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diagnosis by screening has a diminishing impact on

mortality.20 This may now be the case for breast cancer, where

adjuvant therapy can substantially reduce mortality from

early disease whether it is diagnosed clinically or by

mammographic screening.16,19,20,21,22,23,24

The analytic techniques that are used to evaluate

population-based mammographic screening programmes are

also controversial. The advice of WHO-IARC is that

observational studies, especially case-control studies, should

not be used; they were used extensively in a review of

European mammographic screening programmes.3,25 This

WHO advice is important, and echoes earlier cautions

published in the BMJ: "that confounding and selection bias

often distort the findings from observational studies and that

there is a danger that meta-analyses of observational studies

produce very precise but equally spurious results".26

It is increasingly apparent that over-diagnosis of in situ and

invasive breast cancers, which would never have troubled

women in their lifetimes, is substantial and has been

estimated in a meta-analysis as being 52% of women

diagnosed by screening27, although published estimates of

over-diagnosis vary widely.27,28,29,30 Over-diagnosis is a

common consequence of screening asymptomatic people and

finding biological forms of a disease that will never cause

clinical disease. This leads to unnecessary investigations and

unnecessary treatment, so the ratio of mortality reduction

(benefit) to over-diagnosis (harm) consequent upon

mammographic screening for breast cancer in some

countries may now be unfavourable. Evaluations of

mammographic screening programmes that report on overdiagnosis must make

an estimate of the lead time from

screening. It has been reported that modelling generally

overestimates lead time and hence underestimates overdiagnosis as compared to clinical measures of lead time.30

Therefore estimates of over-diagnosis that come from

modelling studies should be viewed with caution.

Today, the dilemma in countries with mammographic

screening programmes is whether the, at most, modest

benefits of mammographic screening are now outweighed by

the harms of over-diagnosis.31 In particular, one of the

advertised benefits of mammographic screening has been

that it detects small breast cancers which can be treated by

partial mastectomy and radiotherapy and so preserves the

breast.20 Unfortunately, it is now apparent that external beam

radiotherapy, which is the usual mode of administering

radiotherapy to the breast after breast-conserving surgery,

can later cause cancer of the lung and/or accelerated

atherosclerosis of the left anterior descending artery

predisposing to myocardial infarction, since both the lungs

and heart lie just a few centimetres beneath the breasts.

Therefore, more women treated with radiotherapy in this

way may die from these complications than avoid death from

breast cancers detected by screening.20,32 It is important to

emphasize that studies of mammographic screening, which

do not measure all-cause mortality as well as breast cancerspecific mortality,

will not detect these lung cancer and

myocardial infarct deaths and therefore give a spurious

picture of the benefits of screening.32

The balance of benefits and harms for mammographic

screening is critical in low- and middle-income countries,

where the incidence of breast cancer is lower than in highincome countries and where breast cancer is more likely

to be

a premenopausal disease, with most women diagnosed with

breast cancer at less than 50 years of age.

1,33 Since

mammographic screening is more sensitive in

postmenopausal women, who have less dense breasts than

premenopausal women, this combination of lower incidence

and mainly premenopausal breast cancer means that,

compared with high-income countries, many more women will

have to be screened in low- and middle-income countries to

detect one breast cancer.1 For example, it has been calculated

that in a low- or middle-income country where the incidence

of breast cancer is half that of the United States "for women

aged 40 to 49 years, more than 3,800 women would need to

be invited for screening at the cost of more than 41,000 visits

for mammography and more than 4,000 false-positive

diagnoses, in order to prevent one death from breast cancer

during 11 years of follow up".

1This should give pause for thought

to governments contemplating introducing mammographic

screening in low- and middle-income countries.

In the United States, where the incidence of breast cancer

is one of the highest worldwide34, the cost effectiveness

of mammography has been estimated to be $US

30,000-100,000 per quality adjusted life year gained.1 Even

though a mammogram may be cheaper to deliver in a lowand middle-income country,

because of the sensitivity and

incidence issues described above, when compared with a

high-income country, the cost-effectivenss of mammography

in a low- and middle-income country may be worse.

Finally, there has only been one mammographic screening

RCT reported for a non-European-derived population which

was carried out in Singapore, where a low participation rate

amongst Chinese women resulted in selection bias in favour

of women of higher socioeconomic status and education in

the screened group and no mortality outcomes were

reported.35

The debate about the balance of benefits and harms of

mammographic screening has important implications for all

DISEASE-SPECIFIC CANCER CONTROL

100 CANCER CONTROL 2014

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