Bertrand Tehard

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.

Alcohol and genetic polymorphisms: effect on risk of alcohol-related cancer

Public health guidelines aim to limit the consumption of alcoholic beverages worldwide and the subsequent health burden. In particular, alcohol consumption is an avoidable risk factor for cancer. In human beings, ethanol in alcoholic drinks is mainly oxidised in the liver by alcohol dehydrogenases to acetaldehyde, and is further detoxified to acetate by aldehyde dehydrogenases. Functional variants in genes involved in alcohol metabolism result in differences between individuals in exposure to carcinogenic acetaldehyde, suggesting a possible interaction of genetic susceptibility and alcohol exposure in cancer. We reviewed available studies of the combined effects of alcohol drinking and genetic polymorphisms on alcohol-related cancer risk. Most available data were for polymorphisms in alcohol and folate metabolism. We give an overview of published studies on the combined effects of alcohol drinking and polymorphisms in genes for alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), cytochrome P450 2E1, and methylene-tetrahydrofolate reductase on the risk of alcohol-related cancer. Current data lend support to a role of polymorphisms ADH1B and ALDH2 combined with alcohol consumption in cancer. Other available data are insufficient or inconclusive, highlighting the need for additional studies.

Effect of Physical Activity on Women at Increased Risk of Breast Cancer: Results from the E3N Cohort Study

Purpose: There is a need to investigate the type, duration, frequency, and intensity of physical activity that are critical to reduce the risk of breast cancer, and if this relation differs among subgroups of women. Methods: We analyzed the relation between physical activity and breast cancer incidence between 1990 and 2002 (n = 3,424 cases), among 90,509 women of the French E3N cohort, ages between 40 and 65 years in 1990. We gave special attention to effect modification by body mass index (BMI), family history of breast cancer, parity, and hormone replacement therapy (HRT). Results: A linear decrease in risk of breast cancer was observed with increasing amounts of moderate (Ptrend < 0.01) and vigorous (Ptrend < 0.0001) recreational activities. Compared with women who reported no recreational activities, those with more than five weekly hours of vigorous recreational activity had a relative risk of 0.62 (0.49-0.78). This decrease was still observed among women who were overweight, nulliparous, had a family history of breast cancer, or used HRT. Compared with the whole cohort, among nulliparous women, the reduction of risk observed was of a higher magnitude, although the test for heterogeneity did not reach statistical significance. Conclusion: A risk reduction of breast cancer was particularly observed with vigorous recreational activity. Further investigations are needed to confirm that intensity is an important variable to consider in risk reduction and to identify the precise biological mechanisms involved in such a risk reduction. (Cancer Epidemiol Biomarkers Prev 2006;15(1):57–64)

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.

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.

Serum C-peptide levels and breast cancer risk: Results from the European Prospective Investigation into Cancer and Nutrition (EPIC)

It has been hypothesized that chronic hyperinsulinemia, a major metabolic consequence of physical inactivity and excess weight, might increase breast cancer risk by direct effects on breast tissue or indirectly by increasing bioavailable levels of testosterone and estradiol. Within the European Prospective Investigation into Cancer and Nutrition (EPIC), we measured serum levels of C‐peptide—a marker for pancreatic insulin secretion—in a total of 1,141 incident cases of breast cancer and 2,204 matched control subjects. Additional measurements were made of serum sex hormone binding globulin (SHBG) and sex steroids. Conditional logistic regression models were used to estimate breast cancer risk for different levels of C‐peptide. C‐peptide was inversely correlated with SHBG and hence directly correlated with free testosterone among both pre and postmenopausal women. C‐peptide and free estradiol also correlated positively, but only among postmenopausal women. Elevated serum C‐peptide levels were associated with a nonsignificant reduced risk of breast cancer diagnosed up to the age of 50 years [odds ratio (OR) = 0.70, (95% confidence interval (CI), 0.39–1.24); ptrend = 0.05]. By contrast, higher levels of C‐peptide were associated with an increase of breast cancer risk among women above 60 years of age, however only among those women who had provided a blood sample under nonfasting conditions [OR = 2.03, (95% CI, 1.20–3.43); ptrend = 0.01]. Our results do not support the hypothesis that chronic hyperinsulinemia generally increases breast cancer risk, independently of age. Nevertheless, among older, postmenopausal women, hyperinsulinemia might contribute to increasing breast cancer risk.

C-peptide, IGF-I, sex-steroid hormones and adiposity: A cross-sectional study in healthy women within the European Prospective Investigation into Cancer and Nutrition (EPIC)

Objectives: The risk of some cancers is positively associated with body weight, which may influence circulating levels of sex-steroid hormones, insulin and IGF-I. Interrelationships between these hormones and the associations with adiposity were evaluated in healthy women participating in the European Prospective Investigation into Cancer and Nutrition (EPIC).Methods: A cross-sectional analysis was performed on anthropometric and hormonal data from 743 pre- and 1217 postmenopausal women. Body mass index (BMI) and waist circumference were used as indicators of adiposity. C-peptide, Insulin Growth Factor (IGF)-I, Insulin Growth Factor binding protein (IGFBP)-3, androgens, estrogens and sex hormone binding globulin (SHBG) were measured by immunoassays; free sex steroid concentrations were calculated.Results: BMI and waist circumference were positively correlated with estrogens in postmenopausal women and with C-peptide, free testosterone and inversely with SHBG in all women. C-peptide and IGF-I were inversely correlated with SHBG, and positively with free sex steroids in postmenopausal women. IGF-I was positively associated with postmenopausal estrogens and androgen concentrations in all women.Conclusions: Sex-steroid concentrations appear to be regulated along several axes. Adiposity correlated directly with estrogens in postmenopausal women and with insulin, resulting in lower SHBG and increased levels of free sex steroids. Independent of adiposity and insulin, IGF-I was associated with decreased SHBG levels, and increased concentrations of androgens and postmenopausal estrogens.

Several anthropometric measurements and breast cancer risk: results of the E3N cohort study

Objective:To investigate the association between various anthropometric characteristics and breast cancer.Design:Longitudinal prospective cohort study. Follow-up between 1995 and 2000.Subjects:In total, 69 116 women (age: 45–70 years; mean follow-up: 3.6 years), 275 premenopausal and 860 postmenopausal incident invasive breast cancers.Measurements:Self-reported height, weight, breast, thorax, waist and hip circumferences and calculated body mass index (BMI) and waist-to-hip ratio (WHR) at baseline.Results:A slight increase in risk with increasing height was found. Weight, BMI, thorax and waist circumferences and WHR were negatively related to breast cancer risk among premenopausal women. The relationships became non significant after additional adjustment for BMI. An increased risk of premenopausal breast cancer with an android body shape (WHR>0.87) might possibly be confined to obese women. Among postmenopausal women, all anthropometric measurements of corpulence were positively associated with breast cancer risk but became non significant after additional adjustment for BMI. No difference in risk of postmenopausal breast cancer according to HRT use was observed.Conclusion:The study confirmed that adiposity was negatively associated to premenopausal breast cancer risk and positively associated to postmenopausal breast cancer risk. Further studies will be needed to specify clearly the association between WHR and breast cancer risk, particularly before menopause.

Genetic Variation in the Growth Hormone Synthesis Pathway in Relation to Circulating Insulin-Like Growth Factor-I, Insulin-Like Growth Factor Binding Protein-3, and Breast Cancer Risk: Results from the European Prospective Investigation into Cancer and Nutrition Study

Insulin-like growth factor-I (IGF-I) stimulates cell proliferation and can enhance the development of tumors in different organs. Epidemiologic studies have shown that an elevated level of circulating IGF-I is associated to increased risk of breast cancer as well as other cancers. Genetic variants affecting the release or biological action of growth hormone (GH), the main stimulator of IGF-I production, may predict circulating levels of IGF-I and have an effect on cancer risk. We tested this hypothesis with a large case-control study of 807 breast cancer patients and 1,588 matched control subjects nested within the European Prospective Investigation into Cancer and Nutrition. We genotyped 22 common single nucleotide polymorphisms in 10 genes involved in GH production and action (GHRH, GHRHR, SST, SSTR1-SSTR5, POU1F1, and GH1), and in parallel, we measured serum levels of IGF-I and IGFBP-3, its major binding protein, in samples of cases and controls. SST and SSTR2 polymorphisms showed weak but statistically significant associations with breast cancer risk. SSTR5 polymorphisms were associated with IGF-I levels, whereas one polymorphism in GHRHR and one in POU1F1 were associated with IGFBP-3 levels. Our conclusion is that common genetic variation in the GH synthesis pathway, as measured by single nucleotide polymorphisms selected in the present study, is not a major determinant of IGF-I and IGFBP-3 circulating levels, and it does not play a major role in altering breast cancer risk.

Anthropometry, breast cancer and menopausal status: Use of repeated measurements over 10 years of follow-up: Results of the French E3N women's cohort study

The association between weight, BMI and breast cancer was analyzed on 94,805 women of the E3N cohort according to their menopausal status. Seven hundred eighty‐six incident invasive premenopausal breast cancers and 1,522 incident invasive postmenopausal breast cancers occurred during a mean follow‐up of 9.7 years. Weight and BMI were updated every 24 months and considered as time‐dependent variables. Data were analyzed using multivariate Cox proportional hazards models. Trend RRs of premenopausal breast cancer were 0.97 (0.92–1.01) for a 5 kg increase in weight and 0.96 (0.91–1.01) for a 2 kg/m2 increase in BMI, adjusted for other known risk factors. Opposite trend RRs were found after menopause: 1.05 (1.02–1.08) for weight and 1.06 (1.02–1.09) for BMI, respectively, for similar increases. Women with a BMI of over 30 kg/m2 had a RR of premenopausal breast cancer of 0.66 (0.40–1.10) compared to those with a BMI of between 18.5 and 25 kg/m2. Postmenopausal women with a BMI of over 30 kg/m2 had a RR of breast cancer of 1.23 (1.00–1.59). The increase in risk of postmenopausal breast cancer with increased weight or BMI was similar whatever the HRT used, although the point estimates were higher in HRT users. We strongly recommend to use anthropometric measurements updated during follow‐up to assess the effect of weight, BMI on breast cancer risk.