Katharina Buck

Meta-analyses of lignans and enterolignans in relation to breast cancer risk

BACKGROUND Epidemiologic studies that examined whether lignans, the most important class of phytoestrogens in the Western diet, protect against breast cancer have yielded inconsistent results. OBJECTIVE In this study, we conducted meta-analyses on the association between lignans and breast cancer risk. DESIGN We performed a systematic MEDLINE search to identify epidemiologic studies published between 1997 and August 2009. We calculated pooled risk estimates (REs) for total lignan exposure, dietary lignan intake, enterolignan exposure, and blood or urine concentrations of enterolactone and according to menopausal and estrogen receptor (ER) status of tumors. RESULTS We included 21 studies (11 prospective cohort studies and 10 case-control studies) in the meta-analyses. Lignan exposure was not associated with an overall breast cancer risk (RE: 0.92; 95% CI: 0.81, 1.02; P for heterogeneity = 0.004). However, in postmenopausal women, high lignan intake was associated with a significant reduced risk of breast cancer (13 studies; RE: 0.86; 95% CI: 0.78, 0.94; P for heterogeneity = 0.32). Breast cancer risk was also inversely associated with enterolignan exposure (4 studies; RE: 0.84; 95% CI: 0.71, 0.97) but not with blood or urine enterolactone concentrations. The associations were not significantly different between ER-status subgroups (6 studies). CONCLUSIONS High lignan exposure may be associated with a reduced breast cancer risk in postmenopausal women. Additional work is warranted to clarify the association between lignan exposure and breast cancer risk.

Tumor-infiltrating lymphocytes in colorectal tumors display a diversity of T cell receptor sequences that differ from the T cells in adjacent mucosal tissue

Tumors from colorectal cancer (CRC) are generally immunogenic and commonly infiltrated with T lymphocytes. However, the details of the adaptive immune reaction to these tumors are poorly understood. We have accrued both colon tumor samples and adjacent healthy mucosal samples from 15 CRC patients to study lymphocytes infiltrating these tissues. We apply a method for detailed sequencing of T-cell receptor (TCR) sequences from tumor-infiltrating lymphocytes (TILs) in CRC tumors at high throughput to probe T-cell clones in comparison with the TCRs from adjacent healthy mucosal tissue. In parallel, we captured TIL counts using standard immunohistochemistry. The variation in diversity of the TIL repertoire was far wider than the variation of T-cell clones in the healthy mucosa, and the oligoclonality was higher on average in the tumors. However, the diversity of the T-cell repertoire in both CRC tumors and healthy mucosa was on average 100-fold lower than in peripheral blood. Using the TCR sequences to identify and track clones between mucosal and tumor samples, we determined that the immune response in the tumor is different than in the adjacent mucosal tissue, and the number of shared clones is not dependent on distance between the samples. Together, these data imply that CRC tumors induce a specific adaptive immune response, but that this response differs widely in strength and breadth between patients.

Postmenopausal Sex Hormones in Relation to Body Fat Distribution

Being overweight or obese increases the risk of postmenopausal breast cancer. A potential reason may be the frequently observed positive association of BMI with endogenous sex hormones and its negative association with sex hormone‐binding globulin (SHBG). The purpose of this study was to investigate whether a womans body fat distribution shows a BMI‐independent association with these breast cancer‐related biomarkers. Performing cross‐sectional analyses among 1,180 postmenopausal women, we assessed whether associations of surrogates for an abdominal (waist circumference; waist‐to‐hip ratio, WHR) and gluteofemoral (hip circumference) fat distribution with estrone, total and free estradiol, androstenedione, total and free testosterone, and SHBG changed after adjustment for, or stratification by, BMI. All anthropometric measures were positively associated with estrogens and free testosterone, and negatively with SHBG. After adjustment for BMI, associations of free estradiol, free testosterone, and SHBG with both waist circumference and WHR remained significant, but all initially significant associations with hip circumference were abolished. In stratified analyses, waist circumference and WHR correlated with free estradiol, free testosterone, and SHBG in women with a BMI < 30 kg/m2 but not in women with a BMI ≥ 30 kg/m2. The latter suggests that in obese women, a possibly unique effect of abdominal fat on these biomarkers may be masked by the already large amount of overall body fat. On the whole, our results indicate that waist circumference and WHR, but not hip circumference, are associated with SHBG and SHBG‐related sex hormones (free estradiol and free testosterone) independently of BMI.

Estimated enterolignans, lignan-rich foods, and fibre in relation to survival after postmenopausal breast cancer

Background:Lignans – oestrogenic substances present in various foods – are associated with postmenopausal breast cancer risk, but not much is known regarding their effects on survival.Methods:In a follow-up study of 2653 postmenopausal breast cancer patients diagnosed between 2001 and 2005, vital status and causes of death were verified through end of 2009. Hazard ratios (HRs) and 95% confidence intervals (CIs) for estimated enterolignans, lignan-rich foods, and dietary fibre in relation to overall survival (OS) and breast cancer-specific survival (BCSS) were assessed using Cox proportional hazards models stratified by age at diagnosis and adjusted for prognostic/confounding factors.Results:Median follow-up time was 6.4 years, and 321 women died, 235 with breast cancer. High estimated enterolactone and enterodiol levels were associated with significantly lower overall mortality (highest quintile, HR=0.60, 95% CI=0.40–0.89, PTrend=0.02 and HR=0.63, 95% CI=0.42–0.95, PTrend=0.02, respectively). Fibre intake was also associated with a significantly lower overall mortality. Differentiated by median fibre intake, associations with estimated enterolignans were still evident at low but not high fibre intake. There was no effect modification by oestrogen receptor status and menopausal hormone therapy.Conclusion:Postmenopausal breast cancer patients with high estimated enterolignans may have a better survival.

Serum Enterolactone and Prognosis of Postmenopausal Breast Cancer

PURPOSE Lignans--plant-derived compounds with estrogen-dependent and -independent anticarcinogenic properties--have been associated with postmenopausal breast cancer risk, but data are limited regarding their effect on survival. Dietary lignans are metabolized to enterolignans, which are subsequently absorbed and become bioavailable. PATIENTS AND METHODS We assessed the prognosis of 1,140 postmenopausal patients with breast cancer age 50 to 74 years who were diagnosed between 2002 and 2005. Vital status through the end of 2009 was ascertained via local population registries, and deaths were verified by death certificates. Information on recurrences and secondary tumors was verified by clinical records and attending physicians. Associations of postdiagnostic serum enterolactone (a biomarker for dietary lignans) with overall survival and distant disease-free survival were assessed by using Cox proportional hazards models stratified by age at diagnosis and adjusted for prognostic factors. RESULTS Median enterolactone levels for deceased patients and those still alive were 17.0 and 21.4 nmol/L, respectively. During a median of 6.1 years of follow-up after diagnosis, 162 deaths were confirmed. Higher serum enterolactone levels were associated with significantly reduced hazard ratios (HRs) for death (HR per 10 nmol/L increment, 0.94; P = .04; HR for the highest quartile, 0.58; 95% CI, 0.34 to 0.99). For distant disease, HR was 0.94 per 10 nmol/L increment (P = .08) and 0.62 (95% CI, 0.35 to 1.09) for the highest quartile. The highest quartile of serum enterolactone was associated with a significantly reduced risk of death only for estrogen receptor-negative tumors (HR, 0.27; 95% CI, 0.08 to 0.87) but not for estrogen receptor-positive tumors (HR, 0.91; 95% CI, 0.45 to 1.84: P for heterogeneity = .09). CONCLUSION Postmenopausal patients with breast cancer who have high serum enterolactone levels may have better survival.

Dietary patterns and survival in German postmenopausal breast cancer survivors

Background:Research on the association between dietary patterns and breast cancer survival is very limited.Methods:A prospective follow-up study was conducted in Germany, including 2522 postmenopausal breast cancer patients diagnosed in 2001–2005 with available food frequency questionnaire data. Vital status, causes of death, and recurrences were verified through the end of 2009. Principle component factor analysis was used to identify pre-diagnostic dietary patterns. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with Cox proportional hazards models.Results:Two major dietary patterns were identified: ‘healthy’ (high intakes of vegetables, fruits, vegetable oil, sauces/condiments, and soups/bouillons) and ‘unhealthy’ (high intakes of red meat, processed meat, and deep-frying fat). Increasing consumption of an ‘unhealthy’ dietary pattern was associated with an increased risk of non-breast cancer mortality (highest vs lowest quartile: HR, 3.69; 95% CI, 1.66–8.17; P-trend <0.001). No associations with breast cancer-specific mortality and breast cancer recurrence were found. The ‘healthy’ dietary pattern was inversely associated with overall mortality (HR, 0.74; 95% CI, 0.47–1.15; P-trend=0.02) and breast cancer recurrence (HR, 0.71; 95% CI, 0.48–1.06; P-trend=0.02) in stage I–IIIa patients only.Conclusion:Increasing intake of an ‘unhealthy’ pre-diagnostic dietary pattern may increase the risk of non-breast cancer mortality, whereas increasing intake of a ‘healthy’ pattern may reduce the risk of overall mortality and breast cancer recurrence.

The Association Between Dietary Lignans, Phytoestrogen-Rich Foods, and Fiber Intake and Postmenopausal Breast Cancer Risk: A German Case-Control Study

Phytoestrogens are structurally similar to estrogens and may affect breast cancer risk by mimicking estrogenic/antiestrogenic properties. In Western societies, whole grains and possibly soy foods are rich sources of phytoestrogens. A population-based case-control study in German postmenopausal women was used to evaluate the association of phytoestrogen-rich foods and dietary lignans with breast cancer risk. Dietary data were collected from 2,884 cases and 5,509 controls using a validated food-frequency questionnaire, which included additional questions phytoestrogen-rich foods. Associations were assessed using conditional logistic regression. All analyses were adjusted for relevant risk and confounding factors. Polytomous logistic regression analysis was performed to evaluate the associations by estrogen receptor (ER) status. High and low consumption of soybeans as well as of sunflower and pumpkin seeds were associated with significantly reduced breast cancer risk compared to no consumption (OR = 0.83, 95% CI = 0.70–0.97; and OR = 0.66, 95% CI = 0.77–0.97, respectively). The observed associations were not differential by ER status. No statistically significant associations were found for dietary intake of plant lignans, fiber, or the calculated enterolignans. Our results provide evidence for a reduced postmenopausal breast cancer risk associated with increased consumption of sunflower and pumpkin seeds and soybeans.

Enterolactone concentrations and prognosis after postmenopausal breast cancer: Assessment of effect modification and meta‐analysis

We previously reported that high concentrations of enterolactone, a lignan metabolite, are associated with lower mortality in 1,140 breast cancer patients from Germany. Using an extended set of 2,182 patients aged 50–74 years at diagnosis (2001–2005) and prospectively followed up until 2009, we investigated whether the association with mortality differs by lifestyle factors and tumor characteristics. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using multivariable Cox regression. Potential differential effects by tumor characteristics and lifestyle factors were assessed and a meta‐analysis of five studies addressing lignan exposure and breast cancer prognosis was performed to summarize evidence. Median enterolactone concentrations were 17.4 (±30.5 standard deviation) and 22.9 nmol L−1 (±44.8), respectively, for 269 deceased and 1,913 patients still alive. High enterolactone concentrations were significantly associated with lower all‐cause mortality (per 10 nmol L−1: HR 0.94, 95% CI 0.90–0.98), breast cancer‐specific mortality (HR 0.94, 0.89–0.99), and distant disease‐free survival (HR 0.94, 0.90–0.98). Associations were found for stage 0–IIIA but not for stage IIIB–IV disease (phet = 0.01) and were stronger in patients with BMI <25 kg m−2 than those with BMI ≥25 (phet = 0.04). In patients with healthy lifestyle (BMI <25, nonsmoker, physically active), the inverse association with all‐cause mortality was still apparent (HR 0.92, 0.85–0.99). The meta‐analysis yielded significant associations both for all‐cause (HR 0.57, 0.42–0.78) and breast cancer‐specific mortality (HR 0.54, 0.39–0.75). Our findings show that high lignan exposure is associated with reduced mortality in breast cancer patients. The inverse association observed in this study cannot be entirely explained by a healthy lifestyle.

Impact of folic acid fortification on global DNA methylation and one-carbon biomarkers in the Women's Health Initiative Observational Study cohort

DNA methylation is an epigenetic mechanism that regulates gene expression and can be modified by one-carbon nutrients. The objective of this study was to investigate the impact of folic acid (FA) fortification of the US food supply on leukocyte global DNA methylation and the relationship between DNA methylation, red blood cell (RBC) folate, and other one-carbon biomarkers among postmenopausal women enrolled in the Womens Health Initiative Observational Study. We selected 408 women from the highest and lowest tertiles of RBC folate distribution matching on age and timing of the baseline blood draw, which spanned the pre- (1994–1995), peri- (1996–1997), or post-fortification (1998) periods. Global DNA methylation was assessed by liquid chromatography-tandem mass spectrometry and expressed as a percentage of total cytosine. We observed an interaction (P = 0.02) between fortification period and RBC folate in relation to DNA methylation. Women with higher (vs. lower) RBC folate had higher mean DNA methylation (5.12 vs. 4.99%; P = 0.05) in the pre-fortification period, but lower (4.95 vs. 5.16%; P = 0.03) DNA methylation in the post-fortification period. We also observed significant correlations between one-carbon biomarkers and DNA methylation in the pre-fortification period, but not in the peri- or post-fortification period. The correlation between plasma homocysteine and DNA methylation was reversed from an inverse relationship during the pre-fortification period to a positive relationship during the post-fortification period. Our data suggest that (1) during FA fortification, higher RBC folate status is associated with a reduction in leukocyte global DNA methylation among postmenopausal women and; (2) the relationship between one-carbon biomarkers and global DNA methylation is dependent on folate availability.

Physical activity and endogenous sex hormones in postmenopausal women: to what extent are observed associations confounded or modified by BMI?

ObjectivesTo investigate associations between physical activity and endogenous sex hormones after menopause with a special focus on confounding and effect modification by body mass index (BMI).MethodsA cross-sectional study among 1,260 postmenopausal women was conducted. Generalized linear models were used to compare levels of total leisure-time physical activity, sports activities, bicycling, and walking with levels of sex hormones and sex-hormone-binding-globulin (SHBG).ResultsHigher sports activity levels were significantly associated with lower levels of estrone and total and free testosterone in multivariate adjusted models. After additional adjustment for BMI, associations with estrone and free testosterone were attenuated; the association with total testosterone remained unchanged. No physical activity variable was significantly related to total and free estradiol, androstenedione, or SHBG. We did not observe effect modification by BMI.ConclusionsSports activities may lead to lower levels of estrone and testosterone in postmenopausal women. While effects on estrone and free testosterone seem to be largely mediated by BMI, effects on total testosterone appear to be mainly independent of BMI. The BMI-independent effects on these hormones (especially on total testosterone) could at least partly explain why physical activity has been frequently reported to be preventive for postmenopausal breast cancer, even after accounting for BMI.