Hormonal aspects in the causation of human breast cancer: epidemiological hypotheses reviewed, with special reference to nutritional status and first pregnancy.

Epidemiology of breast cancer has identified early age at menarche, late first pregnancy, low parity and late menopause as risk factors, but in addition genetic factors, height, weight and living in western countries play a significant role. The international variation in incidence is almost exclusively due to non-genetic factors. Hypotheses in prevention-oriented research are reviewed: 1. obesity-related oestrogen production as a stimulus of the tumour in postmenopausal women; 2. nutritional status and energy expenditure during puberty and adolescence, developed for fertility and fecundity and extended later to breast cancer; 3. reproductive life during early adulthood, age at first pregnancy and its specific effects on breast tissues. The message of preventability of breast cancer is that mammary epithelial differentiation should come early. Our insight concerning events in puberty and early adulthood can be consolidated in one concept on the risk of extended proliferation of breast epithelium during early adulthood in the absence of full differentiation induced by pregnancy. The combined effects of Western-type nutrition, lack of exercise and Western-type women's emancipation sets the stage for breast cancer already at a young age. Since it is unlikely that emancipated women in affluent societies will return to the original life-style of getting pregnant as soon as it is biologically possible, a novel daring way of protection has to be considered. Could a "Breast Differentiation Pill" be developed to offer protection?

Risk factors for breast cancer at various ages.

A brief overview is presented of breast cancer risk factors with particular reference to the time in a woman's life when they seem to operate. High incidence of the disease in Western societies is associated with early ovarian maturation and late onset of reproduction. In biologic terms this means proliferation without differentiation of breast cells over a long period of time.

Endometrial cancer in a cohort screened for breast cancer.

In a cohort of 25,000 women aged 40-65 years at intake in a periodic screening programme for breast cancer the occurrence of endometrial cancer was studied during a follow-up period of up to 18 years. The authors examined whether they could confirm the existence of a number of relationships between this cancer and some reproductive and anthropometric factors which had been found in several case-control studies and in a few cohort studies. A comparison was made between 147 cases of endometrial cancer occurring during the period of follow-up and a random sample of 900 women taken from the cohort (334 being premenopausal and 566 postmenopausal on the day of intake). An inverse relationship between number of children and endometrial cancer risk was found in the older group; the excess risk among nulliparous women was stronger in married than in single women. Late age at menopause (after age 52) was associated with increased risk. Use of oestrogenic drugs on day of intake for alleviating perimenopausal complaints (reported in 8% of women) increased risk, especially in the younger group. Body weight was positively associated with risk (with an odds ratio of 4 in those over 80 kg) among postmenopausal women. Because there appeared to be a moderately strong risk associated with tall height, especially among postmenopausal women, Quetelet's index performed less well than body weight itself. Nevertheless, subscapular and triceps skinfold thicknesses confirmed an effect of fatness on risk. These results are discussed with reference to other epidemiological studies, in particular two cohort studies from Norway. The effect of height, convincingly shown by Tretli and Magnus in 1990, is explained in a way which does not assume causal mechanisms operating at a young age: absolute fat mass rather than relative weight is regarded as the main determinant of risk in postmenopausal women.

A comparative study of risk factors for hyperplasia and cancer of the endometrium.

A cohort study has been carried out to investigate risk factors for cancer as well as hyperplasia of the endometrium. Over the 13 years for which we followed 25,000 women aged 40-65 (who took part in a population-based screening programme for breast cancer), 111 cases of endometrial cancer and 109 cases of endometrial hyperplasia were diagnosed. A comparison of the outcome between the two disease entities revealed that large body weight among postmenopausal women and the use of oestrogenic drugs at all ages were risk factors for both cancer and hyperplasia of the endometrium. However, reproductive histories and premenopausal steroid profiles differed. Steroid excretion determinations in urine samples collected years before diagnosis provided further evidence in favour of the hypothesis of unopposed action of oestrogens in the aetiology of endometrial cancer. In women who were to develop endometrial hyperplasia or cancer the obesity-oestrogen relationship was stronger than in those who remained free of endometrial disease during the period of follow-up. The possible significance of differences in aromatase activity among the obese is considered.

Regularity and length of menstrual cycles in women aged 41-46 in relation to breast cancer risk: results from the DOM-project.

The effect of regularity and length of the menstrual cycle on breast cancer risk was studied prospectively in 78 cases and 383 age-matched controls who participated in a breast cancer screening programme, the DOM-project, in Utrecht, the Netherlands. Before entering the screening programme when they were aged 41-46, the women kept a menstrual calendar during at least three consecutive cycles. Cycles were considered to be irregular if any of three cycles was shorter than 21 days or longer than 35 days and/or if variation between cycle lengths was more than five days. Women with irregular cycles had a significantly reduced risk of breast cancer (odds ratio = 0.44; 95% confidence interval 0.22-0.86) after adjustment for age at menarche, age at first birth, parity, Quetelet's index and family history of breast cancer. Among regularly menstruating women, long cycles (28 days or more) were not significantly associated with increased risk of breast cancer (odds ratio 1.17; 95% confidence interval 0.66-2.09). To the extent that irregular menstrual cycles reflect anovulatory cycles, our findings support the hypothesis that the cumulative number of regular ovulatory cycles increases breast cancer risk.

Urinary cotinine and lung cancer risk in a female cohort.

In a cohort of women aged 40-64 at entry, 12 h urine samples were obtained at the beginning of a follow-up period of up to 15 years in which incident cases of lung cancer were registered as well as deaths from lung cancer. In this cohort a nested case-control study (n = 397) was carried out by measuring urinary cotinine. The method for quantitation of cotinine was sensitive enough to study lung cancer risk not only in active smokers but also in passive smokers. The results seem to indicate that cotinine estimations in single 12 h samples of urine are enough to predict lung cancer risk. Relative risk rose with increasing levels of nicotine intake already in the range associated with passive smoking. The smoking-related risk of adenocarcinoma was much less than that of other lung carcinomas.

Urinary nicotine metabolite excretion and lung cancer risk in a female cohort.

A nested lung cancer case-control study was carried out using 397 12 h urine samples originally collected from a cohort of over 26,000 women aged 40-64 at entry who were then followed for up to 15 years. The urine samples from active smokers were first identified using a simple qualitative method and their total nicotine metabolites/creatinine ratios then determined by automated colorimetric methods. The results obtained demonstrated the capacity of nicotine metabolite estimations in a single 12 h sample of urine to predict the subsequent risk of lung cancer. The risk of lung cancer among the biochemically proven active smokers during this period was 7.8 times that of the non-smokers, suggesting that the dose-response relationship between smoking and lung cancer is no less step in women than in men. The smoking-related risk of adenocarcinoma was less than that of other lung carcinomas. It is suggested that this biochemical epidemiology approach to exploring the relationship between smoking and lung cancer could profitably be applied to the study of other smoking-related diseases.

Obesity and subcutaneous fat patterning in relation to survival of postmenopausal breast cancer patients participating in the DOM-project.

The effect of obesity and fat distribution on survival of breast cancer patients was studied prospectively in 241 women with a natural menopause who participated in a breast cancer screening project, the DOM-project in Utrecht, The Netherlands. Mean follow-up time was 9.1 years and endpoint of interest was death from breast cancer. Fat distribution was assessed by contrasting groups of subscapular and triceps skinfold thickness. No significant differences in survival time between more obese (Quetelet's index > or = 26 kg/m2) and leaner (Quetelet's index < 26 kg/m2) patients or between patients with central fat distribution and patients with peripheral fat distribution were observed. Analyses were stratified by axillary node status, estrogen receptor status, and way of detection (by first screening or afterwards). Results of the stratified analyses were suggestive of a modifying effect of these factors. The absence of an association between obesity and survival time might be explained by two counteracting mechanisms. On the one hand obesity might be related to impaired survival, due to a tumor growth promoting effect of extra-ovarian estrogens. On the other hand obesity might be related to improved survival in a screened population, because obese patients profit more from screening by earlier detection of tumors than leaner counterparts.

Validity of urinary biomarkers of exposure to tobacco smoke following prolonged storage.

BACKGROUND: The utility of using biomarkers of smoking in epidemiological studies depends not only on the validity and precision of the laboratory procedure but often on the long-term stability of the analytes of interest in stored biological samples. METHODS: We retrieved urine samples collected in 1976-1977 from women included in a cohort study in Utrecht and for whom information on smoking status was available. Creatinine and thiocyanate were measured in 1976-1977 on fresh samples. Cotinine and creatinine were analysed in 1988 on urine stored at -20 degrees C. RESULTS: Measurements of creatinine more than 10 years apart showed a correlation of 0.95 and equal means. Cotinine measurements made in 1988 allowed a clear separation of smokers and non-smokers (sensitivity 92%, specificity 100%), suggesting that concentrations retained their discriminant value even after 10 years of storage. CONCLUSION: These results emphasize the possibilities offered by long-term storage, under proper conditions, of biological samples for subsequent determination of analytes which may emerge as the study progresses.

Age at menarche and breast cancer risk in nulliparous women.

Early age at menarche is a known risk factor for breast cancer, some inconsistency in the literature not withstanding. Relative risks for an early menarcheal onset as compared to a late onset vary from 1.0 to 1.9. To avoid (residual) confounding by parity-related factors a case-control study was conducted among nulliparous women. 135 cases and 540 controls were selected from two population-based screening projects for breast cancer in The Netherlands. Four controls were matched to each case for year of birth, for screening-centre, and for number of screening examinations. Women with a menarcheal age of 10 or 11 years showed a 2.2 times (95% confidence interval: 1.2-4.0) higher risk for breast cancer compared to women who had their first menstrual period at 12 years of age or older.

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.

A feasibility study on weight reduction in obese postmenopausal breast cancer patients.

An attempt was made to undertake a randomized clinical trial of weight reduction in obese postmenopausal breast cancer patients as an adjuvant to primary surgical and radiotherapeutic treatment. The rationale was to improve prognosis which has been shown to be worse in the obese (probably because of its effect on extra-ovarian oestrogen production). Difficulties in recruiting a sufficient number of patients and the introduction of tamoxifen as anti-oestrogenic adjuvant therapy led to the decision to modify the aim of the study by limiting it to a feasibility study in 102 patients. In three hospitals in The Netherlands and in two hospitals in Poznan, Poland these patients were randomized in intervention and control groups according to a 3:2 ratio. Weight reduction in the intervention group was achieved by dietary means, ie caloric restriction was adapted to personal needs and behaviour of the patients. After 1 year a median weight loss of 6 kg was reached in both countries. In the Netherlands further follow-up indicated that this result could be maintained for another 2 years.