Pure fruit juice and fruit consumption and the risk of CVD: the European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL) study.

Dietary guidelines for pure fruit juice consumption differ between countries, regarding the question whether pure fruit juice is an acceptable alternative for fruit. Currently, little is known about pure fruit juice consumption and the risk of CVD. In this prospective cohort study, we studied the association of pure fruit juice and fruit consumption with the incidence of fatal and non-fatal CVD, CHD and stroke and investigated the differences in association with pure fruit juice consumption between low and high fruit consumers. A validated FFQ was used to estimate dietary intake of 34 560 participants (26·0 % men and 74·0 % women) aged 20-69 years from the European Prospective Investigation into Cancer and Nutrition-Netherlands study. Adjusted hazard ratios (HR) were estimated using Cox regression after average follow-up of 14·6 years. Compared with no consumption, pure fruit juice consumption up to 7 glasses/week - but not consumption of ≥8 glasses - was significantly associated with reduced risk of CVD and CHD, with HR from 0·83 (95 % CI 0·73, 0·95) to 0·88 (95 % CI 0·80, 0·97). Consumption of 1-4 and 4-8 glasses/week was significantly associated with lower risk of stroke with HR of 0·80 (95 % CI 0·64, 0·99) and 0·76 (95 % CI 0·61, 0·94), respectively. Associations did not differ considerably between low and high fruit consumers. The highest three quintiles of fruit consumption (≥121 g/d) were significantly associated with lower incidence of CVD, with HR of 0·87 (95 % CI 0·78, 0·97) and 0·88 (95 % CI 0·80, 0·98). In conclusion, although we observed favourable associations of moderate pure fruit juice consumption with CVD, for now consumption of whole fruit should be preferred because the evidence of the health benefits of fruit is more conclusive.

Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2.

INTRODUCTION: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. METHODS: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. RESULTS: The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. CONCLUSIONS: The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.

Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers.

INTRODUCTION: Current attempts to identify genetic modifiers of BRCA1 and BRCA2 associated risk have focused on a candidate gene approach, based on knowledge of gene functions, or the development of large genome-wide association studies. In this study, we evaluated 24 SNPs tagged to 14 candidate genes derived through a novel approach that analysed gene expression differences to prioritise candidate modifier genes for association studies. METHODS: We successfully genotyped 24 SNPs in a cohort of up to 4,724 BRCA1 and 2,693 BRCA2 female mutation carriers from 15 study groups and assessed whether these variants were associated with risk of breast cancer in BRCA1 and BRCA2 mutation carriers. RESULTS: SNPs in five of the 14 candidate genes showed evidence of association with breast cancer risk for BRCA1 or BRCA2 carriers (P < 0.05). Notably, the minor alleles of two SNPs (rs7166081 and rs3825977) in high linkage disequilibrium (r² = 0.77), located at the SMAD3 locus (15q22), were each associated with increased breast cancer risk for BRCA2 mutation carriers (relative risk = 1.25, 95% confidence interval = 1.07 to 1.45, P(trend) = 0.004; and relative risk = 1.20, 95% confidence interval = 1.03 to 1.40, P(trend) = 0.018). CONCLUSIONS: This study provides evidence that the SMAD3 gene, which encodes a key regulatory protein in the transforming growth factor beta signalling pathway and is known to interact directly with BRCA2, may contribute to increased risk of breast cancer in BRCA2 mutation carriers. This finding suggests that genes with expression associated with BRCA1 and BRCA2 mutation status are enriched for the presence of common genetic modifiers of breast cancer risk in these populations.

Common genetic variation of insulin-like growth factor-binding protein 1 (IGFBP-1), IGFBP-3, and acid labile subunit in relation to serum IGF-I levels and mammographic density.

Mammographic density is strongly related to increased breast cancer risk. Accumulating evidence indicates that a role for the IGF-pathway in mammographic density and breast cancer development. Here, we investigate whether common genetic variation in this pathway influences insulin-like growth factor-I (IGF-I) levels and mammographic density. In 1,916 premenopausal women within the Prospect-EPIC cohort, we examined associations of 14 haplotype tagging SNPs in the ALS, IGFBP1, and IGFBP3 genes with IGF-I circulating levels and mammographic density. In 657 women, who became postmenopausal during follow-up, we investigated how these SNPs were related with the decrease in density over menopause. Linear regression models were used for statistical analysis. None of the ALS or IGFBP3 SNPs were statistically significantly associated with IGF-I levels or mammographic density. The CC genotype for rs1908751 (IGFBP1) was associated with lower levels of IGF-I (110.9 ng/ml) compared to the CT/TT genotypes (115.7 ng/ml) (P = 0.04). Women with the CC genotype also had lower percent density, although not statistically significantly (P = 0.12). Women carrying the AA genotype for rs1995051 (IGFBP1) showed that borderline significantly lower IGF-I levels (P = 0.06) and significantly lower mammographic density (40.3% compared to 43.5% in the GG/GA genotypes; P = 0.05). No relationships were found for any of the SNPs in relation with changes in breast density over menopause. These findings suggest that common genetic variation in the IGFBP1 gene is weakly related to IGF-I levels and mammographic density. Our results do not provide support for such a role of genetic variants in the IGFBP3 and ALS genes.

Dietary fiber, magnesium, and glycemic load alter risk of type 2 diabetes in a multiethnic cohort in Hawaii.

The influence of dietary fiber, magnesium (Mg), and glycemic load (GL) on diabetes was examined in the Hawaii component of the Multiethnic Cohort. The 75,512 Caucasian, Japanese American, and Native Hawaiian participants aged 45-75 y at baseline completed a FFQ. After 14 y of follow-up, 8587 incident diabetes cases were identified through self-reports and health plans. We applied Cox regression stratified for age at cohort entry and adjusted for ethnicity, BMI, physical activity, education, and total energy with further stratifications by sex and ethnicity. When comparing extreme quintiles, total fiber intake was associated with reduced diabetes risk among all men [hazard ratio (HR): 0.75; 95% CI: 0.67, 0.84; P-trend < 0.001) and women (HR: 0.95; 95% CI: 0.85, 1.06; P-trend = 0.05). High intake of grain fiber reduced diabetes risk significantly by 10% in men and women. High vegetable fiber intake lowered risk by 22% in all men but not women. Mg intake reduced risk (HR = 0.77 and 0.84 for men and women, respectively) and, due to its strong correlation with fiber (r = 0.83; P < 0.001), may explain the protective effect of fiber. The top GL quintile was associated with a significantly elevated diabetes incidence in Caucasian men and in all women except Japanese Americans. Overall, several associations were more pronounced in Caucasians than in the other groups. These findings suggest that protection against diabetes can be achieved through food choices after taking into account body weight, but, due to differences in commonly consumed foods, risk estimates may differ by ethnic group.

Epidemiologic studies of isoflavones & mammographic density.

Isoflavones, phytoestrogens in soy beans with estrogen-like properties, have been examined for their cancer protective effects. Mammographic density is a strong predictor of breast cancer. This review summarizes studies that have examined the association between isoflavones and breast density. Observational investigations in Hawaii and Singapore suggest slightly lower breast density among women of Asian descent with regular soy intake, but two larger studies from Japan and Singapore did not observe a protective effect. The findings from seven randomized trials with primarily Caucasian women indicate that soy or isoflavones do not modify mammographic density. Soy foods and isoflavone supplements within a nutritional range do not appear to modify breast cancer risk as assessed by mammographic density.

IGF1, IGFBP1, and IGFBP3 genes and mammographic density: the Multiethnic Cohort.

Insulin-like growth factor-I (IGF-I) has mitogenic properties and stimulates cell growth. In this analysis, we investigated the relation between common genetic variation in IGF1, IGFBP1, and IGFBP3, and mammographic density among 819 women of Hawaiian, European, and Japanese ancestry from the Multiethnic Cohort Study. Mammographic density was assessed using a quantitative computer-assisted method. Previously identified tag single nucleotide polymorphisms (SNPs) for IGF1 (26 tag SNPs) and IGFBP1/IGFBP3 (22 tag SNPs) were genotyped among the 819 women. Mixed models were conducted to evaluate the associations between genetic variation and mammographic density. Two SNPs were borderline statistical significantly associated with mammographic density: rs35539615 on IGFBP1 (p = 0.05) and rs2453839 on IGFBP3 (p = 0.01). Rs35767on IGF1 (p = 0.03) was also associated with mammographic density, although in opposite direction of what was expected from previous findings with IGF-I levels. The majority of SNPs were, however, not associated with mammographic density. Analyses stratified by ethnicity showed similar results as the overall analyses for IGF1 and IGFBP1. However, for 4 SNPs in the IGFBP3 gene, the minor allele was associated with lower mammographic density in Japanese Americans and higher mammographic density in Caucasians. Given the large number of SNPs tested and the few borderline significant results, we only found weak evidence that genetic variations in IGFBP1 or IGFBP3 may be related to mammographic density. Ethnicity may modify these relations.

Mammographic density and matrix metalloproteinases in breast tissue.

Mammographic density is a strong risk factor for breast cancer, yet the underlying histopathologic correlates are not clear. Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) play important roles in multiple stages of tumorigenesis. This study examined the association between mammographic density and expression of MMPs 1, 3, 9, and 12 and TIMP3 in benign and malignant breast tissue of 277 women with mainly Caucasian and Japanese ancestry. Tissue microarrays with up to 4 benign and 4 malignant cores per woman were stained immunohistochemically and evaluated. Digitized prediagnostic mammograms were assessed for densities using a computer-assisted method. General linear models adjusted for known confounders were applied to estimate mean densities by staining category. Strong expression of all MMPs was about twice as frequent in malignant as in benign tissue, while TIMP3 expression in stromal tissue was higher in benign than malignant cores. For MMP3 and 9, less than 10% of cores stained positive; thus, they were not further analyzed. None of the markers showed a statistically significant association with breast density in the entire study population and ethnic-specific results were conflicting and difficult to explain. Although not statistically significant, mean density was consistently lower with more extensive TIMP3 expression in stromal and epithelial tissue. These findings indicate that the higher breast cancer risk in women with dense breasts may be influenced by lower TIMP3 expression. However, future investigations into activities and ratios of additional proteases and their inhibitors as well as other pathways, such as inflammation, are needed.

Soy consumption and histopathologic markers in breast tissue using tissue microarrays.

This study examined the relation of soy intake with hormonal and proliferation markers in benign and malignant breast tissue using tissue microarrays (TMAs). TMAs with up to 4 malignant and 4 benign tissue samples for 268 breast cancer cases were constructed. Soy intake in early life and in adulthood was assessed by questionnaire. The TMAs were stained for estrogen receptor (ER) alpha, ERbeta, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2/neu), proliferating cell nuclear antigen (PCNA), and Ki-67 using standard immunohistochemical methods. Logistic regression was applied for statistical analysis. A higher percentage of women showed positive marker expression in malignant than in benign tissue. With one exception, HER2/neu, no significant associations between soy intake and pathologic markers were observed. Early life soy intake was associated with lower HER2/neu and PCNA staining of malignant tissue. In benign tissue, early life soy intake showed higher ER and PR expression, but no difference in proliferation markers. The results of this investigation provide some assurance that soy intake does not adversely affect markers of proliferation. TMAs were shown to be a useful tool for epidemiologic research.

Mammographic density and epithelial histopathologic markers.

BACKGROUND: We explored the association of mammographic density, a breast cancer risk factor, with hormonal and proliferation markers in benign tissue from tumor blocks of pre-and postmenopausal breast cancer cases. METHODS: Breast cancer cases were recruited from a case-control study on breast density. Mammographic density was assessed on digitized prediagnostic mammograms using a computer-assisted method. For 279 participants of the original study, we obtained tumor blocks and prepared tissue microarrays (TMA), but benign tissue cores were only available for 159 women. The TMAs were immunostained for estrogen receptor alpha (ERalpha) and beta (ERbeta), progesterone receptor (PR), HER2/neu, Ki-67, and Proliferating Cell Nuclear Antigen (PCNA). We applied general linear models to compute breast density according to marker expression. RESULTS: A substantial proportion of the samples were in the low or no staining categories. None of the results was statistically significant, but women with PR and ERbeta staining had 3.4% and 2.4% higher percent density. The respective values for Caucasians were 5.7% and 11.6% but less in Japanese women (3.5% and -1.1%). Percent density was 3.4% higher in women with any Ki-67 staining and 2.2% in those with positive PCNA staining. CONCLUSION: This study detected little evidence for an association between mammographic density and expression of steroid receptors and proliferation markers in breast tissue, but it illustrated the problems of locating tumor blocks and benign breast tissue samples for epidemiologic research. Given the suggestive findings, future studies examining estrogen effects in tissue, cell proliferation, and density in the breast may be informative.

Diabetes incidence based on linkages with health plans: the multiethnic cohort.

OBJECTIVE: Using the Hawaii component of the Multiethnic Cohort (MEC), we estimated diabetes incidence among Caucasians, Japanese Americans, and Native Hawaiians. RESEARCH DESIGN AND METHODS: After excluding subjects who reported diabetes at baseline or had missing values, 93,860 cohort members were part of this analysis. New case subjects were identified through a follow-up questionnaire (1999-2000), a medication questionnaire (2003-2006), and linkage with two major health plans (2007). We computed age-standardized incidence rates and estimated hazard ratios (HRs) for ethnicity, BMI, education, and combined effects of these variables using Cox regression analysis. RESULTS: After a total follow-up time of 1,119,224 person-years, 11,838 incident diabetic case subjects were identified with an annual incidence rate of 10.4 per 1,000 person-years. Native Hawaiians had the highest rate with 15.5, followed by Japanese Americans with 12.5, and Caucasians with 5.8 per 1,000 person-years; the adjusted HRs were 2.65 for Japanese Americans and 1.93 for Native Hawaiians. BMI was positively related to incidence in all ethnic groups. Compared with the lowest category, the respective HRs for BMIs of 22.0-24.9, 25.0-29.9, and > or =30.0 kg/m(2) were 2.10, 4.12, and 9.48. However, the risk was highest for Japanese Americans and intermediate for Native Hawaiians in each BMI category. Educational achievement showed an inverse association with diabetes risk, but the protective effect was limited to Caucasians. CONCLUSIONS: Within this multiethnic population, diabetes incidence was twofold higher in Japanese Americans and Native Hawaiians than in Caucasians. The significant interaction of ethnicity with BMI and education suggests ethnic differences in diabetes etiology.

Various doses of soy isoflavones do not modify mammographic density in postmenopausal women.

Soy isoflavones have functional similarity to human estrogens and may protect against breast cancer as a result of their antiestrogenic activity or increase risk as a result of their estrogen-like properties. We examined the relation between isoflavone supplementation and mammographic density, a strong marker for breast cancer risk, among postmenopausal women. The Osteoporosis Prevention Using Soy (OPUS) study, a multi-site, randomized, double-blinded, and placebo-controlled trial assigned 406 postmenopausal women to 80 or 120 mg/d of isoflavones each or a placebo for 2 y. Percent densities were assessed in digitized mammograms using a computer-assisted method. The mammogram reader did not know the treatment status and the time of mammograms. We applied mixed models to compare breast density by treatment while considering the repeated measures. The mammographic density analysis included 358 women, 88.2% of the OPUS participants; 303 had a complete set of 3 mammograms, 49 had 2, and 6 had only 1 mammogram. At baseline, the groups were similar in age, BMI, and percent density, but mean breast density differed by study site (P = 0.02). A model with all mammograms did not show a treatment effect on any mammographic measure, but the change over time was significant; breast density decreased by 1.6%/y across groups (P < 0.001). Stratification by age and BMI did not reveal any effects in subgroups. In this randomized 2-y trial, isoflavone supplements did not modify breast density in postmenopausal women. These findings offer reassurance that isoflavones do not act like hormone replacement medication on breast density.

Association between breast cancer susceptibility loci and mammographic density: the Multiethnic Cohort.

INTRODUCTION: Mammographic density is a strong risk factor for breast cancer. Our objective was to examine its association with polymorphisms identifying breast cancer susceptibility loci that were ascertained in recent genome-wide association studies. METHODS: Subjects were 825 women who participated in previous case-control studies of mammographic density and genetic factors nested within the Multiethnic Cohort study and were from three ethnic groups (White, Japanese American, Native Hawaiian). Eight polymorphisms (rs2981582 in FGFR2, rs3803662 and rs12443621in TOX3, rs3817198 in LSP1, rs981782 and rs10941679 near HCN1/MRPS30, rs889312 in MAP3K1, and rs13387042 at 2q) were examined. Mammographic density was quantified with a computer-assisted method as the percent dense area: the area of radiologically dense fibroglandular tissue relative to the total breast area that also includes radiologically lucent fatty tissue. RESULTS: The polymorphism rs12443621 in TOX3 was associated with percent dense area; women with at least one G allele (previously associated with increased breast cancer risk) had 3% to 4% higher densities than women with two A alleles. The polymorphism rs10941679 near HCN1/MRPS30 was also associated with percent dense area; women who were homozygous for the G allele (previously associated with increased breast cancer risk) had 4% to 5% lower densities than women with at least one A allele. The other polymorphisms were not associated with percent dense area. CONCLUSIONS: The available data suggest that the effects of most of these polymorphisms on breast cancer are not mediated by mammographic density. Some effects may have been too small to be detected. The association with rs12443621 may provide clues as to how variation in TOX3 influences breast cancer risk.

Soy protein containing isoflavones and mammographic density in a randomized controlled trial in postmenopausal women.

BACKGROUND: The relatively high dietary intake of soy in Asian countries has been hypothesized to, at least partly, explain the lower breast cancer incidence patterns in these countries compared with the Western world. The aim of the present study was to determine the effect of daily soy supplementation on mammographic density, one of the strongest known risk factors for breast cancer. METHODS: A double-blind, randomized, controlled trial was conducted to compare the effects of soy protein intake containing 99 mg isoflavones daily with intake of milk protein (placebo) for the duration of 1 year. Two hundred and two Dutch postmenopausal women ages 60 to 75 years were randomized. Mammographic density was assessed using a quantitative computer-assisted method on digitized mammograms. Equol producer status was assessed in plasma provided at the final visit (soy group) or after a 3-day challenge with soy after the trial was finished (placebo group). RESULTS: A total of 175 women completed the baseline visits and at least one follow-up visit and were included in the intention-to-treat analyses. For 126 women, both pre- and post-trial mammograms were available. Mammographic density decreased in both study arms, but the decrease did not differ significantly between intervention and placebo groups. Equol producer status did not modify the results. CONCLUSION: The results of this trial do not support the hypothesis that a diet high in soy protein among postmenopausal women decreases mammographic density.

Common genetic variation in the IGF-1 gene, serum IGF-I levels and breast density.

INTRODUCTION: High breast density is one of the strongest known risk factors for developing breast cancer. Insulin-like growth factor I (IGF-I) is a strong mitogen and has been suggested to increase breast cancer risk by increasing the amount of dense tissue in the female breast. OBJECTIVES: We wanted to investigate the effect of common variation in the IGF-1 gene on serum IGF-I levels and on breast density. DESIGN AND METHODS: Mammograms and blood samples of 1,928 premenopausal participants of the Dutch Prospect-EPIC cohort were collected at baseline. Using a haplotype tagging approach, 16 single nucleotide polymorphisms (SNP) from three blocks covering the IGF-1 gene were genotyped in all study participants. Breast density was assessed using a quantitative computer-assisted method. For a subgroup of women, who went through menopause within 5 years after recruitment (n=656), premenopausal IGF-I levels and additionally postmenopausal breast density were determined. False positive report probabilities (FPRP) for statistically significant relations were calculated using the Wacholder method. RESULTS: The minor alleles of five SNPs in block 3 were significantly associated with elevated levels of IGF-I (rs9989002, rs2033178, rs7136446, rs978458, rs6220; P-values: 0.01-0.04). The same SNPs were related with modestly higher percent breast density before menopause and-in the subgroup of women that became postmenopausal during follow-up-with a modestly higher percent breast density after menopause. The most significant result, i.e. the relation between rs6220 and IGF-I levels, had an FPRP<0.5 assuming prior probabilities of 0.01 and higher. CONCLUSION: Common genetic variation in the IGF-1 gene is related to circulating levels of IGF-I, but the relationship with breast density is indecisive.

Implications for prostate cancer of insulin-like growth factor-I (IGF-I) genetic variation and circulating IGF-I levels.

BACKGROUND: Elevated levels of circulating IGF-I have consistently been associated with increased prostate cancer risk. We recently found a haplotype in the 3' region of the IGF-I gene associated with increased risk of prostate cancer, and we hypothesized that the observed association is mediated by circulating IGF-I. MATERIALS AND METHODS: We analyzed haplotypes and three haplotype-tagging single nucleotide polymorphisms (htSNPs) in the 3' region of the IGF-I gene in relation to circulating levels IGF-I in 698 control subjects from the CAncer Prostate in Sweden (CAPS) study and 575 cases and controls from the prospective Northern Sweden Health and Disease Cohort (NSHDC) study. We also performed a meta-analysis of these two and four other association studies on genetic variation in the 3' region of the IGF-I gene in relation to circulating IGF-I levels. RESULTS: The IGF-I haplotype previously associated with prostate cancer risk, labeled "TCC," was associated with elevated levels of IGF-I in the CAPS study (P = 0.02), but not in the NSHDC study. In contrast, two of the three IGF-I htSNPs tagging this haplotype, rs6220 and rs7136446, were associated with elevated levels of IGF-I in the NSHDC (P = 0.03 and P = 0.04, respectively), but not in the CAPS study. In the meta-analysis, the TCC haplotype and the rs6220 SNP were associated with elevated levels of circulating IGF-I (P = 0.001 and P < 0.0001, respectively). CONCLUSIONS: Genetic variation in the 3' region of the IGF-I gene seems to influence circulating levels of IGF-I. This observation is consistent with the hypothesis that variation in the IGF-I gene plays a role in prostate cancer susceptibility by influencing circulating levels of IGF-I.

No relationship between circulating levels of sex steroids and mammographic breast density: the Prospect-EPIC cohort.

BACKGROUND: High breast density is associated with increased breast cancer risk. Epidemiologic studies have shown an increase in breast cancer risk in postmenopausal women with high levels of sex steroids. Hence, sex steroids may increase postmenopausal breast cancer risk via an increase of breast density. The objective of the present study was to study the relation between circulating oestrogens and androgens as well as sex hormone binding globulin (SHBG) in relation to breast density. METHODS: We conducted a cross-sectional study among 775 postmenopausal women, using baseline data of a random sample of the Prospect-EPIC study. Prospect-EPIC is one of two Dutch cohorts participating in the European Prospective Investigation into Cancer and Nutrition, and women were recruited via a breast cancer screening programme. At enrolment a nonfasting blood sample was taken and a mammogram was made. Oestrone, oestradiol, dehydroepiandrosterone sulfate, androstenedione, testosterone and SHBG levels were measured, using double-antibody radioimmunoassays. Concentrations of free oestradiol and free testosterone were calculated from the measured oestradiol, testosterone and SHBG levels Mammographic dense and nondense areas were measured using a semiquantitative computerized method and the percentage breast density was calculated. Mean breast measures for quintiles of hormone or SHBG levels were estimated using linear regression analyses. RESULTS: Both oestrogens and testosterone were inversely related with percent breast density, but these relationships disappeared after adjustment for BMI. None of the sex steroids or SHBG was associated with the absolute measure of breast density, the dense area. CONCLUSION: The results of our study do not support the hypothesis that sex steroids increase postmenopausal breast cancer risk via an increase in breast density.

Premenopausal insulin-like growth factor-I serum levels and changes in breast density over menopause.

BACKGROUND: A high proportion of glandular and stromal tissue in the breast (percentage breast density) is a strong risk factor for breast cancer development. Insulin-like growth factor-I (IGF-I) is hypothesized to influence breast cancer risk by increasing breast density. OBJECTIVES: We studied the relation between premenopausal circulating IGF-I levels and premenopausal and postmenopausal, absolute nondense and dense area, and percentage breast density as well as changes in these measures over menopause. DESIGN AND METHODS: Mammograms and blood samples of 684 premenopausal participants of the Prospect-European Prospective Investigation into Cancer and Nutrition cohort were collected at baseline. A second mammogram of these women was collected after they became postmenopausal. Premenopausal IGF-I levels were measured in serum. Premenopausal and postmenopausal breast measures were assessed using a computer-assisted method. Mean values of breast measures were calculated for quartiles of serum IGF-I using linear regression analysis. RESULTS: Women with higher premenopausal IGF-I levels showed a slightly smaller decrease in dense area over menopause (-12.2 cm2 in the highest versus -12.9 cm2 in the lowest quartile; P trend = 0.58) and, at the same time, a smaller increase in the nondense (fat) area (P trend = 0.09). Due to the changes over menopause, high premenopausal IGF-I serum levels were associated with lower nondense area (P trend = 0.05), somewhat higher dense area (P trend = 0.66), and consequently higher percentage breast density (P trend = 0.02) after menopause. CONCLUSION AND DISCUSSION: Women with higher premenopausal IGF-I levels have a smaller increase in nondense area and also a slightly smaller decrease in absolute dense area during menopause, resulting in higher breast density after menopause.

Plasma phytoestrogens and subsequent breast cancer risk.

PURPOSE: Phytoestrogens are plant compounds that are structurally and functionally similar to mammalian estrogens. By competing for estrogen receptors, phytoestrogens possibly inhibit binding of the more potent endogenous estrogens and decrease their potential effects on breast cancer risk. We investigated the association between plasma phytoestrogen levels and breast cancer risk in a prospective manner. PATIENTS AND METHODS: We performed a nested case-control study within the Prospect cohort, one of the two Dutch cohorts participating in the European Prospective Investigation into Cancer and Nutrition. A total of 383 women (87 pre- or perimenopausal women [mean age, 52 years] and 296 postmenopausal women [mean age, 59 years]) who developed breast cancer were selected as case subjects and were matched to 383 controls, on date of blood sampling. Plasma levels of isoflavones (daidzein, genistein, glycitein, O-desmethylangolensin, and equol) and lignans (enterodiol and enterolactone) were measured. The isotope dilution liquid chromatography/tandem mass-spectrometry method incorporating triply 13C-labeled standards was used for all analyses. Breast cancer odds ratios were calculated for tertiles of phytoestrogen plasma levels using conditional logistic regression analysis. RESULTS: For genistein, the risk estimate for the highest versus the lowest tertile was 0.68 (95% CI, 0.47 to 0.98). Similar protective effects, although not statistically significant, were seen for the other isoflavones. Lignan levels did not appear to be related to breast cancer risk. Results were the same in pre- or perimenopausal women, and in postmenopausal women. CONCLUSION: High genistein circulation levels are associated with reduced breast cancer risk in the Dutch population. No effects of lignans on breast cancer risk were observed.

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.