Nils Bjurstam

Long-term effects of mammography screening: updated overview of the Swedish randomised trials

BACKGROUNDnThere has been much debate about the value of screening mammography. Here we update the overview of the Swedish randomised controlled trials on mammography screening up to and including 1996. The Kopparberg part of the Two-County trial was not available for the overview, but the continuation of the Malmö trial (MMST II) has been added. The article also contains basic data from the trials that have not been presented before. Methods The trials (n=247010, invited group 129750, control group 117260) have been followed up by record linkage to the Swedish Cancer and Cause of Death Registers. The relative risks (RR) for breast cancer death and mortality were calculated for the invited and the control groups. The trial-specific as well as the age-specific effects were analysed. RRs were calculated by the density method, with total person-time experience of the cohort by time interval of follow-up as a basis for estimating mortality rates. We calculated weighted RRs and 95% CI with the Mantel-Haenszel procedure.nnnFINDINGSnThe median trial time-the time from randomisation until the first round was completed for the control group or if the control group was not invited, until end of follow-up-was 6.5 years (range 3.0-18.1). The median follow-up time, the time from randomisation, to the end of follow-up, was 15.8 years (5.8-20.2). There were 511 breast cancer deaths in 1864770 women-years in the invited groups and 584 breast cancer deaths in 1688440 women-years in the control groups, a significant 21% reduction in breast cancer mortality (RR=0.79, 95% CI 0.70-0.89). The reduction was greatest in the age group 60-69 years at entry (33%). Looking at 5-year age groups, there were statistically significant effects in the age groups 55-59, 60-64, and 65-69 years (RR=0.76, 0.68, and 0.69, respectively). There was a small effect in women 50-54 years at randomisation (RR=0.95). The benefit in terms of cumulative breast cancer mortality started to emerge at about 4 years after randomisation and continued to increase to about 10 years. Thereafter the benefit in absolute terms was maintained throughout the period of observation. The age-adjusted relative risk for the total mortality was 0.98 (0.96-1.00).nnnINTERPRETATIONnThe advantageous effect of breast screening on breast cancer mortality persists after long-term follow-up. The recent criticism against the Swedish randomised controlled trials is misleading and scientifically unfounded.

Breast cancer screening with mammography: overview of Swedish randomised trials

Despite encouraging results from screening trials the efficacy of mammography in reducing mortality remains somewhat controversial. Five studies have been done in Sweden. This overview, based on 282,777 women followed for 5-13 years in randomised trials in Malmö, Kopparberg, Ostergötland, Stockholm, and Gothenburg, reveals a 24% (95% confidence interval 13-34%) significant reduction of breast cancer mortality among those invited to mammography screening compared with those not invited. To avoid the potential risk of differential misclassification causes of death were assessed by an independent end-point committee after a blinded review of all fatal breast cancer cases. The mortality reduction was similar, irrespective of the end-point used for evaluation (breast cancer as underlying cause of death or breast cancer present at death). There was a consistent risk reduction associated with screening in all studies, although the point estimate of the relative risk for all ages varied non-significantly between 0.68 and 0.84. The cumulative breast cancer mortality by time since randomisation was estimated at 1.3 per 1000 within 6 years in the invited group compared with 1.6 in the control group. The corresponding figures after 9 years are 2.6 and 3.3 and after 12 years 3.9 and 5.1. The largest reduction of breast cancer mortality (29%) was observed among women aged 50-69 at randomisation. Among women 40-49 there was a non-significant 13% reduction. In this younger age group cumulative breast cancer mortality was similar in the invited and control group during the first 8 years of follow-up. After 8 years there was a difference in favour of the invited women. There was no evidence of any detrimental effect of screening in terms of breast cancer mortality in any age group. Among women aged 70-74 years screening seems to have had only a marginal impact.

Determination of Cause of Death Among Breast Cancer Cases in the Swedish Randomized Mammography Screening Trials: A comparison between official statistics and validation by an endpoint committee

Between 1976 and 1982, four randomized mammography screening trials started in five screening centres in Sweden, involving 282,777 women (156,911 invited and 125,866 controls) with the aim to study if invitation to screening reduced the breast cancer mortality. An overview of the trials was performed to reduce the confidence intervals for the relative risk estimates. All 1,296 deaths occurring in women with breast cancer detected after randomization were evaluated by an independent endpoint committee (EPC), consisting of four physicians who reviewed collected medical information that was blinded regarding mammography screening. If there was disagreement between the EPC members at the initial individual evaluation the final classification was made at consensus meetings. In only 6.9% (n = 89) of the cases was there disagreement as to whether breast cancer was or was not the underlying cause of death. It was also found that breast cancer as underlying cause of death and breast cancer as underlying or contributory cause of death according to Statistics Sweden resulted in relative risk estimates very similar to those based on the classification by the EPC. The study thus supports the use of official health statistics in the evaluation of randomized breast screening trials in Sweden.

Implementation of service screening with mammography in Sweden: from pilot study to nationwide programme.

Establishment of mammography screening in Sweden has progressed logically from pilot study through clinical trials to service screening. Screening with mammography for early detection of breast cancer has been provided by all Swedens 26 county councils since 1997. It took 23 years from the initial pilot study through clinical trials to the establishment of mammography service screening through out Sweden.In the screening rounds completed by 1995–96, and provided by all but one county council, 1 040 000 women participated, corresponding to 81% of those invited. The national average recall rate was 2.2%, and consequently 23 000 women were recalled for additional investigations. Eleven county councils invited women aged 40–74, six invited women aged 50–69, the remaining eight invited women between both these age intervals.Mammography outside screening programmes—clinical mammography—is available throughout Sweden. About 100 000 women a year were referred for clinical mammography and about 50% of these were either younger or older than those invited for screening. A negative relation between the use of clinical mammography and participation in the screening programmes was noticed.

The Swedish Randomised Mammography Screening Trials: Analysis of Their Effect on the Breast Cancer Related Excess Mortality

Objective –To apply an indirect method for estimation of the breast cancer related excess mortality in the Swedish randomised mammography screening trials. Setting –Randomised trials on mammography screening have, in Sweden, been performed in the counties of Kopparberg (W) and Östergötland (E), the so called WE study, and in the three largest cities in Sweden, Stockholm (southern part), Gothenburg, and Malmö. An overview of the trials was presented in the Lancet in 1993 and included 156 911 women in the invited group and 125 866 in the control group. Methods –The excess mortality in the breast cancer subgroups was estimated by indirect standardisation using official national cause of death statistics according to Statistics Sweden as a reference. Results—The estimated reduction of the breast cancer related mortality was 24% for the whole group (40–74 years at randomisation). The corresponding figures for the age groups 40–49, 50–59, and 60–69 years were 6%, 28%, and 34% respectively. Conclusion –The results are very similar to those presented earlier based on the traditional comparison of the breast cancer mortality in the invited and in the control group. This analysis further strengthens previous reports on a beneficial effect of mammography screening, which is especially pronounced in the age group 50–69.

An overview of the Swedish randomised mammography trials: total mortality pattern and the representivity of the study cohorts

Objectives –To analyse the cause of death pattern in the cohorts of women included in the Swedish randomised mammography screening trials by comparing the groups of invited and control women both with each other and with the general population of Swedish women. Setting –Since 1977 four randomised trials of mammography screening have been performed in Sweden: Malmö, Kopparberg and ÖOstergötland (the two county trial), Stockholm, and Gothenburg. Design –Overview of four randomised mammography screening trials. Results –The total numbers of deaths in the invited and control groups respectively were 15 695 and 11 887 corresponding to a relative risk (RR) of 1.00. There were no significant differences between the invited and control groups for cause-specific mortality, except for breast cancer. When the total mortality in the invited and the control groups was compared with that for Swedish women in general the standardised mortality ratio was close to 100. Conclusions –The cause of death pattern in the invited group was, except for breast cancer, very similar to that in the control group, showing that the groups were comparable. Similarly, the total mortality including breast cancer mortality in the control group was almost identical to that in Swedish women in general. The same was true, with the exception of breast cancer, for the invited group. These observations confirm that the trial cohorts are representative of Swedish women and indicate that the quantitative results from these trials may safely be generalised to the Swedish population.

Interval cancers in the Norwegian breast cancer screening program: Frequency, characteristics and use of HRT

Breast cancers diagnosed between screening examinations among women who attend a breast cancer screening program are defined as interval cancers. The Norwegian Breast Cancer Screening Program started as a pilot project in 1996, and data from the first 2‐year interval are available. Our study quantifies interval cancers in the pilot project and explores characteristics and factors that may be associated with interval cancer. Interval cancers in the screening population were identified through the Cancer Registry of Norway. The frequency of invasive interval cancer was calculated as cases per 10,000 screened and as observed/expected ratio. Characteristics of the interval cancers were compared to screening‐detected and clinical cancers. Breast density was assessed in a blinded review of 3 categories of screening mammograms. Information on hormone replacement therapy (HRT) use was collected from a questionnaire. The frequency of invasive interval cancers was 18.2 (15.9–20.7) per 10,000 screened and the observed/expected ratio was 0.49 (0.43–0.56). The frequency in the second year of the interval was higher than reported from other programs. The median tumor size of the interval cancers was 19.5 mm and 44.0% of the patients had affected axillary lymph nodes. The interval cancer cases had higher proportions of dense breasts and reported use of HRT compared to screen normal and screening‐detected cases. The reported frequency of interval cancers is similar to comparable programs. The interval cancers differed significantly from the cancers detected in the first screening round and were more similar to clinical cancers. Interval cancer was associated with dense breasts and use of HRT. Screening programs must keep these associations in focus.

Number and characteristics of breast cancer cases diagnosed in four periods in the screening interval of a biennial population-based screening programme.

Objective To describe the distribution and prognostic tumour characteristics of interval breast cancers diagnosed in four periods after index screen (1-6, 7-12, 13-18 and 19+ months) in a population-based screening programme inviting women aged 50–69 years to biennial screening. Setting The Norwegian Breast Cancer Screening Programme (NBCSP) Methods In all, 848 interval breast cancer cases were diagnosed in 437,235 screening examinations. The distribution and prognostic tumour characteristics of the interval cancers diagnosed in four periods in the screening interval will be described. Proportions and rates will be compared by χ2-test. Results A total of 70% of the interval cancers in the NBCSP were diagnosed in the second year of the interval. Except for tumour size (P = 0.027), we found no evidence of adverse prognostic breast characteristics (grade, lymph node involvement, oestrogen and progesterone receptor positive) in invasive tumours diagnosed during the second versus the first year of the screening interval (Chi square P 0.05 for all). The prognostic characteristics of the tumours did not differ by age groups. It was a decreasing interval cancer rate per 10,000 women-years by age. Conclusion The risk of interval cancer increases by time after index screen, and 70% of the interval cancers in the NBCSP were diagnosed in the second year of the interval. Prognostic histological tumour characteristics did not differ by time after index screen, thus mean sojourn time (tumour growth rate) seems important for stating an optimal screening interval in a population-based screening programme.

SCREEN-TRIAL: Softcopy Reading in European Screening Mammography

Reading digital or digitized mammograms from computer monitors is called softcopy reading. Softcopy reading is the only way to fully exploit the diagnostic, logistic and financial benefits of the direct digital acquisition of mammographic images. We focus here on high-volume reading in breast care centers and in population-based screening mammography as it is practiced in the nationwide screening mammography programs in some European countries. Development, evaluation and demonstration of high-volume softcopy reading, is the objective of the SCREEN and SCREEN-TRIAL projects, funded by the European Commission.