Petra H. Lahmann

Body size and breast cancer risk: Findings from the European prospective investigation into cancer and nutrition (EPIC)

The evidence for anthropometric factors influencing breast cancer risk is accumulating, but uncertainties remain concerning the role of fat distribution and potential effect modifiers. We used data from 73,542 premenopausal and 103,344 postmenopausal women from 9 European countries, taking part in the EPIC study. RRs from Cox regression models were calculated, using measured height, weight, BMI and waist and hip circumferences; categorized by cohort‐wide quintiles; and expressed as continuous variables, adjusted for study center, age and other risk factors. During 4.7 years of follow‐up, 1,879 incident invasive breast cancers were identified. In postmenopausal women, current HRT modified the body size–breast cancer association. Among nonusers, weight, BMI and hip circumference were positively associated with breast cancer risk (all ptrend ≤ 0.002); obese women (BMI > 30) had a 31% excess risk compared to women with BMI < 25. Among HRT users, body measures were inversely but nonsignificantly associated with breast cancer. Excess breast cancer risk with HRT was particularly evident among lean women. Pooled RRs per height increment of 5 cm were 1.05 (95% CI 1.00–1.16) in premenopausal and 1.10 (95% CI 1.05–1.16) in postmenopausal women. Among premenopausal women, hip circumference was the only other measure significantly related to breast cancer (ptrend = 0.03), after accounting for BMI. In postmenopausal women not taking exogenous hormones, general obesity is a significant predictor of breast cancer, while abdominal fat assessed as waist–hip ratio or waist circumference was not related to excess risk when adjusted for BMI. Among premenopausal women, weight and BMI showed nonsignificant inverse associations with breast cancer.

Sociodemographic factors associated with long-term weight gain, current body fatness and central adiposity in Swedish women

OBJECTIVES: To examine sociodemographic factors associated with long-term adult weight gain and current general and central adiposity in women.DESIGN: Cross-sectional analysis based on data from the Malmö Diet and Cancer prospective cohort Study (MDCS), Sweden.SUBJECTS: 5464 women aged 45–73 y, who participated in the MDCS between 1994 and 1996.MEASUREMENTS: Weight change was defined as the difference between measured weight and recalled weight at age 20. Body composition was estimated from bioelectrical impedance analysis. Waist circumference and waist-hip ratio (WHR) were indicators of central obesity. Sociodemographic factors studied included reproductive, lifestyle and socioeconomic characteristics obtained from a questionnaire.RESULTS: At current age 13% of all women were obese (BMI≥30), and nearly one-third had a body fat content of >33%. Since age 20, the majority of women (77%) had gained more than 10% of their initial weight. On average, the mean weight change was 12.6±10.0 kg during adult life. Age-adjusted group mean comparisons identified a number of significant sociodemographic variables predicting past weight gain and current obesity. In multivariate analysis, significant independent correlates of weight gain were: age, initial small body size, high parity, early menarche, non-use of hormone therapy, low self-rated health, non-smoking, no consumption of alcohol, sedentary leisure activity, past change in diet, retirement, low education, low socioeconomic status, and low socioeconomic status of origin. Many of the same variables were independently associated with current waist circumference, WHR, and percentage body fat.CONCLUSIONS: Large weight gain during adult life and a high rate of overweight were observed in this group of Swedish women. Many sociodemographic characteristics were associated with long-term weight gain and recent obesity indices. Initial BMI, smoking, age, physical activity and early socioeconomic status accounted for most of the explained variance in weight change. The findings indicate the importance of identifying environmental determinants of both weight gain and attained fatness, as well as fat distribution.

Endogenous sex hormones and endometrial cancer risk in women in the European Prospective Investigation into Cancer and Nutrition (EPIC)

Epidemiological data show that reproductive and hormonal factors are involved in the etiology of endometrial cancer, but there is little data on the association with endogenous sex hormone levels. We analyzed the association between prediagnostic serum concentrations of sex steroids and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition using a nested case–control design of 247 incident endometrial cancer cases and 481 controls, matched on center, menopausal status, age, variables relating to blood collection, and, for premenopausal women, phase of menstrual cycle. Using conditional regression analysis, endometrial cancer risk among postmenopausal women was positively associated with increasing levels of total testosterone, free testosterone, estrone, total estradiol, and free estradiol. The odds ratios (ORs) for the highest versus lowest tertile were 2.66 (95% confidence interval (CI) 1.50–4.72; P=0.002 for a continuous linear trend) for estrone, 2.07 (95% CI 1.20–3.60; P=0.001) for estradiol, and 1.66 (95% CI 0.98–2.82; P=0.001) for free estradiol. For total and free testosterone, ORs for the highest versus lowest tertile were 1.44 (95% CI 0.88–2.36; P=0.05) and 2.05 (95% CI 1.23–3.42; P=0.005) respectively. Androstenedione and dehydroepiandrosterone sulfate were not associated with risk. Sex hormone-binding globulin was significantly inversely associated with risk (OR for the highest versus lowest tertile was 0.57, 95% CI 0.34–0.95; P=0.004). In premenopausal women, serum sex hormone concentrations were not clearly associated with endometrial cancer risk, but numbers were too small to draw firm conclusions. In conclusion, relatively high blood concentrations of estrogens and free testosterone are associated with an increased endometrial cancer risk in postmenopausal women.

Physical Activity and Breast Cancer Risk: The European Prospective Investigation into Cancer and Nutrition

There is convincing evidence for a decreased risk of breast cancer with increased physical activity. Uncertainties remain, however, about the role of different types of physical activity on breast cancer risk and the potential effect modification for these associations. We used data from 218,169 premenopausal and postmenopausal women from nine European countries, ages 20 to 80 years at study entry into the European Prospective Investigation into Cancer and Nutrition. Hazard ratios (HR) from multivariate Cox regression models were calculated using metabolic equivalent value–based physical activity variables categorized in quartiles, adjusted for age, study center, education, body mass index, smoking, alcohol use, age at menarche, age at first pregnancy, parity, current oral contraceptive use, and hormone replacement therapy use. The physical activity assessment included recreational, household, and occupational activities. A total physical activity index was estimated based on cross-tabulation of these separate types of activity. During 6.4 years of follow-up, 3,423 incident invasive breast cancers were identified. Overall, increasing total physical activity was associated with a reduction in breast cancer risk among postmenopausal women (Ptrend = 0.06). Specifically, household activity was associated with a significantly reduced risk in postmenopausal (HR, 0.81; 95% confidence interval, 0.70-0.93, highest versus the lowest quartile; Ptrend = 0.001) and premenopausal (HR, 0.71; 95% confidence interval, 0.55-0.90, highest versus lowest quartile; Ptrend = 0.003) women. Occupational activity and recreational activity were not significantly related to breast cancer risk in both premenopausal and postmenopausal women. This study provides additional evidence for a protective effect of physical activity on breast cancer risk. (Cancer Epidemiol Biomarkers Prev 2007;16(1):36–42)

Anthropometric factors and risk of endometrial cancer: the European prospective investigation into cancer and nutrition

ObjectiveTo examine the association between anthropometry and endometrial cancer, particularly by menopausal status and exogenous hormone use subgroups.MethodsAmong 223,008 women in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, there were 567 incident endometrial cancer cases during 6.4 years of follow-up. The analysis was performed with Cox proportional hazards modeling.ResultsWeight, body mass index (BMI), waist and hip circumferences and waist–hip ratio (WHR) were strongly associated with increased risk of endometrial cancer. The relative risk (RR) for obese (BMI 30– < 40 kg/m2) compared to normal weight (BMI < 25) women was 1.78, 95% CI = 1.41–2.26, and for morbidly obese women (BMI ≥ 40) was 3.02, 95% CI = 1.66–5.52. The RR for women with a waist circumference of ≥88 cm vs. <80 cm was 1.76, 95% CI = 1.42–2.19. Adult weight gain of ≥20 kg compared with stable weight (±3 kg) increased risk independent of body weight at age 20 (RR = 1.75, 95% CI = 1.11–2.77). These associations were generally stronger for postmenopausal than premenopausal women, and oral contraceptives never-users than ever-users, and much stronger among never-users of hormone replacement therapy compared to ever-users.ConclusionObesity, abdominal adiposity, and adult weight gain were strongly associated with endometrial cancer risk. These associations were particularly evident among never-users of hormone replacement therapy.

Long-term weight change and breast cancer risk: the European prospective investigation into cancer and nutrition (EPIC)

We examined prospectively the association between weight change during adulthood and breast cancer risk, using data on 1358 incident cases that developed during 5.8 years of follow-up among 40 429 premenopausal and 57 923 postmenopausal women from six European countries, taking part in the European prospective investigation into cancer and nutrition study. Multivariate Cox regression models were used to calculate hazard ratios according to weight change (kg), defined as the weight difference between age at enrolment and age 20 adjusted for other risk factors. Changes in weight were not associated with premenopausal breast cancer risk. In postmenopausal women, weight gain was positively associated with breast cancer risk only among noncurrent hormone replacement therapy (HRT) users (P-trend ⩽0.0002). Compared to women with a stable weight (±2 kg), the relative risk for women who gained 15–20 kg was 1.50 (95% confidence interval (CI) 1.06–2.13). The pooled RR per weight gain increment of 5 kg was 1.08 (95% CI 1.04–1.12). Weight gain was not associated with breast cancer risk in current HRT users, although, overall, these women experienced a much higher risk of breast cancer compared with nonusers. Our findings suggest that large adult weight gain was a significant predictor of breast cancer in postmenopausal women not taking exogenous hormones.

Anthropometric measures, endogenous sex steroids and breast cancer risk in postmenopausal women: A study within the EPIC cohort

In a large case–control study on breast cancer risk and serum hormone concentrations, nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, we examined to what extent the relationship of excess body weight with breast cancer risk may be explained by changes in sex steroids. Height, weight, waist and hip circumferences, and serum measurements of testosterone [T], androstenedione [Δ4], dehydroepiandrosterone sulphate [DHEAS], estradiol [E2], estrone [E1] and sex‐hormone binding globulin [SHBG] were available for 613 breast cancer cases, and 1,139 matched controls, who were all menopausal at the time of blood donation. Free T [fT] and free E2 [fE2] were calculated using mass action equations. Breast cancer risk was related to body mass index (BMI) (RR = 1.11 [0.99–1.25], per 5 kg/m2 increase in BMI), and waist (RR = 1.12 [1.02–1.24], per 10 cm increase) and hip circumferences (RR = 1.14 [1.02–1.27], per 10 cm increase). The increase in breast cancer risk associated with adiposity was substantially reduced after adjustment for any estrogens, especially for fE2 (from 1.11 [0.99–1.25] to 0.99 [0.87–1.12], from 1.12 [1.02–1.24] to 1.02 [0.92–1.14] and from 1.14 [1.02–1.27] to 1.05 [0.93–1.18] for BMI, waist and hip circumferences, respectively). A modest attenuation in excess risk was observed after adjustment for fT, but the remaining androgens had little effect on the association of body adiposity with breast cancer. Our data indicate that the relationship of adiposity with breast cancer in postmenopausal women could be partially explained by the increases in endogenous estrogens, and by a decrease in levels of SHBG.

Alcohol intake and breast cancer risk: the European Prospective Investigation into Cancer and Nutrition (EPIC)

ObjectiveMost epidemiologic studies have suggested an increased risk of breast cancer with increasing alcohol intake. Using data from 274,688 women participating in the European Prospective Investigation into Cancer and Nutrition study (EPIC), we investigated the relation between alcohol intake and the risk of breast cancer.MethodsIncidence rate ratios (IRRs) based on Cox proportional hazard models were calculated using reported intake of alcohol, recent (at baseline) and lifetime exposure. We adjusted for known risk factors and stratified according to study center as well as potentially modifying host factors.ResultsDuring 6.4 years of follow up, 4,285 invasive cases of breast cancer within the age group 35–75 years were identified. For all countries together the IRR per 10 g/day higher recent alcohol intake (continuous) was 1.03 (95% confidence interval (CI): 1.01–1.05). When adjusted, no association was seen between lifetime alcohol intake and risk of breast cancer. No difference in risk was shown between users and non-users of HRT, and there was no significant interaction between alcohol intake and BMI, HRT or dietary folate.ConclusionThis large European study supports previous findings that recent alcohol intake increases the risk of breast cancer.

Polymorphisms of genes coding for insulin-like growth factor 1 and its major binding proteins, circulating levels of IGF-I and IGFBP-3 and breast cancer risk: results from the EPIC study

Insulin-like growth factor I (IGF-I) stimulates cell proliferation and can enhance the development of tumours in different organs. Epidemiological studies have shown that an elevated level of circulating IGF-I is associated with increased risk of breast cancer, as well as of other cancers. Most of circulating IGF-I is bound to an acid-labile subunit and to one of six insulin-like growth factor binding proteins (IGFBPs), among which the most important are IGFBP-3 and IGFBP-1. Polymorphisms of the IGF1 gene and of genes encoding for the major IGF-I carriers may predict circulating levels of IGF-I and have an impact on cancer risk. We tested this hypothesis with a case–control study of 807 breast cancer patients and 1588 matched control subjects, nested within the European Prospective Investigation into Cancer and Nutrition. We genotyped 23 common single nucleotide polymorphisms in IGF1, IGFBP1, IGFBP3 and IGFALS, and measured serum levels of IGF-I and IGFBP-3 in samples of cases and controls. We found a weak but significant association of polymorphisms at the 5′ end of the IGF1 gene with breast cancer risk, particularly among women younger than 55 years, and a strong association of polymorphisms located in the 5′ end of IGFBP3 with circulating levels of IGFBP-3, which confirms previous findings. Common genetic variation in these candidate genes does not play a major role in altering breast cancer risk in Caucasians.

Diet, serum insulin-like growth factor-I and IGF-binding protein-3 in European women

Objective:The aim of this study was to examine the relationship of diet with serum insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 in women.Design:Cross-sectional study.Setting and subjects:The population are 2109 women who were control subjects in a case–control study of breast cancer nested in the European Prospective Investigation into Cancer and Nutrition. Control subjects were randomly chosen among risk sets consisting of female cohort members alive and free of cancer (except non-melanoma skin cancer) at the time of diagnosis of the index case. Matching criteria were age at enrolment, follow-up time, time of the day of blood collection and study centre. Diet was measured through validated questionnaires. Serum hormone concentrations were measured by enzyme-linked immunosorbent assays. The relationship between serum IGF-I, IGFBP-3, and intake of nutrients and foods was explored by linear regression in models adjusted for energy intake, age, body mass index, smoking, physical activity, centre and laboratory batch.Results:Serum IGF-I levels were positively related to protein intake (P trend<0.001), but not related to energy, fat or carbohydrate intake. Positive relationships were observed with the intake of milk (P trend=0.007), calcium (P trend<0.001), magnesium (P trend=0.003), phosphorus (P trend<0.001), potassium (P trend=0.002), vitamin B6 (P trend=0.03), vitamin B2 (P trend=0.001) and inverse relationships with vegetables (P trend=0.02) and beta-carotene (P trend=0.02). IGFBP-3 was not related with most of the nutrients and foods in this study.Conclusions:In this population, circulating IGF-I is modestly related with the intake of protein and minerals, and with milk and cheese, while IGFBP-3 does not appear to be related with diet.