Screening for breast cancer.
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Biomedical subjects
Publications and source records attributed to L Tabar.
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The sojourn time, time spent in the preclinical detectable phase (PCDP) for chronic diseases, for example, breast cancer, plays an important role in the design and assessment of screening programmes. Traditional methods to estimate it usually assume a uniform incidence rate of preclinical disease from a randomized control group or historical data. In this paper, a two-parameter Markov chain model is proposed and developed to explicitly estimate the preclinical incidence rate (lambda 1) and the rate of transition from preclinical to clinical state (lambda 2, equivalent to the inverse of mean sojourn time) without using control data. A new estimate of sensitivity is proposed, based on the estimated parameters of the Markov process. When this method is applied to the data from the Swedish two-county study of breast cancer screening in the age group 70-74, the estimate of MST is 2.3 with 95 per cent CI ranging from 2.1 to 2.5, which is close to the result based on the traditional method but the 95 per cent CI is narrower using the Markov model. The reason for the greater precision of the latter is the fuller use of all temporal data, since the continuous exact times to events are used in our method instead of grouping them as in the traditional method. Ongoing and future researches should extend this model to include, for example, the tumour size, nodal status and malignancy grade, along with methods of simultaneously estimating sensitivity and the transition rates in the Markov process.
BACKGROUND: Several studies have found a smaller effect of breast cancer screening on breast cancer mortality in women aged younger than 50 years compared with older women. Various possible reasons have been suggested for this, but none firmly is established. METHODS: The Swedish Two-County Study is a randomized trial of breast cancer screening of women aged 40-74 years, comprising with 133,065 women with a 13-year follow-up of 2467 cancers. The Breast Cancer Detection Demonstration Project (BCDDP) is a nonrandomized screening program in the United States, with a 14-year follow-up of 3778 cancers in women aged 40-74 years. The Swedish results by age were updated. The lesser effect of screening at ages 40-49 years was investigated in terms of sojourn time (the duration of the preclinical but detectable phase) size, lymph node status, and histologic type of the tumors diagnosed in the Swedish Study and their subsequent effect on survival using survival data from both studies. RESULTS: In the Swedish Trial, a 30% reduction in mortality associated with the invitation to screening of women aged 40-74 years was maintained after 13-years of follow-up. The reduction was 34% for women aged 50-74 years and 13% for women aged 40-49 years. Results indicated that the reduced effect on mortality for women aged 40-49 years was due to a differential effect of screening on the prognostic factors of tumor size, lymph node status, and histologic type. The mean sojourn times in the age groups 40-49 years, 50-59 years, 60-69 years, and 70-74 years were 1.7, 3.3, 3.8, and 2.6 years, respectively. CONCLUSIONS: These results suggest that much, although not all, of the smaller effect of screening on mortality in women aged 40-49 years is due to faster progression of a substantial proportion of tumors in this age group and the rapid increase in incidence during this decade of life. It is concluded that the interval between screenings should be shortened to achieve a greater benefit in this age group. It is estimated that a 19% reduction in mortality would result from an annual screening regime.
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The relationship between mammographic patterns and reproductive and menstrual factors was examined in 3640 Norwegian women, aged 40-56 years, participating in the Third Tromsö study conducted in 1986-87. Epidemiological data were obtained from questionnaires. The mammograms were categorised into five groups. This categorisation is based on anatomic-mammographic correlations, following three-dimensional (thick slice technique) histopathologic-mammographic comparisons, rather than simple pattern reading. Patterns 1-3 were combined into a low-risk group and patterns 4 and 5 into a high-risk group for analysis. Women who had more than four children were 90% less likely to have a high-risk pattern than nulliparous women (OR = 0.09, 95% CI 0.04-0.16) controlling for age, weight, height and menopausal status. Furthermore, those who first gave birth over 34 years of age were more than twice as likely to have a high-risk pattern than those giving birth in their teens (OR = 2.37, 95% CI 1.23-4.56) adjusting for parity. Among post-menopausal women, age at menarche was negatively (P for trend = 0.015) and late age at menopause positively (P for trend = 0.072) related to high-risk patterns. Among premenopausal women, age at menarche was positively related to high-risk patterns (P for trend = 0.001). Also, menopausal status rather than age was associated with high-risk patterns. These findings support the opinion that reproductive and menstrual factors are involved in determining the mammographic parenchymal pattern among perimenopausal women.
OBJECTIVE: To assess the effect of mammographic screening for breast cancer in women aged 65 years or over. SETTING: The Swedish two county trial of screening for breast cancer, in which 77,080 women aged 40-74 (21,925 aged 65-74) were randomly allocated to receive regular mammographic screening for breast cancer, and 55,985 women aged 40-74 (15,344 aged 65-74) were allocated to an unscreened control group. METHODS: One group was screened every 33 months on average, except for those aged 40-49 at randomisation who were screened every 24 months. The control group was screened once at the conclusion of the trial. The main statistical analysis was the comparison of cumulative mortality with 13 years of follow up between the screened and control groups, in age groups 50-64 and 65-74, using Poisson regression. This was complemented by subsidiary analyses assessing the lead time, sensitivity, and predicted mortality from the size, node status, and grade of tumours diagnosed in the screened and control groups. RESULTS: In the age group 65-74 at randomisation there was a significant reduction in breast cancer mortality in the screened group, with a relative mortality of 0.68 and 95% confidence interval of 0.51 to 0.89. This was backed up by the results of the analyses of lead time, sensitivity, and tumour characteristics. CONCLUSIONS: Women aged 65 or more who are regularly screened can expect a reduced risk of dying from breast cancer.
OBJECTIVE: To assess the effect of screening for breast cancer in women aged 40-49 in the Swedish two county trial, in terms of mortality reduction, advanced cancer reduction, mode of detection, and the histology of tumours detected. SETTING: The Swedish two county trial of screening for breast cancer, in which 77,080 women aged 40-74 (19,844 aged 40-49) were randomly allocated to receive regular invitation to mammographic screening for breast cancer, and 55,985 women aged 40-74 (15,604 aged 40-49) were allocated to an unscreened control group. METHODS: The screening interval in the younger age group was two years and in the older age group about three years. Statistical analysis of mortality and incidence rates was performed by Poisson regression. Relative survival was estimated using proportional hazards regression. RESULTS: The relative mortality for the group invited to screening compared with the control group was 0.87 (95% confidence interval 0.54 to 1.41) in the 40-49 age group, in close agreement with the relative incidence of advanced cancers. For Kopparberg county the relative mortality was 0.73 (95% CI 0.37 to 1.41) and for Ostergotland 1.02 (95% CI 0.52 to 1.99). The lesser effect in the 40-49 group as a whole was largely due to a higher rate of interval cancers in this age group, and the occurrence in Ostergotland of a higher number of cancers after randomisation, but before screening started, and in women who refused screening. The higher interval cancer rate was consistent with the higher proportion of ductal grade 3 and medullary cancers in women aged 40-49 at diagnosis. CONCLUSIONS: A major difficulty in screening women aged 40-49 is the rapid progression of a subset of tumours arising in this age group. Shortening the screening interval from two years would be necessary to achieve a higher mortality reduction.
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The issue of whether to screen women aged 40-49 for breast cancer is debated usually in terms of the potential mortality reduction achievable by the application of screening in this age group. Theories regarding why a significant reduction in mortality has not been observed in trials relate to the biologic behavior of tumors in this age group and the screening process itself. Survival curves with respect to node status, size, and grade of the tumor were compared among age groups in the Swedish two-county trial. In the Kopparberg part of this trial, for the 40-49 age group, predicted survival was calculated from the size, node status, and grade of cancers detected during the trial in comparison with those found in two later series of tumors, one from the 1989-1992, Kopparberg screening program, the other from the British Columbia screening program, the other from the British Columbia screening program that began in 1988. The Kopparberg arm of the Swedish two-county study used single-view mammography with extended processing but without grid; the two more recent programs used two-view mammography with extended processing and the grid. Both the Kopparberg programs used a 2-year interval. The effects of grade, node status, and size on survival in the 40-49 age group were very similar to their effects in older age groups. Predicted survival from the latter Kopparberg series was essentially the same as that for the earlier. The mortality reduction in this age group in the Kopparberg part of the Swedish two-county trial was 26%. The survival results indicate no biologic reason why screening should not be able, theoretically, to reduce mortality. Nonsignificant reductions in mortality have been observed in the Kopparberg part of the two-county trial and in the overview of Swedish trials. The similar predictive results for the two-view and one-view trials suggest that the most likely way to achieve further reductions in mortality is to reduce the interval between screens, possibly to 1 year.
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The results of the Swedish two-county study are analysed with respect to tumour size, nodal status and malignancy grade, and the relationship of these prognostic factors to screening and to survival. It is shown that these factors can account for much of the differences in survival between incidence screen detected, interval and control group cancers but to a lesser extent for cancers detected at the prevalence screen where length bias is greatest. Furthermore, examination of the relationships among the prognostic factors and mode of detection indicates that malignancy grade, as a measure of inherent malignant capacity, evolves as a tumour grows. The proportion of cancers with poor malignancy grade is several fold lower for cancers of diameter less than 15 cm than for cancers greater than 30 cm, independent of the length bias of screening. The implications of these findings for screening frequency are briefly discussed.
The Swedish two county trial of breast cancer screening is now in its tenth year. This paper presents detailed results on mortality from breast cancer and from all other causes, and on the population denominators at risk for each of the first 8 years of follow up, for each county separately. These data represent a two year update on the last major report. Results show an increasingly significant deficit in deaths from breast cancer among the 77,092 women invited to screening relative to the 56,000 not invited (RR = 0.68, p = 0.002), with no significant difference between the effects of screening in the two counties (p = 0.5). These results remain the same when adjusted for age. Analysis of all cause deaths shows no significant effect of screening (p = 0.5), nor was there any significant effect of screening on deaths from all causes other than breast cancer (p = 0.9). The rates of deaths from intercurrent illness in breast cancer cases were almost identical in the group invited to screening and the group not invited (p = 0.7). This result remained the same when adjusted for age. We calculate that in the age group 50-69 at entry, one breast cancer death was prevented per 4000 woman/years, per 1460 mammographic examinations, per 13.5 biopsies, and per 7.4 breast cancers detected.
Sensitometrically exposed film strips and clinical mammograms from single-emulsion Kodak Ortho M SO-177 and double-emulsion Kodak T-Mat M II films were processed in separate film processors set up for standard and extended-cycle processing. For the extended-cycle method, it is necessary to use a process that is dedicated to mammographic films only. Radiation dose reductions of approximately 30% for Ortho M film and 13% for T-Mat M II film were achieved with the extended-cycle process. In the mammogram comparisons, higher-contrast images were obtained with Ortho M film in the extended-cycle process, which allowed for improved demonstration of marginal structural characteristics of soft-tissue masses and better differentiation of benign and malignant tumors. No significant differences in contrast were observed in the T-Mat M II mammograms obtained with the extended-cycle process.
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The relationship between tumour size and lymph node metastases was examined in screening-detected and clinically detected breast cancers. The data used were from a randomized trial of breast cancer screening with mammography. 964 cancers were reviewed, in both arms of the trial, in women aged 40-74. Lymph node status was significantly related to detection method (P less than 0.001), metastases being less common in screening-detected cancers. Node status was also significantly related to tumour size (P less than 0.001), metastases being commoner in larger tumours. Similarly, tumour size was significantly associated with detection method (P less than 0.001), smaller tumours being detected by screening. No significant interaction was observed among all three factors, indicating that the relationship between node status and tumour size did not change with detection method. When detection method was replaced with randomly allocated study (invited to screening) and control (not invited to screening) groups, the same results were observed. It is concluded that if screening detects tumours with a different natural history to that of those which surface clinically, this is not reflected in the relationship between tumour size and lymph node metastases.
The changes in the demand for surgical inpatient care created by mammographic screening for breast cancer were analysed by comparing two counties, one with and one without a mass screening campaign. A comprehensive computerised register of inpatient care in the region was used. The results indicate that population based screening offered to women above 40 years and repeated every two to three years will increase the number of operations required for breast cancer and inpatient days by at least 150% during the initial screening round. During the second round the figures tend to return to previous levels. Of decisive importance for the demands on health service resources are the specificity of screening, the duration of the first screening round, and the age groups included.
In women drawn from a randomised, population-based trial of mammography screening for breast cancer the overall actuarial survival and disease-free survival for up to 7 years of observation were similar in 94 patients with interval cancers and 178 control patients with cancer diagnosed independent of screening. The similarity was confirmed by multiple regression analysis. These results contradict the hypothesis that a high growth rate of the primary tumour is associated with a greater metastatic potential and do not support the concept that patients with interval cancers should receive more aggressive local or systemic treatment.