Swedish two-county trial: impact of mammographic screening on breast cancer mortality during 3 decades.

PURPOSE: To estimate the long-term (29-year) effect of mammographic screening on breast cancer mortality in terms of both relative and absolute effects. MATERIALS AND METHODS: This study was carried out under the auspices of the Swedish National Board of Health and Welfare. The board determined that, because randomization was at a community level and was to invitation to screening, informed verbal consent could be given by the participants when they attended the screening examination. A total of 133 065 women aged 40-74 years residing in two Swedish counties were randomized into a group invited to mammographic screening and a control group receiving usual care. Case status and cause of death were determined by the local trial end point committees and, independently, by an external committee. Mortality analysis was performed by using negative binomial regression. RESULTS: There was a highly significant reduction in breast cancer mortality in women invited to screening according to both local end point committee data (relative risk [RR] = 0.69; 95% confidence interval: 0.56, 0.84; P < .0001) and consensus data (RR = 0.73; 95% confidence interval: 0.59, 0.89; P = .002). At 29 years of follow-up, the number of women needed to undergo screening for 7 years to prevent one breast cancer death was 414 according to local data and 519 according to consensus data. Most prevented breast cancer deaths would have occurred (in the absence of screening) after the first 10 years of follow-up. CONCLUSION: Invitation to mammographic screening results in a highly significant decrease in breast cancer-specific mortality. Evaluation of the full impact of screening, in particular estimates of absolute benefit and number needed to screen, requires follow-up times exceeding 20 years because the observed number of breast cancer deaths prevented increases with increasing time of follow-up.

Effectiveness of population-based service screening with mammography for women ages 40 to 49 years: evaluation of the Swedish Mammography Screening in Young Women (SCRY) cohort.

BACKGROUND: The effectiveness of mammography screening for women ages 40 to 49 years still is questioned, and few studies of the effectiveness of service screening for this age group have been conducted. METHODS: Breast cancer mortality was compared between women who were invited to service screening at ages 40 to 49 years (study group) and women in the same age group who were not invited during 1986 to 2005 (control group). Together, these women comprise the Mammography Screening of Young Women (SCRY) cohort, which includes all Swedish counties. A prescreening period was defined to facilitate a comparison of mortality in the absence of screening. The outcome measure was refined mortality, ie, breast cancer death for women who were diagnosed during follow-up at ages 40 to 49 years. Relative risks (RRs) with 95% confidence intervals (CIs) were estimated. RESULTS: There was no significant difference in breast cancer mortality during the prescreening period. During the study period, there were 803 breast cancer deaths in the study group (7.3 million person-years) and 1238 breast cancer deaths in the control group (8.8 million person-years). The average follow-up was 16 years. The estimated RR for women who were invited to screening was 0.74 (95% CI, 0.66-0.83), and the RR for women who attended screening was 0.71 (95% CI, 0.62-0.80). CONCLUSIONS: In this comprehensive study, mammography screening for women ages 40 to 49 years was efficient for reducing breast cancer mortality.

Absolute numbers of lives saved and overdiagnosis in breast cancer screening, from a randomized trial and from the Breast Screening Programme in England.

OBJECTIVES: To estimate the absolute numbers of breast cancer deaths prevented and the absolute numbers of tumours overdiagnosed in mammographic screening for breast cancer at ages 50-69 years. SETTING: The Swedish Two-County randomized trial of mammographic screening for breast cancer, and the UK Breast Screening Programme in England, ages 50-69 years. METHODS: We estimated the absolute numbers of deaths avoided and additional cases diagnosed in the study group (active study population) of the Swedish Two-County Trial, by comparison with the control group (passive study population). We estimated the same quantities for the mortality and incidence rates in England (1974-2004 and 1974-2003, respectively). We used Poisson regression for statistical inference. RESULTS: A substantial and significant reduction in breast cancer mortality was associated with screening in both the Two-County Trial (P < 0.001) and the screening programme in England (P < 0.001). The absolute benefits were estimated as 8.8 and 5.7 breast cancer deaths prevented per 1000 women screened for 20 years starting at age 50 from the Two-County Trial and screening programme in England, respectively. The corresponding estimated numbers of cases overdiagnosed per 1000 women screened for 20 years were, respectively, 4.3 and 2.3 per 1000. CONCLUSIONS: The benefit of mammographic screening in terms of lives saved is greater in absolute terms than the harm in terms of overdiagnosis. Between 2 and 2.5 lives are saved for every overdiagnosed case.

Tumor size and breast cancer detection: what might be the effect of a less sensitive screening tool than mammography?

In some limited-resource areas, a state-of-the-art mammography program is not affordable. In such circumstances, one might consider a less resource-intensive, but also less sensitive screening tool such as clinical breast examination (CBE). We used data from the Swedish Two-County Trial to estimate the shift in tumor size resulting from invitation to mammographic screening. By postulating a lesser benefit of a less sensitive screening tool (CBE), particularly in terms of detecting very small tumors, we predicted its likely effect on tumor size distribution. In addition, using the observed association between tumor size and nodal status, and between tumor size and fatality, we predicted the likely benefit in terms of reductions in node-positive disease and in breast cancer mortality. An invitation to mammographic screening was associated with a 27% reduction in the number of node-positive tumors and a 31% reduction in the number of breast cancer deaths. We estimate that in the trial population, screening with CBE alone would have led to an 11% reduction in node-positive tumors and an 11% reduction in breast cancer deaths (approximately 42 deaths prevented per 1,000 cases). Assuming instead a tumor size distribution typical of a limited-resource setting (70% of tumors are 30 mm at presentation), we estimate that screening with CBE alone would lead to a 13% reduction in node-positive tumors and a 12% reduction in breast cancer deaths (approximately 72 deaths prevented per 1,000 cases). Thus, although the relative benefit of CBE is only slightly greater in the limited-resource setting, the absolute reduction in deaths per case is about 70% higher. Our findings suggest that a less sensitive tool might be expected to confer a breast cancer mortality reduction about half of that observed with mammography.

Influence of review design on percentages of missed interval breast cancers: retrospective study of interval cancers in a population-based screening program.

PURPOSE: To retrospectively investigate whether different review designs have an influence on the estimate of missed interval cancer in a population-based breast cancer screening program. MATERIALS AND METHODS: The Norwegian Breast Cancer Screening Program invites women aged 50-69 years to undergo biennial screening mammography. The current study was part of the evaluation and scientific aspects of the screening program and thus was covered by the general ethical approval of the screening program as a part of the Cancer Registry of Norway. All participants signed an informed consent that specified that data related to their screening visit could be used for evaluation and scientific purposes. Six radiologists (9-34 years of experience in mammography) reviewed previously obtained bilateral two-view screening and diagnostic mammograms of 231 interval cancers, 117 screening-detected cancers, and 373 normal cases. Four review designs were used: individual and paired blinded review and individual and consensus informed review. A five-point interpretation scale was used to reclassify the cancers into missed cancers, minimal signs, and true cancers. The number and proportion of subgroups were estimated with 95% confidence intervals. RESULTS: Of 231 interval cancers, 46 (19.9%) were reclassified as missed cancers with the mixed blinded individual review and 54 (23.4%) were classified as missed cancers with the mixed blinded paired review. Eighty-three cancers (35.9%) were classified as missed cancers with individual informed review, and 78 (33.8%) were classified as missed cancers with consensus informed review. Thirty-nine cancers (16.8%) were reclassified as missed when four or more radiologists assigned a score of 2 or more (probably benign or more suspicious); three cancers (1.3%) were reclassified as missed when a score of 4 or more (probably malignant or more suspicious) was assigned. CONCLUSION: The percentage of interval cancers classified as missed ranged from 1.3% to 35.9% according to review design. To encourage learning, a review protocol should include both blinded and informed designs.

Overdiagnosis and overtreatment of breast cancer: estimates of overdiagnosis from two trials of mammographic screening for breast cancer.

Randomised controlled trials have shown that the policy of mammographic screening confers a substantial and significant reduction in breast cancer mortality. This has often been accompanied, however, by an increase in breast cancer incidence, particularly during the early years of a screening programme, which has led to concerns about overdiagnosis, that is to say, the diagnosis of disease that, if left undetected and therefore untreated, would not become symptomatic. We used incidence data from two randomised controlled trials of mammographic screening, the Swedish Two-county Trial and the Gothenburg Trial, to establish the timing and magnitude of any excess incidence of invasive disease and ductal carcinoma in situ (DCIS) in the study groups, to ascertain whether the excess incidence of DCIS reported early in a screening trial is balanced by a later deficit in invasive disease and provide explicit estimates of the rate of 'real' and non-progressive 'overdiagnosed' tumours from the study groups of the trials. We used a multistate model for overdiagnosis and used Markov Chain Monte Carlo methods to estimate the parameters. After taking into account the effect of lead time, we estimated that less than 5% of cases diagnosed at prevalence screen and less than 1% of cases diagnosed at incidence screens are being overdiagnosed. Overall, we estimate overdiagnosis to be around 1% of all cases diagnosed in screened populations. These estimates are, however, subject to considerable uncertainty. Our results suggest that overdiagnosis in mammography screening is a minor phenomenon, but further studies with very large numbers are required for more precise estimation.

Time-dependent effects on survival in breast carcinoma: results of 20 years of follow-up from the Swedish Two-County Study.

BACKGROUND: Tumor size, lymph node status, and histologic grade are reported to be important predictors of survival in the first 5 years after the diagnosis of invasive breast carcinoma. However, to the authors' knowledge, the effect of these factors in the longer term (>10 years after diagnosis) is not yet clear. METHODS: It is now >20 years since the Swedish Two-County Trial of breast carcinoma screening with mammography was instigated and long-term follow-up is now available to December 1998. In the current study, the authors analyzed the effects of tumor size, lymph node status, and tumor grade on survival to death from breast carcinoma using Cox regression and frailty models that allow the baseline hazard and/or effect of a covariate to vary with time. RESULTS: The effects of tumor size, lymph node status, and tumor grade were shown to progressively diminish with time from diagnosis. The Cox regression model with time-varying coefficients and a dampening parameter then was fitted to allow for the attenuation of prognostic effects; tumor size, lymph node status, and tumor grade were all found to be highly significant (P<0.001). CONCLUSIONS: The results of the current study suggest that long-term survival in women with invasive breast carcinoma could be modelled satisfactorily using either frailty models or Cox regression models with time-varying coefficients. The results also suggest that the value of tumor grade, lymph node status, and tumor size at the time of diagnosis have a lasting influence on subsequent survival, albeit attenuated in later years. The long-term effects of these prognostic factors may explain the fact that the impact of mass screening programs on breast carcinoma mortality rates is still apparent many years later.

Mammography service screening and mortality in breast cancer patients: 20-year follow-up before and after introduction of screening.

BACKGROUND: The long term effect of mammographic service screening is not well established. We aimed to assess the long-term effect of mammographic screening on death from breast cancer, taking into account potential biases from self-selection, changes in breast cancer incidence, and classification of cause of death. METHODS: We compared deaths from breast cancer diagnosed in the 20 years before screening was introduced (1958-77) with those from breast cancer diagnosed in the 20 years after the introduction of screening (1978-97) in two Swedish counties, in 210000 women aged 20-69 years. We also compared deaths from all cancers and from all causes in patients diagnosed with breast cancer in the 20 years before and after screening was introduced. In the analysis, data were stratified into age-groups invited for screening (40-69 years) and not invited (20-39 years), and by whether or not the women had actually received screening. We also analysed mortality for the 40-49-year age-group separately. FINDINGS: The unadjusted risk of death from breast cancer dropped significantly in the second screening period compared with the first in women aged 40-69 years (relative risk [RR] 0.77 [95% CI 0.7-0.85]; p<0.0001). No such decline was seen in 20-39 year olds. After adjustment for age, self-selection bias, and changes in breast-cancer incidence in the 40-69 years age-group, breast-cancer mortality was reduced in women who were screened (0.56; 0.49-0.64 p<0.0001), in those who were not screened (0.84 [0.71-0.99]; p=0.03), and in screened and unscreened women combined (0.59 [0.53-0.66]; p<0.0001). After adjustment for age, self-selection bias, and changes in incidence in the 40-49-year age-group, deaths from breast cancer fell significantly in those who were screened (0.52 [0.4-0.67]; p<0.0001); and in all women, screened and unscreened combined (0.55 [0.44-0.7] p<0.0001) but not in unscreened women (p=0.2). In both 40-69-year and 40-49-year age-groups, reductions in deaths from all cancers and from all-causes in women with breast cancer were consistent with these results. INTERPRETATION: Taking account of potential biases, changes in clinical practice and changes in the incidence of breast cancer, mammography screening is contributing to substantial reductions in breast cancer mortality in these two Swedish counties.