
Integrated test results
Mammography
test results
Total
+
+
88
187
275
Total
116
2481
2597
28
2294
2322
IRB indicates institutional review board. Positive reference standard is a diagnosis of cancer within 365 days of
the initial screening examination. Negative reference standard is the absence of a diagnosis of cancer at 1 year
follow-up or, for 3 cases, double prophylactic mastectomy. Early second-year screens contribute to the refer-
ence standard within the 365-day window.
a
A Breast Imaging Reporting Data System score of greater than 3 was considered a positive test result; a score
of 3 or less, negative. One thousand eight hundred thirty participants with both negative mammographic
and negative ultrasonographic results were imputed as having a negative integrated reading.
b
Because of the paired design, missing reference standard data would not bias the comparison of mammog-
raphy with integrated mammography and ultrasound but may affect generalizability.
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Page 5
ticipant underwent both screening mo-
dalities).
32,33
The paired-study design
eliminates confounding by partici-
pant characteristics in the primary com-
parison between modalities.
Of 2725 eligible participants en-
rolled, only 3.23% (88) were ex-
cluded due to missing data. Thirteen
(0.48%) never completed imaging and
75 (2.75%) yielded no reference stan-
dard information (Figure 1). The analy-
sis cohort, consisting of all eligible par-
ticipants with assessment data and
reference standard (n=2637), was com-
pared with the full eligible study co-
hort (n=2725) on baseline character-
istics to detect potential biases
(Table 1). We note that among the 88
participants with missing data, we
would expect only 1 cancer if the data
are missing at random.
RESULTS
There were no differences in demo-
graphics or risk factors between the
analysis cohort of 2637 (4786 breasts)
and the overall eligible group of 2725.
(Figure 1 and Table 1). The mean (SE)
age at enrollment was 55 years (0.2;
range, 25-91 years). Fourteen hun-
dred women (53.09%) had a personal
history of breast cancer. Nine of 23
women who carried either the BRCA-1
or BRCA-2 mutation also had a his-
tory of breast cancer, as did 4 of 8
women who had undergone chest or
mediastinal radiation. Seventy-three
percent of participants had under-
gone mammography in no less than 11
full months to no more than 14 months
before entering the study, 11% had prior
screening ultrasound, and 7% had prior
contrast-enhanced breast magnetic
resonance imaging at least a year be-
fore entering the study.
Forty of 2637 participants (1.5%)
were diagnosed with cancer, 39 of
whom had breast cancer: 6, DCIS; 20,
invasive ductal carcinoma (IDC) with
or without DCIS; 3, invasive lobular car-
cinoma; and 10, mixed invasive duc-
tal and lobular carcinoma with or with-
out DCIS. One participant had
melanoma metastatic to axillary nodes
with no evidence of cancer in the
breasts. One patient with IDC had con-
tralateral DCIS (41 total breasts with
cancer). Four patients had multifocal
invasive cancer (45 total malignant le-
sions). Median size of invasive can-
cers (considering only the largest per
participant) was 12.0 mm (range, 4-40
mm; interquartile range [IQR], 8-18
mm; mean [SE], 14 [1.5] mm; 95% CI,
Table 2. Summary of Performance Characteristics of Screening With Combined Mammography Plus Ultrasound Compared With Mammography
Alone at the Participant Level
a
Mammography
Plus Ultrasound
b
Mammography
Alone
Comparison of Mammography
Plus Ultrasound vs
Mammography Alone
Ultrasound
Alone
d
Difference P Value
c
Yield per 1000
No./total 31/2637 20/2637 20/2636
% (95% CI) 11.8 (8 to 16.6) 7.6 (4.6 to 11.7) 4.2 (1.1 to 7.2) .003 7.6 (4.6 to 11.7)
Sensitivity
No./total 31/40 20/40 20/40
% (95% CI) 77.5 (61.6 to 89.2) 50 (33.8 to 66.2) 27.5 (9.5 to 45.5) .003 50.0 (33.8 to 66.2)
Specificity
No./total 2322/2597 2481/2597 2383/2596
% (95% CI) 89.41 (88.16 to 90.57) 95.53 (94.67 to 96.30) −6.12 (−7.24 to −5) .001 91.80 (90.67 to 92.82)
Area under ROC curve
BI-RADS 0.91 (0.84 to 0.96) 0.78 (0.67 to 0.87) 0.13 (0.04 to 0.22) .003 0.80 (0.70 to 0.88)
% Probability of malignancy 0.90 (0.83 to 0.95) 0.68 (0.53 to 0.80) 0.23 (0.10 to 0.35) .001 0.75 (0.62 to 0.85)
Odds Ratio
e
Positive predictive value
No./total 31/306 20/136 20/233
% (95% CI) 10.1 (7.0 to 14.1) 14.7 (9.2 to 21.8) 0.65 .03 8.6 (5.3 to 13.0)
Negative predictive value
No./total 2322/2331 2481/2501 2383/2403
% (95% CI) 99.61 (99.27 to 99.82) 99.20 (98.77 to 99.51) 2.08 .004 99.17 (98.72 to 99.49)
Abbreviations: BI-RADS, Breast Imaging Reporting Data System; CI, confidence interval; NPV, negative predictive value; PPV, positive predictive value; ROC, receiver operating
characteristic.
a
Estimates are rounded for presentation. For the comparison column, the counts are replaced by the metric of comparison. Calculations include 1 malignancy that was considered
suspicious on mammography and was considered probably benign after integration with ultrasound and 1 malignancy that was not seen on initial imaging that was discovered
to be melanoma (from prior primary in back) metastatic to axillary lymph nodes and diagnosed 205 days after study entry.
b
This table displays screening data. After complete diagnostic workup, results for mammography plus ultrasound are as follows: yield, 31 of 807 participants, 38.4 per 1000 (95%
CI, 26.2-54.1); sensitivity, 31 of 35 participants, 88.6% (95% CI, 73.3%-96.8%); specificity, 550 of 772 participants, 71.2% (95% CI, 67.9%-74.4%); PPV, 31of 253 participants,
12.3%, (95% CI, 8.5%-16.9%); 550 of 554 participants, 99.3% (95% CI, 98.2%-99.8%); area under the curve BI-RADS, 0.91 (95% CI, 0.84-0.95); and area under the curve
percentage of probability of malignancy, 0.90 (95% CI, 0.83-0.94).
c
Testing H
0
: mammography plus ultrasound is equivalent to mammography alone.
d
Ultrasound results were included for completeness. The study was not designed to permit direct comparison of mammography with ultrasound alone. For one participant, the
ultrasound alone interpretation was not available.
e
Odds ratios compare the odds of PPV or NPV for mammography plus ultrasound with the odds of PPV or NPV for mammography alone. The method of comparison is given by
Leisenring et al,
30
which accounts for the paired design but does not readily permit the construction of a CI.
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11.1-17.4 mm). Axillary lymph node
staging was performed for 25 partici-
pants with invasive cancer, with nodal
metastases found in 5 (20%, including
the melanoma); axillary staging was not
performed for 6 participants with re-
current breast cancer nor was it per-
formed for 3 others.
At the participant level, based on
BI-RADS assessments, 20 of 40 (50%)
of cancers were identified on mammog-
raphy for a yield of 7.6 per 1000 (Table 2
and T
ABLE 3); 5 of 6 DCIS lesions (83%)
were seen only on mammography. Fif-
teen invasive cancers, with a median size
of 12 mm (range, 4-25 mm; IQR, 7-20
mm; mean [SE], 14 [1.9] mm; 95% CI,
9.9-18.2 mm) were seen on mammog-
raphy, with axillary nodes negative in 7
of 10 participants (70%) with staging.
Seven invasive cancers were suspicious
only on mammography and 8 were sus-
picious on both mammography and on
ultrasound. Ultrasound alone depicted
cancer in 12 participants: 1, DCIS, and
11, invasive cancers with median size of
10 mm (range, 5-40 mm; IQR, 6-15 mm;
mean [SE] mm, 12.6 [3.0]; 95% CI,
6.0-19.1 mm), with axillary nodes nega-
tive in 8 of 9 participants (89%) with
staging. One 4-mm IDC lesion consid-
ered suspicious initially on mammog-
raphy (true positive on mammogra-
phy) was downgraded to a BI-RADS
score of 3 after integration with ultra-
sound (false negative on mammogra-
phy plus ultrasound), even though it was
still recalled for additional mammo-
graphic views (thought to be probably
benign after recall, and benign at the
6-month follow-up), and was diag-
nosed when the patient presented with
palpable metastatic adenopathy 264 days
after study entry. This is not included
among interval cancers.
Thirty-one cancers were depicted in
2637 participants by the combination
of mammography plus ultrasound, pro-
ducing a yield of 11.8 per 1000 women
and an increased yield due to ultra-
sound of 4.2 per 1000 (95% CI, 1.1-
7.2; Table 2) over mammography alone.
The diagnostic accuracy of mammog-
raphy alone was 0.78 (95% CI, 0.67-
0.87), for ultrasound alone was 0.80
(95% CI, 0.70-0.88), and for com-
bined mammography plus ultrasound
was 0.91 (95% CI, 0.84-0.96, Table 2,
F
IGURE 2). The AUC for mammogra-
phy plus ultrasound did not change
Table 3. Sensitivity, Specificity, and Positive Predictive Value by Participant for Mammography Alone vs Combined Mammography Plus Ultrasound
BI-RADS Score
Total No.
Speci-
ficity,
%
PPV
Level,
%
Total No.
Women
Breast
Cancer
Cumulative
No.
Sensitivity of
Detecting
Cancer, %
Core or Surgical
Biopsy
Cyst Aspiration
Only
Atypical
Biopsy
Women
True
Posi-
tives All Invasive Women
a
Lesions Women Lesions Women
b
Lesions
Mammography Alone
5, Highly suggestive of
malignancy
5 4 5 4 10.0 8.8 99.96 80.0 5 5 0 0 0 0
4C, Moderate suspicion 9 4 14 8 20.0 20.6 99.77 57.1 9 12 0 1 1 1
4B, Intermediate suspicion 32 7 46 15 37.5 32.4 98.81 32.6 22 24 1 2 0 0
4A, Low suspicion 90 5
c
136 20
c
50.0 44.1 95.53 14.7 33 43 3 6 2 2
3, Probably benign 177 1 313 21 52.5 47.1 88.76 6.7 16 19 12 16 0 0
2, Benign
d
1421 14 1734 35 87.5 88.2 34.58 2.0 112 131 37 59 7 7
1, Negative 903 5 2637 40 100 100 0 1.5 70 85 18 29 6 8
Mammography Plus Ultrasound
5, Highly suggestive of
malignancy
6 5 6 5 12.5 11.8 99.96 83.3 6 8 0 1 0 0
4C, Moderate suspicion 26 12 32 17 42.5 47.1 99.42 53.1 26 35 0 0 2 2
4B, Intermediate suspicion 68 10 100 27 67.5 67.6 97.19 27.0 58 73 5 9 4 4
4A, Low suspicion 206 4 306 31 77.5 73.5 89.41 10.1 112 128 42 74 6 6
3, Probably benign 401 4
c
707 35
c
87.5 85.3 74.12 5.0 40 49 17 22 3 5
2, Benign 98 0 805 35 87.5 85.3 70.35 4.3 3 3 1 1 0 0
1, Negative
d
1832
e
5 2637 40 100 100 0 1.5 22 23 6 6 1 1
Abbreviations: BI-RADS, Breast Imaging Reporting Data System.
a
Includes 1 prophylactic mastectomy with ductal carcinoma in situ in a patient with contralateral invasive ductal cancer, but does not include 3 negative double-prophylactic mas-
tectomies nor 5 other contralateral prophylactic mastectomies.
b
Atypical includes atypical ductal hyperplasia or lobular hyperplasia, lobular carcinoma in situ, atypical papilloma, and radial sclerosing lesion
c
One 4-mm invasive ductal cancer was considered BI-RADS 4a on mammography, missed on ultrasound, and classified as BI-RADS 3 on integrated mammography plus ultra-
sound. This was diagnosed when the participant presented with palpable metastatic adenopathy 264 days after study entry.
d
The participant with cancer due to melanoma presenting with axillary metastases was classified as BI-RADS 2 on mammography and BI-RADS 1 on integrated mammography
plus ultrasound.
e
Investigators were not asked to integrate findings on mammography plus ultrasound if both examination results recommended routine follow-up. These cases were analyzed as
having negative results on mammography plus ultrasound. Of 1832 cases analyzed as BI-RADS 1 on mammography plus ultrasound, 342 were BI-RADS 2 on mammography,
318 were BI-RADS 2 on ultrasound, 747 were BI-RADS 2 on both; 2 were BI-RADS 3 on initial mammography and downgraded to BI-RADS 1 after integration with ultrasound;
the remaining 423 were BI-RADS 1 on both mammography and ultrasound.
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when incorporating full diagnostic
workup that included additional mam-
mographic views.
Defined as the percentage of partici-
pants with a BI-RADS 4a assessment or
higher, without a diagnosis of cancer
in the following 12 months, the false-
positive rate for mammography alone
was 4.4% (136 had a BI-RADS score of
4a or higher, of whom 20 had cancer:
116 were false positive of 2637 partici-
pants [95% CI, 3.7%-5.3%; Table 3]);
for ultrasound alone, the false-
positive rate was 8.1% (213 of 2637;
95% CI, 7.1%-9.2%); and for com-
bined mammography plus ultrasound
was 10.4% (275 of 2637; 95% CI, 9.3%-
11.7%). In 5.2% of participants (136 of
2637; 95% CI, 4.3%-6.1%), ultra-
sound, but not mammography, re-
sulted in a suspicious assessment and
biopsy and 8.8% (12 of 136; 95% CI,
4.6%-14.9%) of these participants had
cancer. Seventy-one participants had
only a cyst aspiration, without a bi-
opsy, with no malignancies among
these lesions; 43 of these participants
had a suspicious assessment only on ul-
trasound and 2 had a suspicious assess-
ment only on mammography.
T
ABLE 4 details the recommendations
by modality. To calculate the PPV1
6
of
recall, the number of participants with
cancer are divided by those who were re-
called for additional evaluation, biopsy,
or both. For mammography, 21 partici-
pants werediagnosed with cancer among
of 276 participants who underwent ad-
ditional evaluation or biopsy, or both for
a PPV1 of 7.6% (95% CI, 4.8%-11.4%);
for ultrasound the PPV1 was 22 of 337
(6.5%; 95%CI, 4.1%-9.7%); and for com-
bined integrated mammography plus ul-
trasound, 32of 436, 7.3% (95% CI,5.1%-
10.2%). Of those 276 participantsrecalled
from routine mammography, after com-
plete diagnostic workup,84 participants
were recommended for biopsy, of whom
19 had cancer, resulting in a PPV2
6
of
22.6% (95% CI, 14.2%-33%). For ultra-
sound, 21 of 235 patients with a biopsy
recommendation after workup had can-
cer, resulting in a PPV2 of 8.9% (95% CI,
5.6%-13.3%). Although 1 of these can-
cers was classified as BI-RADS 3 based on
the initial ultrasound, it was nevertheless
worked up and classified as BI-RADS 4b
on mammography.After mammography
plus ultrasound and a full diagnostic
workup, 31 of 276 participants who had
undergone biopsy had cancer, resulting
in a PPV2 of mammography plus ultra-
sound of 11.2% (95% CI, 7.8%-15.6%).
Short Interval Follow-up
and BI-RADS 3
Based on mammographic results, 177
women (6.7%) were classified as BI-
RADS 3 (Table 3); of those, 1 (0.6%) was
diagnosed with cancer detected at the
early second screen, 363 days after study
entry (after initial additional mammo-
graphic recall at time 0 for unrelated be-
nign findings). Three hundred twenty-
one participants (12.2%) were classified
as BI-RADS 3 based on ultrasono-
graphic screening, 5 of whom (1.6%)
were diagnosed with cancer within the
first 12 months of follow-up. Of the 5
participants with cancer who were clas-
sified as BI-RADS 3 on ultrasound, 3
were BI-RADS 5 on mammography and
were diagnosed from 1 to 23 days after
initial screens were completed. Two
women had interval cancers that were
identified incidentally as a result of a
6-month follow-up ultrasound for com-
plicated cysts (the first was a 7-mm IDC
found at surgery in adjacent tissue af-
ter a core biopsy result of LCIS from the
lesion being followed up; the other was
a 27-mm IDC-DCIS adjacent to the cyst
being followed up). Both participants
were node negative.
Based on results from mammogra-
phy, short-interval follow-up was rec-
ommended for 59 (2.2%) of 2637 par-
ticipants (95% CI, 1.7%-2.9%), and
based on ultrasound, recommenda-
tions for short-term follow-up were
made for 227 (8.6%) participants (95%
CI, 7.6%-9.7%). Two hundred twenty
of these recommendations were based
on ultrasound alone. Two hundred
eighty-six participants (10.8%) were
Figure 2. Sensitivity and Specificity of Mammography Plus Ultrasound in Detecting Breast
Cancer
1.0
0.6
0.4
0.8
0.2
0
0 0.2 0.4
0.6 0.4 0.2 00.81.0
0.80.6 1.0
1–Specificity
Specificity
Sensitivity
Mammography
Fitted curve
Empirical points
Mammography + ultrasound
Fitted curve
Empirical points
Ultrasound
Fitted curve
Empirical points
Receiver operating characteristic (ROC) curves were calculated based on a bivariate, binomial model (See “Meth-
ods” section for details). Table 2 presents summary characteristics for these curves. The ultrasound ROC is in-
cluded for completeness; the study was not designed to permit direct comparison to ultrasound alone. The fitted
area under the curve for mammography alone is 0.78 (95% confidence interval [CI], 0.67-0.87); for mammog-
raphy plus ultrasound, 0.91 (95% CI, 0.84-0.96); and for ultrasound alone, 0.80 (95% CI, 0.70-0.88).
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recommended for short-term fol-
low-up after mammography plus ul-
trasound (95% CI, 9.7%-12.1%).
Initial assessments of 27 partici-
pants as BI-RADS 3, 7 as BI-RADS 4a,
and 1 as BI-RADS 4b based on mam-
mography were downgraded to BI-
RADS 2 after integrating mammo-
graphic and ultrasonographic results.
Similarly, initial assessments of 26 par-
ticipants as BI-RADS 3, 3 as BI-RADS
4a, 4 as BI-RADS 4b, and 1 as BI-
RADS 5 based on ultrasound were
downgraded to a BI-RADS score of 2 af-
ter integrating ultrasonographic and
mammographic results.
Interval Cancers
Eight participants had cancer not con-
sidered suspicious on either mammog-
raphy or ultrasound, with cancer iden-
tified during the 12 months after initial
screening, ie, interval cancers. Three
node-negative cancers (an 8-mm IDC
and ILC, a 35-mm ILC, and a 20-mm
IDC-DCIS) were identified at the sec-
ond screen (performed early, after 11
full months), with biopsies taken from
359 to 364 days after study entry. One
participant noted a palpable lump, with
biopsy showing a 12-mm mixed IDC/
ILC 337 days after study entry. One par-
ticipant presented with skin recur-
rence of prior breast cancer 231 days
after study entry. Two cancers were
found at the 6-month follow-up ultra-
sound as detailed in the section on
short-interval follow-up. One non-
breast malignancy was identified in the
interval in a participant with prior mela-
noma of the back, who, 6 years later,
developed a palpable axillary mass due
to metastatic adenopathy, with no evi-
dence of malignancy within the breasts.
Thus, the interval cancer rate was 8 of
40 (20%) if the melanoma case is in-
cluded as cancer, or 7 of 39 (18%) if not;
only 2 of 39 participants (5.1%) with
breast cancer were identified because
of symptoms in the interval between
screenings—or 3 of 39 (7.8%), if one
includes the 4-mm IDC seen on initial
mammography but not on additional
imaging or at the 6-month follow-up,
but which was diagnosed when the par-
ticipant presented with palpable meta-
static adenopathy 264 days after study
entry. A ninth breast had cancer not
seen on either mammography or ultra-
sound: DCIS was identified only at pro-
phylactic mastectomy after diagnosis of
contralateral multifocal IDC seen only
on ultrasound.
Cancers seen only on ultrasound
were evenly distributed across breast
density categories (T
ABLE 5). The data
were inconclusive with respect to most
differences between film-screen and
digital mammography; however,
slightly higher specificity was ob-
served with digital mammography than
with film screen (97.0% vs 94.7%,
P=.007).
In 1400 women with a personal his-
tory of breast cancer, 28 (2.0%) were
found to have cancer, with 9 of 28
(32%) seen only on ultrasound
(Table 5). Cancers were evenly distrib-
uted between the breast ipsilateral to the
initial cancer and contralateral dis-
ease. Among 1237 women with risk fac-
tors other than a personal history of
breast cancer, 12 (1.0%) were found to
have cancer, 3 of which cancers (25%)
were seen only on ultrasound. Signifi-
cantly more cancers overall were found
in women with a personal history of
cancer (P=.03), but there was no dif-
ference in supplemental yield of ultra-
sound in women with or without a per-
sonal history of breast cancer.
The median time to perform screen-
ing breast ultrasound was 19 minutes
(range, 2-90; IQR, 12-27, mean [SE],
20.8 [0.3], 95% CI, 20.3-21.3 minutes)
for a bilateral scan and 9 minutes for a
unilateral scan (range, 1 to 70; IQR, 5-15;
mean [SE], 11.6 [0.4], 95% CI, 10.7-
12.4 minutes). A median of another 2.0
minutes was spent in the room with the
participant (range, 0-19; IQR, 2-3; mean
[SE], 2.7 [0.04]; 95% CI, 2.6-2.7 min-
utes). For 869 (33.0%) of 2637 partici-
pants, the investigator scanned at least
1 axilla while performing ultrasono-
graphic scanning of the breast(s). Ninety-
four percent of breasts were less than
4 cm thick.
COMMENT
Supplemental physician-performed
screening ultrasound increases the can-
cer detection yield by 4.2 cancers per
1000 women at elevated risk of breast
cancer, as defined in this protocol (95%
CI, 1.1-7.2 cancers per 1000) on a single,
prevalent screen. This is similar to rates
Table 4. Summary of Recommendations After Screening Mammography, Ultrasound,
Combined Mammography Plus Ultrasound, and After Diagnostic Workup
Recommendation
No. of Cancers/No. of Participants With This Recommendation (%)
Mammography Ultrasound
Mammography
Plus Ultrasound
After Additional
Evaluation
Additional imaging 15/249 (6.0)
a
4/98 (4.1)
b
8/175 (4.6) 0/6
Biopsy
c
4/21 (19.0) 12/195 (6.2) 20/239 (8.4) 31/272 (11.4)
Additional imaging
and biopsy
2/6 (33.3) 6/44 (13.6) 4/22 (18.2) 0/4
Short-interval
follow-up
0/59 3/227 (1.3) 3/286 (1.0) 3/336 (0.9)
Annual follow-up
d
19/2302 (0.8) 15/2072 (0.7) 5/1915 (0.3) 6/2019 (0.3)
Missing 0/1
Total 40/2637 (1.5) 40/2637 (1.5) 40/2637 (1.5) 40/2637 (1.5)
a
One participant with a 4-mm invasive ductal cancer was given a 4a Breast Imaging Reporting Data System (BI-RADS)
score on mammography and was recommended for additional imaging. Ultrasound was negative, and the participant
was given a BI-RADS score of 3 with recommendation for short-interval follow-up on integrated mammography plus
ultrasound. Cancer was diagnosed when the participant presented with palpable metastatic adenopathy 264 days after
study entry. Another participant was recalled for additional imaging of calcifications thought to be a BI-RADS score of 3
on screening and benign on additional imaging, with cancer diagnosed 363 days after study entry due to a finding on the
(early) 12-month screen.
b
Two participants with cancer were classified as BI-RADS 3 on ultrasound with a recommendation for additional imaging.
One had a BI-RADS 4b lesion on mammography and was biopsied. The other was recommended for short-interval
follow-up after integrated mammography plus ultrasound and was diagnosed at the 6-month follow-up ultrasound.
c
Biopsy includes cyst aspirations for diagnostic uncertainty: 1 prompted by mammography and ultrasound; 46 only by
ultrasound; 52 after combined mammography plus ultrasound integrated interpretation, and 49 after any additional evalu-
ation was completed.
d
The participant with cancer due to axillary metastasis from melanoma was recommended for routine follow-up on all imaging.
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of ultrasound-only cancers of 2.7 to
4.6 cancers per 1000 women screened
in other series.
8,13-17,24
As in prior stud-
ies, the vast majority of cancers seen
only on ultrasound were invasive be-
cause DCIS is difficult to see on ultra-
sound. All but 1 cancer seen only on ul-
trasound was node negative. Invasive
cancers not seen on mammography can
be expected to present as interval can-
cers with a worse prognosis: detection
of asymptomatic, mammographically oc-
cult, node-negative invasive carcino-
mas with ultrasound should reduce mor-
tality from breast cancer, although
mortality was not an end point of this
study.
Strengths of our study include its
matching within a participant, and
examinations performed by radiolo-
gists who were masked to results
of the other examination. Random-
ized order of these tests helped con-
trol biases of recruiting women with
vague mammographic abnormalities.
Furthermore, these results were
consistent and generalizable across
21 international centers. The ra-
diologist investigators in this trial
were all specialists in breast imaging
who met experience requirements
and completed qualification tasks.
As such, our results may vary slightly
from those observed in general prac-
tice, even though similar results were
observed by Kaplan
16
for which study
technologists performed screening
ultrasound. Educational materials
used for radiologist investigator
training in ultrasound lesion detec-
tion and characterization are ar-
chived by ACRIN.
The use of the Gail and Claus
models to calculate risk may have
affected the racial distribution of par-
ticipants, for the Gail model is
known to underestimate risk in Afri-
can Americans.
34
Neither model has
been validated in other races other
than whites,
34,35
although Gail et al
36
have recently validated a new risk
assessment tool based on data from
the Contraceptives and Reproductive
Experiences (CARE) Study, which
involved African American women
(which was not available for use in
this protocol).
In our elevated-risk study popula-
tion, enriched in women with dense
breasts, mammographic sensitivity was
only 50% (95% CI, 33.8%-66.2%) and
the sensitivity of mammography plus
ultrasound was 77.5% (95% CI, 61.6%-
Table 5. Summary of Cancers Identified by Participant as a Function of Breast Density, Mammogram Type, and Eligibility Risk Factor
No. (%) of
Participants
in the
Analysis Set
(n = 2637)
No. of Cancers (No. Invasive)
All Cancers
BI-RADS Score 3
BI-RADS Score 3,
Mammography
Plus Ultrasound
b
Mammography
Alone
a
Ultrasound
Alone
Mammography
Plus
Ultrasound
Total 2637 (100.0) 40 (34) 12 (7) 12 (11) 8 (8) 8 (8)
Breast density, %
c
25 53 (2.0)
26-40 297 (11.3) 6 (4) 3 (2) 3 (2)
41-60 811 (30.7) 14 (13) 4 (3) 4 (4) 3 (3) 3 (3)
61-80 968 (36.7) 11 (9) 3 (1)
a
2 (2) 4 (4) 2 (2)
80 506 (19.2) 9 (8) 2 (1) 3 (3) 1 (1) 3 (3)
b
Missing 2 (0.1)
Total 2637 (100.0) 40 (34) 12 (7) 12 (11) 8 (8) 8 (8)
Mammogram type
Digital 923 (35.0) 14 (14) 3 (3) 4 (4) 3 (3) 4 (4)
Film-screen 1714 (64.9) 26 (20) 9 (4)
a
8 (7) 5 (5) 4 (4)
b
Total 2637 (100.0) 40 (34) 12 (7) 12 (11) 8 (8) 8 (8)
Eligibility risk factor
Personal history of breast cancer 1400 (53.1) 28 (25) 7 (5) 9 (8) 7 (7) 5 (5)
b
Lifetime risk 25% 497 (18.8) 5 (4) 3 (2)
a
1 (1) 1 (1)
5-y risk, Gail model
2.5% 403 (15.3) 4 (4) 2 (2) 1 (1) 1 (1)
1.7% and extremely dense breasts 223 (8.5) 2 (1) 1 (0) 1 (1)
ADH, ALH, LCIS, or atypical papilloma
d
83 (3.1) 1 (0) 1 (0)
Mutation in BRCA1 or BRCA2 genes 23 (0.9)
History of prior chest and/or mediastinal
and/or axillary irradiation
8 (0.3)
Total 2637 (100.0) 40 (34) 12 (7) 12 (11) 8 (8) 8 (8)
Abbreviations: ADH, atypical ductal hyperplasia, ALH, atypical lobular hyperplasia; LCIS, lobular carcinoma in situ.
a
One invasive ductal cancer seen on initial mammography was classified as probably benign (BI-RADS 3) after integrated interpretation with ultrasound and had breast density between
41% and 60%, mammographic type film-screen, and lifetime risk of 25% or higher.
b
Melanoma case had breast density of more than 80%, mammographic type film-screen, and personal history of breast cancer.
c
Breast density is overall visually estimated breast density. All participants were visually judged to have at least heterogeneously dense parenchyma in at least 1 quadrant of the breast(s)
on prior mammography, except for 43 participants who had no prior mammography.
d
A patient originally included in this group for the analysis set was receiving chemoprevention therapy. Her basis of eligibility is unknown as reported by the site, even though her reported
family history yields a lifetime Gail model risk exceeding 25%. She did not have cancer.
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89.2%; Table 2). From a detection
standpoint, it may be reasonable to of-
fer supplemental screening ultra-
sound to women with similar risk cri-
teria. As stated, dense breast tissue is
common: approximately half of women
younger than 50 years and a third of
older women have dense breast paren-
chyma.
5
Approximately 6% of women
presenting for routine annual mam-
mography have a personal history of
breast cancer,
29
and 15% have a family
history of breast cancer.
29
Our ongoing study, allowing for con-
trast-enhanced breast magnetic reso-
nance imaging (MRI) within 8 weeks of
the final 24-month mammography and
ultrasound screening round, may soon
shed some light on the possible com-
petitive roles of ultrasound and MRI as
adjuncts to mammographic screening for
breast cancer. Across 4 other series for
which screening mammography, ultra-
sound, and MRI had been performed for
women at very high risk of breast can-
cer, the combined sensitivity of mam-
mography and ultrasound averaged 55%
vs 93% after combined mammography
and MRI.
37-40
There appears to be no role
for screening ultrasound in women un-
dergoing screening MRI, even though ul-
trasound may be helpful in guiding bi-
opsy of suspicious findings seen first on
MRI.
37-40
Ultrasound may be more ap-
propriate than MRI for screening women
of intermediate risk due to its reduced
cost relative to MRI. Many of the can-
cers seen only on MRI are small, node-
negative invasive cancers.
37-40
Unlike ul-
trasound, MRI readily depicts DCIS,
41
although DCIS remains overrepre-
sented among false-negative MRI exami-
nations.
42
It is uncertain whether detec-
tion of DCIS is required or whether
detection of node-negative invasive breast
cancer is sufficient for a screening test.
It will be important to see the stage dis-
tribution of breast cancers in subse-
quent rounds of screening with mam-
mography plus ultrasound in this study
and to know how many invasive can-
cers will be seen only on MRI at the 24-
month time point.
Despite a 20% interval cancer rate (8
of 40 participants with cancer) in our
series, none of the interval breast car-
cinomas were node positive; the only
interval cancer that was node positive
was a nonbreast cancer (melanoma
metastatic to axillary nodes). Another
cancer considered suspicious on ini-
tial mammography (and therefore not
included among “interval cancers”) was
considered probably benign after full di-
agnostic workup and went unbiop-
sied until the patient presented with pal-
pable, metastatic nodes, yet was only
4 mm in size at eventual detection. One
interval cancer was a skin recurrence
of prior breast cancer.
Ultrasound is well tolerated, the tech-
nology is widely available, and it does
not require intravenous contrast ma-
terial. If, however, screening ultra-
sound is to be widely implemented, sev-
eral major issues remain. First, it will
be very important to know the role of
annual screening ultrasound in addi-
tion to mammography, and such a study
is in progress with participants in this
protocol. The time to perform bilat-
eral screening ultrasound is problem-
atic, at a median of 19 minutes. This
does not include comparison to prior
studies, discussion of results with pa-
tients, nor creation of a final report, al-
though the time may be artificially pro-
longed by protocol requirements to
measure each lesion other than a simple
cyst in 2 planes and to fully character-
ize each such lesion with and without
spatial compounding and with and
without color or power Doppler. Nine-
teen minutes is considerably longer
than the average 4 minutes 39 sec-
onds reported by Kolb et al
8
for physi-
cians scanning or the average 10 min-
utes reported by Kaplan
16
for
technologists. Currently, there is only
a single billing code for breast ultra-
sound (current procedural terminol-
ogy code 76645), and Medicare global
reimbursement is $85 in 2008, which
does not fully cover the costs of per-
forming and interpreting the examina-
tion. Outcomes similar to those of our
physician-performed study have been
reported with technologist-performed
ultrasound,
16
and specialized training
of technologists is encouraged to
counter a current shortage of quali-
fied physician and technologist person-
nel. Further validation of technologist-
performed screening breast ultrasound
is encouraged. Automated whole-
breast ultrasound may facilitate imple-
mentation and profitability of screen-
ing ultrasound but will result in
hundreds of images to be reviewed and
stored, with attendant increased capi-
tal and professional costs and poten-
tial increased malpractice exposure;
validation of such methods is needed.
The full costs of screening breast ul-
trasound in this protocol, including the
costs of induced additional testing and
biopsy, are being analyzed and re-
ported separately.
The final barrier to implementing
screening ultrasound is the risk of false-
positive results. The performance char-
acteristics of mammography were
within accepted ranges (10.5% re-
called for additional imaging or bi-
opsy; 3.2% of participants biopsied af-
ter full workup, with 23% proving
malignant; 2.2% recommended for
short interval follow-up). We ob-
served a 5.4% recall rate for ultra-
sound (142 of 2637 recommended for
additional imaging), which may be ar-
tificially low in this series because phy-
sicians performed the screening ultra-
sound and could directly evaluate
lesions in real-time. Of 2637 partici-
pants, 233 (8.8%) participants had find-
ings considered suspicious on ultra-
sound with 136 participants having
suspicious findings on ultrasound but
not mammography and prompting bi-
opsy, and 235 participants (8.9%) were
recommended for biopsy based on ul-
trasound after full workup. Only 20 of
233 (8.6%) of participants with suspi-
cious ultrasonographic findings—12
(8.8%) of 136 of those with suspi-
cious findings biopsied based on ultra-
sound alone—and 21 of 235 (8.9%) of
participants whose lesions were rec-
ommended for biopsy based on ultra-
sound proved to have cancer. The 8.8%
to 8.9% PPV of biopsies prompted by
ultrasound in our study is similar to the
11% rate seen across prior series.
20,43
Di-
agnostic uncertainty for complicated
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Page 11
cysts remains a major source of false-
positive results, with 43 participants un-
dergoing only cyst aspiration in-
cluded among those with a suspicious
finding on ultrasound. Elastography, in
which the deformability of the mass is
assessed during ultrasound, can help
distinguish complicated cysts from sus-
picious solid masses and should re-
duce this source of false positives.
44
An-
other 227 participants (8.6%) were
recommended for short interval fol-
low-up based on ultrasound, similar to
the 6.3% rate across other series.
8,15,16,45
Whether the risk of false-positive re-
sults with ultrasound will diminish in
our study population with subsequent
screening rounds, as has been seen with
mammography
46
and in small series
with both ultrasound and MRI
37
is un-
der evaluation. We have been sepa-
rately quantifying patient anxiety and
discomfort (ie, “process utility”
47
) in-
duced by addition of screening ultra-
sound.
CONCLUSION
The addition of a single screening ultra-
sonographic examination to mammog-
raphy for women at elevated risk of breast
cancer results in increased detection of
breast cancers that are predominantly
small and node-negative. We defined el-
evated risk using a variety of criteria, in-
cluding personal history of breast can-
cer, prior atypical biopsy, and elevated
risk by Gail or Claus models or both. Re-
cent literature
43
suggests that any com-
bination of factors that confers 3-fold
relative risk compared with women with-
out the risk factor would be “high risk,”
including dense breast tissue.
9
Across all
series to date, over 90% of cancers seen
only on ultrasound have been in women
with more than 50% dense breast tis-
sue,
20,24
although 3 of 12 cancers (25%)
seen only on ultrasound in this series
were in women with only 26% to 40%
dense breast tissue (as visually esti-
mated), suggesting that women with
other risk factors may benefit from
screening ultrasound even if their breast
tissue is less dense. The age at which to
begin screening women at increased risk
would reasonably derive from the age at
which the risk of breast cancer is equal
to that for an average woman aged 40 or
50 years, depending on national policy.
9
The detection benefit of a single
screening ultrasound in women at el-
evated risk of breast cancer is now well
validated. However, it comes with a
substantial risk of false-positive re-
sults (ie, biopsy with benign results
and/or short interval follow-up). Our
results should be interpreted in the con-
text of recent guidelines recommend-
ing annual MRI in women at very high
risk of breast cancer.
25
Importantly,
evaluation of annual (incidence) screen-
ing ultrasound is continuing in ACRIN
6666, as is evaluation of a single screen-
ing MRI in these women.
Author Affiliations: American Radiology Services Inc,
Johns Hopkins Green Spring, Lutherville, Maryland (Dr
Berg); Center for Statistical Sciences, Brown Univer-
sity, Providence, Rhode Island (Drs Blume and Cor-
mack and Ms Marques); Feinberg School of Medi-
cine, Northwestern University, Chicago, Illinois (Dr
Mendelson); CERIM, Buenos Aires, Argentina (Dr Le-
hrer); Weinstein Imaging Associates, Pittsburgh, Penn-
sylvania (Dr Bo¨ hm-Ve´ lez); University of North Caro-
lina School of Medicine, Chapel Hill (Dr Pisano);
University of Toronto, Sunnybrook and Women’s Hos-
pital, Toronto, Ontario, Canada (Dr Jong); University
of Texas Southwestern Medical Center, Dallas (Dr
Evans); Mayo Clinic, Rochester, Minnesota (Dr Mor-
ton); University of Cincinnati, Cincinnati, Ohio (Dr Ma-
honey); Keck School of Medicine, University of South-
ern California, Los Angeles (Dr Larsen); Forum Health,
Western Reserve Care System, Youngstown, Ohio (Dr
Barr); Mallinckrodt Institute of Radiology, Washing-
ton University School of Medicine, St Louis, Missouri
(Dr Farria); American College of Radiology, Philadel-
phia, Pennsylvania (Ms Boparai).
Author Contributions: Dr Blume had full access to all
of the data in the study and takes responsibility for
the integrity of the data and the accuracy of the data
analysis.
Study concept and design: Berg, Blume, Mendelson,
Pisano.
Acquisition of data: Berg, Blume, Mendelson, Lehrer,
Bo¨ hm-Ve´ lez, Pisano, Jong, Evans, Morton, Mahoney,
Hovanessian-Larsen, Barr, Farria, Boparai.
Analysis and interpretation of data: Berg, Blume,
Cormack, Mendelson, Pisano, Marques.
Drafting of the manuscript: Berg, Blume, Cormack,
Marques.
Critical revision of the manuscript for important in-
tellectual content: Berg, Blume, Mendelson, Lehrer,
Bo¨ hm-Ve´ lez, Pisano, Jong, Evans, Morton, Mahoney,
Hovanessian-Larsen, Barr, Farria, Boparai.
Statistical analysis: Blume, Cormack, Marques.
Obtained funding: Berg, Blume.
Administrative, technical, or material support: Berg,
Mendelson, Lehrer, Pisano, Jong, Morton, Barr,
Boparai.
Study supervision: Berg, Blume.
Financial Disclosures: Dr Berg reports that she has served
as a consultant to Naviscan PET Systems, MediPattern,
and Siemens and has received equipment support from
Siemens and a travel grant from General Electric. Dr Men-
delson reports that she is a member of the scientific ad-
visory boards of MediPattern and Siemens and has re-
ceived equipment support from Philips. Dr Bo¨ hm-
Ve´ lez reports that she is a member of the physicians
advisory board of MediPattern. Dr Pisano reports that
her laboratory receives research support from General
Electric, Hologic, Konica, Sectra, and Siemens. Dr Jong
reports that she has a research collaboration with Gen-
eral Electric. Dr Evans reports that he is a member of
the scientific advisory board of Hologic. Dr Mahoney
reports that she is a consultant to Johnson & Johnson
and SenoRx. Dr Larsen reports that she receives equip-
ment support from Naviscan PET Systems. Dr Barr re-
ports that he is a member of the ultrasound advisory
boards of and has received equipment support from Si-
emens and Philips. The remaining coauthors report no
financial disclosures.
ACRIN 6666 Site Investigators: Allegheny-Singer Re-
search Institute, Pittsburgh, Pennsylvania: William R.
Poller, MD, principal investigator (PI), Michelle Huerbin,
research associate (RA); American Radiology Services–
Johns Hopkins Green Spring, Baltimore, Maryland:
Wendie A. Berg, MD, PhD (PI), Barbara E. Levit, RT
(RA); Beth Israel Deaconess Medical Center, Boston,
Massachusetts:Janet K. Baum, MD, and Valerie J. Fein-
Zachary, MD (PIs), Suzette M. Kelleher, BA (RA);
CERIM, Buenos Aires: Daniel E. Lehrer, MD (PI), Maria
S. Ostertag (RA); Duke University Medical Center,
Durham, North Carolina: Mary Scott Soo, MD (PI),
Brenda N. Prince, RT (RA); Mayo Clinic, Rochester,
Minnesota: Marilyn J. Morton, DO (PI), Lori M.
Johnson, AAS (RA); Feinberg School of Medicine,
Northwestern University, Chicago, Illinois: Ellen B.
Mendelson, MD (PI), Marysia Kalata, AA (RA); Radi-
ology Associates of Atlanta, Atlanta, Georgia: Han-
del Reynolds, MD (PI), Y. Suzette Wheeler, RN, MSHA
(RA); Radiology Consultants/Forum Health, Young-
stown, Ohio: Richard G. Barr, MD, PhD (PI), Marilyn
J. Mangino, RN (RA); Radiology Imaging Associates,
Denver, Colorado: A. Thomas Stavros, MD (PI), Margo
Valdez (RA); Sunnybrook Health Sciences Centre, Uni-
versity of Toronto, Toronto, Ontario, Canada: Rob-
erta A. Jong, MD (PI), Julie H. Lee, BSC (RA); Thomas
Jefferson University Hospital, Philadelphia, Pennsyl-
vania: Catherine W. Piccoli, MD, and Christopher R.
B. Merritt, MS, MD (PIs), Colleen Dascenzo (RA); David
Geffen School of Medicine at University of Califor-
nia Los Angeles Medical Center, Los Angeles: Anne
C. Hoyt, MD (PI), Roslynn Marzan, BS (RA); Univer-
sity of Cincinnati Medical Center, Cincinnati, Ohio:
Mary C. Mahoney, MD (PI), Monene M. Kamm, AS
(RA); University of North Carolina, Chapel Hill: Etta
D. Pisano, MD (PI), Laura A. Tuttle, MA (RA), Keck
School of Medicine, University of Southern Califor-
nia, Los Angeles: Linda Hovanessian Larsen, MD (PI),
Christina E. Kiss, AA (RA); University of Texas M. D.
Anderson Cancer Center, Houston: Gary J. Whit-
man, MD (PI), Sharon R. Rice, AA (RA); University of
Texas Southwestern Medical Center, Dallas: W. Phil
Evans, MD (PI), Kimberly T. Taylor, AA (RA); Wash-
ington University School of Medicine, St. Louis, Mis-
souri: Dione M. Farria, MD, MPH (PI), Darlene J. Bird,
RT, AS (RA); and Weinstein Imaging Associates, Pitts-
burgh, Pennsylvania: Marcela Bo¨ hm-Ve´ lez, MD, (PI),
Antoinette Cockroft (RA).
Funding/Support: The study was funded by the Avon
Foundation and grants CA 80098 and CA 79778 from
the National Cancer Institute.
Role of the Sponsors: The Avon Foundation was not
involved in the design and conduct of the study; col-
lection, management, analysis, and interpretation of
the data; and preparation, review, or approval of the
manuscript. The trial was conducted by the Ameri-
can College of Radiology Imaging Network, a mem-
ber of the National Cancer Institute’s Clinical Trials Co-
operative Groups Program, and was developed and
carried out adhering to the standard cooperative group
processes. These processes include review of and in-
put about the trial design from the NCI’s Cancer
Therapy Evaluation Program (CTEP). Upon CTEP’s ap-
proval of the research protocol, the NCI was not in-
ULTRASOUND PLUS MAMMOGRAPHY SCREENING
2162 JAMA, May 14, 2008—Vol 299, No. 18 (Reprinted with Corrections) ©2008 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ on 02/25/2013
Page 12
volved in the design and conduct of the study; col-
lection, management, analysis, and interpretation of
the data; and preparation, review, or approval of the
manuscript.
Additional Contributions: We thank Amanda M. Ad-
ams, MPH, Center for Statistical Sciences, Brown Uni-
versity, Providence, Rhode Island, for assistance with
data analysis; Eric A. Berns, PhD, University of Colo-
rado, Denver, for ultrasound quality assurance; Cyn-
thia B. Olson, MBA, MHS, and Sophia Sabina, MBA,
American College of Radiology (ACR), Philadelphia,
Pennsylvania, for administrative assistance; Glenna J.
Gabrielli, BS, Stephanie Clabo, BS, CCRP, Jillene De-
Bari, BA, and Judy M. Green, RT(M) at ACR for data
management; Cheryl L. Crozier, RN, ASQ, CQA, and
Josephine Schloesser, AS, RT(R)(M), CCRP at ACR for
monitoring; Anthony M. Levering, AS, RT(R)(CT)
(MR) at ACR for image management; and Nancy S.
Fredericks, MBA, at ACR for communications sup-
port. We also thank Cecilia M. Brennecke, MD, and
other colleagues at American Radiology Services, Johns
Hopkins Green Spring, for their support; and Mark D.
Schleinitz, MD, MS, at Brown University, Barbara K.
LeStage, BS, MHP, consultant to the ACR, Edward A.
Sickles, MD, University of California, San Francisco
Medical Center, and Elizabeth A. Patterson, MD, Se-
attle, Washington, for engaging in helpful discus-
sions. We are indebted to the many investigators, coin-
vestigators, and research associates at the clinical sites.
No one was compensated beyond their usual salary
for their efforts for this study.
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ULTRASOUND PLUS MAMMOGRAPHY SCREENING
©2008 American Medical Association. All rights reserved. (Reprinted with Corrections) JAMA, May 14, 2008—Vol 299, No. 18 2163
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    • "Lower BD has been shown to be associated with lower breast cancer risk [6] . Therefore, mammographic breast density (MBD) information can be used in combination with other risk factors for breast cancer risk stratification, and selection of more appropriate screening pathways such as ultrasound [7] , magnetic resonance imaging (MRI) [8] or digital breast tomosynthesis (DBT) [9] to enhance visualization features of cancer in dense breasts [3]. MBD information can also be used for monitoring the efficacy of chemopreventive strategies101112 . "
    [Show abstract] [Hide abstract] ABSTRACT: PURPOSE: To assess the performance of QuantraTM in reproducing BI-RADS® mammographic breast density (MBD) assessment. METHODS: Two methods of MBD assessment were used (QuantraTM and BI-RADS®). Volumetric breast density measurement from 292 raw projection images was performed using QuantraTM. BI-RADS® assessment was performed by three radiologists and a majority report (consensus of at least two radiologists) was generated. Interreader agreement (κ), agreement, and the sensitivity and specificity of QuantraTM in reproducing BI-RADS® rating were calculated on a four-grade (1, 2, 3, and 4) and two-grade (1–2 vs. 3–4) scale. RESULTS: The majority BI-RADS® report in the dataset consisted of 9.6% (n = 28), 35.3% (n = 103), 27.1% (n = 79), and 28.1% (n = 82) for BI-RADS® 1, 2, 3, and 4 respectively. Intra-reader agreement (κ) was 0.86 (95%CI: 0.83 – 0.91) to 0.88 (95%CI: 0.85 – 0.93) on a four-grade and 0.88 (95%CI: 0.83 – 0.92) to 0.91 (95%CI: 0.88 – 0.95) on a two-grade scale. Inter-reader agreement (κ) was substantial [0.66 (95%CI: 0.62 – 0.71) to 0.75 (95%CI: 0.70 – 0.81)] on a four-grade scale and substantial to almost perfect [0.77 (95%CI: 0.73 – 0.82) to 0.89 (95%CI: 0.84 – 0.93)] on a two-grade scale. QuantraTM correctly classified 35.7%, 91.2%, 88.6%, and 50.3% of BI-RADS® 1, 2, 3, and 4 respectively. It also demonstrated 91.3% sensitivity and 83.6% specificity in reproducing BI-RADS® on a two-grade scale (1–2 vs. 3–4). CONCLUSION: QuantraTM has limited performance in reproducing BI-RADS® rating on a four-grade scale, however, highly reproduces BI-RADS® assessment on a two-grade scale. © (2016) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE). Downloading of the abstract is permitted for personal use only.
    Full-text · Article · Mar 2016 · Proceedings of SPIE - The International Society for Optical Engineering
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    • "Conventional B-mode US is used as an adjunct to mammography for breast imaging to improve sensitivity [1]–[4]. However, B-mode US has shown low specificity in the differentiation of benign from malignant breast masses [5]–[9]. To increase specificity , breast masses are categorized according to the Breast Imaging-Reporting and Data System (BI-RADS) criteria defined by the American College of Radiology (ACR) [10], [11]. "
    [Show abstract] [Hide abstract] ABSTRACT: In this work, tissue stiffness estimates are used to differentiate between benign and malignant breast masses in a group of pre-biopsy patients. The rationale is that breast masses are often stiffer than healthy tissue; furthermore, malignant masses are stiffer than benign masses. The comb-push ultrasound shear elastography (CUSE) method is used to noninvasively assess a tissue???s mechanical properties. CUSE utilizes a sequence of simultaneous multiple laterally spaced acoustic radiation force (ARF) excitations and detection to reconstruct the region of interest (ROI) shear wave speed map, from which a tissue stiffness property can be quantified. In this study, the tissue stiffnesses of 73 breast masses were interrogated. The mean shear wave speeds for benign masses (3.42 ?? 1.32 m/s) were lower than malignant breast masses (6.04 ?? 1.25 m/s). These speed values correspond to higher stiffness in malignant breast masses (114.9 ?? 40.6 kPa) than benign masses (39.4 ?? 28.1 kPa and p < 0.001), when tissue elasticity is quantified by Young???s modulus. A Young???s modulus >83 kPa is established as a cut-off value for differentiating between malignant and benign suspicious breast masses, with a receiver operating characteristic curve (ROC) of 89.19% sensitivity, 88.69% specificity, and 0.911 for the area under the curve (AUC).
    Full-text · Article · Sep 2015 · IEEE Transactions on Ultrasonics Ferroelectrics and Frequency Control
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    • "Measuring BD is important for breast cancer risk prediction and for recommending appropriate imaging pathway. Women with increased BD need further imaging such as Ultrasound (US) or Magnetic Resonance Imaging (MRI) to better visualize structures within the dense tissue [6, 7]. However, a number BD features such as the method of measurement, ACR BIRADS density definitions and legislative requirements around informing woman are not standardized. "
    [Show abstract] [Hide abstract] ABSTRACT: The purpose of this study is to investigate whether having a mammogram on differing manufacturer equipment will affect a woman's breast density (BD) measurement. The data set comprised of 40 cases, each containing a combined image of the left craniocaudal (LCC) and left mediolateral oblique (LMLO). These images were obtained from 20 women age between 42–89 years. The images were acquired on two imaging systems (GE and Hologic) one year apart. Volumetric BD was assessed by using Volpara Density Grade (VDG) and average BD% (AvBD%). Twenty American Board of Radiology (ABR) examiners assessed the same images using the BIRADS BD scale 1-4. Statistical comparisons were performed on the means using Mann-Whitney, on correlation using Spearman's rank coefficient of correlation and agreement using Cohen's Kappa. The absolute median BIRADS difference between GE and Hologic was 0.225 (2.00 versus 2.00; p<0.043). The VDG measures for GE was not statistically different to Hologic (2.00 versus 2.00; p<0.877), likewise the median AvBD% for the GE and Hologic systems showed no difference (6.51 versus 6.79; p<0.935). BIRADS for GE and Hologic systems showed strong positive correlation (ρ=0.904; p<0.001), while the VDG (ρ=0.978; p<0.001) and AvBD% (ρ=0.973; p<0.001) showed very strong positive correlations. There was a substantial agreement between GE and Hologic systems for BIRADS density shown with Cohen's Kappa (κ=0.692; p<0.001), however the systems demonstrated an almost perfect agreement for VDG (κ=0.933; p<0.001).
    Full-text · Article · Mar 2015 · Proceedings of SPIE - The International Society for Optical Engineering
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