On the basis of direct observations we found a 10% rate of over-diagnosis of breast cancer 15 years after the end of the Malmö mammographic screening trial. This trial was population based, randomisation was by individual, and the trial time was longer and more screening rounds were completed than in any other trial of screening for breast cancer. The randomised design was maintained for almost five years after the trial had ended. The control groups of the 15 oldest birth cohorts were never invited for screening.
Earlier studies on over-diagnosis (cases that would never have come to clinical attention without screening) were mostly carried out in the setting of a screening service and included estimates and statistical modelling that should be taken into account when comparing the results. A Norwegian study showed 50% over-diagnosis, but follow-up was insufficient.6
A recent Swedish study of increasing incidence of invasive breast cancer after the introduction of screening showed 21-54% excess incidence depending on age.7
The authors did point out the possibility that the observed incidence could be caused by increased use of hormone replacement therapy or by changes in childbirth alone or in combination with screening. Evaluation of the Nijmegen programme in 1989, which used geographically distinct controls, showed an excess of 11% of breast cancer over a 12 year period, which is in line with our results.10
A recent study using statistical modelling, based on two trials (Swedish two-county and Gothenburg trials) suggests a much lower rate of over-diagnosis (1%).11
One study showed that a relatively large proportion of ductal cancer in situ lesions detected at prevalent and incident screens would be progressive if left untreated. They concluded that over-diagnosis of this type of cancer was a minor problem due owing to the low detection rate.12
This would be in line with our results where excess incidence was in the main not generated by in situ cancer, which was the case in an Italian study.4
Some studies did not include ductal cancer in situ in the main analyses,7,10
whereas others carried out analyses both with and without this type of cancer.6,8
We believe that in situ cancers should be included in analyses.
The main explanation for the excess number of cases in the invited group is the lead time of cases detected by screening. Owing to death due to intercurrent disease some of the cases would never have come to clinical attention. In addition some cases may have been non-progressive and therefore would never become noticeable in the absence of screening. This means that a long follow-up is necessary to estimate the magnitude of over-diagnosis and that analysis after only a few screening rounds is insufficient. In our study about 60% of the women aged 55-69 years at randomisation had died by the end of follow-up.
Age at randomisation
When screening ends a reduction in breast cancer incidence is expected in the former invited groups. Among women aged 55-69 at randomisation, however, we found only a modest reduction during period 2. The lead time has been shown to be longer in older women than in younger women.13,14
This fact together with an age dependent increasing general death rate could explain the remaining substantial over-diagnosis at the end of the period of observation. Møller et al recently showed a 32% reduction in breast cancer incidence in Swedish women past the upper age limit of their screening programme.15
The women in our study were older when screening stopped, which may explain the difference.
No definite conclusions can be drawn for over-diagnosis in the younger cohorts as the control groups were later screened. This resulted in an equalisation of the cumulative rate at first but at the end a not statistically significant 8% higher incidence in the former invited group. In other trials almost no excess incidence was shown when the control group was invited, which is to be interpreted as similar rates of over-diagnosis in both groups.8
Exclusion of prevalent cases
We analysed the extent of excess incidence after exclusion of prevalent cases (the first two screening rounds) and found a remaining, but reduced, excess incidence. This shows that the excess incidence is not just related to prevalent cases in a population exposed to screening. Two screening rounds correspond to four years, and the average lead time has been estimated to be two to four years depending on age.13,14
Most of the prevalent cases in the invited group and their corresponding cases in the control group should therefore have been accounted for. An increasing incidence at incident screens could be due to higher sensitivity of the screening procedure, which in turn may be due to improvements in mammography, increased knowledge among radiologists, or changes in the criteria for recall.
Factors influencing over-diagnosis
Attendance rates for screening decrease with age, as shown in both the Malmö mammographic screening trial and in the subsequent service screening programme.16,17
On the other hand, women who had been screened in the Malmö trial were more likely to attend the service screening programme17
and probably also to undergo mammography after screening had ended. Furthermore, mammography of asymptomatic women outside the trial in the control groups may lead to underestimation of over-diagnosis.
It is widely agreed that screening using mammography can reduce mortality from breast cancer.18-24
The rate of over-diagnosis is another issue to be considered in the ongoing discussion about clinical and public health implications of breast cancer screening.
What is already known on this topic
Rates of over-diagnosis in screening for breast cancer have been estimated at 5% to 50%
Evidence from randomised controlled trials is lacking
What this study adds
Over-diagnosis of breast cancer was 10% in women randomised to screening at age 55-69 years compared with an unscreened control group
Calculations are based on direct observations of follow-up 15 years after the end of a randomised controlled trial