Supplemental MRI Screening for Women with Extremely Dense Breast Tissue.

BACKGROUND: Extremely dense breast tissue is a risk factor for breast cancer and limits the detection of cancer with mammography. Data are needed on the use of supplemental magnetic resonance imaging (MRI) to improve early detection and reduce interval breast cancers in such patients. METHODS: In this multicenter, randomized, controlled trial in the Netherlands, we assigned 40,373 women between the ages of 50 and 75 years with extremely dense breast tissue and normal results on screening mammography to a group that was invited to undergo supplemental MRI or to a group that received mammography screening only. The groups were assigned in a 1:4 ratio, with 8061 in the MRI-invitation group and 32,312 in the mammography-only group. The primary outcome was the between-group difference in the incidence of interval cancers during a 2-year screening period. RESULTS: The interval-cancer rate was 2.5 per 1000 screenings in the MRI-invitation group and 5.0 per 1000 screenings in the mammography-only group, for a difference of 2.5 per 1000 screenings (95% confidence interval [CI], 1.0 to 3.7; P<0.001). Of the women who were invited to undergo MRI, 59% accepted the invitation. Of the 20 interval cancers that were diagnosed in the MRI-invitation group, 4 were diagnosed in the women who actually underwent MRI (0.8 per 1000 screenings) and 16 in those who did not accept the invitation (4.9 per 1000 screenings). The MRI cancer-detection rate among the women who actually underwent MRI screening was 16.5 per 1000 screenings (95% CI, 13.3 to 20.5). The positive predictive value was 17.4% (95% CI, 14.2 to 21.2) for recall for additional testing and 26.3% (95% CI, 21.7 to 31.6) for biopsy. The false positive rate was 79.8 per 1000 screenings. Among the women who underwent MRI, 0.1% had either an adverse event or a serious adverse event during or immediately after the screening. CONCLUSIONS: The use of supplemental MRI screening in women with extremely dense breast tissue and normal results on mammography resulted in the diagnosis of significantly fewer interval cancers than mammography alone during a 2-year screening period. (Funded by the University Medical Center Utrecht and others; DENSE ClinicalTrials.gov number, NCT01315015.).

Effects of exercise in breast cancer patients: implications of the trials within cohorts (TwiCs) design in the UMBRELLA Fit trial.

PURPOSE: The Trials within Cohorts (TwiCs) design aims to overcome problems faced in conventional RCTs. We evaluated the TwiCs design when estimating the effect of exercise on quality of life (QoL) and fatigue in inactive breast cancer survivors. METHODS: UMBRELLA Fit was conducted within the prospective UMBRELLA breast cancer cohort. Patients provided consent for future randomization at cohort entry. We randomized inactive patients 12-18 months after cohort enrollment. The intervention group (n = 130) was offered a 12-week supervised exercise intervention. The control group (n = 130) was not informed and received usual care. Six-month exercise effects on QoL and fatigue as measured in the cohort were analyzed with intention-to-treat (ITT), instrumental variable (IV), and propensity scores (PS) analyses. RESULTS: Fifty-two percent (n = 68) of inactive patients accepted the intervention. Physical activity increased in patients in the intervention group, but not in the control group. We found no benefit of exercise for dimensions of QoL (ITT difference global QoL: 0.8, 95% CI = - 2.2; 3.8) and fatigue, except for a small beneficial effect on physical fatigue (ITT difference: - 1.1, 95% CI = - 1.8; - 0.3; IV: - 1.9, 95% CI = - 3.3; - 0.5, PS: - 1.2, 95% CI = - 2.3; - 0.2). CONCLUSION: TwiCs gave insight into exercise intervention acceptance: about half of inactive breast cancer survivors accepted the offer and increased physical activity levels. The offer resulted in no improvement on QoL, and a small beneficial effect on physical fatigue. TRIAL REGISTRATION: Netherlands Trial Register (NTR5482/NL.52062.041.15), date of registration: December 07, 2015.

Breast Cancer Risk After Recent Childbirth: A Pooled Analysis of 15 Prospective Studies.

Background: Parity is widely recognized as protective for breast cancer, but breast cancer risk may be increased shortly after childbirth. Whether this risk varies with breastfeeding, family history of breast cancer, or specific tumor subtype has rarely been evaluated. Objective: To characterize breast cancer risk in relation to recent childbirth. Design: Pooled analysis of individual-level data from 15 prospective cohort studies. Setting: The international Premenopausal Breast Cancer Collaborative Group. Participants: Women younger than 55 years. Measurements: During 9.6 million person-years of follow-up, 18 826 incident cases of breast cancer were diagnosed. Hazard ratios (HRs) and 95% CIs for breast cancer were calculated using Cox proportional hazards regression. Results: Compared with nulliparous women, parous women had an HR for breast cancer that peaked about 5 years after birth (HR, 1.80 [95% CI, 1.63 to 1.99]) before decreasing to 0.77 (CI, 0.67 to 0.88) after 34 years. The association crossed over from positive to negative about 24 years after birth. The overall pattern was driven by estrogen receptor (ER)-positive breast cancer; no crossover was seen for ER-negative cancer. Increases in breast cancer risk after childbirth were pronounced when combined with a family history of breast cancer and were greater for women who were older at first birth or who had more births. Breastfeeding did not modify overall risk patterns. Limitations: Breast cancer diagnoses during pregnancy were not uniformly distinguishable from early postpartum diagnoses. Data on human epidermal growth factor receptor 2 (HER2) oncogene overexpression were limited. Conclusion: Compared with nulliparous women, parous women have an increased risk for breast cancer for more than 20 years after childbirth. Health care providers should consider recent childbirth a risk factor for breast cancer in young women. Primary Funding Source: The Avon Foundation, the National Institute of Environmental Health Sciences, Breast Cancer Now and the UK National Health Service, and the Institute of Cancer Research.

Comparison of prognostic models to predict the occurrence of colorectal cancer in asymptomatic individuals: a systematic literature review and external validation in the EPIC and UK Biobank prospective cohort studies.

OBJECTIVE: To systematically identify and validate published colorectal cancer risk prediction models that do not require invasive testing in two large population-based prospective cohorts. DESIGN: Models were identified through an update of a published systematic review and validated in the European Prospective Investigation into Cancer and Nutrition (EPIC) and the UK Biobank. The performance of the models to predict the occurrence of colorectal cancer within 5 or 10 years after study enrolment was assessed by discrimination (C-statistic) and calibration (plots of observed vs predicted probability). RESULTS: The systematic review and its update identified 16 models from 8 publications (8 colorectal, 5 colon and 3 rectal). The number of participants included in each model validation ranged from 41 587 to 396 515, and the number of cases ranged from 115 to 1781. Eligible and ineligible participants across the models were largely comparable. Calibration of the models, where assessable, was very good and further improved by recalibration. The C-statistics of the models were largely similar between validation cohorts with the highest values achieved being 0.70 (95% CI 0.68 to 0.72) in the UK Biobank and 0.71 (95% CI 0.67 to 0.74) in EPIC. CONCLUSION: Several of these non-invasive models exhibited good calibration and discrimination within both external validation populations and are therefore potentially suitable candidates for the facilitation of risk stratification in population-based colorectal screening programmes. Future work should both evaluate this potential, through modelling and impact studies, and ascertain if further enhancement in their performance can be obtained.

Mediterranean diet adherence and risk of pancreatic cancer: A pooled analysis of two Dutch cohorts.

3w?>Studies investigating the association of Mediterranean diet (MD) adherence with pancreatic cancer risk are limited and had inconsistent results. We examined the association between MD adherence and pancreatic cancer incidence by pooling data from the Netherlands Cohort Study (NLCS, 120,852 subjects) and the Dutch cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-NL, 40,011 subjects). MD adherence was assessed using alternate and modified Mediterranean diet scores (aMED and mMED, respectively), including and excluding alcohol. After median follow-ups of 20.3 (NLCS) and 19.2 (EPIC-NL) years, 449 microscopically confirmed pancreatic cancer (MCPC) cases were included in study-specific multivariable Cox models. Study-specific estimates were pooled using a random-effects model. MD adherence was not significantly associated with MCPC risk in pooled and study-specific analyses, regardless of sex and MD score. Pooled hazard ratios (95% confidence interval) for high (6-8) compared to low (0-3) values of mMED excluding alcohol were 0.66 (0.40-1.10) in men and 0.94 (0.63-1.40) in women. In never smokers, mMED excluding alcohol seemed to be inversely associated with MCPC risk (nonsignificant). However, no association was observed in ever smokers (pheterogeneity = 0.03). Hazard ratios were consistent across strata of other potential effect modifiers. Considering MD scores excluding alcohol, mMED-containing models generally fitted better than aMED-containing models, particularly in men. Although associations somewhat differed when all pancreatic cancers were considered instead of MCPC, the overall conclusion was similar. In conclusion, MD adherence was not associated with pancreatic cancer risk in a pooled analysis of two Dutch cohorts.

One-carbon metabolism biomarkers and risk of urothelial cell carcinoma in the European prospective investigation into cancer and nutrition.

Published associations between dietary folate and bladder cancer risk are inconsistent. Biomarkers may provide more accurate measures of nutrient status. This nested case-control analysis within the European Prospective Investigation into Cancer and Nutrition (EPIC) investigated associations between pre-diagnostic serum folate, homocysteine, vitamins B6 and B12 and the risk of urothelial cell carcinomas of the bladder (UCC). A total of 824 patients with newly diagnosed UCC were matched with 824 cohort members. Serum folate, homocysteine, and vitamins B6 and B12 were measured. Odds ratios (OR) and 95% confidence intervals (CI) for total, aggressive, and non-aggressive UCC were estimated using conditional logistic regression with adjustment for smoking status, smoking duration and intensity, and other potential confounders. Additionally, statistical interaction with smoking status was assessed. A halving in serum folate concentrations was moderately associated with risk of UCC (OR: 1.18; 95% CI: 0.98-1.43), in particular aggressive UCC (OR: 1.34; 95% CI: 1.02-1.75; p-heterogeneity = 0.19). Compared to never smokers in the highest quartile of folate concentrations, this association seemed only apparent among current smokers in the lowest quartile of folate concentrations (OR: 6.26; 95% CI: 3.62-10.81, p-interaction = 0.07). Dietary folate was not associated with aggressive UCC (OR: 1.26; 95% CI: 0.81-1.95; p-heterogeneity = 0.14). No association was observed between serum homocysteine, vitamins B6 and B12 and risk of UCC. This study suggests that lower serum folate concentrations are associated with increased UCC risk, in particular aggressive UCC. Residual confounding by smoking cannot be ruled out and these findings require confirmation in future studies with multiple measurements.

Dietary folate intake and pancreatic cancer risk: Results from the European prospective investigation into cancer and nutrition.

Pancreatic cancer (PC) has an exceptionally low survival rate and primary prevention strategies are limited. Folate plays an important role in one-carbon metabolism and has been associated with the risk of several cancers, but not consistently with PC risk. We aimed to investigate the association between dietary folate intake and PC risk, using the standardised folate database across 10 European countries. A total of 477,206 participants were followed up for 11 years, during which 865 incident primary PC cases were recorded. Folate intake was energy-adjusted using the residual method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. In multivariable analyses stratified by age, sex, study centre and adjusted for energy intake, smoking status, BMI, educational level, diabetes status, supplement use and dietary fibre intake, we found no significant association between folate intake and PC risk: the HR of PC risk for those in the highest quartile of folate intake (≥353 µg/day) compared to the lowest (<241 µg/day) was 0.81 (95% CI: 0.51, 1.31; ptrend = 0.38). In current smokers, a positive trend was observed in PC risk across folate quartiles [HR = 4.42 (95% CI: 1.05, 18.62) for ≥353 µg/day vs. <241 µg/day, ptrend = 0.01]. Nonetheless, there was no significant interaction between smoking and dietary folate intake (pinteraction = 0.99). We found no association between dietary folate intake and PC risk in this large European study.

CA19-9 and apolipoprotein-A2 isoforms as detection markers for pancreatic cancer: a prospective evaluation.

Recently, we identified unique processing patterns of apolipoprotein A2 (ApoA2) in patients with pancreatic cancer. Our study provides a first prospective evaluation of an ApoA2 isoform ("ApoA2-ATQ/AT"), alone and in combination with carbohydrate antigen 19-9 (CA19-9), as an early detection biomarker for pancreatic cancer. We performed ELISA measurements of CA19-9 and ApoA2-ATQ/AT in 156 patients with pancreatic cancer and 217 matched controls within the European EPIC cohort, using plasma samples collected up to 60 months prior to diagnosis. The detection discrimination statistics were calculated for risk scores by strata of lag-time. For CA19-9, in univariate marker analyses, C-statistics to distinguish future pancreatic cancer patients from cancer-free individuals were 0.80 for plasma taken ≤6 months before diagnosis, and 0.71 for >6-18 months; for ApoA2-ATQ/AT, C-statistics were 0.62, and 0.65, respectively. Joint models based on ApoA2-ATQ/AT plus CA19-9 significantly improved discrimination within >6-18 months (C = 0.74 vs. 0.71 for CA19-9 alone, p = 0.022) and ≤ 18 months (C = 0.75 vs. 0.74, p = 0.022). At 98% specificity, and for lag times of ≤6, >6-18 or ≤ 18 months, sensitivities were 57%, 36% and 43% for CA19-9 combined with ApoA2-ATQ/AT, respectively, vs. 50%, 29% and 36% for CA19-9 alone. Compared to CA19-9 alone, the combination of CA19-9 and ApoA2-ATQ/AT may improve detection of pancreatic cancer up to 18 months prior to diagnosis under usual care, and may provide a useful first measure for pancreatic cancer detection prior to imaging.

Circulating insulin-like growth factor I in relation to melanoma risk in the European prospective investigation into cancer and nutrition.

Insulin-like growth factor-I (IGF-I) regulates cell proliferation and apoptosis, and is thought to play a role in tumour development. Previous prospective studies have shown that higher circulating concentrations of IGF-I are associated with a higher risk of cancers at specific sites, including breast and prostate. No prospective study has examined the association between circulating IGF-I concentrations and melanoma risk. A nested case-control study of 1,221 melanoma cases and 1,221 controls was performed in the European Prospective Investigation into Cancer and Nutrition cohort, a prospective cohort of 520,000 participants recruited from 10 European countries. Conditional logistic regression was used to estimate odds ratios (ORs) for incident melanoma in relation to circulating IGF-I concentrations, measured by immunoassay. Analyses were conditioned on the matching factors and further adjusted for age at blood collection, education, height, BMI, smoking status, alcohol intake, marital status, physical activity and in women only, use of menopausal hormone therapy. There was no significant association between circulating IGF-I concentration and melanoma risk (OR for highest vs lowest fifth = 0.93 [95% confidence interval [CI]: 0.71 to 1.22]). There was no significant heterogeneity in the association between IGF-I concentrations and melanoma risk when subdivided by gender, age at blood collection, BMI, height, age at diagnosis, time between blood collection and diagnosis, or by anatomical site or histological subtype of the tumour (Pheterogeneity≥0.078). We found no evidence for an association between circulating concentrations of IGF-I measured in adulthood and the risk of melanoma.

Heterogeneity of Colorectal Cancer Risk Factors by Anatomical Subsite in 10 European Countries: A Multinational Cohort Study.

BACKGROUND & AIMS: Colorectal cancer located at different anatomical subsites may have distinct etiologies and risk factors. Previous studies that have examined this hypothesis have yielded inconsistent results, possibly because most studies have been of insufficient size to identify heterogeneous associations with precision. METHODS: In the European Prospective Investigation into Cancer and Nutrition study, we used multivariable joint Cox proportional hazards models, which accounted for tumors at different anatomical sites (proximal colon, distal colon, and rectum) as competing risks, to examine the relationships between 14 established/suspected lifestyle, anthropometric, and reproductive/menstrual risk factors with colorectal cancer risk. Heterogeneity across sites was tested using Wald tests. RESULTS: After a median of 14.9 years of follow-up of 521,330 men and women, 6291 colorectal cancer cases occurred. Physical activity was related inversely to proximal colon and distal colon cancer, but not to rectal cancer (P heterogeneity = .03). Height was associated positively with proximal and distal colon cancer only, but not rectal cancer (P heterogeneity = .0001). For men, but not women, heterogeneous relationships were observed for body mass index (P heterogeneity = .008) and waist circumference (P heterogeneity = .03), with weaker positive associations found for rectal cancer, compared with proximal and distal colon cancer. Current smoking was associated with a greater risk of rectal and proximal colon cancer, but not distal colon cancer (P heterogeneity = .05). No heterogeneity by anatomical site was found for alcohol consumption, diabetes, nonsteroidal anti-inflammatory drug use, and reproductive/menstrual factors. CONCLUSIONS: The relationships between physical activity, anthropometry, and smoking with colorectal cancer risk differed by subsite, supporting the hypothesis that tumors in different anatomical regions may have distinct etiologies.

Potential for Reducing Time to Referral for Colorectal Cancer Patients in Primary Care.

PURPOSE: An optimal diagnostic process in primary care is pivotal for reducing cancer-related disease burden. This study aims to explore reasons for long times to referral for Dutch colorectal cancer (CRC) patients in primary care. METHODS: A retrospective cohort study of anonymized free-text primary care records from the Julius General Practitioners' Network database, linked to the Netherlands Cancer Registry. Patients with a confirmed CRC diagnosis from 2007 through 2011 that symptomatically presented in primary care were included. Median time and interquartile ranges from presentation in primary care to referral were calculated for multiple patient and presentation characteristics. Associations of these characteristics with long time to referral (75th percentile was ≥59 days) were examined with log-binomial regression analyses. Routes to referral of patients with the longest times to referral were explored using thematic free-text analyses (90th percentile at ≥219 days). RESULTS: Among the 309 people with CRC, patients who were female, did not have a registered family history, had a history of malignancy, lacked alarm symptoms at presentation, or had hemorrhoids at physical examination were at risk for longer time to referral in univariable analyses (longer median durations and/or univariable association with the 75th percentile). Only presentation without alarm symptoms showed a statistically significant association with long duration (75th percentile) in multivariable analysis (relative risk = 1.7; 95% CI, 1.1-2.6). Thematic exploration of the diagnostic routes to referral of patients with the longest durations (90th percentile) showed 2 dominating themes: "alternative working diagnosis" and "suboptimal diagnostic strategies," and included the sub-themes "omitting to reconsider an initial diagnosis" and "lacking follow-up." CONCLUSIONS: Long time to referral for CRC in primary care is mainly related to low cancer suspicion. There is potential for reducing the longest times to referral for patients with CRC in primary care, with earlier reconsideration of the initial hypothesis and implementation of strict follow-up consultations.

Mediterranean diet adherence and risk of esophageal and gastric cancer subtypes in the Netherlands Cohort Study.

BACKGROUND: Mediterranean diet (MD) adherence has been associated with reduced risks of esophageal and gastric cancer (subtypes) in a limited number of studies. We prospectively investigated associations between MD adherence and risks of esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), gastric cardia adenocarcinoma (GCA), and gastric non-cardia adenocarcinoma (GNCA) in a Dutch cohort. METHODS: Analyses were conducted using data from the 120852 participants of the Netherlands Cohort Study (NLCS), who were aged between 55 and 69 years at enrollment. Various MD scores, with and without alcohol, were calculated to estimate MD adherence. Using 20.3 years of follow-up, 133 ESCC, 200 EAC, 191 GCA, and 586 GNCA cases could be included in multivariable Cox regression analyses. RESULTS: Of the investigated scores, the alternate Mediterranean diet score without alcohol (aMEDr) performed best. aMEDr was inversely associated with risks of GCA and GNCA in men and women. However, statistical significance was only reached in men [ptrend: 0.019 (GCA), 0.016 (GNCA)]. Furthermore, higher aMEDr values were significantly associated with a reduced ESCC risk in men [HRper two-point increment (95% CI) = 0.57 (0.41-0.80), ptrend = 0.013], but not in women (pheterogeneity = 0.008). There was no evidence of an association between aMEDr and EAC risk. Educational level was a significant effect modifier for the association between aMEDr and GNCA risk (pheterogeneity = 0.0073). CONCLUSIONS: Higher MD adherence was associated with reduced risks of ESCC, GCA, and GNCA in the NLCS. However, the decreased ESCC risk might be limited to men.

Coffee and tea drinking in relation to the risk of differentiated thyroid carcinoma: results from the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

PURPOSE: Coffee and tea constituents have shown several anti-carcinogenic activities in cellular and animal studies, including against thyroid cancer (TC). However, epidemiological evidence is still limited and inconsistent. Therefore, we aimed to investigate this association in a large prospective study. METHODS: The study was conducted in the EPIC (European Prospective Investigation into Cancer and Nutrition) cohort, which included 476,108 adult men and women. Coffee and tea intakes were assessed through validated country-specific dietary questionnaires. RESULTS: During a mean follow-up of 14 years, 748 first incident differentiated TC cases (including 601 papillary and 109 follicular TC) were identified. Coffee consumption (per 100 mL/day) was not associated either with total differentiated TC risk (HRcalibrated 1.00, 95% CI 0.97-1.04) or with the risk of TC subtypes. Tea consumption (per 100 mL/day) was not associated with the risk of total differentiated TC (HRcalibrated 0.98, 95% CI 0.95-1.02) and papillary tumor (HRcalibrated 0.99, 95% CI 0.95-1.03), whereas an inverse association was found with follicular tumor risk (HRcalibrated 0.90, 95% CI 0.81-0.99), but this association was based on a sub-analysis with a small number of cancer cases. CONCLUSIONS: In this large prospective study, coffee and tea consumptions were not associated with TC risk.

Effect of diet with or without exercise on abdominal fat in postmenopausal women - a randomised trial.

BACKGROUND: We assessed the effect of equivalent weight loss with or without exercise on (intra-) abdominal fat in postmenopausal women in the SHAPE-2 study. METHODS: The SHAPE-2 study is a three-armed randomised controlled trial conducted in 2012-2013 in the Netherlands. Postmenopausal overweight women were randomized to a diet (n = 97), exercise plus diet (n = 98) or control group (n = 48). Both intervention groups aimed for equivalent weight loss (6-7%) following a calorie-restricted diet (diet group) or a partly supervised intensive exercise programme (4 h per week) combined with a small caloric restriction (exercise plus diet group). Outcomes after 16 weeks are amount and distribution of abdominal fat, measured by magnetic resonance imaging (MRI) with the use of the three-point IDEAL Dixon method. RESULTS: The diet and exercise plus diet group lost 6.1 and 6.9% body weight, respectively. Compared to controls, subcutaneous and intra-abdominal fat reduced significantly with both diet (- 12.5% and - 12.0%) and exercise plus diet (- 16.0% and - 14.6%). Direct comparison between both interventions revealed that the reduction in subcutaneous fat was statistically significantly larger in the group that combined exercise with diet: an additional 10.6 cm2 (95%CI -18.7; - 2.4) was lost compared to the diet-only group. Intra-abdominal fat loss was not significantly larger in the exercise plus diet group (- 3.8 cm2, 95%CI -9.0; 1.3). CONCLUSIONS: We conclude that weight loss of 6-7% with diet or with exercise plus diet reduced both subcutaneous and intra-abdominal fat. Only subcutaneous fat statistically significantly reduced to a larger extent when exercise is combined with a small caloric restriction. TRIAL REGISTER: NCT01511276 (clinicaltrials.gov), prospectively registered.

Effect of exercise and/or reduced calorie dietary interventions on breast cancer-related endogenous sex hormones in healthy postmenopausal women.

BACKGROUND: Physical inactivity and being overweight are modifiable lifestyle risk factors that consistently have been associated with a higher risk of postmenopausal breast cancer in observational studies. One biologic hypothesis underlying this relationship may be via endogenous sex hormone levels. It is unclear if changes in dietary intake, physical activity, or both, are most effective in changing these hormone levels. OBJECTIVE: This systematic review and meta-analysis examines the effect of reduced caloric dietary intake and/or increased exercise levels on breast cancer-related endogenous sex hormones. METHODS: We conducted a systematic literature search in MEDLINE, Embase, and Cochrane's Central Register of Controlled Trials (CENTRAL) up to March 2017. Main outcome measures were breast cancer-related endogenous sex hormones. Randomized controlled trials (RCTs) reporting effects of reduced caloric intake and/or exercise interventions on endogenous sex hormones in healthy, physically inactive postmenopausal women were included. Studies including women using hormone therapy were excluded. The methodological quality of each study was assessed by the Cochrane's risk of bias tool. RESULTS: From the 2599 articles retrieved, seven articles from six RCTs were included in this meta-analysis. These trials investigated 1588 healthy postmenopausal women with a mean age ranging from 58 to 61 years. A combined intervention of reduced caloric intake and exercise, with durations ranging from 16 to 52 weeks, compared with a control group (without an intervention to achieve weight loss) resulted in the largest beneficial effects on estrone treatment effect ratio (TER) = 0.90 (95% confidence interval (CI) = 0.83-0.97), total estradiol TER = 0.82 (0.75-0.90), free estradiol TER = 0.73 (0.66-0.81), free testosterone TER = 0.86 (0.79-0.93), and sex hormone biding globulin (SHBG) TER = 1.23 (1.15-1.31). A reduced caloric intake without an exercise intervention resulted in significant effects compared with control on total estradiol TER = 0.86 (0.77-0.95), free estradiol TER = 0.77 (0.69-0.84), free testosterone TER = 0.91 (0.84-0.98), and SHBG TER = 1.20 (1.06-1.36). Exercise without dietary change, versus control, resulted in borderline significant effects on androstenedione TER = 0.97 (0.94-1.00), total estradiol TER = 0. 97 (0.94-1.00), and free testosterone TER = 0. 0.97 (0.95-1.00). CONCLUSIONS AND RELEVANCE: This meta-analysis of six RCTs demonstrated that there are beneficial effects of exercise, reduced caloric dietary intake or, preferably, a combination of exercise and diet on breast cancer-related endogenous sex hormones in physically inactive postmenopausal women.

The combined effect of mammographic texture and density on breast cancer risk: a cohort study.

BACKGROUND: Texture patterns have been shown to improve breast cancer risk segregation in addition to area-based mammographic density. The additional value of texture pattern scores on top of volumetric mammographic density measures in a large screening cohort has never been studied. METHODS: Volumetric mammographic density and texture pattern scores were assessed automatically for the first available digital mammography (DM) screening examination of 51,400 women (50-75 years of age) participating in the Dutch biennial breast cancer screening program between 2003 and 2011. The texture assessment method was developed in a previous study and validated in the current study. Breast cancer information was obtained from the screening registration system and through linkage with the Netherlands Cancer Registry. All screen-detected breast cancers diagnosed at the first available digital screening examination were excluded. During a median follow-up period of 4.2 (interquartile range (IQR) 2.0-6.2) years, 301 women were diagnosed with breast cancer. The associations between texture pattern scores, volumetric breast density measures and breast cancer risk were determined using Cox proportional hazard analyses. Discriminatory performance was assessed using c-indices. RESULTS: The median age of the women at the time of the first available digital mammography examination was 56 years (IQR 51-63). Texture pattern scores were positively associated with breast cancer risk (hazard ratio (HR) 3.16 (95% CI 2.16-4.62) (p value for trend <0.001), for quartile (Q) 4 compared to Q1). The c-index of texture was 0.61 (95% CI 0.57-0.64). Dense volume and percentage dense volume showed positive associations with breast cancer risk (HR 1.85 (95% CI 1.32-2.59) (p value for trend <0.001) and HR 2.17 (95% CI 1.51-3.12) (p value for trend <0.001), respectively, for Q4 compared to Q1). When adding texture measures to models with dense volume or percentage dense volume, c-indices increased from 0.56 (95% CI 0.53-0.59) to 0.62 (95% CI 0.58-0.65) (p < 0.001) and from 0.58 (95% CI 0.54-0.61) to 0.60 (95% CI 0.57-0.63) (p = 0.054), respectively. CONCLUSIONS: Deep-learning-based texture pattern scores, measured automatically on digital mammograms, are associated with breast cancer risk, independently of volumetric mammographic density, and augment the capacity to discriminate between future breast cancer and non-breast cancer cases.

Mitochondrial DNA copy number variation, leukocyte telomere length, and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

BACKGROUND: Leukocyte telomere length (LTL) and mitochondrial genome (mtDNA) copy number and deletions have been proposed as risk markers for various cancer types, including breast cancer (BC). METHODS: To gain a more comprehensive picture on how these markers can modulate BC risk, alone or in conjunction, we performed simultaneous measurements of LTL and mtDNA copy number in up to 570 BC cases and 538 controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. As a first step, we measured LTL and mtDNA copy number in 96 individuals for which a blood sample had been collected twice with an interval of 15 years. RESULTS: According to the intraclass correlation (ICC), we found very good stability over the time period for both measurements, with ICCs of 0.63 for LTL and 0.60 for mtDNA copy number. In the analysis of the entire study sample, we observed that longer LTL was strongly associated with increased risk of BC (OR 2.71, 95% CI 1.58-4.65, p = 3.07 × 10- 4 for highest vs. lowest quartile; OR 3.20, 95% CI 1.57-6.55, p = 1.41 × 10- 3 as a continuous variable). We did not find any association between mtDNA copy number and BC risk; however, when considering only the functional copies, we observed an increased risk of developing estrogen receptor-positive BC (OR 2.47, 95% CI 1.05-5.80, p = 0.04 for highest vs. lowest quartile). CONCLUSIONS: We observed a very good correlation between the markers over a period of 15 years. We confirm a role of LTL in BC carcinogenesis and suggest an effect of mtDNA copy number on BC risk.

Nonsteroidal anti-inflammatory drug use and breast cancer risk in a European prospective cohort study.

Experimental studies have shown a protective effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on breast cancer development. However, results from epidemiological cohort studies are less consistent. Our objective was to assess the association between NSAID use and breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC is a prospective cohort study initiated in 1992 in 10 European countries. Self-reported information on NSAID use at baseline has been collected in five EPIC countries. Multivariable Cox regression models were used to estimate hazard ratios for the association of NSAID use with breast cancer incidence with adjustment for potential confounders. We also assessed effect modification by breast cancer risk factors and examined the associations within specific breast cancer subtypes. Among the 140,981 women included in the analysis, 7% were regularly using NSAIDs at baseline. During a median follow-up time period of 13 years, 7,379 incident breast cancer cases were diagnosed (816 in situ and 6,563 invasive). There were no statistically significant associations between NSAID use and breast cancer risk, overall and by subtypes. However, a statistically significant interaction was observed for invasive cases between NSAID use and ever use of menopausal hormonal therapy (MHT) among postmenopausal women [MHT users: HRNSAID use = 0.84 (0.73-0.96); non MHT users: HRNSAID use = 1.08 (0.93-1.25); pinteraction = 0.05]. Our results indicate potential effect modification of MHT use on the association between use of NSAIDs and breast cancer risk which deserves in-depth investigation in studies with accurate data on both NSAID and MHT use.

Pre-diagnostic circulating insulin-like growth factor-I and bladder cancer risk in the European Prospective Investigation into Cancer and Nutrition.

Previous in vitro and case-control studies have found an association between the insulin-like growth factor (IGF)-axis and bladder cancer risk. Circulating concentrations of IGF-I have also been found to be associated with an increased risk of several cancer types; however, the relationship between pre-diagnostic circulating IGF-I concentrations and bladder cancer has never been studied prospectively. We investigated the association of pre-diagnostic plasma concentrations of IGF-I with risk of overall bladder cancer and urothelial cell carcinoma (UCC) in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 843 men and women diagnosed with bladder cancer between 1992 and 2005 were matched with 843 controls by recruitment centre, sex, age at recruitment, date of blood collection, duration of follow-up, time of day and fasting status at blood collection using an incidence density sampling protocol. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression with adjustment for smoking status. No association was found between pre-diagnostic circulating IGF-I concentration and overall bladder cancer risk (adjusted OR for highest versus lowest fourth: 0.91, 95% CI: 0.66-1.24, ptrend = 0.40) or UCC (n of cases = 776; 0.91, 0.65-1.26, ptrend = 0.40). There was no significant evidence of heterogeneity in the association of IGF-I with bladder cancer risk by tumour aggressiveness, sex, smoking status, or by time between blood collection and diagnosis (pheterogeneity > 0.05 for all). This first prospective study indicates no evidence of an association between plasma IGF-I concentrations and bladder cancer risk.