The effects of exercise on the quality of life of patients with breast cancer (the UMBRELLA Fit study): study protocol for a randomized controlled trial.

BACKGROUND: Meta-analyses of randomized controlled trials (RCTs) have shown that exercise has beneficial effects on quality of life (QoL) in patients with breast cancer. However, these effects were often small. Blinding in an exercise trial is not possible, which has the possible disadvantage of difficult accrual, drop-out after randomization to control and contamination between study groups (controls adopting the behaviour of the intervention group). The cohort multiple randomized controlled trial (cmRCT) is an alternative for conventional RCTs and has the potential to overcome these disadvantages. METHODS: This cmRCT will be performed within the Utrecht cohort for Multiple BREast cancer intervention studies and Long-term evaLuAtion (UMBRELLA). Patients with breast cancer who visit the radiotherapy department of the University Medical Center Utrecht are asked to participate in UMBRELLA. Patients give consent for collection of medical information, providing patient-reported outcomes through regular questionnaires and randomization into future intervention studies. Patients who fulfill the UMBRELLA Fit study eligibility criteria (12 to 18 months post inclusion in UMBRELLA, low physical activity level) will be randomly allocated to the intervention or control group (1:1 ratio). Patients randomized to the intervention group will be offered a 12-week exercise programme. The control group will not be informed. Regular cohort measurements will be used for outcome assessment. Feasiblity (including participation, contamination, generalizability and retention) of the cmRCT design and effects of the intervention on QoL will be evaluated. DISCUSSION: We will examine the feasibility of the cmRCT design in exercise-oncology research and compare this with conventional RCTs. Furthermore, the effectiveness of an exercise intervention on the QoL of patients with breast cancer in the short term (6 months) and long term (24 months) will be studied. TRIAL REGISTRATION: Netherlands Trial Register, NTR5482/NL.52062.041.15 . Retrospectively registered on 7 December 2015.

Pre-diagnostic polyphenol intake and breast cancer survival: the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

The aim was to investigate the association between pre-diagnostic intakes of polyphenol classes (flavonoids, lignans, phenolic acids, stilbenes, and other polyphenols) in relation to breast cancer survival (all-cause and breast cancer-specific mortality). We used data from the European Prospective Investigation into Cancer and Nutrition cohort. Pre-diagnostic usual diet was assessed using dietary questionnaires, and polyphenol intakes were estimated using the Phenol-Explorer database. We followed 11,782 breast cancer cases from time of diagnosis until death, end of follow-up or last day of contact. During a median of 6 years, 1482 women died (753 of breast cancer). We related polyphenol intake to all-cause and breast cancer-specific mortality using Cox proportional hazard models with time since diagnosis as underlying time and strata for age and country. Among postmenopausal women, an intake of lignans in the highest versus lowest quartile was related to a 28 % lower risk of dying from breast (adjusted model: HR, quartile 4 vs. quartile 1, 0.72, 95 % CI 0.53; 0.98). In contrast, in premenopausal women, a positive association between lignan intake and all-cause mortality was found (adjusted model: HR, quartile 4 vs. quartile 1, 1.63, 95 % CI 1.03; 2.57). We found no association for other polyphenol classes. Intake of lignans before breast cancer diagnosis may be related to improved survival among postmenopausal women, but may on the contrary worsen the survival for premenopausal women. This suggests that the role of phytoestrogens in breast cancer survival is complex and may be dependent of menopausal status.

Coffee and tea consumption and risk of pre- and postmenopausal breast cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort study.

INTRODUCTION: Specific coffee subtypes and tea may impact risk of pre- and post-menopausal breast cancer differently. We investigated the association between coffee (total, caffeinated, decaffeinated) and tea intake and risk of breast cancer. METHODS: A total of 335,060 women participating in the European Prospective Investigation into Nutrition and Cancer (EPIC) Study, completed a dietary questionnaire from 1992 to 2000, and were followed-up until 2010 for incidence of breast cancer. Hazard ratios (HR) of breast cancer by country-specific, as well as cohort-wide categories of beverage intake were estimated. RESULTS: During an average follow-up of 11 years, 1064 premenopausal, and 9134 postmenopausal breast cancers were diagnosed. Caffeinated coffee intake was associated with lower risk of postmenopausal breast cancer: adjusted HR=0.90, 95% confidence interval (CI): 0.82 to 0.98, for high versus low consumption; Ptrend=0.029. While there was no significant effect modification by hormone receptor status (P=0.711), linear trend for lower risk of breast cancer with increasing caffeinated coffee intake was clearest for estrogen and progesterone receptor negative (ER-PR-), postmenopausal breast cancer (P=0.008). For every 100 ml increase in caffeinated coffee intake, the risk of ER-PR- breast cancer was lower by 4% (adjusted HR: 0.96, 95% CI: 0.93 to 1.00). Non-consumers of decaffeinated coffee had lower risk of postmenopausal breast cancer (adjusted HR=0.89; 95% CI: 0.80 to 0.99) compared to low consumers, without evidence of dose-response relationship (Ptrend=0.128). Exclusive decaffeinated coffee consumption was not related to postmenopausal breast cancer risk, compared to any decaffeinated-low caffeinated intake (adjusted HR=0.97; 95% CI: 0.82 to 1.14), or to no intake of any coffee (HR: 0.96; 95%: 0.82 to 1.14). Caffeinated and decaffeinated coffee were not associated with premenopausal breast cancer. Tea intake was neither associated with pre- nor post-menopausal breast cancer. CONCLUSIONS: Higher caffeinated coffee intake may be associated with lower risk of postmenopausal breast cancer. Decaffeinated coffee intake does not seem to be associated with breast cancer.

Coffee and tea consumption, genotype-based CYP1A2 and NAT2 activity and colorectal cancer risk-results from the EPIC cohort study.

Coffee and tea contain numerous antimutagenic and antioxidant components and high levels of caffeine that may protect against colorectal cancer (CRC). We investigated the association between coffee and tea consumption and CRC risk and studied potential effect modification by CYP1A2 and NAT2 genotypes, enzymes involved in the metabolization of caffeine. Data from 477,071 participants (70.2% female) of the European Investigation into Cancer and Nutrition (EPIC) cohort study were analyzed. At baseline (1992-2000) habitual (total, caffeinated and decaffeinated) coffee and tea consumption was assessed with dietary questionnaires. Cox proportional hazards models were used to estimate adjusted hazard ratio's (HR) and 95% confidence intervals (95% CI). Potential effect modification by genotype-based CYP1A2 and NAT2 activity was studied in a nested case-control set of 1,252 cases and 2,175 controls. After a median follow-up of 11.6 years, 4,234 participants developed CRC (mean age 64.7 ± 8.3 years). Total coffee consumption (high vs. non/low) was not associated with CRC risk (HR 1.06, 95% CI 0.95-1.18) or subsite cancers, and no significant associations were found for caffeinated (HR 1.10, 95% CI 0.97-1.26) and decaffeinated coffee (HR 0.96, 95% CI 0.84-1.11) and tea (HR 0.97, 95% CI 0.86-1.09). High coffee and tea consuming subjects with slow CYP1A2 or NAT2 activity had a similar CRC risk compared to non/low coffee and tea consuming subjects with a fast CYP1A2 or NAT2 activity, which suggests that caffeine metabolism does not affect the link between coffee and tea consumption and CRC risk. This study shows that coffee and tea consumption is not likely to be associated with overall CRC.

Menopausal hormone therapy and risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition.

Menopausal hormone therapy (HT) may influence colorectal cancer risk. A total of 136,275 postmenopausal women from the European Prospective Investigation into Cancer and Nutrition were followed for an average of 9 years, during which time 1,186 colorectal cancers were diagnosed. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models stratified by center and age, and adjusted for body mass index, smoking, diabetes, physical activity and alcohol consumption. Compared to never use of HT at study enrollment, current use of estrogen-only (HR, 1.02; 95% CI, 0.79-1.31) or estrogen plus progestin (HR, 0.94; 95% CI, 0.77-1.14) was not significantly associated with the risk of colorectal cancer, and these associations did not vary by recency, duration, route of administration, regimen or specific constituent of HT. Our results show no significant association of estrogen-only or estrogen plus progestin therapy with colorectal cancer risk.

Menopausal hormone therapy and breast cancer risk: impact of different treatments. The European Prospective Investigation into Cancer and Nutrition.

Menopausal hormone therapy (MHT) is characterized by use of different constituents, regimens and routes of administration. We investigated the association between the use of different types of MHT and breast cancer risk in the EPIC cohort study. The analysis is based on data from 133,744 postmenopausal women. Approximately 133,744 postmenopausal women contributed to this analysis. Information on MHT was derived from country-specific self-administered questionnaires with a single baseline assessment. Incident breast cancers were identified through population cancer registries or by active follow-up (mean: 8.6 yr). Overall relative risks (RR) and 95% confidence interval (CI) were derived from country-specific Cox proportional hazard models estimates. A total of 4312 primary breast cancers were diagnosed during 1,153,747 person-years of follow-up. Compared with MHT never users, breast cancer risk was higher among current users of estrogen only (RR: 1.42, 95% CI 1.23-1.64) and higher still among current users of combined MHT (RR: 1.77, 95% CI 1.40-2.24; p = 0.02 for combined vs. estrogen-only). Continuous combined regimens conferred a 43% (95% CI: 19-72%) greater risk compared with sequential regimens. There was no significant difference between progesterone and testosterone derivatives in sequential regimens. There was no significant variation in risk linked to the estrogenic component of MHT, neither for oral vs. cutaneous administration nor for estradiol compounds vs. conjugated equine estrogens. Estrogen-only and combined MHT uses were associated with increased breast cancer risk. Continuous combined preparations were associated with the highest risk. Further studies are needed to disentangle the effects of the regimen and the progestin component.

Menopausal hormone therapy and risk of endometrial carcinoma among postmenopausal women in the European Prospective Investigation Into Cancer and Nutrition.

Estrogen-only menopausal hormone therapy (HT) increases the risk of endometrial cancer, but less is known about the association with other types of HT. Using Cox proportional hazards regression, the authors examined the association of various types of HT with the risk of endometrial cancer among 115,474 postmenopausal women recruited into the European Prospective Investigation into Cancer and Nutrition between 1992 and 2000. After a mean follow-up period of 9 years, 601 incident cases of endometrial cancer were identified. In comparison with never users of HT, risk of endometrial cancer was increased among current users of estrogen-only HT (hazard ratio (HR) = 2.52, 95% confidence interval (CI): 1.77, 3.57), tibolone (HR = 2.96, 95% CI: 1.67, 5.26), and, to a lesser extent, estrogen-plus-progestin HT (HR = 1.41, 95% CI: 1.08, 1.83), although risks differed according to regimen and type of progestin constituent. The association of HT use with risk was stronger among women who were older, leaner, or had ever smoked cigarettes. The finding of a strong increased risk of endometrial cancer with estrogen-only HT and a weaker association with combined HT supports the hypothesis that progestins have an attenuating effect on endometrial cancer risk. The increased risk associated with tibolone use requires further investigation.

Coffee and tea intake and risk of brain tumors in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort study.

BACKGROUND: In a recent US cohort study, total coffee and tea consumption was inversely associated with risk of glioma, and experimental studies showed that caffeine can slow the invasive growth of glioblastoma. OBJECTIVE: The objective was to examine the relation between coffee and tea intake and the risk of glioma and meningioma in a large European cohort study, the European Prospective Investigation into Cancer and Nutrition (EPIC). DESIGN: Data on coffee and tea intake were collected from men and women recruited into the EPIC cohort study. Over an average of 8.5 y of follow-up, 343 cases of glioma and 245 cases of meningioma were newly diagnosed in 9 countries. We used Cox proportional hazards models to examine the relation between coffee and tea and brain tumors. RESULTS: We observed no associations between coffee, tea, or combined coffee and tea consumption and risk of either type of brain tumor when using quantiles based on country-specific distributions of intake. However, a significant inverse association was observed for glioma risk among those consuming ≥100 mL coffee and tea per day compared with those consuming <100 mL/d (hazard ratio: 0.66; 95% CI: 0.44, 0.97; P = 0.03). The association was slightly stronger in men (hazard ratio: 0.59; 95% CI: 0.34, 1.01) than in women (hazard ratio: 0.74; 95% CI: 0.42, 1.31), although neither was statistically significant. CONCLUSIONS: In this large cohort study, we observed an inverse association between total coffee and tea consumption and risk of glioma that was consistent with the findings of a recent study. These findings, if further replicated in other studies, may provide new avenues of research on gliomas.

Coffee and tea intake and risk of breast cancer.

Known risk factors account for about 10-15% of breast cancer incidence suggesting that lifestyle exposures are crucial in its etiology. Previous epidemiological studies on the association between coffee and tea consumption and breast cancer risk have been inconsistent. We investigated the association of coffee and tea consumption with the risk of breast cancer among women in EPIC-NL cohort, a population-based prospective cohort in Netherlands with 27,323 participants. Exposure was measured by a validated food frequency questionnaire, and the outcome was verified by direct linkage with the Netherlands Cancer Registry. A total of 681 invasive primary breast cancers were diagnosed in 9.6 years of follow-up. Coffee intake increased the risk of breast cancer by more than twofold as compared to non-consumers (HR; 2.25, 95% CI; 1.30-3.90). This association did not hold after multivariate adjustment which resulted in a HR of 1.17, 95% CI; 0.65-2.12. After adjustment to breast cancer risk factors and lifestyle, no association was observed between intake of coffee or tea and risk of breast cancer across all categories of intake. These results were also not altered by body mass index (BMI). Coffee and tea consumption does not seem to be related to the risk of breast cancer in women.

Variations in plasma phytoestrogen concentrations in European adults.

Dietary phytoestrogens may play a role in chronic disease occurrence. The aim of our study was to assess the variability of plasma concentrations in European populations. We included 15 geographical regions in 9 European countries (Denmark, France, Germany, Greece, Italy, Spain, Sweden, The Netherlands, and UK) and a 16th region, Oxford, UK, where participants were recruited from among vegans and vegetarians. All subjects were participants of the European Prospective Investigation into Cancer and Nutrition (EPIC). Plasma concentrations of 3 isoflavones (daidzein, genistein, and glycitein), 2 metabolites of daidzein [O-desmethylangolensin (O-DMA) and equol] and 2 mammalian lignans (enterodiol and enterolactone) were measured in 1414 participants. We computed geometric means for each region and used multivariate regression analysis to assess the influence of region, adjusted for gender, age, BMI, alcohol intake, smoking status, and laboratory batch. Many subjects had concentrations below the detection limit [0.1 microg/L (0.4 nmol/L)] for glycitein (80%), O-DMA (73%) and equol (62%). Excluding subjects from Oxford, UK, the highest concentrations of isoflavones were in subjects from the Netherlands and Cambridge, UK [2-6 microg/L (7-24 nmol/L); P < 0.05], whereas concentrations for lignans were highest in Denmark [8 microg/L (27 nmol/L); P < 0.05]. Isoflavones varied 8- to 13-fold, whereas lignans varied 4-fold. In the vegetarian/vegan cohort of Oxford, concentrations of isoflavones were 5-50 times higher than in nonvegetarian regions. Region was the most important determinant of plasma concentrations for all 7 phytoestrogens. Despite the fact that plasma concentrations of phytoestrogens in Europe were low compared with Asian populations, they varied substantially among subjects from the 16 different regions.

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.

Fish consumption and breast cancer risk. The European Prospective Investigation into Cancer and Nutrition (EPIC).

There is current interest in fish consumption and marine omega-3 (n-3) fatty acids and breast cancer risk. Some in vitro and animal studies have suggested an inhibitory effect of marine n-3 fatty acids on breast cancer growth, but the results from epidemiological studies that have examined the association between fish consumption and breast cancer risk in humans are inconsistent. We examined fish consumption and breast cancer risk in 310,671 women aged between 25 and 70 yr at recruitment into the European Prospective Investigation Into Cancer and Nutrition (EPIC). The participants completed a dietary questionnaire between 1992-98 and were followed up for incidence of breast cancer for a median of 6.4 yr. Hazard ratio for breast cancer by intake of total and lean and fatty fish were estimated, stratified by study centre and adjusted for established breast cancer risk factors. During follow-up, 4,776 invasive incident breast cancers were reported. No significant associations between intake of total fish and breast cancer risk were observed, hazard ratio (HR) 1.01 (95% confidence interval [CI] 0.99-1.02; p = 0.28 per 10 g fish/day). When examining lean and fatty fish separately, we found a positive significant association only in the highest quintile for fatty fish (HR 1.13, 95% CI 1.01-1.26), but test for trend was not significant (p = 0.10). No associations with breast cancer risk were observed when the study participants were subdivided by menopausal status. Although the period of follow-up is relatively short, the results provide no evidence for an association between fish intake and breast cancer risk.

Dietary determinants of circulating insulin-like growth factor (IGF)-I and IGF binding proteins 1, -2 and -3 in women in the Netherlands.

OBJECTIVE: Epidemiological studies suggest that individuals with elevated plasma concentrations of insulin-like growth factor (IGF-I) are at increased risk of developing cancer. We assessed whether dietary intake of total energy, protein, alcohol, phytoestrogens and related foods, and tomatoes and lycopene was associated with plasma levels of IGF-I and IGF binding proteins (IGFBPs) in Dutch women. METHODS: A cross-sectional study was conducted in 224 premenopausal and 162 postmenopausal women, aged 49-69, participating in the Prospect-EPIC study in the Netherlands. Diet was assessed using a food frequency questionnaire. RESULTS: In postmenopausal women, higher alcohol intake was associated with lower plasma IGFBP-1 concentrations (alcohol 1.4 to 20 g/day: 20% decrease in IGFBP-1; p = 0.04), and higher intake of plant lignans was associated with higher IGFBP-1 concentrations (plant lignans 0 to 1 mg/day: 59% increase in IGFBP-1; p =0.02). Higher soy intake was associated with higher plasma IGFBP-2 concentrations in premenopausal women (soy 0 to 2.5 g/day: 3% increase in IGFBP-2; p = 0.04). No independent associations of dietary factors with IGF-I or IGFBP-3 concentrations were observed. However, in premenopausal women alcohol intake was inversely associated with IGF-I and positively associated with IGFBP-3 after mutual adjustment. CONCLUSIONS: In this study population, with limited variation in dietary intake, total energy, protein, phytoestrogens and lycopene were not associated with IGF-I and IGFBP-3. Alcohol was inversely, and some measures of phytoestrogen intake were positively associated with plasma IGFBP-1 or -2 concentrations. The roles of IGFBP-1 and -2 in relation to IGF-I bioactivity and cancer deserve further investigation.