ORIGINAL ARTICLE

Mammographic breast cancer screening: after the dust has settled

Peter Boyle

Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy

INTRODUCTION

Breast cancer is still a major public health issueworldwide; according to present estimates, 1 millionwomen will be diagnosed with breast cancer this year.There are no longer any countries in which the incidenceis truly low. In the European Union, there are 1 millionwomen alive today with breast cancer and over 100 000deaths each year. Death can frequently occur at an agewhen a woman has maximal social responsibility. It is acommon cause of cancer and cancer death and canfrequently be a dreadful disease. Progress in breastcancer control is slow but steady with recent proof-of-concept in Tamoxifen intervention1 giving a cause forhope for the future.

Clinical and pathological considerations clearly de-monstrate that survival following the diagnosis andtreatment of breast cancer at an ‘early’ stage is muchbetter than when the disease is locally advanced ormetastatic. Mammography can detect tumours at aclinically undetectable stage; such tumours have a verygood prognosis and many can be cured by appropriatetreatment. Since the publication of the results of theGreater New York Trial2 and the Swedish Two-CountyTrial3 in the 1970s and 1980s, there has been a generalconsensus that screening for breast cancer with mam-mography reduces mortality from the disease. Theresults of these pioneering trials have for the most partbeen subsequently confirmed by later trials in Sweden,Canada and the United Kingdom. Although somedebated issues endure, most notably issues of cost-effectiveness of screening in particular age groups, theevidence that screening reduces deaths from breast cancer

has grown and the consensus has remained. Results fromtrials were adequately promising that routine, populationscreening was either recommended or introduced asPublic Health Policy in a number of populations.

Questions about the quality of the trial data wereraised by G�tzsche and Olsen4 and vigorously debated.This challenge was renewed when The Lancet publisheda research letter by Olsen and G�tzsche5 describing theiroverview of the mammographic screening trials andreaching a startling conclusion. It was asserted that ‘ythe reliable evidence does not indicate any survivalbenefit of mass screening for breast cancer,’ andmaintain that screening leads to more aggressivetreatment. The publication has not prompted any majorrethinking of screening policy in the United Kingdom,Sweden, the Netherlands or the United States, and mostof the scientific community remains unconvinced by thearguments. To see why, consider the figure (Fig. 1)showing the published results of the mammographicscreening trials. Overwhelmingly, the results indicate asubstantial and significant reduction in breast cancermortality with invitation to screening. The data in thesetrials have undergone repeated independent scrutinyand recent evidence suggests that in organised servicescreening programmes, the benefit may be greater thanthat observed in the trials.6

The situation was in striking contrast to the views ofthe media and the general public, where frequentlymajor concerns were raised that screening was doing nogood and may even be doing harm. The temperaturewas further raised when the PDQ Committee in theUnited States, in a highly publicised meeting, thendown-graded their position on the quality of theevidence on mammographic screening.

The controversy regarding the efficacy of mammo-graphic screening is clearly one of the most importantissues in cancer control at the present time. If recentconclusions questioning the efficacy of mammography

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The Breast (2003) 12, 351–356

0960-9776/$ - see front matter r 2003 Published by Elsevier Ltd.

doi:10.1016/S0960-9776(03)00135-8

Address correspondence to: Prof. Peter Boyle, Director, Division of

Epidemiology and Biostatistics, European Institute of Oncology,

Via Ripamonti 435, 20141 Milan, Italy. Tel.: +39 257489815;

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351

are correct, then we may have been harming women. Ifthese conclusions are incorrect, discouraging women notto be screened could cost lives. At very least, thesituation has undoubtedly caused confusion in theminds of women worldwide, as well as in those of theirdoctors. Given the importance of breast cancer as aninternational public health problem, if there are trulysuch limitations to the available evidence on the efficacyof mammography, then we really need to know urgentlyand advise women accordingly.

EVALUATION OF THE EVIDENCE

Following these controversial publications, there havebeen several approaches to re-evaluate the body ofevidence. A major overview has been published and twoWorking Groups have been convened: the work of thesegroups has generally been conducted in private. Therewas a Global Summit on Mammographic Screening

which was open to the public and where all the issueswere discussed and debated. The findings were thenpresented the following day to the 1000 plus delegates tothe fourth Milan Breast Cancer Meeting.

SWEDISH OVERVIEW

Many of the trials of mammographic screening havebeen conducted by different research groups in Sweden:it is because of this effort that so much data are

available about the effects of this intervention. Datawere included from randomised trials conducted in

Sweden: in Malmo (MMST I and II), .Osterg .otland partof Two-county (WE), Stockholm and G .oteborg. Causeof death determination was carried out by Blind reviewby an independent endpoint committee. All informationwas blinded with respect to group.

The authors argued convincingly that the criticismsmade against the Swedish trials by Gotzsche and Olsenare misleading and scientifically unfounded. The medianfollow-up time was 15.8 years among women who wereaged 40–74 at time of randomisation. There was astatistically significant 21% reduction in breast cancermortality (RR=0.79, 95% CI (0.70, 0.89)) amongwomen in this overview.

The overview concluded that the advantageous effectof breast screening in terms of breast cancer mortalitypersists after long-term follow-up and that recentcriticisms made against the Swedish Randomised Con-trolled Trials are misleading and scientifically un-founded.7

IARC MONOGRAPH

A Working Group of the International Agency for

Cancer Research (IARC), which met in Lyon on 5–12March 2002, consisted of 24 experts from 11 countries.The quality of the seven trials was carefully assessed, asa result of which it was concluded that many of the

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Fig. 1

352 The Breast

criticisms raised by Gotzsche and Olsen were unsub-stantiated.

The Working Group8 concluded that trials haveprovided sufficient evidence for the efficacy of mammo-

graphy screening between 50 and 69 years. For womenaged 40–49 years, there is only limited evidence of areduction. It was also concluded that the effectiveness ofnational screening programmes varies due to differencesin coverage of the female population, quality ofmammography, treatment and other factors. Organisedscreening programmes are more effective in reducing therate of death from breast cancer than sporadic screeningof selected groups of women. The Working Group alsoconcluded that there is insufficient evidence that clinicalbreast examination or self-examination reduce mortalityfrom breast cancer.

Further, those criticisms of substance did notinvalidate the evidence that screening by mammographyreduced mortality from breast cancer in women of 50–69years of age. In women who participated in screeningprogrammes this was estimated at reduction 35%. Forwomen of 40–49, evidence for a reduction in mortalitywas limited. It was recognised that the effectiveness ofnational programmes of screening would vary accordingto differences in coverage and compliance, the quality ofthe mammograms, methods of assessment and treat-ment and many other factors. But such organisedprogrammes were more likely to be effective in reducingthe rate of death than was the sporadic screening ofselected groups of women.

UNITED STATES PREVENTIVE SERVICES

TASK FORCE (USPSTF)

The USPSTF, whose mission is ‘to produce evidence-based reviews of preventative interventions provided inprimary care clinical settings, using explicit, transparent,and publicly accountable methods’ has also assessed thecurrent evidence on mammographic screening. Keyelements in this assessment are an evaluation of thequality of the available evidence and the performance ofa meta-analysis wherever possible.

Across eight trials, the reduction in breast cancermortality associated with the women assigned to thescreening arms was between 2% and 32%. Thesummary relative risk in meta-analysis performed9,10

were as follows:

* when consideration was restricted to the seven trialsamong women aged 450 years of age, the odds ratiowas 0.77 (95% CI (0.67–0.89));

* when, on methodological grounds, the Canadian andEdinburgh trials are excluded, the odds ratio was 0.75(95% CI (0.63–0.89));

* when the four trials which considered mammographyalone are analysed, the odds ratio is 0.74 (95% CI(0.59–0.93));

* when consideration is fixed on the six trials withwomen aged 40–49 at entry, the odds ratio is 0.83(95% CI (0.64–1.04));

* when consideration is restricted to trials with womenaged 40–49 at entry, and Edinburgh and Canadiantrials are omitted on methodological grounds, theodds ratio is 0.74 (95% CI (0.60–0.92)).

The USPSTF concluded that mammographic screen-ing could be recommended as a Category B interventionon the grounds that the quality of evidence was fair andthe net gain moderate. The reduction in breast cancermortality among women invited to screening appearedto be 23%. Their statement reads: ‘The USPSTFrecommends screening mammography, with or withoutclinical breast examination, every 1–2 years for womenaged 40 and older. The USPSTF concludes that theevidence is insufficient to recommend for or againstroutine clinical breast examination alone. The USPSTFconcludes that the evidence is insufficient to recommendfor or against teaching or performing routine breast self-examination.’

GLOBAL SUMMIT ON MAMMOGRAPHIC

SCREENING

In response to the uncertainty over the efficacy of breastscreening, a Global Summit on Mammographic Screening

was organised at the European Institute of Oncology inMilan between 3 and 5 June 2002. The Summit wasplanned in association with the World Health Organisa-

tion, the European Commission, the American Cancer

Society, the Centers for Disease Control and Prevention,the American Italian Cancer Foundation, the European

Society for Medical Oncology, the American Society for

Clinical Oncology and the International Union Against

Cancer.The design and recent results from the seven

randomised trials were presented and discussed in detailin the light of each criticism put forward by Gotzscheand Olsen. Some were discarded as being wrong, othershad been addressed by new analyses and shown to be ofminor significance. It was appreciated that conductingsuch large trials over many years is difficult, particularlyas technology, treatment and indeed Public Health

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After the dust has settled 353

Policy can change during their course. The remainingminor considerations did not detract from the conclu-sion that screening mammography reduced the mortal-ity from breast cancer in women receiving an invitationto be screened in well-organised clinical trials: thereduction in breast cancer mortality appeared to bebetween 21% and 23% according to recent estimates.Those participating fully could expect greater benefit.There was unanimity that with the current evidence from

randomised trials, taking full account of any limitations to

their methodology, there were no grounds for stopping on-

going screening programmes nor planned programmes.

Those attending the Milan Global Summit on Mam-

mographic Screening believed that the criticisms whichhad been raised against the trials had been fullyaddressed, that the ‘book’ on screening trials shouldnow be closed, and that future activities shouldconcentrate on the evaluation of organised programmesof mammographic screening, on exploring methods toensure full participation, particularly amongst deprivedwomen and on the development of new technologies forearly diagnosis. During the meeting there were pre-sentations of 14 such organised programmes of popula-tion screening; those of longer duration demonstratingtentative trends towards mortality reduction. Viabledata from more recently established programmes tendedto have similar values for many of the intermediateendpoints (e.g., stage of disease) as seen in the longer-established programmes, which was encouraging.

The World Health Organisation (WHO) Collaborating

Centre for Cancer Prevention and Control has had awork programme approved to determine methods toevaluate organised screening programmes. Representa-tives of organised programmes would be invited to ameeting, the work schedule to include developing theminimal data set required to evaluate such programmes,creating a database and identifying those programmeswhich were better or worse than expected and thereasons for such differences.

Mammographic screening is only one step in the totalmanagement of the woman with breast cancer. Toooften it is assumed that breast cancer mortality rates willdecrease through more mammographic screening. Thisgoal can only be attained through rigorous, high-qualityscreening, diagnosis and treatment. As has been shownfrom long-term established programmes in UnitedKingdom, Sweden, Finland and the Netherlands,recognition of the importance of the multidisciplinaryteam in the assessment of mammographic abnormalitieshad ‘spun over’ into the symptomatic sector leading tothe development of integrated multidisciplinary breast-care centres. Staffed by dedicated surgeons, radiologistsand pathologists working alongside breast-care nurses,

counselling and other support personnel, these centresoffer optimum care for women with breast cancer andcan quickly integrate new knowledge about breastcancer treatment into their protocols.

DISCUSSION AND PRESENT SITUATION

Now that the dust has settled with a general consensusin favour of the efficacy of mammographic screening,there are certain key questions to be posed andanswered. For example, how did Gotzsche and Olsencome to such different conclusions from everyone else?The cynic, looking at Fig. 1, would say that the only wayto show that mammographic screening is ineffective is toeliminate the majority of the information available fromthe randomised trials. The problem lies in their dualstrategy of exclusion of all but the Malm .o and Canadatrials on the basis of alleged methodological inferiority,and their use of all-cause mortality rather than breastcancer mortality as the endpoint.

Their criteria for these methodological choices areavailable in a longer document available from theInternet. From this document it is evident that theclassification of both study and endpoint quality arebased on highly subjective judgements and misinterpre-tation of the individual trials. Examples include:11

* ‘inconsistencies’ claimed in the number of deaths inthe Two-County Study are not inconsistencies atall;12

* although it is claimed that in the HIP study that causeof death classification was unreliable because in theblinded review of cause of death in the ‘dubious’cases, plausible alternative explanations were notapparently considered;

* there are arithmetic inconsistencies within OG’sreport – for example the total numbers of all-causedeaths at 7 years which they report for the Two-County Study are smaller than the numbers reportedfor the age subgroup 50+;

* death rates in women with breast cancer from causesother than breast cancer are inappropriately calcu-lated relative to the numbers of cases rather than tothe person-years among cases.

The mistakes and misinterpretations above are notgood grounds for doubting conclusions based onmillions of person-years of experimental evidence.Remarks on cardiovascular sequelae of radiotherapyapply to archaic forms of radiotherapy that were lessattentive of radiation technique and target than currentpractice.13 The assertion that screening leads to more

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354 The Breast

aggressive surgery is based on selective and methodolo-gically unsound analyses. It is believed by the fact thatthe epoch of mammography has led to a substantialmove away from mastectomy towards breast-conservingsurgery.14

It is clear therefore that OG’s review is seriouslyflawed and provides no grounds for the scientificcommunity to alter the conclusion that breast cancerscreening does indeed lead to a substantial reduction inmortality from the disease. Women invited to breastscreening should not be intimidated, and overworkedstaff who go to great lengths to make screening work,should not have their morale damaged by poor-qualityreviews such as that of OG. To discourage an earlydetection procedure which has been shown in trial aftertrial to reduce breast cancer mortality, on the basis of anerror-prone review in a field in which one is not anexpert, seems to be questionable in the extreme.

CONCLUSIONS

Forty years of clinical trials, the contribution ofhundreds of scientists and health workers and thededication of hundreds of thousands of women toparticipate in studies lasting for decades, has resulted inadequate evidence to support the efficacy of mammo-graphic screening and its transfer from the researcharena to that of Public Health Policy. The benefit intrials is estimated to be between 21%7 and 23%.8

The reduction among women who participate fully isgreater.

The recent Global Summit on Mammographic Screen-

ing should be the last time all the trials are discussed: theevidence of benefit is convincing and there is no littleinformation to be derived from raking over the membersof these trials once again. In this sense, this representsthe closing of one volume and the opening of anothersince attention needs to focus from now onwards on theevaluation of the effectiveness of organised (service)screening. The time has arrived to develop internationalstandards required to help determine the efficacy of suchprogrammes. It is also essential to include informationabout treatments in the evaluation of screening pro-grammes. It is clear that the best outcome in aprogramme will only come in the presence of the mostappropriate treatment.

Women should be reassured that participation inmammographic screening can have a beneficial effect onbreast cancer death rates. Doctors should be reassuredthat mammographic screening, in programmes withquality assurance procedures in place, are beneficial towomen. Doctors should encourage their women patients

to participate in such programmes, and make specialefforts to get women from lower socio-economic groupsto participate. In addition, women should be informedabout potential areas of conflict in the evidence.

It is also essential to keep in mind that mammographyis an old (and some would argue an obsolete)technology. The immediate future is filled with questionsregarding the evaluation of new screening tests. Tech-nology will offer many possibilities in the near futureand it is not feasible to perform randomised trials,involving tens of thousands of women followed formany years, with breast cancer death as an endpoint.There remains essential methodological work to bedone.

More importantly, the issue of the evidence support-ing mammographic screening in women under the age of50 needs careful consideration and urgent resolution.Published and unpublished overviews of the availabledata concur in an odds ratio less than 1.0 and theconfidence interval slightly over this value. The United

States Preventive Services Task Force findings are quitetypical. When consideration is fixed on the six trials withwomen aged 40–49 at entry, the odds ratio is 0.83 (95%CI (0.64–1.04)) and when the Edinburgh and Canadiantrials are omitted on methodological grounds, the oddsratio is 0.74 (95% CI (0.60–0.92)). The upper bound ofthe 95% confidence interval for the odds ratio is justabove or just under 1.0.

Without offering any position, it does appear strangethat in most countries women of this age are excludedfrom organised screening programmes. Of course,women who start participation in trials at this age willundoubtedly benefit from screening as they pass the ageof 50 and continue to be screened. On the other hand,over 40% of the years of life lost due to breast cancerdiagnosed before the age of 80 years are attributable tocases presenting symptomatically at ages 35–49 years.This underlines the necessity to address this issueurgently. This may be one of the very few uses wherethe existing randomised trial data could be usefullyemployed. However, it is essential that this be donequickly and openly.

The other major issue relates to whether mammo-graphic screening should be done in organised orunorganised programmes, recognising that in Europeorganised screening programmes do not exist in allcountries. Results appear to be better from organisedprogrammes and much of this effect is due to the highlevels of quality control of all parts of the screeningprocess.14 It is imperative that similar quality controlstandards are effected in unorganised programmes andthat all cases detected are managed in a state-of-the-artmanner. I believe that the evidence to support mammo-

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After the dust has settled 355

graphic screening among women between 50 and 69, inthe European Union, is sufficiently strong that everywomen in this age range has the right to participate in anorganised screening programme with high qualitycontrol standards and audit15 built in. The right toparticipate has to be matched by the obligation of eachGovernment to have such a programme in place fortheir female population.

Acknowledgements

It is a pleasure to acknowledge that this work wasconducted within the framework of support from theAssociazione Italiana per la Ricerca sul Cancro (AIRC)and the World Health Organisation CollaboratingCentre.

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