addition of ultrasound to mammography in the case of dense ...article clinical study addition of...

ARTICLEClinical Study

Addition of ultrasound to mammography in the case of densebreast tissue: systematic review and meta-analysisMatejka Rebolj 1, Valentina Assi2, Adam Brentnall1, Dharmishta Parmar1 and Stephen W. Duffy1

BACKGROUND: Mammography is less effective in detecting cancer in dense than in fatty breasts.METHODS: We undertook a systematic search in PubMed to identify studies on women with dense breasts who underwentscreening with mammography supplemented with ultrasound. A meta-analysis was undertaken on the proportion of cancersdetected only by ultrasound, out of all screen-detected cancers, and the proportion of women with negative mammography whowere referred for assessment following ultrasound screening.RESULTS: Twenty-nine studies satisfied our inclusion criteria. The proportion of total cancers detected only by ultrasound was 0.29(95% CI: 0.27–0.31), consistent with an approximately 40% increase in the detection of cancers compared to mammography. In thestudied populations, this translated into an additional 3.8 (95% CI: 3.4–4.2) screen-detected cases per 1000 mammography-negativewomen. About 13% (32/248) of cancers were in situ from 17 studies with information on this subgroup. Ultrasound approximatelydoubled the referral for assessment in three studies with these data.CONCLUSIONS: Studies have consistently shown an increased detection of breast cancer by supplementary ultrasound screening.An inclusion of supplementary ultrasound into routine screening will need to consider the availability of ultrasound and diagnosticassessment capacities.

British Journal of Cancer https://doi.org/10.1038/s41416-018-0080-3

INTRODUCTIONSince the publication of the randomised trials showing asignificant breast cancer mortality reduction with the offer ofbreast screening with mammography, large numbers of screeningprogrammes have been instituted worldwide.1–4 These pro-grammes are estimated to prevent substantial numbers of breastcancer deaths2–4 and standards have been developed to monitorand maintain the quality of the services.5,6

One area where there is room for improvement is the lowersensitivity of mammographic screening in women with densebreast tissue.7 Since the introduction of legislation in the USArequiring disclosure of mammographic density to screenees, therehas been considerable international interest in potential variationin screening regimen based on breast density.8,9 Possible tacticsinclude increased frequency of screening in the case of densebreast tissue,10 but in both the USA and Europe, there is muchinterest in supplemental imaging in addition to mammogra-phy.8,11,12 The latter option seems logical, since if a test is shownto be less sensitive in a population, using a different test may bemore effective than applying the same test more frequently.While there is strong evidence that magnetic resonance

imaging confers a substantial improvement in sensitivity, particu-larly in high-risk groups,13 it remains an expensive option andrequires considerable commitment from the screenee.14 There istherefore interest in the use of ultrasound, hand-held or

automatic, in addition to mammography in the case of densebreast tissue.12,15 A policy decision regarding the use of adjunctiveultrasound for screening in dense breasts would need to beinformed by evidence on the increase in breast cancer detectioncapability, the resource and human costs of the ultrasoundimaging, and the resource and human costs of further diagnosticworkup as a result of positive ultrasound findings. A decisionwould also need to be made as to how to define the dense tissuesubgroup of the population, as there are many methods ofmeasuring breast density.7

In this paper, we review the published literature on the use ofultrasound in addition to mammography in screening womenwith dense breast tissue. We summarise in quantitative terms thelikely benefit in terms of increased breast cancer detection, andthe effect on the increased diagnostic activity, specifically in termsof recall rates for assessment. The benefit and the requireddiagnostic activity are further discussed in the context of a routinemammography screening service such as the one implementedby the NHS Breast Screening Programme.

MATERIALS AND METHODSInclusion criteria and PICOS termsMethods and inclusion criteria were specified in advance,although the protocol was not registered. Studies had to report

www.nature.com/bjc

Received: 20 December 2017 Revised: 7 March 2018 Accepted: 19 March 2018

1Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Barts & The London School of Medicine and Dentistry, Queen Mary University of London, CharterhouseSquare, London EC1M 6BQ, UK and 2Edinburgh Clinical Trials Unit, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UKCorrespondence: Stephen W. Duffy ([email protected])These authors contributed equally: Matejka Rebolj, Valentina Assi.

© The Author(s) 2018 Published by Springer Nature on behalf of Cancer Research UK

http://orcid.org/0000-0001-9597-645X

http://orcid.org/0000-0001-9597-645X

http://orcid.org/0000-0001-9597-645X

http://orcid.org/0000-0001-9597-645X

http://orcid.org/0000-0001-9597-645X

mailto:[email protected]

data on breast cancers, either invasive or ductal carcinomas in situ(DCIS), detected in consecutive or randomly selected women withdense breasts. No limitation was imposed for the women’s age,the breast density classification system used in the study, or theproportion of the included women who had additional breastcancer risk factors. These women were screened with mammo-graphy and had undergone supplemental screening with ultra-sound, the latter at least in case mammography was negative.As the focus was on the detection at screening, we excluded

studies of women with symptoms, and any cancers diagnosedafter normal screening tests (i.e., interval cancers). We alsoexcluded studies where women receiving mammography screen-ing were different from women receiving ultrasound examina-tions, or where breast cancers in dense breasts were not reportedseparately from those in fatty breasts. Studies published beforeyear 2000 were excluded as the ultrasound imaging technologyhas developed considerably in terms of quality in recent decades.No language restrictions were imposed. In case of duplicate

publications, the report with the most complete data was includedin the meta-analysis.

Literature searchThe search was developed by D.P. and S.D. The investigatorssearched PubMed on 29 June 2016 using the following criteria:[ultrasound AND breast AND screening AND (“density” OR“dense”)], limited to publication date from 1 January 2000 onward.The search was updated on 26 July 2017 to identify any newpublications since 1 June 2016. All analyses were based onpublished data, but study authors were contacted, if necessary, forfurther clarifications that concerned study eligibility.Two authors (S.D., M.R.) independently screened the abstracts of

all retrieved records, with a subgroup also screened by D.P.Reference lists of all reviews and other types of secondarypublications (including letters, news items, etc.) were checked foradditional primary data. Two authors (either S.D. or V.A., and M.R.)independently assessed full texts for inclusion and retrievedinformation on study and population characteristics and onscreening outcomes into pre-specified tables. Two authors (V.A.,M.R.) independently evaluated study quality following the QualityAssessment of Diagnostic Accuracy Studies (QUADAS) Version 2evaluation tool.16 Any discrepancies were resolved throughconsensus.

Statistical analysisThe primary aim was to measure the relative increase in cancerdetection from supplemental ultrasound screening. For thispurpose, we considered those studies reporting the number ofcancers detected only by ultrasound (r) and the total number ofcancers detected (n, by mammography and ultrasound supple-mental screening). A meta-analysis was undertaken on theproportion p= r/n detected only by ultrasound. This may berelated to the percentage increase through q= r/(n−r)=(p−1−1)−1. To help stabilise the binomial variance, an arcsin(r/n)0.5 transformation was applied,17 on which scale standardfixed-effect (FE) (inverse variance) and random-effect (RE) meta-analysis estimates were obtained.18 Results were back-transformed to proportions for presentation; exact confidenceintervals for individual studies were presented in forest plots.Evidence for departure from the FEs model was assessed using theI2 statistic (ratio of between-study variance to total variance).Funnel plot is a standard visual instrument examining therelationship between the effect estimate and a measure of studyprecision in order to investigate potential reporting or otherbiases.19 As study sizes and standard errors were not reported forall studies, we examined p against total number of cancers on asquare root scale, centred around an overall p from the totalnumber of cancer detected only by ultrasound divided by totalcancers. Prediction intervals were obtained from the inverse

binomial transformation, and plotted using a loess smoother toaid interpretation.The secondary aim was to determine the additional detection of

breast cancer and referrals for assessment per 1000 women withmammography negative results. A meta-analysis was undertakenon the absolute numbers of detected cancers and referrals owingonly to ultrasound examinations. The 95% confidence intervalswere calculated as exact binomial intervals.Furthermore, we investigated the associations between the

variables of interest using Pearson correlation coefficients (ρ)weighted by study size (number of all screened women or numberof women with negative mammography).In the studies where the same women underwent several

screening rounds, the unit of observation was an individualscreening episode. There were no pre-defined sub-groups.Analysis was undertaken using the meta and weights packages

for statistical software R 3.4.1.20–22

RESULTSSearch resultsThe original search identified 716 unique records (Fig. 1). Theupdated search identified 174 records. In total, 29 studies satisfiedour inclusion criteria. Although several reviews had beenpublished,23,24 no previous meta-analysis could be identified.In total, 13 studies compared mammography and supplemental

ultrasound screening to screening using mammography alone inthe same women.12,15,25–35 Ten of these studies were undertakenin general populations of women with dense breasts15,25–31,34,35

and three studies were in women with additional risk factors12,32,33

(Table 1). An additional 16 studies were undertaken usingultrasound in women with negative mammography,8,36–50 ofwhich one46 was in women with additional risk factors. Tenstudies were undertaken in the USA,8,15,27,40,44–47,49,50 six inItaly,25,30,31,33,36,39 five in South Korea,34,37,41,43,48 and one each inChina,26 Israel,38 Singapore,42 Austria,28 Thailand,29 Germany32 andSweden,35 and one study was undertaken in multiple countries(USA, Argentina, Canada).12 All studies with reported data on agealso included women below 50 years, but age breakdowns for thestudied outcomes were not reported systematically. Twelvestudies reported women undergoing a clinical breast examinationprior to an ultrasound examination8,27,30,32–34,38–42,46 (Supplemen-tary Table 1). As reported, mammography was read with knowl-edge of ultrasound imaging in three studies29,37,39 but in anotherthree studies the interpretation of ultrasound imaging wasblinded to mammographic findings.12,32,33 Screening was under-taken either in organised programmes or in other settings, e.g.allowing women and/or their doctors to self-refer.Breast density was defined predominantly using the American

College of Radiology’s Breast Imaging–Reporting and Data System(BI–RADS). Four studies defined dense breasts as BI–RADScategories 2 to 4 (i.e., including breasts with ≥25% fibroglandulartissue),27–29,38 whereas 24 studies defined dense breasts asBI–RADS 3 or 4 (i.e. including breasts with ≥50% fibroglandulartissue).8,12,15,25,26,30–32,34–37,39–50 One study reported classifyingbreasts as dense if fibroglandular tissue occupied >50% of thebreast as a mean of two mammographic views but did notexplicitly explain the classification system.33

Extra detection of breast cancersThe main analysis included 1692 breast cancers detected in12 studies reporting detection of breast cancer in the entirescreening population, of which 494 (29%) were detected only bysupplemental ultrasound (a relative detection rate of 141%, withthe increased detection calculated as 494/(1692–494), seeStatistical Analysis and Table 2). The overall FE estimate of theproportion of total cancers detected by ultrasound was 0.29 (95%CI: 0.27–0.31); the estimate of an RE distribution mean was 0.31

Ultrasound screening for women with dense breastsM Rebolj et al.

2

1234567890();,:

(95% CI: 0.25–0.37). Both measures were very close despitesubstantial between-study variation (I2= 81% (95% CI: 68–89%);Fig. 2a). The results suggest that detection rates are on averageincreased by approximately 40% with supplemental ultrasoundcompared to mammography alone. In the only six studiesreporting detection separately for DCIS and invasive cases, DCIScases represented only a smaller proportion of the cases detectedby ultrasound. The FE estimate, almost identical to the REestimate, was 0.10 (95% CI: 0.05–0.16), consistent with an increasein the detection of 11%. The study by Brancato and colleagues30

was not included as the total number of cancers in women

undergoing supplemental ultrasound screening was unknown; asensitivity analysis where it was included did not materially alterthe results.A funnel plot is shown in Fig. 3. There is a small suggestion of

publication bias due to the two small studies reporting largeeffects, but this was tempered a little by a couple of larger studieswith smaller effect sizes.Subgroups were investigated to assess whether the variation

between studies could be explained by (1) studies that includedBI–RADS density 2 as ‘dense’; (2) study year (a proxy for digital vs.film mammography); or (3) extent of other risk factors. Although

Records identified through the originaldatabase search

(N=716)

Records after duplicates removed(N=716)

Records excluded(N=792)

Full-text articles excluded,with reasons

(N=69)

Not (only) screening or otherselections (N=25)

Results not reported by breast density(N=22)

Mammography and/or ultrasoundresults not reported separately, or indifferent women (N=11)

Duplicate publications (N=5)

Other aspects of using ultrasound(N=2)

No cases detected by eithermammography or ultrasound (N=2)

Not a full publication (N=1)

Cancers not reported separately fromother lesions (N=1)

Records screened(N=890)a

Updated search(N=174)b

Iden

tific

atio

n

Full-text articles assessedfor eligibility

(N=98)

Studies included inqualitative synthesis

(N=29)

Studies included inquantitative synthesis

(meta-analysis)(N=29)

Scr

eeni

ngE

ligib

ility

Incl

uded

Fig. 1 PRISMA flow diagram of study selection. Baseline search undertaken on 29 June 2016. Update search undertaken on 26 July 2017.a Reference lists of reviews and similar publications were examined for any additional studies reporting primary data. The latter studies wereincluded in the counts of articles assessed for eligibility, and, if they satisfied the inclusion criteria, they were included in the meta-analysis.b This number may have included duplicate records compared to the original search. No new studies reporting primary data were identifiedthrough reviews and similar secondary publications in the updated search, suggesting that the pool of the relevant studies had beenexhausted


3

Table1.

Gen

eral

descriptionofthestudiesincluded

inthemeta-an

alysis

Authors,

pub

licationye

arScreen

ing

pop

ulation

Additional

risk

factorsa

Description

ofthestud

ied

pop

ulation

Exclusioncriteria

Defi

nitionof

den

sebreasts

Typeof

MX

Typeof

US

Buch

berger

etal28

All

No

Undergoingscreen

ing

Cyst,recentMX+orPE

+,M

X+byaseco

nd

read

erBI–RADS2–

4Screen

-film

Han

d-held

Kuhlet

al32

All

Yes

Asymptomatic

women

NR

BI–RADS3–

4Screen

-film

Han

d-held

Kap

lan40

MX-

No

Asymptomatic

women

presentingfor

screen

ingMX

NR

BI–RADS3–

4Film

-screen

Han

d-held

Kolb

etal27

All

No

Asymptomatic

women

SymptomsonpriorCBE

BI–RADS2–

4Screen

-film

Han

d-held

Crystal

etal38

MX-

No

Asymptomatic

women

Can

cers

whose

retrospective

lyreview

edMX

revealed

avisible

massorweredetermined

tobe

palpab

leonre-examinationbyasurgeo

n

BI–RADS2–

4Film

-screen

Han

d-held

Brancato

etal30

All

No

Asymptomaticwomen

self-referringto

MXoutsideofthepopulation-based

screen

ingprogramme

USperform

edin

>1month

BI–RADS3–

4NR

Han

d-held

DeFeliceet

al.,3

1All

No

RoutineMXexam

ination,

spontaneo

uslyrequested

NR

BI–RADS3–

4Screen

-film

Han

d-held

Sardan

elliet

al.,3

3All

Yes

Asymptomatic

women

<25

years,pregnan

cy,lactation,cu

rren

tch

emotherap

y,term

inal

illness,co

ntraindication

toMRim

aging

>50

%fibroglandular

den

sity

Screen

-film

Han

d-held

Weinsteinet

al46

MX-

Yes

Researchscreen

ing

NR

BI–RADS3–

4Film

-screen

Han

d-held

Bae

etal34

All

No

Asymptomatic

women

withnon-

palpab

lebreastcancer

MXfindingsat

review

iden

tified

asaco

rrelateof

US-detectedbreastcancer,notreatm

ent

BI–RADS3–

4NR

Han

d-held

Corsettiet

al25

All

No

Self-referringto

screen

ing

Symptoms

BI–RADS3–

4Screen

-film

Han

d-held

Youket

al.,41

MX-

No

Asymptomatic

women

undergoing

gen

eral

screen

ing

Nosurgical

biopsy,n

otco

nfirm

edbyasurgical

biopsy,d

idnothaveat

leasta2-year

follo

w-upUS

BI–RADS3–

4Screen

-film

Han

d-held

Berget

al.,

12

All

Yes

Asymptomatic

women

presentingfor

routineMX

Preg

nan

cyorlactation,metastaticdisease,

symptoms,surgeryin

≤12

months,im

plants

BI–RADS3–

4in

≥1

quad

rant

Both

(either-or)

Han

d-held

Hooleyet

al.,8

MX-

No

Screen

ingUSbreastexam

inations

follo

wingthelegal

chan

gein

breast

den

sity

notification

Bilateralm

astectomy,mostrecentMX>12

month

ornone

BI–RADS3–

4Digital

Han

d-held

Leonget

al.,

42

MX-

No

Asymptomatic

women

undergoing

routineMX

NR

BI–RADS3–

4Digital

Han

d-held

Weigertan

dStee

nbergen

,44

MX-

No

Screen

ingUSbreastexam

inations

follo

wingthelegal

chan

gein

breast

den

sity

notification

NR

BI–RADS3–

4NR

Han

d-held


4

Table

1continue

d

Authors,

pub

licationye

arScreen

ing

pop

ulation

Additional

risk

factorsa

Description

ofthestud

ied

pop

ulation

Exclusioncriteria

Defi

nitionof

den

sebreasts

Typeof

MX

Typeof

US

Girardiet

al.,

39

MX-

No

Asymptomatic

self-referringwomen

Symptoms,exam

inationat

other

institutions

BI–RADS3–

4Digital

Han

d-held

Wan

get

al.,26

All

No

Ruralwomen

withscreen

-detected

cancerwhoacceptedMXan

dUS

before

treatm

ent

MissingMX

BI–RADS3–

4NR

Han

d-held

Korpraphonget

al.,

29

All

No

Asymptomatic

women

undergoing

voluntary

screen

ing

Symptoms,history

ofbreastcancer,previous

atyp

ical

ductal

hyp

erplasia,

atyp

ical

lobular

hyp

erplasiaorLC

IS

BI–RADS2–

4Digital

Han

d-held

Brem

etal.,15

All

No

Asymptomatic

women

attendingfor

MXscreen

ing

Symptoms,proceduresortreatm

entin

≤1year,

pregnan

cyorlactation,d

isco

rdan

tbreastden

sity

classificationtech

nicianvs.rad

iologist

BI–RADS3–

4Digital

Automated

Chan

get

al37

MX-

No

Asymptomatic

women

seeking

prevalence

breastscreen

ing

Nofollo

w-up>12

afterscreen

ing,h

istory

of

breastorovarian

cancers,chestirradiation,B

RCA

positive,p

ositive

orsuspiciousMX

BI–RADS3–

4Digital

Han

d-held

Hwan

get

al43

MX-

No

Asymptomatic

women

undergoing

screen

ing

Symptoms,nofollo

w-up≥1year

afterscreen

ing

BI–RADS3–

4Digital

Han

d-held

Weigertan

dStee

nbergen

45

MX-

No

Screen

ingUSbreastexam

inations

follo

wingthelegal

chan

gein

breast

den

sity

notification

NR

BI–RADS3–

4NR

Han

d-held

Kim

etal48

MX-

No

Consecu

tive

women

undergoing

screen

ingwithMXan

dUS

>1USin

1year

withnorm

alpriorUS,

knownrisk

factors

other

than

den

sebreasts,n

osurgeryor

follo

w-upin

12months

BI–RADS3–

4Digital

Han

d-held

Tagliafico

etal36

MX-

No

Asymptomatic

women

self-referring

forMXscreen

ing

History

ofbreastcancer,pregnan

cy,lactation,

implants

BI–RADS3–

4Digital

Han

d-held

Wilczeket

al35

All

No

Asymptomatic

women

invitedfor

servicescreen

ingMX

Curren

tlypregnan

t,breastfee

ding,p

revious

breastsurgery,history

ofbreastcancerdiagnosis

and/ortreatm

entin

past12

months

BI–RADS3–

4Digital

Automated

Destouniset

al50

MX-

No

Screen

ingUSbreastexam

inations

follo

wingthelegal

chan

gein

breast

den

sity

notification

Symptoms

BI–RADS3–

4Digital

Han

d-held

Klevo

set

al49

MX-

No

Asymptomatic

women

undergoing

routineMX

≥20

%lifetim

erisk

ofbreastcancer,personal

history

ofbreastcancer

BI–RADS3–

4Digital

Han

d-held

Weigert47

MX-

No

Screen

ingUSbreastexam

inations

follo

wingthelegal

chan

gein

breast

den

sity

notificationb

NR

BI–RADS3–

4NR

Han

d-held

BI-R

ADS2den

sity:b

reasts

withscatteredareasoffibroglandularden

sity

(sometim

esdefi

ned

as25

–50

%fibroglandulartissue),BI-R

ADS3den

sity:b

reasts

withheterogen

eouslyden

setissue(50–

75%),BI-RADS4

den

sity:b

reasts

withextrem

elyden

sebreasttissue(>75

%),MXmam

mography,NRnotreported

,USultrasound

a Women

withrisk

factors

other

than

den

sebreasts

may

havebee

nincluded

inallstudies,in

variab

leproportions.Astudywas

categorisedas

“Yes”ifthead

ditionalrisk

factors

wereaselectioncriterionforinclusion.bTh

efirsttw

oyearsofscreen

ingwithultrasoundwereexcluded

from

thisreview

,asthe

datawerealread

yreported

inthetw

opreviouspublications.44,45


5

Table2.

Studyoutcomes

Stud

yMam

mog

raphyf

Ultrasoun

din

MX-wom

enf

Positive

screen

ingou

tcom

es

N screen

sDetectedcancers

N screen

sAdditionally

detectedcancers

Type(thresh

old)e

Mam

mog

raphy

Ultrasoun

din

MX-wom

en

N (DCIS)

Per

1000

N (DCIS)

Per10

00N

Per10

00N

Per10

00

Wholescreen

ingpop

ulation

Buch

berger

etal28

8970

142(47)

15.8

(5.2)

8103

32(5)g

3.9(0.6)

NR

NR

NR

NR

NR

Kuhlet

al32

NR

3(1)

NR

NR

1(1)

NR

NR

NR

NR

NR

NR

Kolb

etal27

13,547

946.9

12,193

483.9

Biopsy

(actual)

423

3132

026

Brancato

etal30

26,973

156a

5.8

5227

20.4

Test+(U3–

5)NR

NR

108

21

Test+(U4–

5)NR

NR

234

Biopsy

(actual)

NR

NR

296

DeFeliceet

al31

NR

8NR

1754

126.8

Test+(U3–

5)/Biopsy

(rec)

NR

NR

187

36

Sardan

elliet

al33

NR

6(1)

NR

NR

1(0)

NR

NR

NR

NR

NR

NR

Bae

etal34

NR

515

NR

NR

227

NR

NR

NR

NR

NR

NR

Corsettiet

al25

7224

20(4)

2.8(0.6)

NR

32(4)

NR

Biopsy

(actual)

NR

NR

427

NR

Berget

al12

7473

59(18)

7.9(2.4)

6714

32(2)

4.8(0.3)

Test+(3–5)

759

102

836

125

Biopsy

(actual)

162

2244

967

Wan

get

al26

NR

176

NR

NR

56NR

NR

NR

NR

NR

NR

Korpraphonget

al29

14,483

865.9

NR

19NR

NR

NR

NR

NR

NR

Brem

etal15

15,318

82(31)

5.4(2.0)

13,017

30(2)

2.3(0.2)

Test+(0)

2301

150

2063

158

Biopsy

(rec)

610

4056

944

Biopsy

(actual)

586

3855

242

Wilczeket

al35

1668

74.2

1645

42.4

Test+(SE3–

5)23

1423

14

Biopsy

(actual)

11h

712

7

Mam

mog

raphy-neg

ativewom

en

Kap

lan40

NR

NR

NR

1862

5(1)

2.7(0.5)

Test+(def)b

NR

NR

250

134

Biopsy

(rec)

NR

NR

5630

Crystal

etal38

NR

NR

NR

1517

7(0)

4.6(0)

Test+(def)c

NR

NR

9059

Biopsy

(actual)

NR

NR

3825

Weinsteinet

al46

NR

NR

NR

363a

3(0)

8.3(0)

NR

NR

NR

NR

NR

Youket

al41

NR

NR

NR

446

1124

.7Test+(3–5)

NR

NR

134

300

Test+(4–5)

NR

NR

5111

4

Hooleyet

al8

NR

NR

NR

648

3(1)

4.6(1.5)

Test+(3–5)

NR

NR

153

236

Test+(4–5)

NR

NR

3859

Biopsy

(rec)

NR

NR

6499

Biopsy

(actual)

NR

NR

6397


6

Table

2continue

d

Stud

yMam

mog

raphyf

Ultrasoun

din

MX-wom

enf

Positive

screen

ingou

tcom

es

N screen

sDetectedcancers

N screen

sAdditionally

detectedcancers

Type(thresh

old)e

Mam

mog

raphy

Ultrasoun

din

MX-wom

en

N (DCIS)

Per

1000

N (DCIS)

Per10

00N

Per10

00N

Per10

00

Leonget

al42

NR

NR

NR

141

2(1)

14.2

(7.1)

Test+(U3–

4)NR

NR

2417

0

Test+(U4)

NR

NR

1499

Biopsy

(rec)

NR

NR

1499

Weigertan

dStee

nbergen

44

NR

NR

NR

8647

27(4)

3.1(0.5)

Test+(3–5)

NR

NR

1196

138

Test+(4–5)

NR

NR

429

50

Biopsy

(rec)

NR

NR

429

50

Girardiet

al39

NR

NR

NR

9960

222.2

NR

NR

NR

NR

NR

Chan

get

al37

NR

NR

NR

990

5(2)

5.1(2.0)

Test+(3–5)

NR

NR

366

370

Test+(4–5)

NR

NR

8485

Hwan

get

al43

NR

NR

NR

1349

8(1)

5.9(0.7)

NR

NR

NR

NR

NR

Weigertan

dStee

nbergen

45

NR

NR

NR

10,282

23(9)

2.2(0.9)

Test+(3–5)

NR

NR

1310

127

Test+(4–5)

NR

NR

435

42

Biopsy

(rec)

NR

NR

435

42

Kim

etal48

NR

NR

NR

3171

9(2)

2.8(0.6)

Test+(3–5/md)

NR

NR

831

262

Test+(4–5/md)

NR

NR

131

41

Biopsy

(rec)

NR

NR

131

41

Biopsy

(actual)

NR

NR

147

46

Tagliafico

etal36

NR

NR

NR

3231

23(1)

7.1(0.3)

Test+(3–5)

NR

NR

145

45

Test+(4–5)

NR

NR

8827

Biopsy

(actual)

NR

NR

4715

Destouniset

al50

NR

NR

NR

5434

18(0)

3.3(0)

Test+(3–5)

NR

NR

194

36

Test+(4–5)

NR

NR

100

18

Biopsy

(actual)

NR

NR

104

19

Klevo

set

al49

NR

NR

NR

394

0(0)

0(0)

Test+(3–5)

NR

NR

6917

5

Test+(4–5)

NR

NR

1948

Biopsy

(rec)

NR

NR

2461

Biopsy

(actual)

NR

NR

2666

Weigert47

NR

NR

NR

7459

21(1)

2.8(0.1)

Test+(3–5)

NR

NR

727

97

Test+(4–5)

NR

NR

201

27

Biopsy

(rec)

NR

NR

201

27

DCISductal

carcinomain

situ,mdmodified

BI–RADScategorisation(complicated

cysts≤5mm

observed

ascircumscribed

,homogen

ousan

dhyp

oechoic

lesionsorcircumscribed

oval-shap

edsolid

masses

≤5mm

withoutan

ysuspiciousUSfeaturesweredowngraded

toBI–RADS2),M

X-mam

mographyneg

ativewomen

,NRnotreported

,rec

reco

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ded

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ned

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itecturald

istortionoracousticshad

owing

cDefi

ned

as:complexcystsorsolid

lesionseIn

moststudies,screen

ingtestoutcomes

werereco

rded

usingtheBI–RADSsystem

fWithor

withoutad

ditionalphysicalexam

ination/clin

icalbreastexam

ination

gMightincludesomewomen

withab

norm

almam

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partsofM

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atawerenotreported

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ination,an

dwereco

untedin

the“healthy”

group.


7

small differences were observed, these did not appear to explainthe variation between studies (Fig. 2b-d).Per 1000 screens in women with negative mammography,

ultrasound detected on average ca. 4 additional cases of breastcancer (FE: 3.8, 95% CI: 3.4–4.2; RE: 4.0, 95% CI: 3.1–5.1; as shown inFig. 4, this estimate was based on all 23 studies that reportednumbers of screened women with negative mammography). Thiswas slightly higher, 5 per 1000, in two studies of women withadditional risk factors.12,46 In the 17 studies separating DCIS frominvasive cases, approximately 13% (32/248) were DCIS.Although for all studies with reported data a large number of

cases were detected by both screening methods (SupplementaryTable 2), there were a considerable number of cases that weredetected by only one method.Where data were available, there appeared to be no strong and

significant correlation between the number of cancers detectedby mammography and those additionally detected only byultrasound, neither when additional detection by ultrasound wasconsidered in absolute (ρ weighted by number of women in thestudy= 0.23, P= 0.62) nor in relative (weighted ρ= –0.48, P=0.27) terms.

Impact on recall for assessmentRecall for assessment after supplemental ultrasound screeningcould be compared to recall after mammography on data fromthree studies,12,15,35 two from the USA and one from Sweden.Here, supplemental ultrasound approximately doubled thenumber of screens with non-normal findings (Table 2). In two

Overall

A

C D

B

Fixed effect modelRandom effects modelHeterogeneity: I2 = 81%, �2 = 0.009, p < 0.01

Heterogeneity: I2 = 83%, �2 = 0.0091, p < 0.01



Heterogeneity: I2 = 0%, �2 = 0, p = 0.42




Heterogeneity: I2 = 81%, �2 = 0.009, p < 0.01Heterogeneity: I2 = 81%, �2 = 0.009, p < 0.01

Sardanelli et al. 2007Korpraphong et al. 2014Buchberger et al. 2000Wang et al. 2013Kuhl et al. 2000Brem et al. 2015Bae et al. 2011Kolb et al. 2002Berg et al. 2012Wilczek et al. 2016De Felice et al. 2007Corsetti et al. 2011

11932561

3022748324

1232

USonly

1692

7105174232

411274214291112052

M+US(Total)

0.29 [0.27; 0.31]0.31 [0.25; 0.37]

0.14 [0.00; 0.58]0.18 [0.11; 0.27]0.18 [0.13; 0.25]0.24 [0.19; 0.30]0.25 [0.01; 0.81]0.27 [0.19; 0.36]0.31 [0.27; 0.34]0.34 [0.26; 0.42]0.35 [0.25; 0.46]0.36 [0.11; 0.69]0.60 [0.36; 0.81]0.62 [0.47; 0.75]

Proportion US[95%CI]

0 0.2 0.4 0.6 0.8 1

Dense definition

Fixed effect model

BIRADS−2+

BIRADS−3+

Fixed effect model

Fixed effect model

Korpraphong et al. 2014Buchberger et al. 2000Kolb et al. 2002

Sardanelli et al. 2007Wang et al. 2013Kuhl et al. 2000Brem et al. 2015Bae et al. 2011Berg et al. 2012Wilczek et al. 2016De Felice et al. 2007Corsetti et al. 2011

193248

156

130

22732

41232

USonly

1692

421

271

105174142

7232

4112742

91112052

M+US(Total)

0.29 [0.27; 0.31]

0.23 [0.19; 0.27]

0.31 [0.28; 0.33]

0.18 [0.11; 0.27]0.18 [0.13; 0.25]0.34 [0.26; 0.42]

0.14 [0.00; 0.58]0.24 [0.19; 0.30]0.25 [0.01; 0.81]0.27 [0.19; 0.36]0.31 [0.27; 0.34]0.35 [0.25; 0.46]0.36 [0.11; 0.69]0.60 [0.36; 0.81]0.62 [0.47; 0.75]


0 0.2 0.4 0.6 0.8 1

Epoch

Fixed effect model

2000−2011

2012−2017

Fixed effect model

Fixed effect model

Sardanelli et al. 2007Buchberger et al. 2000Kuhl et al. 2000Bae et al. 2011Kolb et al. 2002De Felice et al. 2007Corsetti et al. 2011

Korpraphong et al. 2014Wang et al. 2013Brem et al. 2015Berg et al. 2012Wilczek et al. 2016

1321

227481232

195630324

USonly

1692

1141

551

7174

47421422052

1052321129111

M+US(Total)

0.29 [0.27; 0.31]

0.31 [0.28; 0.33]

0.25 [0.22; 0.29]

0.14 [0.00; 0.58]0.18 [0.13; 0.25]0.25 [0.01; 0.81]0.31 [0.27; 0.34]0.34 [0.26; 0.42]0.60 [0.36; 0.81]0.62 [0.47; 0.75]

0.18 [0.11; 0.27]0.24 [0.19; 0.30]0.27 [0.19; 0.36]0.35 [0.25; 0.46]0.36 [0.11; 0.69]


0 0.2 0.4 0.6 0.8 1

Risk factors

Fixed effect model

Without extra risk factors

With extra risk factors

Fixed effect model

Fixed effect model

Korpraphong et al. 2014Buchberger et al. 2000Wang et al. 2013Brem et al. 2015Bae et al. 2011Kolb et al. 2002Wilczek et al. 2016De Felice et al. 2007Corsetti et al. 2011

Sardanelli et al. 2007Kuhl et al. 2000Berg et al. 2012

19325630

227484

1232

11

32

USonly

1692

1590

102

105174232112742142

112052

74

91

M+US(Total)

0.29 [0.27; 0.31]

0.29 [0.26; 0.31]

0.33 [0.24; 0.43]

0.18 [0.11; 0.27]0.18 [0.13; 0.25]0.24 [0.19; 0.30]0.27 [0.19; 0.36]0.31 [0.27; 0.34]0.34 [0.26; 0.42]0.36 [0.11; 0.69]0.60 [0.36; 0.81]0.62 [0.47; 0.75]

0.14 [0.00; 0.58]0.25 [0.01; 0.81]0.35 [0.25; 0.46]


0 0.2 0.4 0.6 0.8 1

Fig. 2 Additional detection of breast cancer cases with ultrasound in mammography negative women, compared to the detection with stand-alone mammography (based on 12 studies reporting detection by both screening modalities). BI-RADS 2 density: breasts with scattered areas offibroglandular density (sometimes defined as 25–50% fibroglandular tissue). BI-RADS 3 density: breasts with heterogeneously dense tissue(50–75%). BI-RADS 4 density: breasts with extremely dense breast tissue (>75%). CI confidence interval, M mammography, US ultrasound (a)Additional detection, overall results. (b) Additional detection, by definition of breast density. (c) Additional detection, by year of study. (d) Additionaldetection, by whether the study focused on women with additional risk factors

0%

20%

40%

60%

200 400 600 800

Total cancers detected

Per

cent

ultr

asou

nd

Funnel99% limit

95% limit

Fig. 3 Funnel plot of the percentage of cancers detected byultrasound against the total number of cancers detected (based on12 studies reporting detection by both screening modalities)


8

studies, the number of biopsies was also doubled,12,35 whereas inanother study,15 it was almost trebled. Both studies from the USAhad an already high mammography abnormality rate, 10%(BI–RADS 3 to 5)12 and 15% (BI–RADS 0, roughly equivalent toBI–RADS 4–5 in other studies).15 Interestingly, mammographicabnormalities were much more infrequent in the Swedish study,just above 1%,35 which was also lower than the data reported forthe routine screening programme (~3%).51 Another study fromthe USA also reported a sharp, 76%, increase in the number ofbiopsies.27

Per 1000 mammography negative screens, ultrasound waspositive in 110–130 screens (FE: 131, 95% CI: 128–134; RE: 109,95% CI: 80–145) when a positive screen was defined as BI–RADScategories 3–5. Ultrasound would typically prompt a recall forassessment, defined as BI–RADS categories 4–5, in on average85 screens per 1000 (FE: 95% CI: 83–88), although this was lower insmaller studies as evidenced by the RE estimate, 45 per 1000 (95%CI: 26–75). Approximately 50 per 1000 mammography negativescreens were followed by a recommendation for a biopsy (FE: 47/RE: 53). Almost all of the women concerned actually had one,though that was less frequently the case in the smaller studies (FE:40/FE: 28). All these proportions varied considerably amongstudies. Of the 13 studies with reported data, only one includedwomen with additional risk factors, so the higher-than-averagerisk cannot explain the high proportions of women with non-normal ultrasound findings.The data did not suggest a relationship between an (increased)

number of women referred for assessment and an (increased)cancer detection. The correlation between the proportion ofscreens with non-normal ultrasound findings (BI–RADS 3–5 orequivalent) and the extra detected number of cancer cases per1000 mammography negative screens was weak (ρ weighted bynumber of women with negative mammography= 0.25, P= 0.32).The correlations with the proportions of screens with moreseverely abnormal ultrasound findings (BI–RADS 4–5 or equiva-lent), and of screens followed by a biopsy, were also notsignificant (weighted ρ= 0.03 and P= 0.93, and ρ= 0.35 andP= 0.17, respectively).

Quality of the studies and of their reportingAn evaluation of the quality of the studies and of their reportingusing the QUADAS–2 framework revealed some potential issueswith universal applicability of the findings and a potential for biasin terms of patient selection and (the interpretation of) the indextests (Supplementary table 3). These were related to e.g. aninclusion of women with scattered fibroglandular tissue amongthose with “dense” breasts, (retrospective) interpretation ofscreening tests with knowledge from other imaging methods,and exclusion of mammography negative but palpable tumoursafter an adjunct clinical breast examination, as this is not astandard screening procedure in settings such as the UK.

Time investment for ultrasound examinationsThe reporting of time spent performing a screening ultrasounddiffered by study, so no meta-analysis was undertaken for thisoutcome. The time needed for an ultrasound appeared to bearound 10min per woman on average, although the estimateswere highly variable and ranged from mean/median of 5–20(Supplementary Table 4). Additionally, Hooley and colleagues8

reported that the (routine) ultrasound appointments werescheduled at 45-min intervals.

DISCUSSIONMain findingsIn its latest review from 2016, International Agency for Researchon Cancer (IARC) concluded that there is limited evidence for anincreased detection of breast cancer using supplemental ultra-sound in women with dense breasts, citing the lack of randomisedcontrolled trials and study design heterogeneity among thereasons.4 Our meta-analysis, focusing on the most recent studies,showed an on average 40% increase in the detection ofasymptomatic breast cancers. Cases missed by mammographywere detected by ultrasound in all but one (underpowered) study.There are still no data on whether the additional detection by

ultrasound improves mortality from breast cancer, which is in linewith the conclusions made by IARC’s review.4 The cases detected

Study

Fixed effect modelRandom effects model

Brancato et al. 2007Klevos et al. 2017Girardi et al. 2013Weigert & Steenbergen 2015Brem et al. 2015Wilczek et al. 2016Kaplan 2001Weigert 2017Kim et al. 2016Weigert & Steenbergen 2012Destounis et al. 2017Kolb et al. 2002Buchberger et al. 2000Crystal et al. 2003Hooley et al. 2012Berg et al. 2012Chang et al. 2015Hwang et al. 2015De Felice et al. 2007Tagliafico et al. 2016Weinstein et al. 2009Leong et al. 2012Youk et al. 2011

20

22233045

219

2718483273

3258

122332

11

Extracases

104547

5227394

99601028213017164518627459317186475434

1219381031517648

6714990

134917543231363141446

Totalscreened

3.8 [ 3.4; 4.2]4.0 [ 3.1; 5.1]

0.4 [ 0.0; 1.4]0.0 [ 0.0; 9.3]2.2 [ 1.4; 3.3]2.2 [ 1.4; 3.4]2.3 [ 1.6; 3.3]2.4 [ 0.7; 6.2]2.7 [ 0.9; 6.3]2.8 [ 1.7; 4.3]2.8 [ 1.3; 5.4]3.1 [ 2.1; 4.5]3.3 [ 2.0; 5.2]3.9 [ 2.9; 5.2]3.9 [ 2.7; 5.6]4.6 [ 1.9; 9.5]4.6 [ 1.0; 13.5]4.8 [ 3.3; 6.7]5.1 [ 1.6; 11.7]5.9 [ 2.6; 11.7]6.8 [ 3.5; 11.9]7.1 [ 4.5; 10.7]8.3 [ 1.7; 24.0]

14.2 [ 1.7; 50.3]24.7 [12.4; 43.7]

Rate per 1000screened [95%CI]

0 5 10 15 20 25 30

Events per 1000observations

Number extra detected per 1000


Fig. 4 Extra detection of cases of breast cancer per 1000 women with negative mammography (based on 23 studies reporting detection inmammographically negative women). CI confidence interval


9

only by ultrasound were frequently relatively small, however, themajority were invasive cancers. Some studies reported intervalcancers, but for the time being those data appear less informative,as the length of follow-up and the completeness of theascertainment differed substantially between studies. In thefuture, it would be helpful to see results from a large cohort withcomplete ascertainment of interval cancer cases, as this wouldgive us an estimate of the effect of supplementary ultrasound onscreening programme sensitivity and its ability to reduce breastcancer mortality.

Clinical implicationsEven though in women with dense breasts ultrasound detectscancers that are missed by mammography (SupplementaryTable 2), ultrasound should be considered as a supplementalrather than a stand-alone screening method. In studies where allwomen underwent both screening tests, roughly 10–30% of allscreen-detected cases were detectable only on mammography.Currently in England, women 50–70 years of age with dense

breasts are screened with digital mammography every three years,same as women with fatty breasts. In 2015–2016, 1.8 millionwomen were screened, with on average 410 women referred forassessment and 82 having a breast cancer detected per every10,000.52 This means that about 5 women were referred perdiagnosed cancer case. These statistics are unfortunately notreported by breast density but the prevalence of at leastheterogeneously dense breasts (BI–RADS 3–4) among screenedwomen appears to be about 40%.53–58 Women with dense breastshave roughly twice the risk of breast cancer than those with fattybreasts,59 and we assume that the risk of an abnormalmammogram is similarly increased. With these estimates in mind,it can be approximated that among every 10,000 screened women4000 have dense breasts (Supplementary Table 5A). Of the 410referred in total, 234 referrals would be in those with densebreasts, as would be 47 among the 82 cancers detected withmammography. Based on our meta-analysis, 3766 ultrasoundexaminations in mammography negative women would lead to adetection of an additional 15–19 cancer cases, of which 2–3 wouldbe DCIS. The absolute number of additional cancer cases willdepend on the underlying risk in the population but both relativeand absolute meta-analysis results give similar numbers for thisexample. This would necessitate an additional 234 referrals(+100%), or 13–16 per additionally detected cancer case.Mammography screening of women aged 50–70 years withsupplemental ultrasound for 40% with dense breasts would,therefore, necessitate 10,000 mammograms, 3766 ultrasoundexaminations (lasting, on average, around 10min) and 644referrals for assessment (57% more than with mammographyalone), and would detect 97–101 breast cancers (18–23% morethan mammography alone).These calculations suggest that there are important capacity

considerations for an introduction of ultrasound as a supplemen-tary screening method for women with dense breasts. At present,ultrasound is used as part of assessment after positive mammo-graphy, i.e. in 410/10,000 screened women. Hence, the use ofultrasound in screening for 40% of the target population wouldrequire a ten-fold increase in the ultrasound availability. To lessenthe impact on service providers, supplemental ultrasound screen-ing could instead be considered for smaller subgroups of womenwith a particularly increased risk of breast cancer. As an example,ultrasound screening could be reserved for the approximately10% women with extremely dense breasts whose relative risk ofbreast cancer is increased approximately threefold compared tothe rest of the population.53,59,60 Assuming the same supple-mental detection with ultrasound as in the meta analysis, thisstrategy would require 898 instead of 3766 ultrasound examina-tions per 10,000 screened women and a 25% overall increase inreferrals for assessment (an additional 103/10,000). A conservative

estimate of the expected increase in the detection rate, based onthe average effect found in our meta-analysis, would be in theorder of 10% (an additional 8/10,000; Supplementary Table 5B).From the above calculations, it is evident that although the

addition of ultrasound would increase the number of assessments,the major call on resources would be the performance of theultrasound examinations. This could potentially be kept to amanageable level by use of a high density threshold.At present, 31 women per 10,000 screened have an interval

breast cancer diagnosed after negative mammography.61 It islikely that supplementary ultrasound could help decrease this riskby detecting cancers already at screening, but it is not yet clear byhow much because the extent of overdiagnosis for now remainsuncertain. Assuming that, like in mammography,62 also hereoverdiagnosis can explain only a small proportion of cases, theadditional detection by supplementary ultrasound (estimatedabove at 19 or 8 per 10,000), could prove to be clinicallymeaningful in decreasing the overall interval cancer rate.

Strengths and weaknessesWe did a thorough systematic search in the leading medicaldatabase, and, additionally, hand-searched all identified reviewsand similar secondary literature. We used pre-specified selectioncriteria and excluded studies that did not describe routinescreening settings.Although none of the studies was a randomised trial, both

mammography and ultrasound testing in the selected studieswere undertaken sequentially in the same women. This meansthat all women acted as their own controls, thereby accounting forbetween-patient variability. However, we cannot exclude apotential study effect on mammography interpretation particu-larly in the more complex cases, originating from the radiologistsbeing aware that ultrasound will form part of the screeningevaluation.Nevertheless, several studies identified in our search had to be

excluded from the review as they did not report the dataseparately for asymptomatic women undergoing screening, or bytheir breast density. This suggests that a substantial amount of therelevant data may have remained unreported, however, funnelplot analysis suggested only a small effect of a publication bias.Although all studies described asymptomatic women, there

were important differences in their study designs. First, while moststudies defined dense breasts as those with at least hetero-geneous density (≥50% fibroglandular tissue), a handful of studiesreported data for women with at least scattered density (25–49%fibroglandular tissue) where the risk of breast cancer is generallylower59 and mammography tends to be more sensitive.63 Theinclusion of women with scattered density appears to haveslightly diluted the beneficial effect of the ultrasound (proportionof cancers detected by ultrasound 0.23 with BI–RADS 2-4 vs. 0.31with BI–RADS 3–4). Second, intensive additional imaging, includ-ing not just ultrasound but also e.g. magnetic resonance, may be asensible option for women with additional risk factors such asthose who are BRCA 1/2 gene carriers or have a high estimatedlifetime risk of breast cancer.64 The inclusion of studies focusingonly on women with additional risk factors did not seem tosubstantially alter our results (proportion of cancers detected byultrasound with additional risk factors 0.29 vs. 0.33 when womenwere not selected based on additional risk factors). It should benoted, however, that at least a small proportion of high-riskwomen were included in virtually all studies. Third, older studiesused film-screen mammography, which was shown in somestudies to be less sensitive in dense breasts than digitalmammography.55 Adding ultrasound appeared to be slightlymore beneficial after film-screen mammography (proportion ofcancers detected by ultrasound 0.31 vs. 0.25 in digital mammo-graphy). Multiple studies are now underway to further improvethe detection of breast cancer with mammography. An example of


10

new mammography-based technologies is supplemental tomo-synthesis, which appears to significantly improve the overalldetection of breast cancer,65 including that among women withdense breasts.66 Only two studies used the newer automatedultrasound technology;15,35 in both studies, the extra detectionwas close to the pooled estimate. Ultrasound screening wasundertaken by radiographers in one large study using hand-helddevices.26 The additional detection of breast cancer was slightlylower in this study than in the pooled estimate, suggesting that,for radiologist-operated and radiologist-read hand-held ultra-sound screening, the pooled estimate is on the conservative side.Another factor that may have affected the comparisons betweenthe studies is the proportion of studied women undergoingprevalence (first) and incidence (any subsequent) screeningrounds. In mammography screening, breast cancer detectionand the frequency of referral for assessment are both lower in theincidence rounds.52 The same trend was suggested for ultrasoundscreening in the study by Berg and colleagues,12 where ultrasounddetected 70% more cases than mammography in the prevalenceround (14 only by ultrasound vs. 20 by mammography), andthereafter 56% (9 vs. 16) and 39% (9 vs. 23) more cases in the firstand the second incidence rounds, respectively. The frequency ofpositive ultrasound examinations without an underlying cancerabout halved from the prevalence to the incidence rounds, with16% and 8%, respectively. A more detailed reporting of theoutcomes by screening round from other studies would beinformative. Additionally, BI-RADS density classification haschanged over time, with the latest edition published in 2013effectively lowering the threshold for classifying breasts asdense.67 Finally, the studies differed in the degree to whichultrasound image interpretation could be influenced by knowl-edge of mammography imaging and vice versa (although thisdetail was not consistently reported), and in how they selectedtheir study populations, e.g. by whether screening was organisedor opportunistic. All these factors may have led to slightly differentselections of women in terms of their risk profile, and thisheterogeneity needs to be taken into account in the interpretationof the results.

CONCLUSIONStudies have consistently shown an increased detection bysupplementary ultrasound of predominantly small but invasivebreast cancers in women with dense breasts. The feasibility of thisscreening method in routine practice might be at present limitedgiven its resource use, although the strain on the health carecapacities might be manageable by a careful targeting of thehighest-risk women among those with dense breasts.

ACKNOWLEDGEMENTSWe would like to thank Dr. Chao Wang (Centre for Cancer Prevention, WolfsonInstitute of Preventive Medicine) for help with Chinese-language papers. S.W.D. andD.P. contributed to this study as part of the programme of the Policy Research Unit inCancer Awareness, Screening and Early Diagnosis, which receives funding for aresearch programme from the Department of Health Policy Research Programme(106/0001). It is a collaboration between researchers from seven institutions (QueenMary University of London, University College London, King’s College London,London School of Hygiene and Tropical Medicine, Hull York Medical School, DurhamUniversity and Peninsula Medical School). M.R. and A.B. were supported by CancerResearch UK (grants C8162/A16892 and C569/A16891, respectively).

AUTHOR CONTRIBUTIONSM.R. and V.A. performed literature searches, analysed the data and wrote themanuscript. A.B. analysed the data and commented on the manuscript. D.P.performed the literature searches and commented on the manuscript. S.W.D.designed the study, performed the literature searches, analysed the data,commented on the manuscript and made the decision to submit.

ADDITIONAL INFORMATIONSupplementary information is available for this paper at https://doi.org/10.1038/s41416-018-0080-3.

Competing interests: The authors declare no competing interests.

Ethics approval: Ethical approval was not sought as the study was based entirely onpreviously published data.

Availability of data and material: The study was based entirely on previouslypublished data.

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independent review. Br. J. Cancer 108, 2205–2240 (2013).3. Broeders, M. et al. The impact of mammographic screening on breast cancer

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5. Perry, N. B. et al. (eds). European Guidelines for Quality Assurance in Breast CancerScreening and Diagnosis, 4th edn (Office for Official Publications of the EuropeanCommunities, Luxembourg, 2006).

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