Seventeen-year evaluation of breast cancer screening: the DOM project, The Netherlands. Diagnostisch Onderzoek (investigation) Mammacarcinoom.

The DOM project is a non-randomized population-based breast cancer screening programme in Utrecht which started in 1974-75. The 17-year effect has been evaluated by a case-control study of breast cancer deaths during the period 1975-92 in women living in the city of Utrecht, born between 1911 and 1925, whose breast cancers were diagnosed after the initiation of the DOM project. Controls (three for each case) were defined as women having the same year of birth as the case, living in the city of Utrecht at the time the case died, and having had the opportunity of screening in the DOM project. Screening in the period 1975-92 indicated a breast cancer mortality reduction of 46% (odds ratio of 0.54, 95% confidence interval 0.37-0.79). The strongest protective effect was found at a screening interval of 2 years or less (mortality reduction of 62%, odds ratio of 0.38), and for the highest number of screens (mortality reduction of 68%, odds ratio of 0.32 for more than four screens). Exclusion of breast cancer deaths that occurred within 1 year of diagnosis, to allow for 'lead-time' bias, gave an odds ratio of 0.61. Early diagnosis of breast cancer by screening reduces breast cancer mortality in the long term. Bias due to the study design may slightly overestimate the protective effect. A screening programme with a 2-yearly, or smaller, interval between successive screens will improve the protection of screening.

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.

Estimation of reproducibility and relative validity of the questions included in the EPIC Physical Activity Questionnaire.

BACKGROUND: The EPIC core questionnaire on lifestyle contains a number of questions on physical activity designed to rank subjects according to level of physical activity (short PA questionnaire). These questions are based on a more extensive questionnaire designed to measure absolute total energy expenditure (extensive PA questionnaire), that was validated in a pilot study preceding EPIC. Reproducibility and relative validity of the short PA questionnaire were estimated by selecting, from the pilot study data, the answers to a number of questions from the extensive questionnaire that resembled those actually included in the short version. METHODS: The population of the pilot study consisted of 126 men and women aged between 20 and 70 years. Reproducibility was estimated by administering the extensive questionnaire three times: at baseline, and after 5 and 11 months. In order to determine the relative validity of the extensive questionnaire, a 3-day activity diary, repeated four times, was used as the reference method. RESULTS: Over the study period (13 months), mean absolute energy expenditure, estimated from the questions included in the short questionnaire, was fairly constant in men but not in women. REPRODUCIBILITY: Spearman correlation coefficients ranged from 0.47 to 0.89 in men, and from 0.49 to 0.81 in women. RELATIVE VALIDITY: Spearman correlation coefficients between the short questionnaire and the diary were between 0.32 and 0.81 for men, and between 0.28 and 0.72 for women. CONCLUSIONS: The questions selected for the short questionnaire are not suitable for estimating energy expenditure at an absolute level. Reproducibility and relative validity of the ranking of subjects seemed satisfactory and comparable to the extensive questionnaire. The results imply that the short questionnaire is suitable for ranking subjects in the EPIC study.

Relative validity and repeatability of a new questionnaire on physical activity.

BACKGROUND: A physical activity questionnaire was developed with the aim to estimate usual individual daily energy expenditure. The questionnaire focused on the number of hours usually spent on various activities. In a pilot study it was tested for repeatability and validity in a population of 126 Dutch adults (64 men, 62 women). METHODS: For assessment of repeatability the questionnaire was administered three times during the course of 1 year. A four-times-repeated 3-day activity diary was used as a reference instrument to evaluate validity. RESULTS: Differences in mean energy expenditure among repeated administrations of the questionnaire were small and not significant. Spearman's test-retest correlation coefficients for total energy expenditure for men were 0.76 [95% confidence interval (CI) 0.63-0.85] and 0.70 (95% CI 0.54-0.81) at 5 and 11 months, respectively, and for women were 0.58 (95% CI 0.36-0.74) and 0.71 (95% CI 0.54-0.82). There was a significant trend showing increasing mean diary energy expenditure for successive tertiles of questionnaire energy expenditure. The correlation between the questionnaire and the diary was 0.66 (95% CI 0.49-0.78) for men and 0.43 (95% CI 0.18-0.63) for women. CONCLUSIONS: It was concluded that this questionnaire is a useful tool for estimating energy expenditure in epidemiological studies.

Prediction of peripheral fracture risk by quantitative microdensitometry.

BACKGROUND: The purpose of the study was to investigate whether quantitative microdensitometry (QMD) could be used for screening purposes to identify a population with a high risk for peripheral osteoporotic fractures. METHODS: In 1984 bone mineral density (BMD) measurements were made on the index finger of 612 women. Repeated BMD measurements were obtained in 1989 in 440 women. Cox proportional hazards models were used to obtain adjusted estimates of the hazard ratio of a fracture according to BMD or bone loss. Receiver operating characteristic curves were constructed and the areas under the curves (AUC) were compared. RESULTS: Thirty-five women experienced peripheral osteoporotic fractures between the first and the second measurement. Women in the three lowest quartiles of bone density were 1.4-1.8 times (diaphyseal site) and 2.4-2.8 times (metaphyseal site) as likely to experience a fracture as those in the highest quartile. Women in the quartile with the highest bone loss had a risk of 6.9 (diaphyseal site) and 7.5 (metaphyseal site) times higher than women in the lowest quartile. The discriminative power of the measurement as a single test was moderate (AUC 63%); two successive measurements, made with an interval of 5 years to measure bone loss, increased the discriminating power (AUC 74%; P < 0.05). CONCLUSIONS: Phalangeal BMD and bone loss, as measured by QMD, are important risk factors for peripheral osteoporotic fractures, but cannot be used as an efficient screening instrument for selecting women with the highest fracture risk.

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

BACKGROUND: 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. METHODS: Radiologic and histopathologic characteristics were assembled for 104 interval cancers diagnosed within the DOM project, the Utrecht program for the early detection of breast cancer. At a mammographic review for 27 cases, signs of malignant or benign tumor were found (missed cases). For 77 cases no radiologic signs were present on review. Twenty of these cases had a mitotic rate of > 3 and a high tumor growth rate (mean doubling time: 51 days). This combination seemed implausible, therefore, it was thought hypothesized that these tumors were most likely present, although radiologically invisible (masked), at the time of screening. The remaining cases (n = 57) were classified as true interval cancers and further divided into 14 fast-growing cases (mitotic rate > or = 3/high-power field [HPF]) and 43 cases with an intermediate growth rate (mitotic rate < 3/HPF). RESULTS: Factors associated with the masking of tumors were the histologic tumor type, absence of microscopic calcifications, and presence of dense breast tissue. Fast-growing tumors were characterized by a young patient age, absence of microscopic calcifications, and a high percentage of regional lymph node positive tumors. The 5-year survival probability was 100% for missed cases, 70% for masked cases, 80% for cases with an intermediate growth rate, and 54% for fast-growing cases. CONCLUSIONS: It is possible to separate interval breast cancers in true interval cases and cases (most likely) existent at the time of screening. Part of this last group is invisible by mammography (masked).

Repeatability and relative validity of two physical activity questionnaires in elderly women.

In a population of 33 women aged 51-71 yr, two physical activity questionnaires (a modified Baecke questionnaire and the pre-EPIC questionnaire) were tested for repeatability (5 and 11 months). For assessment of relative validity, the questionnaires were compared with a physical activity diary (12 d) as the main reference method, a single 24-h Caltrac accelerometer score, and energy intake estimated from a 24-h dietary recall repeated 12 times. Repeatability of the questionnaires at 5 months was 0.82 (Baecke) and 0.42 (pre-EPIC), at 11 months 0.73 and 0.60, respectively. Correlation with the activity diary was 0.51 for the Baecke and 0.64 for the pre-EPIC questionnaire. Correlation with the Caltrac was 0.22 for both questionnaires, and with energy intake -0.21 and 0.43, respectively. Factor analysis suggested that the questionnaires and the diary measured a common aspect of activity, which could be interpreted as "reported normal physical activity." Women who reported sweating or breathlessness during the past week scored significantly higher only on the Baecke questionnaire. It was concluded that the two questionnaires seemed to be able to rank older women according to physical activity in epidemiological studies.

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.

Urinary excretions of high molecular weight beta-thromboglobulin and albumin are independently associated with coronary heart disease in women, a nested case-control study of middle-aged women in the Diagnostisch Onderzoek Mammacarcinoom (DOM) Cohort, Utrecht, Netherlands.

Increased plasma levels of beta-thromboglobulin, a platelet activation marker, are observed in coronary artery disease. Urinary albumin excretion, a marker of endothelial cell perturbation, is related to cardiovascular disease in diabetes. To test the value of these markers in predicting forthcoming coronary disease, the relations between urinary excretions of high molecular weight beta-thromboglobulin (HMW-beta TGf) and albumin and subsequent coronary disease in a cohort of 15,484 middle-aged women were investigated in a nested case-control study. Baseline questionnaire data and urine samples were available from a breast cancer screening program in Utrecht during 1982-1985. Cases were Utrecht hospital admissions for myocardial infarction (n = 50) or angiographically confirmed coronary disease (n = 28) from 1982-1985 to 1990-1991. Classifying events occurred a median of 5.1 years after baseline. Controls were a random sample from the cohort, individually case matched for baseline examination date and age, at a 1:2 ratio. HMW-beta TG/creatinine ratios (ng/mmol, mean +/- standard error) were 5.3 +/- 0.3 in cases and 4.7 +/- 0.3 in controls; albumin/creatinine ratios (mg/mmol, median) were, respectively, 0.37 and 0.22. Crude odds ratios for classification in the highest compared with the lowest tertiles of HMW-beta TG/creatinine and albumin/creatinine distributions were elevated for cases compared with controls: HMW-beta TG/creatinine odds ratio = 2.4, 95% confidence interval 1.1-5.0; albumin/creatinine odds ratio = 2.1, 95% confidence interval 1.0-4.1. These relations persisted after adjustment for smoking, hypertension, Quetelet index, and menopausal status. Both urinary HMW-beta TG and albumin excretion are markers of coronary disease risk in middle-aged women, indicating that increased platelet activation and endothelial cell perturbation precede coronary heart disease events in women.

Survival in interval breast cancer in the DOM screening programme.

The study describes breast cancer survival of 75 interval cancer cases (cancer occurring within 2 years of a negative screen) detected in women who participated in the DOM screening programme. After mammographic revision, this group was divided into 17 so-called 'missed' cases and 58 'true' interval cases. Ten year survival of these 58 'true' interval cases was 58%, which was not significantly different from that of 219 cancers detected in a non-screened, control group of women, diagnosed with breast cancer before the start of screening (63%; log rank chi 2 test, P = 0.98). Results remained essentially the same after correction for age at diagnosis, tumour size, axillary status and year of diagnosis. Ten year survival of 'true' interval cancers (58%) was slightly worse than that of 'missed' cases (67%; log rank chi 2 test: P = 0.38). This difference could largely be explained by differences in tumour size and axillary status. We conclude that there was no important difference in survival between 'true' interval cancers and non-screened historical controls. This could mean that either this subgroup of interval cancers does not constitute an excess of rapidly growing tumours, or if it does, that a fast growth rate is not associated with an exceptionally poor prognosis.

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

The association between body fat distribution and breast cancer risk was studied in 5923 pre- and 3568 post-menopausal 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 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.

Validity and repeatability of a modified Baecke questionnaire on physical activity.

BACKGROUND: In a pilot study for the European Prospective Investigation into Cancer and Nutrition (EPIC) a modification of the Baecke questionnaire on physical activity was tested for repeatability and relative validity in a population of 134 men and women aged 20-70 years. METHODS: For the assessment of repeatability Pearson's correlation coefficients and percentages of agreement after classification in tertiles were computed between administrations of the questionnaire at baseline, and after 5 and 11 months. Relative validity was determined by comparing the questionnaire to a four times repeated 3-day activity diary. RESULTS: Repeatability after 5 and 11 months was good, with test-retest correlation coefficients between 0.65 and 0.89 for main sections of the questionnaire. The percentages of agreement, exceeding chance (Cohen's kappa) were 57% and 56% for men (at 5 and 11 months respectively) and 41% and 46% for women. The correlations with the diaries were 0.56 in men and 0.44 in women. Agreement apart from chance between classification in tertiles for both methods was 35% for men and 10% for women. CONCLUSIONS: These data show that repeatability is good and relative validity as compared to an activity diary is moderate but well within the range of values found in other studies. The questionnaire is more valid in men than in women.

Calcium and magnesium in human toenails do not reflect bone mineral density.

Nail mineral composition is influenced by several physiological and pathological processes. Potentially, nails could be used to monitor alterations in the level of incorporation of specific elements produced by nutritional abnormalities, disease states or chronic exposure to toxic agents. The purpose of this study was to investigate whether the calcium and magnesium content in nail clippings, as measured by instrumental neutron activation analysis (INAA), correlates with bone mineral density (BMD), as measured by quantitative microdensitometry (QMD), and therefore could be interesting as a screening instrument for osteoporosis. The study involved 220 women, who participated in a breast cancer screening project (the DOM-project) in Utrecht, the Netherlands. The correlations found between Ca and Mg measurements and bone mineral densities were very low (correlation coefficients ranging from 0.03 to 0.18). It is concluded that Ca and Mg measurements in nail clippings by INAA cannot be used for screening purposes in the prevention of osteoporosis.

Nation-wide breast cancer screening in The Netherlands: support for breast-cancer mortality reduction. National Evaluation Team for Breast Cancer Screening (NETB).

The nation-wide 2-yearly breast-cancer screening programme in The Netherlands, for women aged 50-69, started around 1988, and was predicted to result eventually in a 16% reduction in breast-cancer mortality in the total female population. We present the results of screening up to January 1, 1993, and compare these with the predicted results from the cost-effectiveness analysis, on which basis this mortality reduction has been calculated. At least 550,000 women aged 50-69 were invited to screening in 1990-1992, and 75% of these participated. Cancer was suspected from 5,162 examinations and further investigation was therefore required. Excision biopsy was done in 72% of referrals, and 2,515 breast cancers were detected. The results for 404,000 newly invited women compare favourably with expected values (in parentheses): 78% attendance rate (70%), 1.4% screen positive (1.6%), 6.8 cancers detected per 1,000 women screened (6.4) and 38% of these cancers were DCIS or invasive carcinomas smaller than 11 mm in diameter (36%). More data, e.g., on treatment and interval cancers, will follow in the years to come. These first results can be interpreted as strong early signs of a reduction in breast-cancer mortality of at least the predicted size. Screening has sufficiently advanced the diagnosis, as well as or better than expected. Breast cancers diagnosed in this age group without screening are diagnosed at a worse stage than expected. Unfavourable side-effects, especially false-positive referrals, might be kept lower than those reported in other countries.

Effect on breast cancer screening response in The Netherlands of inviting women for an additional scientific investigation.

STUDY OBJECTIVE: The study aimed to determine whether asking women to undertake an additional scientific study would deter them from attending screening for breast cancer. DESIGN: A randomised study was conducted in all women aged 50-70 years who were eligible for breast cancer screening and living in the city of Utrecht. A total of 1863 women were invited for mammography only and 1863 women were invited to participate in the European Prospective Investigation into Cancer and Nutrition (EPIC) in addition to the mammography. SUBJECTS: The study population comprised a random sample of 3726, 15% of the female population of Utrecht aged 50-70 years. MAIN RESULTS: The attendance rate for breast cancer screening was 53%, irrespective of the invitation to participate in the additional scientific study. CONCLUSIONS: Asking women to attend for an investigation in addition to the routine screening procedure for breast cancer did not affect the overall response to screening.

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, Quetelet's 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 Quetelet's 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.

The epidemiological profile of women with an interval cancer in the DOM screening programme.

Risk factors for breast cancer were compared in 107 women with interval breast cancer (cancers occurring within 2 years after a negative screen) and 258 women with breast cancer detected at 1st screening. All women (aged 40-67) were screened in the DOM project (the Utrecht programme for the early detection of breast cancer). Women with an interval cancer reported more often a history of benign breast disease (OR 4.66, 95% C.I. 2.08-10.41) and an artificial menopause (OR 4.07; 95% C.I. 1.74-9.55) than women with a screen detected cancer. Women with an interval cancer were taller than women with a screen detected cancer; this was seen most clearly in women with an artificial menopause (chi 2 for trend = 5.88; p = 0.02) and to a lesser extent in premenopausal women (chi 2 for trend = 1.70; p = 0.19). Premenopausal women with an interval cancer were heavier than women with a screen detected cancer (chi 2 for trend = 4.66; p = 0.03); whereas natural postmenopausal women with an interval cancer were leaner than women with a screen detected cancer (chi 2 for trend = 1.57; p = 0.21). All analyses were done while correcting for age and selected other risk factors for breast cancer. These results suggest that the epidemiological profile of pre- and post-menopausal women with an interval cancer differs from that of women with a screen detected cancer, which might imply a different natural history of these two types of breast tumours.

Cross-sectional and longitudinal study of age-related phalangeal bone loss in adult females.

To establish a comprehensive model for peripheral phalangeal bone loss, bone mass was studied in 1984 and 1989 using quantitative microdensitometry (QMD) in a total of 330 healthy women (age range 43-78.7 years). Bone mass and changes in bone mass were analyzed in relation to age and menopausal status. Ideal and nonideal populations were distinguished to assess the effect of diseases and medication. Both groups showed a decrease in bone mass, which proved to be more dependent on menopausal status than on age. A substantial loss started in the ideal group in the early postmenopausal period and in the nonideal group in the premenopausal period. Because the nonideal group started to lose bone at an earlier stage, the lifetime risk for osteoporosis is higher than in the ideal group.

Clinical heterogeneity of hereditary breast cancer and its impact on screening protocols: the Dutch experience on 24 families under surveillance.

We investigated 24 families who satisfied a set of criteria for hereditary breast cancer. Five families had only breast cancer, four a combination of breast and ovarian cancer and the remaining 15 had also a variety of other cancers. The families include 86 patients, 78 of which had a malignant tumour and the rest had a benign lesion in the breast. The median age at diagnosis of the breast cancer was 47 years. Three of the 24 families were of a late onset variant. 58 of the 86 patients were symptomatic while 18 were identified during presymptomatic screening because of a positive family history. In 10 cases the reason for referral was not known. 56 of the symptomatic patients had a malignant breast lesion, 52% of which were with lymph node metastasis whereas 12 of the screening group had breast cancer with 2 patients showing lymph node involvement (P = 0.06). 22 of the symptomatic patients and none of the screening patients died of breast cancer after a median observation period of 6 and 7 years, respectively (P < 0.05).