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BMJ 2012;345:e7536 doi: 10.1136/bmj.e7536 (Published 16 November 2012) Page 1 of 10

Research

RESEARCH

Prognosis in women with interval breast cancer:

population based observational cohort study

OPEN ACCESS

Mette Kalager physician and postdoctoral researcher , Rulla M Tamimi assistant professor ,1 2 3 1 4

Michael Bretthauer professor , Hans-Olov Adami professor 2 5 1 6

Department of Epidemiology,HarvardSchool of Public Health, Boston, USA; University of Oslo, Faculty of Medicine, Institute ofHealth and Society,1 2

Oslo, Norway; Department of Clinical Research, Telemark Hospital, Skien, Norway; Channing Laboratory, Department of Medicine, Brigham and3 4

Women’s Hospital, Harvard Medical School, Boston, USA; Department of Organ Transplantation, Oslo University Hospital, Rikshospitalet, Oslo,5

Norway; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden6

IntroductionAbstract

Objective To compare the prognosis in women with interval breastWhen mammography screening programmes are fully

cancer (cancer detected after a normal screening mammogram andimplemented, interval cancers comprise asubstantial proportion

before the next scheduled mammogram) with breast cancer detectedof incident breast cancers. Interval cancers may have been

among women not yet invited to mammography screening

overlooked at the last mammography examination or become(non-screened).apparent because they grew so rapidly that the detectable

Design Population based observational study. preclinical phase (sojourn time) was shorter than the screeninginterval.Setting Norwegian breast cancer screening programme, implemented

in different counties from 1996 to 2005. Because interval breast cancers in some studies on average arelarger, of a more advanced stage, and express proliferativeParticipants 7116 women with a diagnosis of breast cancer at age 50 1 2 1

markers more than screen detected tumours, it has beento 72 years; 1816 had interval breast cancer and 5300 had a diagnosis 1 3

suggested that prognosis of interval breast cancers is poorer of breast cancer but had not yet been invited to screening.

than that of screen detected breast cancers. However, prognostic3Main outcome measures Characteristics of the breast tumours, and

studies may be misleading when comparing interval breastsurvival of the women usingKaplan Meier curves andmultivariable Coxcancers with screen detected breast cancers because the screen proportional hazard models.detected breast cancers are affected by length bias sampling,

Results Although interval cancers on average were slightly larger thanlead time bias, and overdiagnosis bias. Therefore the valid

the cancers in women not invited to screening, the histological type or

comparison group for assessment of prognosis in women withstatus of axilliary lymph nodes did not differ noticeably between the twointerval breast cancers is non-screen detected cancers among

groups. Among interval cancers, there were no appreciable trends inwomen not invited to mammography screening, which are

size, nodal status, grade,or hormone receptor positivity associated withunaffected by the biases that screening entails. Comparisons

time since thelast normal mammogram as a marker ofgrowthrate. After with historical groups, as in many previous studies, may also

10 years of follow-up, the survival rates were 79.1% (95% confidencelead to confounding because survival from breast cancer has

interval 75.4% to 82.3%) among women with interval cancers and76.8%improved over time. Only a few, small studies have compared4 5

(75.3% to 78.2%) among women in the non-screened cancer groupthe survival of women with interval breast cancer with those

(hazard ratio 0.98, 95% confidence interval 0.84 to 1.15; P=0.53).with non-screen detected breast cancer, with inconsistent

Analyses stratified by time since last normal mammogram, age atfindings. 6 -1 3

diagnosis, or screening round showed similar results.In this population based study we took advantage of the

Conclusion The prognosis of women with interval breast cancers wasnationwide breast cancer screening programme in Norway,

the same as that of women with breast cancers diagnosed withoutwhich has been gradually implemented over a nine year period. 1 3

mammography screening.This staggered roll out allowed a comparison between womenwith interval breast cancer and those with breast cancer

Correspondence to: M Kalager Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, Boston,

USA [email protected]

No com m e r cial r e use: Se e r ig ht s a nd r ep r int sht tp :/ / www. bm j .co m /p er m issi ons Su bscr ib e: h tt p: / /w ww.b m j. com / subscr ibe


RESEARCH

diagnosed within the same period but before they had been of women with these tumours might be worse than for those

invited to mammography screening. whose breast cancer is overlooked, and with increasing screeningrounds and more experience the prognosis would be worse. WeWe investigated whether breast cancers detected in the intervaltherefore carried out a secondary analysis restricted to intervalafter a normal mammography screening result but before the breast cancers stratified by screening round.next scheduled screening are more lethal and thus may need

more aggressive treatment than non-screen detected breastStudy populationcancers.

From the cancer registry database we retrieved information onMethods date of diagnosis, age at diagnosis, county of residency,

classification of the canceraccording to the pathological tumour,Breast cancer screening programme

node, metastases (pTNM) classification (International UnionSince 1951, reporting of cancer diagnoses to the nationwide Against Cancer guidelines), and tumour stage in all women21

Cancer Registry of Norway has been compulsory by national with a first diagnosis of invasive breast cancer at age 50 to 72legislation. Patients are identified in the registry by their unique years in Norway between 1 January 1996 and 31 December national registration number, assigned to all residents in Norway 2006. Thestage ofbreast tumour is coded as I (localised cancer),and including date of birth. The cancer registry has maintained II (regional cancer), III (cancer fixed to the skin or the chestnearly 100% completeness for solid cancers, including breast wall), or IV (cancer with distant metastases). To determinecancer. whether a diagnosis was made before or after invitation to14 1 5

screening we linked data on all the women to the screeningIn 1996 the Norwegian breast cancer screening programmedatabase at the cancer registry. We then further categorisedstarted in four counties and then expanded gradually, county bywomen with breast cancer diagnosed after invitations tocounty, over the course of nine years. Since 2005, all women4 1 3

screening as interval cancers if they met our criteria.in Norway aged 50-69 years are invited to mammographyscreening every two years. The Central Population Register of From the screening database we further retrieved data on tumour Norway identifies women eligible for screening by their national grade (based on the Nottingham grading system, I-III );2 2

registration number. Invitations are posted to each eligible oestrogen and progesterone receptor status ; pTNM21

woman, suggesting an appointment time. Two radiologists classification; and dates of invitation and attendance to the1 6

independently read two view mammograms (craniocaudal views screening programme. We classified oestrogen and progesteroneand mediolateral oblique views) in accordance with European receptors as positive (=10% positive staining) or negative (<10%guidelines for quality assurance, which are classified according positive staining). These data were not available from the1 7

to a five point interpretation scale reflecting the probability of registry’s database and as a result are not available for womencancer. The decision as to whether further diagnostic not invited to mammography screening. We defined screening18

examinations are necessary is based on the consensus of two rounds by county rather than by individual women. The

experienced radiologists. After this final decision, no further follow-up period was from 1 January 1996 to 31 December diagnostic tests are done before the next scheduled screening 2006. Linkage to the Central Population Register of Norwayinvitation. and the National Death Register allowed censoring at date of

emigration or death. For the purpose of this study we definedFor the purpose of the study we classified women as havingtwo study cohorts:interval cancer if breast cancer was diagnosed within two years

• Interval cancer group —comprising all women with a firstand two months of the last normal screening mammogram butdiagnosis of invasive breast cancer during the interval before invitation to the next screening. Hence the cohort of between two screening rounds or breast cancer diagnosedwomen with interval cancers included only those who werewithin two years and two months after the date of the lastinvited participants in the screening programme but hadnormal examination in the breast cancer screeningnon-screened detected breast cancer. For the present analysis programme between 1996 and 2006.we extended the screening interval by two months because we

retrieved date of diagnosis from two databases that were not • Non-screened cancer group —comprising all women withcompletely in agreement about the date; the additional two a first diagnosis of invasive breast cancer who had not yet

months made it possible to include all women classified as been invited to the breast cancer screening programmehaving interval cancers in the screening database. Among between 1996 and 2006.women who reach the upper age limit of 70 years for invitationto screening, we defined interval cancers as those diagnosed

Statistical analyseswithin two years and two months after the last normal screening

We used the Pearson test to comparetheinterval cancer groupexamination. 2

with the non-screened cancer group according to theWe further divided the cancers into groups (six month intervals)characteristics of the tumours, and we used a linear regressionaccording to the time between the date of diagnosis and the datemodel to test trends across time intervals from a last normalof the last normal screening examination, to explore thescreening result. Using life table techniques we calculated breasthypothesis that more rapidly growing cancers arising shortlycancer specific survival rates and overall survival rates,after a normal screening mammogram have a poorer illustrated by Kaplan-Meier plots, and we compared these rates prognosis. Owing to increased experience by the8 1 9 20

using the log rank test. Censoring occurred at date of emigration,radiologists, screening sensitivity might increase with increasingdate of death from causes other than breast cancer, or the endscreening rounds. Under this assumption the number of cancersof the follow-up period (31 December 2006), whichever cameoverlooked at screening mammography should decline withfirst.time since start of the screening programme. Thus a growingHazard ratios were calculated using Cox proportional hazard proportion of cancers detected between scheduled screeningsmodels. We used likelihood ratio statistics to compare groups.should be true interval cancers. If true interval cancers were aWe adjusted for age at diagnosis by four categories: 50-54,more aggressive subtypeof breast cancers, in theory the survival55-59, 60-64, and 65-72 years. We further adjusted for time


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trends, county of residence, and time since last normal screening for age at diagnosis, year of diagnosis, and county of residencyresult. Because survival from breast cancer differed between (data not shown).counties, we adjusted for county and time trends by including A secondary analysis restricted to interval cancers and stratifiedcounty specific trend variables in the model. We did not adjust4 by screening round showed no evidence that survival wasfor stage at diagnosis owing to the likelihood of stage associated with screening round, either overall or after migration, but we carried out further analyses stratified by23 stratification by time since last normal screening result (tablestage. For interval cancers only, we carried out secondary 4 ). Furthermore, after up to four screening rounds, theanalyses to examine the association and possible interaction of incidence of interval cancers was not associated with number time since last normal screening result and screening round. of screening rounds. When the analysis was restricted to countiesThe proportional hazards assumption was tested by both with a minimum of two years and two months of follow-up after graphical methods and Schoenfeld residuals and it was achieved. examination, the incidence per 100 000 woman years was 163.4All test statistics were two tailed, and we considered P values in the first screening round, 162.5 in the second, 193.3 in the<0.05 to be significant. Calculations were done with the third, and 166.5 in the fourth.statistical package Stata 10.0.

DiscussionResults

The survival of women with adiagnosis of interval breast cancer Table 1 summarises the characteristics of the 1816 women in after a normal mammogram is similar to that of women withthe interval cancer group and the 5300 women in the breast cancer diagnosed before an invitation to a breast cancer

non-screened cancer group. The mean age at diagnosis was screening programme. Contrary to our a priori hypothesis, wesimilar between the groups, whereas the mean follow-up time found no evidence that tumours that become clinically evidentwas 3.6 (SD 2.6, maximum 10.6) years for the interval cancer shortly after the last normal screening result were moregroup and 6.3 (SD 3.0, maximum 11.2) years for the aggressive in terms of larger size, higher grade, higher non-screened cancer group. Compared with the non-screened proportion of node metastases, or lower survival than non-screencancer group, the interval cancer group had a slightly higher detected breast cancers. Among the interval cancers, average proportion of lobular cancers, largetumours (>20 mm diameter), tumour size increased slightly over time since last normalnegative axillary lymph nodes, and stage II rather than stage I screening result, but no other characteristics of the tumour or disease (table 1). The proportion of women who had a sentinel risk of dying from breast cancer varied by time since the lastnode biopsy was about three times higher in the interval cancer normal screening result.group than in the non-screened cancer group. Adjuvant Although several investigators have examined whether intervaltamoxifen was given to 701 (38.6%) of the women in theinterval cancers are associated with poor survival, controversy remains.cancer group and 1912 (36.1%) in the non-screened cancer Previous studies have been limited by small sample size ;7- 10 2 0 24 - 27

group. invalid comparison groups, notably screen detected cancers ;9 25 - 27

Table 2 shows the characteristics of interval breast cancers by or use of historical controls. Furthermore, the findings in8 1 1 1 2

six month intervals from date ofthelast normal screening result. these studies were inconsistent. Analysis based on randomisedThe number of interval cancers increased with increasing time trials of mammography screening found that survival withafter a normal result. The mean tumour diameter for interval interval cancers was similar, better, or poorer than survival7 27 20 24

cancers increased by only 2.2 mm during the two years after a with non-screen detected cancers. Although studies based onnormal screening result (P for trend 0.03). There was no randomised trials have a valid comparison group, chance couldevidence that any other tumour characteristics varied by time explain the inconsistent findings because the sample sizes in allsince last normal screening result. The results were essentially the studies were limited (<100 interval cancers). 7 2 0 24 2 8

the same with shorter intervals (data not shown). In observational studies, where survival rates of women withCumulative breast cancer survival did not differ between the interval cancers are compared with those of women with screentwo groups (P=0.53, fig 1 ). After 10 years of follow-up, the detected cancers or historical controls, or both, survivalsurvival rate among women with interval cancers was 79.1% associated with interval cancers was similar to that of non-screen(95% confidence interval 75.4% to 82.3%) and among women detected cancers in some studies, worse in others, and9 1 1 2 6 1 4

with cancers in the non-screened group was 76.8% (75.3% to worse than screen detected cancers but better than clinically78.2%). Five year and 10 year age adjusted survival estimates detected cancers in studies where interval cancers were by tumour stage at diagnosis were also similar for the study compared with both screen detected and historicalgroups (data not shown). Cumulative overall survival did not controls. However, in these studies comparisons are1 0 12 1 4 2 0

differ between the two groups (P=0.67, fig 2 ). After 10 years likely to be confounded by lead time, overdiagnosis, andof follow-up, the overall survival rate among women with temporal trends in survival from breast cancer. The only4 5 1 1

interval cancers was 72.6% (68.5% to 76.3%) and among women remaining alternative is contemporary patients unaffected bywith cancers in the non-screened group was 68.9% (67.3% to mammography screening. Theoretically, the ideal comparison70.5%). group would be breast cancer diagnosed among unscreened

women who would have attended screening if they had beenTable 3 shows data derived from Cox proportional hazardsinvited. Such a design would eliminate the potential confoundingmodel analyses of age at diagnosis and time since last normal by factors that affect both attendance and outcome. However screening result as possible determinants of a difference insuch a study is not feasible; to our knowledge there is limitedsurvival between the cancer groups. Breast cancer specific

reason in the Norwegian healthcare system to believe in anymortality did not differ between the interval cancer group andsubstantial bias through this mechanism, and this bias, if itthe non-screened cancer group (hazard ratio 0.98, 95%exists, would affect only a small proportion of incident breastconfidence interval 0.84 to 1.15, P=0.81). There was nocancers because the attendance rate in the Norwegianassociation between time since last normal screening result andmammography screening programme is high (77% amongsurvival (table 3). The results did not change after adjustmentinvited women). Overall survival was similar between women


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with interval cancers and those with non-screen detected cancers Funding: This study was fundedby researchgrants fromtheNorwegian

(fig 2), indicating that the results were not influenced by the Research Council and Frontier Science. The funders had no role in the

potential selection bias among women with interval cancer. design and conduct of the study; the collection,management, analysis,

and interpretation of the data; and the preparation, review, or approval

Strengths and limitations of this study of the manuscript.

To date, this population based study is the largest in the area of Competing interests: All authors have completed the ICMJE uniform

interval breast cancer and has the longest follow-up. The disclosure form at www.icmje.org/coi_disclosure.pdf (available on

staggered introduction of the screening programme and the request from the corresponding author) and dec lare: no support from

comparison of interval cancers with non-screen detected breast any organisation for the submitted work; no financial relationships with

cancer avoided major biases. any organisations that might have an interest in the submitted work in

the previous three years; no other relationships or activities that couldThis study, however, has several potential limitations. Because

appear to have influenced the submitted work.only a few of the interval cancers had been individually

Ethical approval: The researchprotocol was approvedby the Norwegianreviewed, we were unable to distinguish true interval cancersSocial Science Data Services 2008. Individual informed consent wasfrom those overlooked when themammograms were examined.not requested.In a previous review in Norway comprising around 200 interval

cancers, 35% were reinterpreted as overlooked, 23% showed Data sharing: No additional data available.

minimal signs of malignancy, and 42% were true intervalcancers, similar to the results of other studies. The 1 Col let t K , St ef ans s on I M , E ide J, Br aat en A , Wang H, E ide GE , et a l. A ba sal ep ithe lial2 9 30 31 3 2

ph enot ype is mo re f r equent i n i nter v al br eas t c anc er s c om par ed wit h sc r een det ec tedoverlooked tumours were on averagelargerand more often node

t um or s . Canc er E pid emi ol Bi oma rk er s P r ev 200 5;14: 1108 -1 2. positive than the true interval cancers. This could be because 2 G illi and FD, J os t e N, S t auber PM , Hun t WC, Ros enb er g R, R edlic h G, et al. B iolo gic

the affected women were reassured by the last normal c har ac t er is ti cs of int er v al and s cr een -d etec t ed br eas t c anc er s. J Nat l Canc er I ns t

20 00;9 2:743 -9 .

mammogram result and therefore delayed seeking medical care. 3 S iht o H, Lundi n J , Le htim äk i T. M ol ecu lar s ubt y pes o f br eas t c anc er d etec t ed in

However, other studies have found no differences in survival m am mo gr aphy s c r eeni ng an d ou ts ide of s c r eening . Clin Canc er Res 20 08;14 :410 3- 10.

4 K alag er M, Hal dor se n T, B r ett hauer M , Hoff G , T hor es en S O, A dam i HO. I mpr ov ed br eas t

between interval cancers classified as true or overlooked. 3 3 3 4 c anc er su rv iv al f ollowi ng i ntr oduc t ion of an o rg aniz ed m am m ogr aphy s c r eeni ng pr ogr am

am ong bot h s c r eened and uns c r eened wom en: a populat ion -b ase d c ohor t s t udy . B re as t

In each Norwegian county, introduction of the breast cancer Can ce r Res 2009; 1:R4 4.

screening programme was preceded by the establishment of 5 Z ac k ri ss on S , J anz on L, M anjer J, And er ss on I . Im pr ov ed s ur vi va l r at e for wom en w ith

specialised multidisciplinary teams. The goal of these teams i nter v al br eas t c anc er — r es ults fr om the br eas t c anc er sc r een ing pr ogr am me in M alm ö,4 1 3

S wede n 197 6- 1999. J Med S c r een 2 007; 14:1 38- 43.

was to provide thebest possible management of all women with 6 W ang H, B ju rs t am N, B jø rn dal H, Br aat en A, E r ik s en L, S kaa ne P , et al . Int er v al c anc er s

newly diagnosed breast cancers in the county, regardless of i n t he Nor wegian br eas t c anc er s cr een ing pr ogr am : fr equ enc y, ch ar act er is t ic s and us e

of HRT. I nt J C anc er 200 1;94: 594- 8.

whether the cancer was diagnosed by mammography screening. 7 Hol mb er g LH, Ada mi HO , Tabar L, B er gs tr öm R. S ur vi va l i n br ea st can ce r dia gnos ed

We have shown previously that this optimised management be tween m am mog ra phic s c r eeni ng e xam in atio ns . Lanc et 198 6;2: 27- 30.

8 B r ek elm ans CT, P eeter s P H, Deur enber g J J , Col lett e HJ . Sur v iv al in int er va l br eas t canc er

entailed a substantial reduction in mortality also among women i n t he DOM s c r eenin g pr og ra mm e. E ur J Canc er 1995; 31:1 830- 5.

with breast cancer not diagnosed by mammography screening. 4 1 3 9 S c hr öen AA , Wobb es T, v an d er S luis RF . Int er v al c ar c ino mas o f t he br eas t: a g ro up wit h

i nter m edia te out co me. J S ur g O nc ol 1996; 63:1 41- 4.Owing to the design of our current study, only women with

10 Col lins S , Woo dman CB J, T hr elf all A, P r ior P . S ur vi va l r at es fr om i nter v al ca nc er s in NHS

interval cancers were managed by multidisciplinary teams. br ea st sc r eeni ng p ro gr amm e. B M J 199 8;316 :832 -3 .

Hence it is conceivable that better treatment eliminated 11 B or dás P, J ons s on H, Ny st r öm L, Lenn er P . S ur vi va l f r om inv as iv e br eas t ca nce r am ong

i nter v al c as es in t he mam m ogr aphy sc r eeni ng pr ogr amm es of nor t her n S wede n. B re as t

altogether a poorer prognosis among the women with interval 20 07;1 6:47- 54 .

cancers than among those with non-screen detected cancers. 12 La wr enc e G , O’S ul liv an E, Kea ri ns O , Tappe nden N, M ar tin K , Wal lis M . S c r eenin g

hi st or ies of inv as iv e br eas t c anc er s d iagnos ed 1989- 20 06 i n t he Wes t M idla nds , UK :

The possible influence of such confounding could not be tested v ar ia tion wit h ti me and im pac t on 10- y ear s ur v iv al. J M ed S c r een 2009; 16: 186- 92.

in our study because it would have required more detailed 13 K ala ger M , Z elen M, Langm ar k F , Ad ami HO . Ef f ec t of s c re ening m amm ogr aph y on

br ea st - c anc er m or t alit y in Nor way . N E ngl J M ed 2010; 363: 1203- 10.individual data on prognostic factors, treatment, and overall 14 La rs en I K, Sm ås tu en M , J ohan nes en T B , Langm ar k F , P ar ki n DM , B r ay F , et al . Data

management. However, the similar proportion of women in qu alit y at t he c anc er Reg is tr y o f Nor way : an ov er vi ew o f co mpa ra bilit y , c om plet enes s ,

each group who received adjuvant tamoxifen treatments provides v ali dit y and t im elines s . E ur J Canc er 2009; 45:1 218- 31.

15 T ingul st ad S , Haldor s en T, N or st ein J , Hagen B , S kj eldes t ad FE . Com plet enes s a nd

some reassurance against a major confounding. ac c ur ac y o f r egis tr at ion of ov ar ia n c anc er in the c anc er r eg is tr y of Nor way . I nt J Canc er

20 02;9 8:907 -1 1.

16 W ang H, K år es en R, Her v ik A , Th or es en S . M amm ogr aph y s cr ee ning in N or way : re sul ts

Conclusions f r om t he fir s t s c r eening r ound in f our c ount ies and co st eff ec ti ve nes s of a m odeledna tio nwide s cr ee ning. Can ce r Caus es Contr ol 20 01;12 :39- 45 .

We conclude that tumours associated with interval breast cancers 17 P er r y N, Br oed er s M , de Wolf C. Eur op ean g uideli nes f or q ualit y as s ur anc e in br eas t

are more likely to be larger than those diagnosed in the absence c anc er sc r een ing and d iagnos is . 2nd edn. O ff ic e for off ic ial publ ic ati ons of t he Eu ro pean

Com m unit ies , 19 96.

of mammography screening; but they have strikingly similar 18 E r z aas A . Q ualit y as s ur anc e man ual of th e nor we gian br eas t c anc er s c r eening pr ogr am

survival outcomes. Furthermore, the characteristics of the [ Nor wegi an]. T he Canc er Re gis tr y of Nor way ; 2003 . www.k r ef tr egi s ter et .no .

19 Cow an WK , A ngus B , G ra y J C, Lunt LG, A l- T ami mi S R. A s tudy of int er va l br eas t c anc er

tumours (except for an increase of 2.2 mm in diameter) and the wi thi n t he NHS br eas t s c r eenin g pr ogr am m e. J C lin Pa thol 200 0;53 :140 -6 .

prognosis of women with interval cancers were not associated 20 F r is ell J , v on Ros en A , Wie ge M , Nil ss on B , Gol dma n S . I nter v al c anc er s and s ur v iv al in

a r andom is ed br eas t c anc er sc r eeni ng tr ial in S to ck hol m. B r eas t Ca nce r Res Tr eat

with time since last mammography. These findings challenge19 92;2 4:11- 6.

the theory of a strong correlation between growth rate and 21 E dge SB , By r d DR, Com pt on CC, Fr it z AG , Gr eene F L, Tr ott i A , eds . AJ CC c anc er s t aging

metastatic behaviour. Our study provides no compelling support m anua l, 7t h ed n. S pr inger - V er lag, 20 10.

22 G alea MH, B la mey RW, E ls ton CE , El lis I O. T he No tt ingham P r ogno st ic I ndex in pr i mar y

for moreaggressive primary treatment of interval breast cancers br ea st can ce r. Br eas t Ca nce r Res Tr eat 19 92;22 :207 -1 9.

than non-screen detected cancers with similar prognostic 23 F eins t ein AR , So si n DM , We lls C K. T he Will Rog er s pheno men on. S tage m igr at ion and

ne w di agnos ti c t ec hniques as a s our c e o f mi sl eading s t ati st ic s f or s ur v iv al in c anc er . N

features. 1 4 E ngl J Med 1985 ;312: 1604 -8 .

24 A nder s s on I , A s pgr en K , Ja nzo n L, Landber g T , L indholm K , Linell F, et al. Ma mm ogr aphic

s c r eenin g an d m or ta lit y f ro m br eas t c anc er : t he M alm ö m amm ogr aph ic t r ial. B M J

Contributors: MK designed the study and did the statistical analysis. 19 88;2 9:943 -8 .

25 V it ak B , S tål O, M åns on J C, T hom as B A, A r nes s on LG , Ek el und L, et al . Int er v al c anc er sMK had full access to the data in the study and takes responsibility for an d c anc er s in non- at tend er s in t he Ös ter gö tlan d m am mogr ap hic s c r eening pr ogr am me .

the integrity of the data and the accuracy of the data analysis. MK, RT, Dur a tion bet ween s cr een ing and d iagnos is , s - phas e fr ac t ion and d is tant r ec ur r enc e. E ur

MB, and HOA interpreted the data and cowrote and edited the paper. J Canc er 1 997;3 3:14 53- 60.

26 Ray s on D, P ay ne JI , A bdol ell M, Bar ne s P J, Mac I nto sh RF , Fol ey T , et al. Co mpa ri so n

of cl inic al- pa thol ogic cha ra ct er is t ic s and out c ome s of t r ue i nter v al and s c r een- det ec ted


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What is already known on this topic

Pre vi ou s r an do mi se d t ria ls o n ma mmo g rap h y s cre en in g f ou n d th a t in t erv al b re ast ca nce rs w ere a sso ci at e d w it h sim il ar , be t t er, or po o rer

su rviv al com pa re d w it h no n -scre e ne d b re as t ca n ce rs

T he se in co nsi st e nt f in di ng s ca n b e e xp la in e d b y sma ll sa mp le size s (< 1 00 in t erv al can ce rs)

Obs erv at i on al st ud ie s su g ge st e d t ha t in te rv al c an ce rs w ere a sso cia t ed w it h p oo r su rvi va l b ut w ere li mit e d b y sm al l sa mp le si ze a nd

in va li d co mp ar iso n g ro up s

What this study adds

I nt e rva l br ea st ca nce rs w e re m ore li ke ly t o b e l a rge r t ha n b re as t c an ce rs d ia gn os ed in th e a b se nce o f m am mo gra p hy s cre en in g

Su rvi val ou t co me s be t we e n t h e t wo ca nc er g ro up s w ere , ho w eve r, st ri kin g ly si mi la r

Our st u dy p ro vid e s n o co m pe ll in g su pp o rt f o r m or e ag g res siv e pr ima ry t re at m en t o f i nt e rva l bre a st c an ce rs t ha n n on -sc ree n in g ca nc ers

wi t h si mi la r pro g no st ic fe a tu re s

i nv as i v e b r e a s t c an ce r a m o ng pa r t i c i p an t s of a Can ad i a n b r e as t s c r e e n in g p r o gr am : a f in di ng s at th e l at es t s c r e en in g: a c o mp a r i s on of tr ue in t e r v a l an d mis s e d inte rv a l c an c e r s .

ne st ed c as e- co ntr ol s tu dy. Clin B re as t Canc er 20 11;1 1:27- 32 . E ur Radiol 199 9;9: 460- 9.

27 De Gr oot e R, Rus h B F J r , Mi laz z o J , W ar den MJ , Roc k o J M. I nt er va l br ea st can ce r: a 34 P or ter G J R, E v ans A J, B ur rel l A J, Lee AHS , El lis IO , Ch akr abar t i J . Int er val br eas t c anc er s :

m or e aggr es s iv e sub se t of br eas t neop las ias . S ur ger y 19 83;9 4:54 3- 7. pr og nos tic fe atur es and su rv i val by s ubty pe and t ime s inc e las t s c r een. J Med S c r een

28 S hap ir o S , Ven et W , St r ax P , Ven et L , Ro es er R. Ten- t o f our te en- ye ar ef fec t of s cr ee ning 20 06;1 3:115 -2 2.

on br eas t c anc er m or tali ty . J Natl Canc er In st 1 982; 69:34 9- 55.Accepted: 1 November 2012

29 Ho fv ind S , Sk aa ne P , V it ak B , Wan g H, T hor es en S, E r ik s en L, et al. I nf luenc e of r ev iew

de si gn on pe rc en tages of m is s ed i nte rv al br eas t c anc er s : a r etr os pe ct s t udy o f int er va l

c anc er s in a po pulat ion- bas ed s c re ening pr ogr am . Radi ology 2005; 237: 437- 43.Cite this as: BMJ 2012;345:e7536

30 Ho fv ind S , Gel ler B , S k aane P . M amm ogr aph ic f eat ur es and his t opat hologi c al f ind ings

of int er va l br ea st can ce rs . A c ta Radi ol 2008; 49: 975- 81. T his is an o pen - access ar t icl e di str ib ut ed u nde r t he t er m s of th e Cr ea ti ve Com m o ns31 V it ak B . I nt er va l c anc er s in the Os t er götl and Mam m ogr aphi c S c re ening P r ogr am:

At tr i but io n Non - com m er ci al Li cense , whi ch per m i ts use , dist r ib ut ion , an d r epr o duct io n i nr adi ologi ca l a naly s is . E ur Radi ol 1998; 8:6 39- 46.

an y m e diu m , pr o vide d th e or ig ina l wor k is pr op er ly cit ed , t he use i s n on com m er ci al an d32 Do min go L , Sa la M, S er v it ja S, Cor omi nas J M , Fer r er F, M ar t ínez J , et al. P hen oty pi c

is ot her w is e in c om pl ian c e wi th t he lic e ns e. S e e: ht t p: // c r eat iv e c om m on s .o r g/ lic e ns es / by -c har ac t er iz at ions and r is k fa ct or s f or int er v al br eas t c anc er s in a popu lat ion- bas ed br eas t

nc/ 2. 0/ and h tt p :/ / cr eat ive com m on s.o r g/ lice nses/ by- n c/2 .0 /l ega lcod e.c anc er s c r eening pr ogr am in B ar c elona, S pain. Canc er Caus es Con tr ol 2 010;2 1:1155 -6 4.

33 V it ak B , Ol se n K E , Må nso n J C, A r nes s on LG , St ål O. T umo r c har ac ter i st ic s an d s ur v iv al

i n pa tie nts with in vas i ve int er v al br eas t c anc er c la ss if ied ac c or ding t o m am mo gr aphic


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Tables

Table 1 | Characteristics of women with breast cancer in interval cancer group and in non-screened cancer group. Values are numbers

(percentages) unless stated otherwise

C ha r ac te r i st ic s I nt er v a l c a nc e r gr oup (n= 1 8 1 6) N on-s c re e ne d c anc e r g roup ( n= 5 30 0 ) P v a lu e

M e an (S D ) ag e a t d i ag n o sis (ye a rs) 5 9 .4 (5 . 7 ) 6 0 .1 (7 . 1 )

H i st o lo g ica l ty p e:

D u ct a l 1 3 7 7 (7 5 . 8 ) 4 1 76 (7 8 . 8) <0 . 0 0 1

L ob u la r 2 4 5 ( 13 . 5 ) 5 3 1 (1 0 . 0 )

Ot h e r 1 9 4 ( 10 . 7 ) 5 9 3 (1 1 . 2 )

Tu m ou r s iz e* :

1 (< 2 0 m m) 9 6 2 ( 56 . 1 ) 2 4 64 (5 9 . 9) <0 . 0 0 1

2 (> 2 0- 50 m m) 5 7 4 ( 33 . 5 ) 1 3 44 (3 2 . 7)

3 (> 5 0 m m) 1 3 7 (8 . 0 ) 1 06 (2 . 6 )

4 (in g ro w t h) 4 2 ( 2. 5 ) 1 97 (4 . 8 )

U n kn ow n 1 0 1 ( 5. 6 )† 1 1 8 9 (2 2 . 4 )†

N o d al st a t us *:

Po s it iv e 9 1 0 ( 54 . 4 ) 2 8 05 (5 8 . 7) <0 . 0 0 1

N e ga t iv e 7 6 4 ( 45 . 6 ) 2 4 91 (4 1 . 3)

M iss in g 1 4 2 ( 7. 8 )† 5 2 0 (9 . 8 )†

S t ag e ‡ :

I 7 5 0 ( 41 . 5 ) 2 6 07 (4 9 . 4) <0 . 0 0 1

I I 9 1 3 ( 50 . 6 ) 2 2 36 (4 2 . 4)

I I I 5 6 ( 3. 1 ) 1 53 (2 . 9 )

I V 8 7 ( 4. 8 ) 2 79 (5 . 3 )

S en t i ne l n o d e b i op sy 8 6 9 ( 47 . 9 ) 7 9 8 (1 5 . 0 ) < 0 . 00 1

Ta m ox if e n ad m in is t er ed 7 0 1 ( 38 . 6 ) 1 9 12 (3 6 . 1) < 0 . 00 1

To t a l N o of d e at h s 2 4 6 ( 13 . 5 ) 1 3 07 (2 4 . 7) < 0 . 00 1

D e a th s f r om b re as t c a nc er 1 9 4 ( 10 . 7 ) 9 7 9 (1 8 . 5 ) < 0 . 00 1

* Ba se d o n p a t ho l og i ca l t u mo u r, n od e , an d me t a st a si s cl a ssi f ic at i on . 21

† % o f t o t a l b re as t ca nc e rs.

‡ I , l o ca li se d br ea st ca n ce r; I I , l ym p h n o de p os it i ve ; I I I , gr ow t h in t o s ki n o r ch e st w al l; a n d I V , m e ta s ta s is. M is sin g in f o rma t i on o n s ta g e : 1 0 in t e rva l c an ce rs an d 25

n o n- scr ee n e d c an c er s.


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Table 2 | Tumour characteristics of interval breast cancers in six month intervals from last normal screening result to diagnoses. Values

are numbers (percentages) unless stated otherwise

Ti me si nc e l as t no rma l s cr e en in g re s ul t (mont hs)

C ha r ac te r i st ic s 19 -2 4 (n= 5 8 4) 0- 6 (n = 18 1 ) 7 -1 2 (n= 4 9 7) 13 -1 8 (n= 5 5 4)

M e an (S D ) t um o ur siz e ( mm ) 1 9. 3 (1 2 . 2) 1 9. 8 (1 1 .8 ) 2 0. 6 (1 2 . 5) 2 1. 5 (1 3 .4 )

N o d e n e ga t i ve 8 6 (5 2 . 1 ) 25 3 (5 4 .5 ) 2 67 (5 2 . 8) 3 04 (5 6 . 4)

M is si ng n od e st a t us * 16 (8 . 8 ) 3 3 (6 . 6) 48 (8 . 7 ) 45 (7 . 7 )

Gr ad e I 3 5 (2 4 . 0 ) 81 (1 9 . 6) 92 (2 0 . 2) 1 30 (2 7 . 0)

Gr ad e I I 6 7 (4 5 . 9 ) 20 6 (4 9 .9 ) 2 14 (4 6 . 9) 2 13 (4 4 . 3)

Gr ad e I I I 4 4 (3 0 . 1 ) 12 6 (3 0 .5 ) 1 50 (3 2 . 9) 1 38 (2 8 . 7)

M is si ng g ra de * 3 5 (1 9 . 3 ) 84 (1 6 . 9) 98 (1 7 . 7) 1 03 (1 7 . 6)

Oe s tr og e n re ce pt o r s ta t u s:

Po s it iv e † 9 2 (7 4 . 8 ) 22 4 (6 9 .6 ) 2 51 (7 1 . 7) 2 45 (7 3 . 8)

N e ga t iv e ‡ 3 1 (2 5 . 5 ) 98 (3 0 . 4) 99 (2 8 . 3) 87 (2 6 . 2)

M iss in g da t a * 5 8 (3 2 . 0 ) 17 5 (3 5 .2 ) 2 04 (3 6 . 8) 2 52 (4 3 . 2)

P ro ge s te ro n e re ce pt o r s ta t u s:

Po s it iv e † 6 4 (5 2 . 9 ) 16 2 (5 1 .1 ) 1 81 (5 3 . 2) 1 74 (5 3 . 2)

N e ga t iv e ‡ 5 7 (4 7 . 1 ) 15 5 (4 8 .9 ) 1 59 (4 6 . 8) 1 53 (4 6 . 8)

M iss in g da t a * 6 0 (3 3 . 2 ) 18 0 (3 6 .2 ) 2 14 (3 8 . 6) 2 57 (4 4 . 0)

* % of t o t al b re as t c a nc er s.

† = 1 0% p o si t ive st a i ni n g. 21

‡ < 1 0% p o si t ive st a i ni n g. 21


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Table 3 | Hazard ratios (95% confidence intervals) for breast cancer specific mortality between breast cancer groups overall and across

age categories

A ge a t di ag nos is (y e a rs )

Ov er a l l 5 0- 54 5 5 -5 9 60 -6 4 6 5 -7 2

H az a rd r a ti o* P H a za rd r a ti o P H a za r d ra ti o P H az a rd r a ti o P H a za rd r a ti o P

V ar i a bl es ( 95 % C I ) v al ue (9 5 % C I ) v a lu e (9 5% C I ) v a l ue (9 5 % CI ) va l ue ( 95 % C I ) v a l ue

N o n -sc re en e d 1 (re f e re n ce ) 1 (re f e re nc e ) 1 (r ef e re n ce ) 1 (re f er en c e) 1 (re f e re n ce ) —

c an ce r g ro u p (n = 5 3 00 (n = 1 50 7 ( n= 1 5 5 8 (n = 9 63 ca nc e rs) (n = 1 6 72

ca n ce rs) ca nc e rs) ca n ce rs ) ca n ce rs)

I n t er va l 0. 9 8 (0 . 84 t o 0 . 81 0 . 8 1 (0 .5 7 t o 0 . 25 1 . 13 (0 . 8 6 t o 0. 3 7 0 . 8 9 ( 0. 6 1 to 0 .5 5 1. 0 2 (0 . 76 t o 0 . 8 9

c an ce r† g ro u p 1 . 15 ) 1 .1 6 ) 1 . 4 9) 1. 3 0 ) 1 . 37 )

(n = 1 8 16 (n = 4 2 9 ca n ce rs) (n = 57 8 c an c er s) (n = 3 99 ca nc e rs) ( n= 4 1 0 ca n ce rs )

ca n ce rs)

M o nt h s s in ce

l as t scr ee n :

0 -6 1. 0 9 (0 . 70 t o 0. 5 3 ‡ 0 . 6 8 (0 .2 8 t o 0. 6 1 ‡ 1 . 61 (0 . 8 0 t o 0 . 8 4‡ 1 . 1 9 ( 0. 4 4 to 0 . 7 8 ‡ 1. 1 2 (0 . 42 t o 0 . 91 ‡

1 . 67 ) 1 .6 5 ) 3 . 2 9) 3. 2 1 ) 3 . 00 )

7 -1 2 0. 9 7 (0 . 74 t o 0 . 8 1 (0 .4 3 t o 1 . 19 (0 . 7 7 t o 0 . 8 2 ( 0. 4 2 to 0. 9 7 (0 . 56 t o

1 . 28 ) 1 .5 3 ) 1 . 8 5) 1. 6 0 ) 1 . 69 )

1 3- 18 1. 0 6 (0 . 82 t o 1 . 0 0 (0 .5 8 t o 1 . 04 (0 . 6 7 t o 1 . 3 7 ( 0. 7 2 to 1. 0 1 (0 . 62 t o

1 . 36 ) 1 .7 6 ) 1 . 6 4) 2. 0 9 ) 1 . 68 )

1 9- 26 0. 8 7 (0 . 66 t o 0 . 6 6 (0 .3 1 t o 1 . 04 (0 . 6 6 t o 0 . 5 2 ( 0. 2 3 to 1. 0 4 (0 . 66 t o

1 . 15 ) 1 .4 0 ) 1 . 6 5) 1. 1 9 ) 1 . 63 )

* Ag e ad j us t ed .

† C a te g o ris e d a s t i me si nc e l a st n or ma l m a mm o gr am (t i me si nc e l a st sc re en ) i n s ix mo n t h i nt e rv al s.

‡ P f o r t re n d.


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Table 4 | Age adjusted hazard ratios (95% confidence intervals) for breast cancer specific mortality among women with interval breast

cancers comparing screening round according to time since last normal screening result

Ti me s i nc e l a s t nor mal s c re e ni ng r es ul t (mo nths )

S cr e e ni ng rou nd (N o of c a nce r s ) O ve r a ll 0- 6 7 -1 2 1 3 -1 8 1 9 -2 4 P for tr e nd

1 (n = 5 64 ) 1 (re f e re nc e) 1 (re f e re n ce ) 1 (r ef e re n ce ) 1 (r ef e re n ce ) 1 ( re f er en ce ) 0. 4 1

2 (n = 4 75 ) 0 .8 9 (0 . 63 t o 1. 2 7 ) 0 . 85 (0 . 2 8 t o 2 ·6 4 ) 1 . 0 6 (0 . 5 5 t o 2 . 06 ) 0 . 5 5 ( 0. 2 9 to 1 . 02 ) 1 . 4 8 (0 .7 6 t o 2 . 8 7) 0. 7 2

3 (n = 3 55 ) 0 .8 6 (0 . 58 t o 1. 2 7 ) 1 . 07 (0 . 3 6 t o 3 ·2 3 ) 1 . 1 8 (0 . 5 8 t o 2 . 41 ) 0 . 3 9 ( 0. 1 7 to 0 . 89 ) 1 . 1 8 (0 .5 4 t o 2 . 6 0) 0. 8 5

4 (n = 2 20 ) 0 .6 9 (0 . 39 t o 1. 2 1 ) 0 . 32 (0 . 0 4 t o 2 ·6 1 ) 0 . 6 6 (0 . 2 2 t o 1 . 94 ) 0 . 4 3 ( 0. 1 5 to 1 . 23 ) 1 . 6 5 (0 .6 4 t o 4 . 2 9) 0. 7 4

5 (n = 1 82 ) 0 .9 9 (0 . 42 t o 2. 3 1 ) 1 . 19 (0 . 3 7 t o 9 ·8 8 ) 0 . 3 8 (0 . 0 5 t o 2 . 93 ) 1 . 3 9 ( 0. 4 0 to 4 . 80 ) — 0. 1 7


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Figures

Fig 1 Cumulative breast cancer survival plot for women with breast cancer by group

Fig 2 Cumulative overall survival plot for women with breast cancer by group


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