H. J. A. Collette

EVALUATION OF SCREENING FOR BREAST CANCER IN A NON-RANDOMISED STUDY (THE DOM PROJECT) BY MEANS OF A CASE-CONTROL STUDY

In 1974 a non-randomised study of the effect of mass screening by physical examination and xeromammography on mortality from breast cancer was started. Of the 20 555 eligible women in the city of Utrecht born between 1911 and 1925 (aged 50-64 at the start of the study), 14 796 attended for screening. Four rounds of screening were carried out. The relative risk of dying from breast cancer among women ever screened compared with women never screened was 0.30 (95% confidence interval 0.13-0.70).

A model for breast cancer screening

A model for breast cancer screening has been developed. When the appropriate screening policy is specified, the model reproduces the detection rates and the incidence of interval cancers as observed in the recent screening projects in Utrecht and Nijmegen, the Netherlands. The model‐predicted mortality rate reduction is in accordance with the results of the Kopparberg/Ostergötland randomized trial in Sweden. Key parameters of the model are the duration of the preclinical stages and the sensitivity of mammography. The average duration is approximately 2 years at age 40 and increases to approximately 5 years at age 70. The sensitivity is high (approximately 95%) for tumors larger than 1 cm. The model is used in the prospective evaluation of effects and costs of various screening policies.

Histopathology and growth rate of interval breast carcinoma: Characterization of different subgroups

Interval breast cancers are defined as carcinomas occurring within 2 years after a negative screening. Distinction has to made between cancers existent at the time of screening but missed for some reason, and fast‐growing, incident cancers. This is important because the natural history and the implications for the treatment of the patient might differ.

Body fat distribution in relation to breast cancer in women participating in the DOM-project

SummaryThe association between body fat distribution and breast cancer risk was studied in 5923 pre- and 3568 postmenopausal women, participating in a breast cancer screening project (the DOM-project in Utrecht, the Netherlands). Cases were fifty six premenopausal women and thirty eight postmenopausal women with breast cancer detected at screening or afterwards. Controls were women participating in the breast cancer screening project without breast cancer. Waist- and hip circumferences, height and weight were measured at screening, before diagnosis of breast cancer.In postmenopausal women the estimated relative risk of women in the upper tertile of waist/hip ratio compared with women in the lower tertile was 1.89 (95% CI 0.80–4.48), (test for trend p = 0.11). The estimated relative risk of women in the upper tertile of waist circumference compared with women in the lower tertile was 2.86 (95% CI I 1.12–7.32), (test for trend p = 0.08). The association between waist circumference and breast cancer was stronger than the association between any of the other anthropometric variables and breast cancer.In premenopausal women the association between fat distribution and breast cancer was equivocal.

A prospective study on obesity and subcutaneous fat patterning in relation to breast cancer in post-menopausal women participating in the DOM project

The associations of body fat and body fat distribution with breast cancer risk were examined in a prospective study in 9,746 post-menopausal women with a natural menopause, aged 49-66 at intake, participating in a breast cancer screening project (the DOM project in Utrecht). During a follow-up period of 15 years (mean follow-up time 12.5 years) 260 women developed breast cancer. Fat distribution, assessed by contrasting groups of subcapsular and triceps skinfold thickness, was found to be unrelated to breast cancer incidence. No significant relationship between body fat, measured either by weight, Quetelets index, triceps skinfold or subscapular skinfold, and breast cancer risk was found when analysed in quartiles. However, women in the upper decile compared with the lower decile of the distribution of Quetelets index were found to have a 1.9 times (95% CI 1.1-3.3) higher risk for breast cancer. These results seemed to be in contrast with the significant positive association between fatness, analysed in quartiles, and breast cancer observed in a cross-sectional study, based on mammographic screening, carried out previously in the same population. Although the differences between the present, prospective, study and our cross-sectional study may be due to chance it may be that there are differences between characteristics of breast cancer detected at screening and subsequently, which influence the associations between measures of fatness and risk of breast cancer.

Age specific sensitivity and sojourn time in a breast cancer screening programme (DOM) in The Netherlands: a comparison of different methods.

STUDY OBJECTIVE: To estimate age dependent sensitivity and sojourn time in a breast cancer screening programme by different methods. POPULATION AND METHODS: The study population comprised women participating in the DOM project--the Utrecht screening programme for the early detection of breast cancer. Breast cancer screening prevalence data and incidence rates after a negative screen were used to estimate age specific sensitivity and mean sojourn time by different methods. MAIN RESULTS: Maximum likelihood estimates of the mean sojourn time varied from one year for women aged 40-49 years to three years for women over the age of 54. Sensitivity was calculated by two different methods. Both pointed to a high sensitivity (around 100%) in the age groups 40-49 and over 55 years. For women aged 50-54, the sensitivity varied from 63% to 100%, depending on the method used and the value of the baseline incidence rate. CONCLUSIONS: Different methods of estimating sensitivity pointed at an acceptable level in women over and under 50 years of age. Sojourn time, and thus the tumour growth rate, seemed to be age dependent. This could mean that the until now disappointing screening results in women under 50 years of age are not so much a result of low sensitivity as of a relatively high tumour growth rate in younger women.

Breast cancer after a negative screen: Follow-up of women participating in the DOM screening programme

First-round screening results for women participating in the DOM project (a screening programme for early detection of breast cancer) are described for the age groups 40-49 and 50-64 at entry. In the younger age group, a low pick-up rate (1.96 per 1000) in proportion to the expected incidence rate in the absence of screening (1.46 per 1000) was found. For the older age group, these rates were 4.25 and 2.03, respectively, per 1000. Interval cancers occurred (relatively) more frequently in younger women. After 2 years the ratio between interval-cancers and screen-detected tumours was about 1:1 in the younger age group and 1:2.5 in the older age group. These different results can be caused by too low a sensitivity of mammography and/or a higher tumour growth rate at a young age. The sensitivity of the screen at various periods of follow-up, was compared: a rapidly decreasing sensitivity of mammography was seen for women under the age of 50, in contrast to a slower decrease for women over this age. This rapid decrease may be caused by a relatively high tumour growth rate in younger women.

Urinary sex hormone excretions in premenopausal women and coronary heart disease risk : A nested case-referent study in the DOM-cohort

The low incidence of coronary heart disease (CHD) in premenopausal women is partly ascribed to protection by endogenous estrogen production. As a consequence, we hypothesized that premenopausal women with low endogenous estrogen production or high androgen production might be at increased risk for CHD. We studied the relationship between urinary sex hormone excretions and CHD risk by means of a nested case-referent study within a cohort of premenopausal (ages 40-49 yrs) women (n = 11,284). This cohort was formed at a breast cancer screening project in 1982-1986 (The Diagnostisch Onderzoek Mammacarcinoom [DOM] Project). Baseline data included self-administered questionnaires and anthropometric measurements. At the time of screening the women were instructed to collect an overnight urine sample on day 22 of three separate cycles. These urine samples were stored at -20 degrees C. Up to June 1991, 45 subjects were admitted to local hospitals on diagnosis of CHD (29 with myocardial infarction, and 16 with angiographically confirmed coronary disease). Referents were sampled from the cohort, matched for age and year of screening in a 1:3 ratio. In a follow-up study, menopausal state of the subjects was assessed yearly by mailed questionnaires. Urinary excretions of estrone-glucuronide, pregnanediol-glucuronide, and testosterone-glucuronide adjusted by creatinine were similar for cases and referents. Cases had no earlier menopause than referents, although cases had more anovulatory cycles. The occurrence of CHD in middle-aged women is not preceded by a low premenopausal endogenous estrogen production or high androgen production. Anovulatory cycles appear more frequently in women who develop CHD many years later.

A cross-sectional study of age-related loss of mineral content of phalangeal bone in men and women

The bone mineral content of the second phalanx of the second digit was studied by quantitative microdensitometry. It is concluded that age-dependent loss of bone is a generalised phenomenon in men and women that occurs at different rates at different ages. In women, an accelerated rate of bone loss is observed between 50 and 57 years of age; in men such an acceleration is observed after 68 years of age. It appears that in a selected “ideal” population (with no disease or medication that may influence bone metabolism) the rate of bone mineral loss in women of 50–57 years of age is greater than in an unselected normal population. Furthermore, especially in the 50–57 years age group, the rate of loss at the midshaft of the phalanx in women is higher than at a site 25% from the proximal end. In men the rate of bone mineral loss at the 25% site exceeds that at midshaft, especially in the 68–75 year age group.

Further evidence of benefits of a (non-randomised) breast cancer screening programme: the DOM project.

STUDY OBJECTIVE--The aim was to demonstrate the benefits of breast cancer screening on mortality. DESIGN--The study was an evaluation of a breast cancer screening programme by means of different approaches: (1) a case-control study, breast cancer deaths being the cases; (2) comparing the numbers of breast cancer deaths in screened and unscreened women; (3) comparing breast cancer mortality before and after start of the programme; (4) comparing breast cancer mortality in different large cities; (5) comparing screening activity with mortality reduction. SETTING--The setting was a breast cancer screening programme in the city of Utrecht, the DOM project, for women aged 50-64 years old at intake, birth cohort 1911-1925. The programme started in 1974, and there were five screening rounds up to 1984. Participation rate in the first round was 72% (14,697 women). MAIN RESULTS--(1) Screening was protective against dying from breast cancer, odds ratio 0.52, with a stronger effect in older women and no evidence of confounding; (2) risk ratio of dying from breast cancer for women in the response group was the same as the odds ratio, 0.52; (3) breast cancer death rate after the start of the project was nearly 20% lower than before the project started; after correcting for women who could not have benefited from screening the reduction was 33%; (4) a rise in breast cancer mortality in birth cohort 1911-1925 seen in other large cities without a screening programme due to aging of the cohort was not seen in the city of Utrecht; (5) mortality reduction followed the screening activity with a time lag of approximately 5 years. CONCLUSIONS--Early diagnosis of breast cancer by mammography reduces breast cancer mortality in women 50-64 years old at intake; different approaches to the evaluation of the project give different estimates of the screening effect, making clear that the effect depends on the intensity of the programme.