Recent results from the Swedish Two-County Trial: the effects of age, histologic type, and mode of detection on the efficacy of breast cancer screening.

The effect of mammographic screening in reducing mortality from breast cancer is known to be smaller and more delayed in women aged 40-49 than in women over 50. In this study, we investigated how these phenomena relate to histology-specific breast cancer incidence and mortality. The data are from 2,468 women with breast cancer who participated in the Swedish Two-County Trial. The overall relative breast cancer mortality of invited to noninvited women aged 40-49 was 0.87, and the relative mortality from poorly differentiated (grade 3) ductal carcinoma was 0.95. These results were not statistically significant. The corresponding relative risks for invited women aged 50-74 were a statistically significant 0.65 and 0.61. We conclude that in this trial, with a two-year interscreening interval, the smaller and later effect of invitation to screening on breast cancer mortality in women 40-49 years old is due to the failure of screening to reduce mortality from grade 3 ductal carcinoma in this age group.

Updated overview of the Swedish Randomized Trials on Breast Cancer Screening with Mammography: age group 40-49 at randomization.

The purpose of this overview is to estimate more precisely the long-term effect of mammography screening by adding four more years of follow-up to women aged 40-49 years in the four Swedish trials on mammography screening. Data from the four, trials were merged and linked to the Swedish Cancer and Cause of Death Register for 1958-1993 and 1951-1993 respectively to identify date of breast cancer diagnosis and cause and date of death. The invited and control groups comprised 48,569 and 40,247 women respectively. At the December 1993 follow-up, 602 and 482 breast cancer cases were identified in the two groups respectively, of which 104 and 111 had breast cancer as the underlying cause of death. This corresponds to a relative risk (RR) of 0.77 (95% CI: 0.59-1.01) for the two groups. In the 40-44 age group at randomization, 94% of breast cancer patients in the study and 89% in the control group were diagnosed before the age of 50; however, among breast cancer deaths in this age group, only two in the invited and five in the control group died after age 50. At follow-up of women 40-44 years at randomization 208 women in the invited and 184 in the control group were reported to the Cancer registry with breast cancer. Out of these 195 (94%) and 163 (89%) respectively were reported before the age of 50. Further, the relative risk for the age group 40-44 years at randomization by age at follow-up was 1.11, 0.51 and 0.46 for the age groups 45-49, 50-54, and 55-59 at follow-up. This study shows a 23% reduction in the breast cancer mortality in women 40-49 years at randomization achieved from a median trial time of 7.0 years, a median follow-up time of 12.8 years, and a screening interval of 18-24 months. Almost all of the effect in the 40-44 year age group at randomization was due to screening before the age of 50.

Sojourn time, sensitivity and positive predictive value of mammography screening for breast cancer in women aged 40-49.

BACKGROUND: In mammographic screening for breast cancer in women aged 40-49, previous studies have found very low estimates of sensitivity and predictive value. Methods of estimation have, however, used primitive models with relatively strong assumptions and less than full use of the data. METHODS: Here we estimate the underlying preclinical incidence, mean sojourn time, sensitivity and positive predictive value by a variety of methods in a randomized trial of mammographic screening (The Swedish Two-County Trial) and a service screening programme (The Florence Programme, 1975-1986) in women aged 40-49 years. RESULTS: In the Two-County study, sensitivity estimates ranged from 72-83% and predictive value from 39-89%. In the Florence programme, sensitivity estimates ranged from 69-85% and predictive value was uniformly estimated as 100%. CONCLUSIONS: The methods involving more explicit modelling of the disease process and fewer assumptions tended to find higher estimates of predictive value in the Two-County study. The results suggest that previously poor sensitivity and predictive value estimates may have been overpessimistic.

Tumour development, histology and grade of breast cancers: prognosis and progression.

Using 1,973 breast tumours from women aged 40-69 participating in the Swedish two-county trial of mammographic screening for breast cancer, we examined the effect of histological type on prognosis and sojourn time (the duration of the preclinical screen-detectable phase) by age. The hypothesis of dedifferentiation, according to which a cancer of mixed malignancy grade drifts towards grade 3 as the more poorly differentiated part of the tumour grows faster than the well-differentiated part, was also assessed. Ductal carcinoma in situ, invasive ductal carcinoma of grade 1, mucinous carcinoma and tubular carcinoma were all associated with good survival. Ductal carcinoma of grade 3 was associated with poor survival. Ductal carcinoma of grade 2, lobular and medullary carcinoma were associated with intermediate survival. These patterns were much the same in women aged 40-49 as in women aged 50-69. In women aged 40-49, sojourn time was estimated at about 2 years regardless of histological type. For women aged 50-69, there was a marked association of sojourn time with histological type, the shortest sojourn time being observed for lobular (2 years) and medullary (1.2 years) carcinoma, and the longest for ductal carcinoma grade 1 (7.7 years) and tubular carcinoma (7.1 years). There was strong evidence of a potential to dedifferentiation. A mover-stayer mixture of Markov chain models estimated that, in women aged 40-54, 91% of ductal tumours have the potential to dedifferentiate and, in women aged 55-69, 38% of ductal tumours have such a potential.

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 Ostergötland (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 populations.

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 Ostergötland (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.

Diagnostic outcome of repeated mammography screening.

Mammographic screening for breast cancer within health service routines was evaluated for the years 1987-1992, with special focus on repeated screening during 1989-1992. The overall attendance rate by women aged 40 to 74 years was 82.8%. During 1989-1992 malignancy was found in 2.6/1000 screened women, giving a 87.4% positive predictive rate at surgery and 95.9% efficiency. Among women aged > or = 45 years, the positive predictive rate was > 94%. Fine-needle aspiration (FNA) biopsy showed invasive cancers in 84% and highly suspected cancer in another 15%; 60% of the lesions were nonpalpable. For first-time (prevalence) screening (1987-1988) the positive predictive rate was 86% and the malignancy yield 6.4/1000. In women aged 40-44 years there were few surgical referrals (1.6%), but the positive predictive rate at surgery was only 48.3%, indicating diagnostic difficulties in young women. The median size of all invasive cancers was 12 mm: 84% were classified as pT1, and 23% had lymph node involvement. Stage II disease was found in 27% of all malignancies. The use of FNA in the diagnostic workup for breast cancer screening is of crucial importance to the maintenance of high positive predictive rates at surgery. Moreover, regular analysis is important even when mammographic screening is incorporated into the routine work of health services.

Efficacy of breast cancer screening by age. New results from the Swedish Two-County Trial.

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.

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.

Effect of breast cancer screening after age 65.

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.

Screening for breast cancer in women aged under 50: mode of detection, incidence, fatality, and histology.

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.

Recurrence-free survival in patients with small breast cancer. An analysis of cancers 10 mm or less detected clinically and by screening.

OBJECTIVE: To evaluate survival of women with small breast cancers (10 mm or less in diameter) in a series almost unaffected by adjuvant medical treatment. DESIGN: Prospective study from a population who were randomly allocated to be screened by mammography. SETTING: University Hospital. SUBJECTS: 324 patients with breast cancers 10 mm or less in diameter who were operated on between 1978-85 (230 detected by screening, 21 interval cases and 73 from the control group). MAIN OUTCOME MEASURES: Recurrence free survival, recurrence rate, and breast cancer mortality alone and in relation to node involvement during a median follow up of 7 years (range 4 months-12.5 years). RESULTS: Survival without distant metastases in life table analyses was 98.7% in 254 node negative cases and 79.3% in 30 node positive cases (p < 0.001). For the whole series survival without distant recurrence was 96.8%. There was no significant difference in recurrence free survival between cancers detected by screening and those detected clinically. Lymph nodes were involved in 9% of the 221 detected by screening compared with 20% of the 89 detected clinically (p < 0.03). CONCLUSION: There was a very low risk of recurrence in small node negative breast cancers (irrespective of the method of detection) indicating that adjuvant treatment may not be necessary for patients with small node negative breast tumours. The good prognosis of these patients also implies that the need for follow up programmes must be discussed because they are probably unnecessary.

Comparison of image quality and mean absorbed dose to the breast for two mammographic films.

A film intended for mammography (Kodak SO 155 MRH-1) was tested and compared to one (Kodak SO 177 Ortho M) used earlier. Both films including the cassette could resolve 20 lp/mm. For a processing time of 90 s the new film gave the same overall image quality and irradiation dose to the breast as the old system. If, instead, the processing time was increased to 150 s, a 43% reduction in kerma could be attained with the new film. With a developing temperature of 36 degrees C and 150 s processing time, the noise is clinically acceptable. A nonparametric test showed no significant difference between the 2 films on the 0.01 level. At an X-ray tube potential difference of 25 kV, the mean absorbed dose to a 4.5-cm-thick breast was reduced from 1.7 mGy with the old combination to 1.0 mGy with the new one. The measurements were made with a moving grid.

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.

Hormone receptors, ploidy and proliferation rate in breast cancers up to 10 mm.

A total of 191 malignant mammary lesions of 10 mm or less in diameter have been analysed with regard to hormone receptor content (107 of 179) and ploidy (112 of 191) in a repeated mammography screening population (second to fourth screening round). Forty-eight per cent were diploid and 68% oestrogen receptor-positive. Mean proliferation rate, calculated as S-phase fraction (SPF), was 6.2 +/- 5.0. Significantly lower SPF was observed in diploid tumours. In very small tumours (less than or equal to 5 mm) SPF was higher as was the fraction of receptor-negative tumours. Among these small cancers a hypothetical high-risk group with SPF greater than or equal to 10% and receptor-negativity will contain 7% of the patients. If SPF and receptor content are chosen as prognostic factors, the latter patients may be a group suitable for adjuvant therapy in treatment schedules.