BMJ  2005;330:220 (29 January), doi:10.1136/bmj.38313.639236.82 (published 13 January 2005)

Paper

Breast cancer mortality in Copenhagen after introduction of mammography screening: cohort study

¹ Institute of Public Health, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark, ² University Hospital Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark, ³ Mammography Screening Clinic, University Hospital Odense, Kløvervænget 10, DK-5000 Odense, Denmark

Abstract

Objectives To evaluate the effect on breast cancer mortality during the first 10 years of the mammography service screening programme that was introduced in Copenhagen in 1991.

Design Cohort study.

Setting The mammography service screening programme in Copenhagen, Denmark.

Participants All women ever invited to mammography screening in the first 10 years of the programme. Historical, national, and historical national control groups were used.

Main outcome measures The main outcome measure was breast cancer mortality. We compared breast cancer mortality in the study group with rates in the control groups, adjusting for age, time period, and region.

Results Breast cancer mortality in the screening period was reduced by 25% (relative risk 0.75, 95% confidence interval 0.63 to 0.89) compared with what we would expect in the absence of screening. For women actually participating in screening, breast cancer mortality was reduced by 37%.

Conclusions In the Copenhagen programme, breast cancer mortality was reduced without severe negative side effects for the participants.

Introduction

Organised, population based, mammography screening was introduced in Copenhagen in 1991. Since then the validity of the trial results and the justification of mammography screening have been debated intensively.^{1 2} Mammography screening was introduced in only three out of 16 administrative regions, so the regions without a programme provide a natural control group during the full period of follow up. In addition, opportunistic screening has been limited.³ Taking advantage of this "natural experiment," and using the nationwide population and health registers in Denmark, we developed a method to determine the effect of mammography screening on breast cancer mortality.⁴ We present here the results of the first 10 years of screening in Copenhagen.

Methods

Model
We used a regression model with a study group, a historical control group, a national control group, and a historical national control group (table). We studied the effect of invitation to, as well as participation in, screening. The end point was mortality due to breast cancer.

View this table: [in this window] [in a new window]   Study areas and time periods of the study and control groups

 

The study group included women invited for screening in Copenhagen during the first five invitation rounds from 1 April 1991 to 31 March 2001. The screening interval was two years. The target group included about 40 000 women aged 50-69 at the start of each invitation round. Only the second invitation round included women aged 50-71. Women moving to Copenhagen received their invitation shortly after their arrival, unless their date of birth was scheduled for invitation later in the round. Invitations did not go to women if they moved out of Copenhagen before their scheduled date for invitation. Women invited for screening remained in the study group even if they moved to another region. We followed up all women from their first date of invitation until death, emigration, or 31 March 2001. We excluded women with prevalent breast cancer before their first invitation date. In total 30 362 women, equivalent to 71% of women in the target population, participated in the first invitation round, a percentage that fell slightly over rounds as women could ask not to be reinvited to the programme.⁵

For all three control groups we constructed five, two year, "pseudo-invitation" rounds and allocated pseudo-invitation dates using the invitation system from the study group. We followed up women from their first pseudo-invitation date until death, emigration, or end of follow up, which was 31 March 1991 for the historical and the historical national control groups, and 31 March 2001 for the national control group. We excluded women with prevalent breast cancer before their first pseudo-invitation date.

Data
We retrieved data on women invited to the programme from the Copenhagen mammography screening register and checked them with the central population register. We "constructed" the control groups from individual records in the central population register. We identified all women with prevalent breast cancer from the Danish cancer register. We followed up the groups for deaths and emigrations in the central population register. Data on underlying cause of death came from the cause of death register. We used the personal identification number issued to all residents of Denmark to link registers.

Statistical analysis
To analyse the effect of invitation to screening, we compared breast cancer death rates in the study group and the control groups, adjusting for age, time period, and region. We used a Poisson regression model with the variables five year age group, exposure, period, and region.⁴ Although we were thereby able to control for time trends and regional differences, we were not able to separate out a potential effect of an interaction between the two from the effect of screening. We therefore had to take into consideration additional data on a potential interaction effect (see bmj.com).

Results

For the period before screening started, Copenhagen had a significantly higher mortality due to breast cancer than the rest of Denmark (relative risk 1.22, 95% confidence interval 1.10 to 1.35), although there was some variation by age group. This had changed in the screening period, where Copenhagen had a lower breast cancer mortality than the rest of Denmark (0.91, 0.80 to 1.05). When we compared Copenhagen in the screening period with the period before screening, the relative risk was significantly lower than 1 (0.80, 0.68 to 0.94). When we compared the rest of Denmark in the screening period with the period before screening, the relative risk was 1.05 (0.99 to 1.11), again with some variation by age group. When we estimated the effect of the combination of invitation to screening and the interaction term between period and region adjusted for age, period, and region, the relative risk was 0.75 (0.63 to 0.89) (see bmj.com for full table of results).

We estimated the cumulative effect of the combination of invitation for screening and the interaction term between period and region by year of follow up and adjusted for age at entry, period, and region (figure). Significance was reached after six years of follow up.

View larger version (23K): [in this window] [in a new window]   Estimated effect on breast cancer mortality of invitation to mammography screening in Copenhagen, cumulated over years of follow up

 

For the participants the estimated effect of combining participation in screening and the interaction term between period and region adjusted for age, period, and region resulted in a relative risk of 0.60 (0.49 to 0.74). On the other hand, women invited for screening who did not participate had a relative risk of 1.15 (0.91 to 1.46). On this basis, we estimated that in a situation without screening, participants would be a selected part of the population, with a relative risk of 0.95 compared with the total population. When we adjusted for this selection bias, the relative risk for the participants was 0.63.

When we used the same method as in the breast cancer mortality analysis, the invited population had a total cancer mortality (excluding breast cancer) close to that expected without screening (relative risk 0.96, 0.91 to 1.01).

Discussion

Breast cancer mortality in Copenhagen was reduced significantly after mammography screening had been introduced. A 25% reduction is the best possible estimate of the size of the mortality reduction achieved with mammography screening. However, the interaction term between period and region also inherent in the 25% estimate, could in theory reflect unsynchronised improvements in treatment. Since 1977, however, all hospital departments involved in diagnosis and treatment of breast cancer patients have used uniform guidelines for histopathology, surgery, radiotherapy, and systemic therapy.⁶ Survival from breast cancer has not differed between Copenhagen and the rest of Denmark since then.⁷ In addition, examination of time trends in breast cancer mortality in the pre-screening period found no interaction or only a negligible interaction between period and region.⁸ On this basis it is reasonable to expect the interaction term between period and region to be small. We also calculated the interaction term for the non-screening counties in Denmark. Copenhagen had the largest drop in mortality and was the only region where this reduction reached significance.

Comparison with other countries
The 25% reduction estimated in our study is consistent with that found in the evaluation of breast cancer screening programmes in England and Wales, Netherlands, and Sweden, although none of these studies is completely unbiased (see bmj.com for details).

Specific considerations
Breast cancer mortality was significantly higher in Copenhagen than in the rest of Denmark in the pre-screening period. This is probably due to regional differences in risk factors since diagnostic procedures and treatment have been organised nationwide since 1977.⁶

The age group 55-59 differed from the remaining age groups with a relative risk of 1.08 (0.68 to 1.72). Although the confidence interval is broad, this is in line with the lack of an effect for women aged 50-54 at randomisation found in other studies.^{9 10} Hormonal factors could play a part.⁹

Mortality reduction in participants
The non-participants in our study had a slightly, although not significantly, higher breast cancer mortality than the general population. The resulting selection bias does not affect the results for all invited women but merely the results for the participants. Adjusting for this selection bias resulted in a relative risk for the participants of 0.63—that is, a mortality that is 37% lower than that expected without screening was seen among participants in the Copenhagen screening programme.

Possible negative effects of mammography screening
Severe negative side effects for the participants were avoided; the introduction of mammography screening in Copenhagen did not lead to an increase in breast cancer incidence apart from the expected prevalence peak.³ In the first four invitation rounds, ductal carcinoma in situ constituted only 11% of the detected cases, owing to a deliberately conservative attitude towards supposedly benign micro-calcifications.⁵ The false positive rate has been relatively high—5.6% after the first screen, 2.9% after the second screen, and 1-2% after subsequent screens.⁵ Most are sorted out at the assessment, and by now, about 80% of women having surgery had invasive breast cancer or ductal carcinoma in situ.⁵ The proportionate interval cancer rate after the first invitation round in Copenhagen was low compared with that of other European programmes.¹¹

What is already known on this topic Most studies of randomised controlled trials have indicated that mammography screening leads to a reduction in breast cancer mortality for certain age groups Evidence is now starting to emerge on the effect of mammography screening in routine healthcare settings, such as service screening What this study adds This study of mammography service screening controlled for regional and historical differences Patients with breast cancers diagnosed before they had received the first invitation to screening were excluded The 25% reduction of breast cancer mortality found in this study therefore indicates that mammography service screening can reduce breast cancer mortality

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This is the abridged version of an article that was posted on bmj.com on 13 January 2005: http://bmj.com/cgi/doi/10.1136/bmj.38313.639236.82

Contributors: See bmj.com

Funding: Danish Medical Research Council; Centre for Evaluation and Medical Technology Assessment in the Danish National Board of Health; the European Commission, Directorate-General SANCO, and Copenhagen Hospital Corporation.

Competing interests: None declared.

Ethical approval: Not required.

References

1. Gøtzsche PC, Olsen O. Is screening for breast cancer with mammography justifiable? Lancet 2000;355: 131-6.
2. Olsen O, Gøtzsche PC. Cochrane review on screening for breast cancer with mammography. Lancet 2001;358: 1340-2.[CrossRef][Web of Science][Medline]
3. Olsen AH, Jensen A, Njor SH, Villadsen E, Schwartz W, Vejborg I, et al. Breast cancer incidence after the start of mammography screening in Denmark. Br J Cancer 2003;88: 362-5.[CrossRef][Web of Science][Medline]
4. Olsen AH, Njor SH, Vejborg I, Schwartz W, Dalgaard P, Jensen M-B et al. A model for determining the effect of mammography service screening. Acta Oncologica 2005 (in press).
5. Vejborg I, Olsen AH, Jensen M-B, Rank F, Tange UB, Lynge E. Early outcome of mammography screening in Copenhagen 1991-99. J Med Screen 2002;9: 115-9.[Abstract/Free Full Text]
6. Fischerman K, Mouridsen HT. Danish Breast Cancer Cooperative Group (DBCG). Structure and results of the organisation. Acta Oncologica 1988;27: 593-6.[Medline]
7. Andreasen AH, Mouridsen HT, Andersen KW, Lynge E, Madsen M, Olesen KP. Improved prognosis of breast cancer. Ugeskr Læger 1994;156: 6512-7.
8. Andreasen AH, Andersen KW, Madsen M, Mouridsen H, Olesen KP, Lynge E. Regional trends in breast cancer incidence and mortality in Denmark prior to mammographic screening. Br J Cancer 1994;70: 133-7.[Medline]
9. Nyström L, Andersson I, Bjurstam N, Frisell J, Nordenskjöld B, Rutqvist LE. Long-term effects of mammography screening: updated overview of the Swedish randomised trials. Lancet 2002;359: 909-19.[CrossRef][Web of Science][Medline]
10. Alexander F, Anderson TJ, Brown HK, Forrest APM, Hepburn W, Kirkpatrick AE, et al. 14 years of follow-up from the Edinburgh randomised trial of breast-cancer screening. Lancet 1999;353: 1903-8.[CrossRef][Web of Science][Medline]
11. Njor SH, Olsen AH, Bellstrøm T, Dyreborg U, Bak M, Axelsson C, et al. Mammography screening in the county of Fyn, November 1993-December 1999. APMIS 2003;111(suppl 110): 1-33.

(Accepted 15 November 2004)

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