Publications by authors named "Marije F Bakker"

34 Publications

The changing microRNA landscape by color and cloudiness: a cautionary tale for nipple aspirate fluid biomarker analysis.

Cell Oncol (Dordr) 2021 Oct 16. Epub 2021 Oct 16.

Department of Pathology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.

Purpose: Investigation of nipple aspirate fluid (NAF)-based microRNAs (miRNAs) as a potential screening tool for women at increased risk of developing breast cancer is the scope of our research. While aiming to identify discriminating NAF-miRNAs between women with different mammographic densities, we were confronted with an unexpected confounder: NAF sample appearance. Here we report and alert for the impact of NAF color and cloudiness on miRNA assessment.

Methods: Seven classes of NAF colors coupled with cloudiness appearance were established. Using 173 NAF samples from 154 healthy women (19 samples were bilaterally collected), the expression of 14 target and 2 candidate endogenous control (EC) miRNAs was investigated using Taqman Advanced miRNA assays to identify significant differential expression patterns between color-cloudiness classes. Inter- and intra-individual variation of miRNA expression was analyzed using the coefficient of variation (CV).

Results: We found that between the seven NAF classes, fold change miRNA expression differences ranged between 2.4 and 19.6 depending on the interrogated miRNA. Clear NAF samples exhibited higher miRNA expression levels compared to cloudy NAF samples with fold change differences ranging between 1.1 and 6.2. Inter-individual and intra-individual miRNA expression was fairly stable (CV < 15 %), but nevertheless impacted by NAF sample appearance. Within NAF classes, inter-individual variation was largest for green samples (CV 6-15 %) and smallest for bloody samples (CV 2-6 %).

Conclusions: Our data indicate that NAF color and cloudiness influence miRNA expression and should, therefore, be systematically registered using an objective color classification system. Given that sample appearance is an inherent feature of NAF, these variables should be statistically controlled for in multivariate data analyses. This cautionary note and recommendations could be of value beyond the field of NAF-miRNAs, given that variability in sample color and cloudiness is likewise observed in liquid biopsies such as urine, cerebrospinal fluid and sputum, and could thereby influence the levels of miRNAs and other biomarkers.
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http://dx.doi.org/10.1007/s13402-021-00641-wDOI Listing
October 2021

Deep Learning for Automated Triaging of 4581 Breast MRI Examinations from the DENSE Trial.

Radiology 2021 Oct 5:203960. Epub 2021 Oct 5.

From the Image Sciences Institute (E.V., B.H.M.v.d.V., K.G.A.G.), Julius Center for Health Sciences and Primary Care (C.H.v.G., M.F.B.), and Department of Radiology (R.M.P., W.B.V.), University Medical Center Utrecht, Utrecht University, Utrecht 3584 CX, the Netherlands.

Background Supplemental screening with MRI has proved beneficial in women with extremely dense breasts. Most MRI examinations show normal anatomic and physiologic variation that may not require radiologic review. Thus, ways to triage these normal MRI examinations to reduce radiologist workload are needed. Purpose To determine the feasibility of an automated triaging method using deep learning (DL) to dismiss the highest number of MRI examinations without lesions while still identifying malignant disease. Materials and Methods This secondary analysis of data from the Dense Tissue and Early Breast Neoplasm Screening, or DENSE, trial evaluated breast MRI examinations from the first screening round performed in eight hospitals between December 2011 and January 2016. A DL model was developed to differentiate between breasts with lesions and breasts without lesions. The model was trained to dismiss breasts with normal phenotypical variation and to triage lesions (Breast Imaging Reporting and Data System [BI-RADS] categories 2-5) using eightfold internal-external validation. The model was trained on data from seven hospitals and tested on data from the eighth hospital, alternating such that each hospital was used once as an external test set. Performance was assessed using receiver operating characteristic analysis. At 100% sensitivity for malignant disease, the fraction of examinations dismissed from radiologic review was estimated. Results A total of 4581 MRI examinations of extremely dense breasts from 4581women (mean age, 54.3 years; interquartile range, 51.5-59.8 years) were included. Of the 9162 breasts, 838 had at least one lesion (BI-RADS category 2-5, of which 77 were malignant) and 8324 had no lesions. At 100% sensitivity for malignant lesions, the DL model considered 90.7% (95% CI: 86.7, 94.7) of the MRI examinations with lesions to be nonnormal and triaged them to radiologic review. The DL model dismissed 39.7% (95% CI: 30.0, 49.4) of the MRI examinations without lesions. The DL model had an average area under the receiver operating characteristic curve of 0.83 (95% CI: 0.80, 0.85) in the differentiation between normal breast MRI examinations and MRI examinations with lesions. Conclusion Automated analysis of breast MRI examinations in women with dense breasts dismissed nearly 40% of MRI scans without lesions while not missing any cancers. ClinicalTrials.gov: NCT01315015 © RSNA, 2021 See also the editorial by Joe in this issue.
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http://dx.doi.org/10.1148/radiol.2021203960DOI Listing
October 2021

Cost-Effectiveness of Magnetic Resonance Imaging Screening for Women With Extremely Dense Breast Tissue.

J Natl Cancer Inst 2021 Nov;113(11):1476-1483

Department of Public Health, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.

Background: Extremely dense breast tissue is associated with increased breast cancer risk and limited sensitivity of mammography. The DENSE trial showed that additional magnetic resonance imaging (MRI) screening in women with extremely dense breasts resulted in a substantial reduction in interval cancers. The cost-effectiveness of MRI screening for these women is unknown.

Methods: We used the MISCAN-breast microsimulation model to simulate several screening protocols containing mammography and/or MRI to estimate long-term effects and costs. The model was calibrated using results of the DENSE trial and adjusted to incorporate decreases in breast density with increasing age. Screening strategies varied in the number of MRIs and mammograms offered to women ages 50-75 years. Outcomes were numbers of breast cancers, life-years, quality-adjusted life-years (QALYs), breast cancer deaths, and overdiagnosis. Incremental cost-effectiveness ratios (ICERs) were calculated (3% discounting), with a willingness-to-pay threshold of €22 000.

Results: Calibration resulted in a conservative fit of the model regarding MRI detection. Both strategies of the DENSE trial were dominated (biennial mammography; biennial mammography plus MRI). MRI alone every 4 years was cost-effective with €15 620 per QALY. Screening every 3 years with MRI alone resulted in an incremental cost-effectiveness ratio of €37 181 per QALY. All strategies with mammography and/or a 2-year interval were dominated because other strategies resulted in more additional QALYs per additional euro. Alternating mammography and MRI every 2 years was close to the efficiency frontier.

Conclusions: MRI screening is cost-effective for women with extremely dense breasts, when applied at a 4-year interval. For a willingness to pay more than €22 000 per QALY gained, MRI at a 3-year interval is cost-effective as well.
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http://dx.doi.org/10.1093/jnci/djab119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8562952PMC
November 2021

Psychosocial factors and cancer incidence (PSY-CA): Protocol for individual participant data meta-analyses.

Brain Behav 2021 Oct 2;11(10):e2340. Epub 2021 Sep 2.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht and Utrecht University, Utrecht, the Netherlands.

Objectives: Psychosocial factors have been hypothesized to increase the risk of cancer. This study aims (1) to test whether psychosocial factors (depression, anxiety, recent loss events, subjective social support, relationship status, general distress, and neuroticism) are associated with the incidence of any cancer (any, breast, lung, prostate, colorectal, smoking-related, and alcohol-related); (2) to test the interaction between psychosocial factors and factors related to cancer risk (smoking, alcohol use, weight, physical activity, sedentary behavior, sleep, age, sex, education, hormone replacement therapy, and menopausal status) with regard to the incidence of cancer; and (3) to test the mediating role of health behaviors (smoking, alcohol use, weight, physical activity, sedentary behavior, and sleep) in the relationship between psychosocial factors and the incidence of cancer.

Methods: The psychosocial factors and cancer incidence (PSY-CA) consortium was established involving experts in the field of (psycho-)oncology, methodology, and epidemiology. Using data collected in 18 cohorts (N = 617,355), a preplanned two-stage individual participant data (IPD) meta-analysis is proposed. Standardized analyses will be conducted on harmonized datasets for each cohort (stage 1), and meta-analyses will be performed on the risk estimates (stage 2).

Conclusion: PSY-CA aims to elucidate the relationship between psychosocial factors and cancer risk by addressing several shortcomings of prior meta-analyses.
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http://dx.doi.org/10.1002/brb3.2340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8553309PMC
October 2021

Reducing False-Positive Screening MRI Rate in Women with Extremely Dense Breasts Using Prediction Models Based on Data from the DENSE Trial.

Radiology 2021 11 17;301(2):283-292. Epub 2021 Aug 17.

From the Department of Radiology (B.M.d.D., S.V.d.L., W.B.V., R.M.P.), Julius Center for Health Sciences and Primary Care (M.F.B., S.V.d.L., E.M.M., C.H.v.G.), and Department of Pathology (P.J.v.D.), University Medical Center Utrecht, Utrecht University, PO Box 85500, 3508 GA Utrecht, the Netherlands; Department of Radiology and Nuclear Medicine, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands (K.M.D.); Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, and GROW School for Oncology and Developmental Biology, Maastricht University, and Department of Medical Imaging, Zuyderland Medical Center, Sittard-Geleen, the Netherlands (M.B.I.L.); Department of Radiology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands (C.E.L.); Department of Radiology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands (R.M.M.); Department of Radiology, Ziekenhuisgroep Twente, Almelo, the Netherlands (J.V.); and Dutch Expert Center for Screening, Nijmegen, the Netherlands (R.M.P.).

Background High breast density increases breast cancer risk and lowers mammographic sensitivity. Supplemental MRI screening improves cancer detection but increases the number of false-positive screenings. Thus, methods to distinguish true-positive MRI screening results from false-positive ones are needed. Purpose To build prediction models based on clinical characteristics and MRI findings to reduce the rate of false-positive screening MRI findings in women with extremely dense breasts. Materials and Methods Clinical characteristics and MRI findings in Dutch breast cancer screening participants (age range, 50-75 years) with positive first-round MRI screening results (Breast Imaging Reporting and Data System 3, 4, or 5) after a normal screening mammography with extremely dense breasts (Volpara density category 4) were prospectively collected within the randomized controlled Dense Tissue and Early Breast Neoplasm Screening (DENSE) trial from December 2011 through November 2015. In this secondary analysis, prediction models were built using multivariable logistic regression analysis to distinguish true-positive MRI screening findings from false-positive ones. Results Among 454 women (median age, 52 years; interquartile range, 50-57 years) with a positive MRI result in a first supplemental MRI screening round, 79 were diagnosed with breast cancer (true-positive findings), and 375 had false-positive MRI results. The full prediction model (area under the receiver operating characteristics curve [AUC], 0.88; 95% CI: 0.84, 0.92), based on all collected clinical characteristics and MRI findings, could have prevented 45.5% (95% CI: 39.6, 51.5) of false-positive recalls and 21.3% (95% CI: 15.7, 28.3) of benign biopsies without missing any cancers. The model solely based on readily available MRI findings and age had a comparable performance (AUC, 0.84; 95% CI: 0.79, 0.88; = .15) and could have prevented 35.5% (95% CI: 30.4, 41.1) of false-positive MRI screening results and 13.0% (95% CI: 8.8, 18.6) of benign biopsies. Conclusion Prediction models based on clinical characteristics and MRI findings may be useful to reduce the false-positive first-round screening MRI rate and benign biopsy rate in women with extremely dense breasts. Clinical trial registration no. NCT01315015 © RSNA, 2021 See also the editorial by Imbriaco in this issue.
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http://dx.doi.org/10.1148/radiol.2021210325DOI Listing
November 2021

Dietary Methyl-Group Donor Intake and Breast Cancer Risk in the European Prospective Investigation into Cancer and Nutrition (EPIC).

Nutrients 2021 May 28;13(6). Epub 2021 May 28.

Office of the Director, International Agency for Research on Cancer, CEDEX 08, 69372 Lyon, France.

(1) Background: Methyl-group donors (MGDs), including folate, choline, betaine, and methionine, may influence breast cancer (BC) risk through their role in one-carbon metabolism; (2) Methods: We studied the relationship between dietary intakes of MGDs and BC risk, adopting data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort; (3) Results: 318,686 pre- and postmenopausal women were followed between enrolment in 1992-2000 and December 2013-December 2015. Dietary MGD intakes were estimated at baseline through food-frequency questionnaires. Multivariable Cox proportional hazards regression models were used to quantify the association between dietary intake of MGDs, measured both as a calculated score based on their sum and individually, and BC risk. Subgroup analyses were performed by hormone receptor status, menopausal status, and level of alcohol intake. During a mean follow-up time of 14.1 years, 13,320 women with malignant BC were identified. No associations were found between dietary intakes of the MGD score or individual MGDs and BC risk. However, a potential U-shaped relationship was observed between dietary folate intake and overall BC risk, suggesting an inverse association for intakes up to 350 µg/day compared to a reference intake of 205 µg/day. No statistically significant differences in the associations were observed by hormone receptor status, menopausal status, or level of alcohol intake; (4) Conclusions: There was no strong evidence for an association between MGDs involved in one-carbon metabolism and BC risk. However, a potential U-shaped trend was suggested for dietary folate intake and BC risk. Further research is needed to clarify this association.
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http://dx.doi.org/10.3390/nu13061843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228096PMC
May 2021

Supplemental Breast MRI for Women with Extremely Dense Breasts: Results of the Second Screening Round of the DENSE Trial.

Radiology 2021 05 16;299(2):278-286. Epub 2021 Mar 16.

From the Julius Center for Health Sciences and Primary Care (S.G.A.V., S.V.d.L., M.F.B., E.M.M., C.H.v.G.), Department of Radiology (S.V.d.L., R.M.P., M.J.E., W.P.T.M.M., M.A.A.J.v.d.B., W.B.V.), and Department of Pathology (P.J.v.D.), University Medical Center Utrecht, Utrecht University, STR 6.131, PO Box 85500, 3508 GA Utrecht, the Netherlands; Dutch Expert Centre for Screening, Nijmegen, the Netherlands (R.M.P.); Department of Radiology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands (R.M.M., N.K.); Department of Radiology, the Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands (P.K.d.K.D.); Department of Radiology, Albert Schweitzer Hospital, Dordrecht, the Netherlands (R.H.C.B.); Department of Radiology and Nuclear Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands (M.B.I.L.); Department of Medical Imaging, Zuyderland Medical Centre, Sittard-Geleen, the Netherlands (M.B.I.L.); Department of Radiology, Jeroen Bosch Hospital, 's-Hertogenbosch, the Netherlands (M.D.F.d.J.); Department of Radiology and Nuclear Medicine, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands (K.M.D.); Department of Radiology, Hospital Group Twente (ZGT), Almelo, the Netherlands (J.V.); and Department of Public Health, Erasmus Medical Center, Rotterdam, the Netherlands (H.J.d.K.).

Background In the first (prevalent) supplemental MRI screening round of the Dense Tissue and Early Breast Neoplasm Screening (DENSE) trial, a considerable number of breast cancers were found at the cost of an increased false-positive rate (FPR). In incident screening rounds, a lower cancer detection rate (CDR) is expected due to a smaller pool of prevalent cancers, and a reduced FPR, due to the availability of prior MRI examinations. Purpose To investigate screening performance indicators of the second round (incidence round) of the DENSE trial. Materials and Methods The DENSE trial (ClinicalTrials.gov: NCT01315015) is embedded within the Dutch population-based biennial mammography screening program for women aged 50-75 years. MRI examinations were performed between December 2011 and January 2016. Women were eligible for the second round when they again had a negative screening mammogram 2 years after their first MRI. The recall rate, biopsy rate, CDR, FPR, positive predictive values, and distributions of tumor characteristics were calculated and compared with results of the first round using 95% CIs and χ tests. Results A total of 3436 women (median age, 56 years; interquartile range, 48-64 years) underwent a second MRI screening. The CDR was 5.8 per 1000 screening examinations (95% CI: 3.8, 9.0) compared with 16.5 per 1000 screening examinations (95% CI: 13.3, 20.5) in the first round. The FPR was 26.3 per 1000 screening examinations (95% CI: 21.5, 32.3) in the second round versus 79.8 per 1000 screening examinations (95% CI: 72.4, 87.9) in the first round. The positive predictive value for recall was 18% (20 of 110 participants recalled; 95% CI: 12.1, 26.4), and the positive predictive value for biopsy was 24% (20 of 84 participants who underwent biopsy; 95% CI: 16.0, 33.9), both comparable to that of the first round. All tumors in the second round were stage 0-I and node negative. Conclusion The incremental cancer detection rate in the second round was 5.8 per 1000 screening examinations-compared with 16.5 per 1000 screening examinations in the first round. This was accompanied by a strong reduction in the number of false-positive results. © RSNA, 2021 See also the editorial by Moy and Gao in this issue.
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http://dx.doi.org/10.1148/radiol.2021203633DOI Listing
May 2021

Causal Effects of Lifetime Smoking on Breast and Colorectal Cancer Risk: Mendelian Randomization Study.

Cancer Epidemiol Biomarkers Prev 2021 05 2;30(5):953-964. Epub 2021 Mar 2.

Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.

Background: Observational evidence has shown that smoking is a risk factor for breast and colorectal cancer. We used Mendelian randomization (MR) to examine causal associations between smoking and risks of breast and colorectal cancer.

Methods: Genome-Wide Association Study summary data were used to identify genetic variants associated with lifetime amount of smoking ( = 126 variants) and ever having smoked regularly ( = 112 variants). Using two-sample MR, we examined these variants in relation to incident breast (122,977 cases/105,974 controls) and colorectal cancer (52,775 cases/45,940 controls).

Results: In inverse-variance weighted models, a genetic predisposition to higher lifetime amount of smoking was positively associated with breast cancer risk [OR per 1-SD increment: 1.13; 95% confidence interval (CI): 1.00-1.26; = 0.04]; although heterogeneity was observed. Similar associations were found for estrogen receptor-positive and estrogen receptor-negative tumors. Higher lifetime amount of smoking was positively associated with colorectal cancer (OR per 1-SD increment, 1.21; 95% CI, 1.04-1.40; = 0.01), colon cancer (OR, 1.31; 95% CI, 1.11-1.55; < 0.01), and rectal cancer (OR, 1.36; 95% CI, 1.07-1.73; = 0.01). Ever having smoked regularly was not associated with risks of breast (OR, 1.01; 95% CI, 0.90-1.14; = 0.85) or colorectal cancer (OR, 0.97; 95% CI, 0.86-1.10; = 0.68).

Conclusions: These findings are consistent with prior observational evidence and support a causal role of higher lifetime smoking amount in the development of breast and colorectal cancer.

Impact: The results from this comprehensive MR analysis indicate that lifetime smoking is a causal risk factor for these common malignancies.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611442PMC
May 2021

The Physiological MicroRNA Landscape in Nipple Aspirate Fluid: Differences and Similarities with Breast Tissue, Breast Milk, Plasma and Serum.

Int J Mol Sci 2020 Nov 11;21(22). Epub 2020 Nov 11.

Department of Pathology, University Medical Center Utrecht, Utrecht University, 3508 GA Utrecht, The Netherlands.

Background: MicroRNAs (miRNAs) target 60% of human messenger RNAs and can be detected in tissues and biofluids without loss of stability during sample processing, making them highly appraised upcoming biomarkers for evaluation of disease. However, reporting of the abundantly expressed miRNAs in healthy samples is often surpassed. Here, we characterized for the first time the physiological miRNA landscape in a biofluid of the healthy breast: nipple aspirate fluid (NAF), and compared NAF miRNA expression patterns with publically available miRNA expression profiles of healthy breast tissue, breast milk, plasma and serum.

Methods: MiRNA RT-qPCR profiling of NAF ( = 41) and serum ( = 23) samples from two healthy female cohorts was performed using the TaqMan OpenArray Human Advanced MicroRNA 754-Panel. MiRNA quantification data based on non-targeted or multi-targeted profiling techniques for breast tissue, breast milk, plasma and serum were retrieved from the literature by means of a systematic search. MiRNAs from each individual study were orderly ranked between 1 and 50, combined into an overall ranking per sample type and compared.

Results: NAF expressed 11 unique miRNAs and shared 21/50 miRNAs with breast tissue. Seven miRNAs were shared between the five sample types. Overlap between sample types varied between 42% and 62%. Highly ranked NAF miRNAs have established roles in breast carcinogenesis.

Conclusion: This is the first study to characterize and compare the unique physiological NAF-derived miRNA landscape with the physiological expression pattern in breast tissue, breast milk, plasma and serum. Breast-specific sources did not mutually overlap more than with systemic sources. Given their established role in carcinogenesis, NAF miRNA assessment could be a valuable tool in breast tumor diagnostics.
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http://dx.doi.org/10.3390/ijms21228466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696615PMC
November 2020

MRI Screening in Women with Dense Breasts. Reply.

N Engl J Med 2020 03;382(13):1284

University Medical Center Utrecht, Utrecht, the Netherlands

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http://dx.doi.org/10.1056/NEJMc1917231DOI Listing
March 2020

Computer-Aided Diagnosis in Multiparametric Magnetic Resonance Imaging Screening of Women With Extremely Dense Breasts to Reduce False-Positive Diagnoses.

Invest Radiol 2020 07;55(7):438-444

From the Image Sciences Institute.

Objectives: To reduce the number of false-positive diagnoses in the screening of women with extremely dense breasts using magnetic resonance imaging (MRI), we aimed to predict which BI-RADS 3 and BI-RADS 4 lesions are benign. For this purpose, we use computer-aided diagnosis (CAD) based on multiparametric assessment.

Materials And Methods: Consecutive data were used from the first screening round of the DENSE (Dense Tissue and Early Breast Neoplasm Screening) trial. In this trial, asymptomatic women with a negative screening mammography and extremely dense breasts were screened using multiparametric MRI. In total, 4783 women, aged 50 to 75 years, enrolled and were screened in 8 participating hospitals between December 2011 and January 2016. In total, 525 lesions in 454 women were given a BI-RADS 3 (n = 202), 4 (n = 304), or 5 score (n = 19). Of these lesions, 444 were benign and 81 were malignant on histologic examination.The MRI protocol consisted of 5 different MRI sequences: T1-weighted imaging without fat suppression, diffusion-weighted imaging, T1-weighted contrast-enhanced images at high spatial resolution, T1-weighted contrast-enhanced images at high temporal resolution, and T2-weighted imaging. A machine-learning method was developed to predict, without deterioration of sensitivity, which of the BI-RADS 3- and BI-RADS 4-scored lesions are actually benign and could be prevented from being recalled. BI-RADS 5 lesions were only used for training, because the gain in preventing false-positive diagnoses is expected to be low in this group. The CAD consists of 2 stages: feature extraction and lesion classification. Two groups of features were extracted: the first based on all multiparametric sequences, the second based only on sequences that are typically used in abbreviated MRI protocols. In the first group, 49 features were used as candidate predictors: 46 were automatically calculated from the MRI scans, supplemented with 3 clinical features (age, body mass index, and BI-RADS score). In the second group, 36 image features and the same 3 clinical features were used. Each group was considered separately in a machine-learning model to differentiate between benign and malignant lesions. We developed a Ridge regression model using 10-fold cross validation. Performance of the models was analyzed using an accuracy measure curve and receiver-operating characteristic analysis.

Results: Of the total number of BI-RADS 3 and BI-RADS 4 lesions referred to additional MRI or biopsy, 425/487 (87.3%) were false-positive. The full multiparametric model classified 176 (41.5%) and the abbreviated-protocol model classified 111 (26.2%) of the 425 false-positive BI-RADS 3- and BI-RADS 4-scored lesions as benign without missing a malignant lesion.If the full multiparametric CAD had been used to aid in referral, recall for biopsy or repeat MRI could have been reduced from 425/487 (87.3%) to 311/487 (63.9%) lesions. For the abbreviated protocol, it could have been 376/487 (77.2%).

Conclusions: Dedicated multiparametric CAD of breast MRI for BI-RADS 3 and 4 lesions in screening of women with extremely dense breasts has the potential to reduce false-positive diagnoses and consequently to reduce the number of biopsies without missing cancers.
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http://dx.doi.org/10.1097/RLI.0000000000000656DOI Listing
July 2020

Nutrient-wide association study of 92 foods and nutrients and breast cancer risk.

Breast Cancer Res 2020 01 13;22(1). Epub 2020 Jan 13.

Department of Community Medicine, UiT The Arctic University of Norway, Tromsø, Norway.

Background: Several dietary factors have been reported to be associated with risk of breast cancer, but to date, unequivocal evidence only exists for alcohol consumption. We sought to systematically assess the association between intake of 92 foods and nutrients and breast cancer risk using a nutrient-wide association study.

Methods: Using data from 272,098 women participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, we assessed dietary intake of 92 foods and nutrients estimated by dietary questionnaires. Cox regression was used to quantify the association between each food/nutrient and risk of breast cancer. A false discovery rate (FDR) of 0.05 was used to select the set of foods and nutrients to be replicated in the independent Netherlands Cohort Study (NLCS).

Results: Six foods and nutrients were identified as associated with risk of breast cancer in the EPIC study (10,979 cases). Higher intake of alcohol overall was associated with a higher risk of breast cancer (hazard ratio (HR) for a 1 SD increment in intake = 1.05, 95% CI 1.03-1.07), as was beer/cider intake and wine intake (HRs per 1 SD increment = 1.05, 95% CI 1.03-1.06 and 1.04, 95% CI 1.02-1.06, respectively), whereas higher intakes of fibre, apple/pear, and carbohydrates were associated with a lower risk of breast cancer (HRs per 1 SD increment = 0.96, 95% CI 0.94-0.98; 0.96, 95% CI 0.94-0.99; and 0.96, 95% CI 0.95-0.98, respectively). When evaluated in the NLCS (2368 cases), estimates for each of these foods and nutrients were similar in magnitude and direction, with the exception of beer/cider intake, which was not associated with risk in the NLCS.

Conclusions: Our findings confirm a positive association of alcohol consumption and suggest an inverse association of dietary fibre and possibly fruit intake with breast cancer risk.
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http://dx.doi.org/10.1186/s13058-019-1244-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958698PMC
January 2020

Adherence to the World Cancer Research Fund/American Institute for Cancer Research cancer prevention recommendations and risk of in situ breast cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

BMC Med 2019 12 2;17(1):221. Epub 2019 Dec 2.

Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.

Background: Even though in situ breast cancer (BCIS) accounts for a large proportion of the breast cancers diagnosed, few studies have investigated potential risk factors for BCIS. Their results suggest that some established risk factors for invasive breast cancer have a similar impact on BCIS risk, but large population-based studies on lifestyle factors and BCIS risk are lacking. Thus, we investigated the association between lifestyle and BCIS risk within the European Prospective Investigation into Cancer and Nutrition cohort.

Methods: Lifestyle was operationalized by a score reflecting the adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations. The recommendations utilized in these analyses were the ones pertinent to healthy body weight, physical activity, consumption of plant-based foods, energy-dense foods, red and processed meat, and sugary drinks and alcohol, as well as the recommendation on breastfeeding. Cox proportional hazards regression was used to assess the association between lifestyle score and BCIS risk. The results were presented as hazard ratios (HR) and corresponding 95% confidence intervals (CI).

Results: After an overall median follow-up time of 14.9 years, 1277 BCIS cases were diagnosed. Greater adherence to the WCRF/AICR cancer prevention recommendations was not associated with BCIS risk (HR = 0.98, 95% CI 0.93-1.03; per one unit of increase; multivariable model). An inverse association between the lifestyle score and BCIS risk was observed in study centers, where participants were recruited mainly via mammographic screening and attended additional screening throughout follow-up (HR = 0.85, 95% CI 0.73-0.99), but not in the remaining ones (HR = 0.99, 95% CI 0.94-1.05).

Conclusions: While we did not observe an overall association between lifestyle and BCIS risk, our results indicate that lifestyle is associated with BCIS risk among women recruited via screening programs and with regular screening participation. This suggests that a true inverse association between lifestyle habits and BCIS risk in the overall cohort may have been masked by a lack of information on screening attendance. The potential inverse association between lifestyle and BCIS risk in our analyses is consistent with the inverse associations between lifestyle scores and breast cancer risk reported from previous studies.
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http://dx.doi.org/10.1186/s12916-019-1444-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886197PMC
December 2019

Supplemental MRI Screening for Women with Extremely Dense Breast Tissue.

N Engl J Med 2019 11;381(22):2091-2102

From the Julius Center for Health Sciences and Primary Care (M.F.B., S.V.L., P.H.M.P., E.M.M., C.H.G.) and the Departments of Radiology (S.V.L., R.M.P., M.J.E., W.P.T.M.M., M.A.A.J.B., W.B.V.) and Pathology (P.J.D.), University Medical Center Utrecht, Utrecht University, Utrecht, the Dutch Expert Center for Screening (R.M.P.) and the Department of Radiology, Radboud University Nijmegen Medical Center (R.M.M., N.K.), Nijmegen, the Department of Radiology, Antoni van Leeuwenhoek Hospital (C.E.L.), and the Department of Radiology and Nuclear Medicine, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam (K.M.D.), Amsterdam, the Department of Radiology, Albert Schweitzer Hospital, Dordrecht (R.H.C.B.), the Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, and the Department of Medical Imaging, Zuyderland Medical Center, Sittard-Geleen (M.B.I.L.), the Department of Radiology, Jeroen Bosch Hospital, 's-Hertogenbosch (M.D.F.J.), the Department of Radiology, Hospital Group Twente, Almelo (J.V.), and the Department of Public Health, Erasmus Medical Center, Rotterdam (H.J.K.) - all in the Netherlands; and the Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, London (P.H.M.P.).

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.).
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http://dx.doi.org/10.1056/NEJMoa1903986DOI Listing
November 2019

Non-occupational physical activity levels of shift workers compared with non-shift workers.

Occup Environ Med 2017 05 21;74(5):328-335. Epub 2016 Nov 21.

Center for Nutrition, Prevention and Health Services, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.

Objectives: Lack of physical activity (PA) has been hypothesised as an underlying mechanism in the adverse health effects of shift work. Therefore, our aim was to compare non-occupational PA levels between shift workers and non-shift workers. Furthermore, exposure-response relationships for frequency of night shifts and years of shift work regarding non-occupational PA levels were studied.

Methods: Data of 5980 non-shift workers and 532 shift workers from the European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL) were used in these cross-sectional analyses. Time spent (hours/week) in different PA types (walking/cycling/exercise/chores) and intensities (moderate/vigorous) were calculated based on self-reported PA. Furthermore, sports were operationalised as: playing sports (no/yes), individual versus non-individual sports, and non-vigorous-intensity versus vigorous-intensity sports. PA levels were compared between shift workers and non-shift workers using Generalized Estimating Equations and logistic regression.

Results: Shift workers reported spending more time walking than non-shift workers (B=2.3 (95% CI 1.2 to 3.4)), but shift work was not associated with other PA types and any of the sports activities. Shift workers who worked 1-4 night shifts/month (B=2.4 (95% CI 0.6 to 4.3)) and ≥5 night shifts/month (B=3.7 (95% CI 1.8 to 5.6)) spent more time walking than non-shift workers. No exposure-response relationships were found between years of shift work and PA levels.

Conclusions: Shift workers spent more time walking than non-shift workers, but we observed no differences in other non-occupational PA levels. To better understand if and how PA plays a role in the negative health consequences of shift work, our findings need to be confirmed in future studies.
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http://dx.doi.org/10.1136/oemed-2016-103878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520260PMC
May 2017

Determining the Lowest Optimally Effective Methotrexate Dose for Individual RA Patients Using Their Dose Response Relation in a Tight Control Treatment Approach.

PLoS One 2016 17;11(3):e0148791. Epub 2016 Mar 17.

Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, The Netherlands.

Objective: To determine the optimal methotrexate dose in individual patients and to explore whether this optimal dose and the level of disease activity at that dose could be predicted.

Methods: Data from CAMERA II trial comparing MTX and MTX with 10 mg of prednisone both in a tight control treatment strategy in early RA was used. For each patient a curve for disease activity over time was fitted and the MTX dose after which further step-up did not result in relevant improvement in disease activity anymore was determined the 'lowest optimally effective MTX dose (LOED)'. The association of demographic and clinical characteristics at baseline with this LOED and with the level of disease activity reached at LOED was studied.

Results: In 204 (100 MTX and 104 MTX with prednisone) out of 236 patients LOED could be defined. 10 mg/wk was the most prevalent LOED in patients treated with MTX and prednisone and 10 mg/wk, 20 mg/wk and 30 mg/wk in the MTX strategy. Although the specific LOED could not reliably be predicted, higher baseline disease activity, height and lower weight were associated with higher LOEDs (i.e at least 15 mg/wk). A score was presented to decide on a starting dose of 10 mg/wk or (at least) 15 mg/wk. The level of disease activity at LOED could not be reliably predicted.

Conclusion: A starting dose of 10 mg/wk might be a good choice for most patients and is frequently already the optimal dose. However, a subgroup of patient can be determined who would require higher MTX doses.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0148791PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795693PMC
August 2016

Plasma carotenoids, vitamin C, tocopherols, and retinol and the risk of breast cancer in the European Prospective Investigation into Cancer and Nutrition cohort.

Am J Clin Nutr 2016 Feb 20;103(2):454-64. Epub 2016 Jan 20.

Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway;

Background: Carotenoids and vitamin C are thought to be associated with reduced cancer risk because of their antioxidative capacity.

Objective: This study evaluated the associations of plasma carotenoid, retinol, tocopherol, and vitamin C concentrations and risk of breast cancer.

Design: In a nested case-control study within the European Prospective Investigation into Cancer and Nutrition cohort, 1502 female incident breast cancer cases were included, with an oversampling of premenopausal (n = 582) and estrogen receptor-negative (ER-) cases (n = 462). Controls (n = 1502) were individually matched to cases by using incidence density sampling. Prediagnostic samples were analyzed for α-carotene, β-carotene, lycopene, lutein, zeaxanthin, β-cryptoxanthin, retinol, α-tocopherol, γ-tocopherol, and vitamin C. Breast cancer risk was computed according to hormone receptor status and age at diagnosis (proxy for menopausal status) by using conditional logistic regression and was further stratified by smoking status, alcohol consumption, and body mass index (BMI). All statistical tests were 2-sided.

Results: In quintile 5 compared with quintile 1, α-carotene (OR: 0.61; 95% CI: 0.39, 0.98) and β-carotene (OR: 0.41; 95% CI: 0.26, 0.65) were inversely associated with risk of ER- breast tumors. The other analytes were not statistically associated with ER- breast cancer. For estrogen receptor-positive (ER+) tumors, no statistically significant associations were found. The test for heterogeneity between ER- and ER+ tumors was statistically significant only for β-carotene (P-heterogeneity = 0.03). A higher risk of breast cancer was found for retinol in relation to ER-/progesterone receptor-negative tumors (OR: 2.37; 95% CI: 1.20, 4.67; P-heterogeneity with ER+/progesterone receptor positive = 0.06). We observed no statistically significant interaction between smoking, alcohol, or BMI and all investigated plasma analytes (based on tertile distribution).

Conclusion: Our results indicate that higher concentrations of plasma β-carotene and α-carotene are associated with lower breast cancer risk of ER- tumors.
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http://dx.doi.org/10.3945/ajcn.114.101659DOI Listing
February 2016

Vegetable and fruit consumption and the risk of hormone receptor-defined breast cancer in the EPIC cohort.

Am J Clin Nutr 2016 Jan 25;103(1):168-77. Epub 2015 Nov 25.

CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Navarre Public Health Institute, Pamplona, Spain;

Background: The recent literature indicates that a high vegetable intake and not a high fruit intake could be associated with decreased steroid hormone receptor-negative breast cancer risk.

Objective: This study aimed to investigate the association between vegetable and fruit intake and steroid hormone receptor-defined breast cancer risk.

Design: A total of 335,054 female participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort were included in this study (mean ± SD age: 50.8 ± 9.8 y). Vegetable and fruit intake was measured by country-specific questionnaires filled out at recruitment between 1992 and 2000 with the use of standardized procedures. Cox proportional hazards models were stratified by age at recruitment and study center and were adjusted for breast cancer risk factors.

Results: After a median follow-up of 11.5 y (IQR: 10.1-12.3 y), 10,197 incident invasive breast cancers were diagnosed [3479 estrogen and progesterone receptor positive (ER+PR+); 1021 ER and PR negative (ER-PR-)]. Compared with the lowest quintile, the highest quintile of vegetable intake was associated with a lower risk of overall breast cancer (HRquintile 5-quintile 1: 0.87; 95% CI: 0.80, 0.94). Although the inverse association was most apparent for ER-PR- breast cancer (ER-PR-: HRquintile 5-quintile 1: 0.74; 95% CI: 0.57, 0.96; P-trend = 0.03; ER+PR+: HRquintile 5-quintile 1: 0.91; 95% CI: 0.79, 1.05; P-trend = 0.14), the test for heterogeneity by hormone receptor status was not significant (P-heterogeneity = 0.09). Fruit intake was not significantly associated with total and hormone receptor-defined breast cancer risk.

Conclusion: This study supports evidence that a high vegetable intake is associated with lower (mainly hormone receptor-negative) breast cancer risk.
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http://dx.doi.org/10.3945/ajcn.114.101436DOI Listing
January 2016

Geographic variation in volumetric breast density between screening regions in the Netherlands.

Eur Radiol 2015 Nov 3;25(11):3328-37. Epub 2015 Jul 3.

Radboud Institute for Health Sciences (Department for Health Evidence, Mailbox 133), Radboud university medical center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.

Objectives: Differences in breast density between populations may explain part of the variation in regional breast cancer screening performance. This study aimed to determine whether regional differences in breast density distribution are present in the Dutch screening population.

Methods: As part of the DENSE trial, mammographic density was measured using a fully-automated volumetric method. The regions in our study were based on the geographic coverage of 14 reading units representing a large part of the Netherlands. General linear models were used.

Results: Four hundred eighty-five thousand and twenty-one screening participants with a median age of 60 years were included (2013-2014). The proportion of women with heterogeneously or extremely dense breasts ranged from 32.5% to 45.7% between regions. Mean percent dense volume varied between 6.51% (95% confidence interval [CI]: 6.46-6.55) and 7.68% (95% CI: 7.66-7.71). Age differences could not explain the variation. Socio-economic status (SES) was positively associated with volumetric density in all analyses (low SES: 6.95% vs. high SES: 7.63%; p trend  < 0.0001), whereas a potential association between urbanisation and breast density only became apparent after SES adjustment.

Conclusion: There appears to be geographic variation in mammographic density in the Netherlands, emphasizing the importance of including breast density as parameter in the evaluation of screening performance.

Key Points: • Mammographic density may affect regional breast cancer screening performance. • Volumetric breast density varies across screening areas. • SES is positively associated with breast density. • Implications of volumetric breast density differences need to be studied further.
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http://dx.doi.org/10.1007/s00330-015-3742-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4595533PMC
November 2015

MR Imaging as an Additional Screening Modality for the Detection of Breast Cancer in Women Aged 50-75 Years with Extremely Dense Breasts: The DENSE Trial Study Design.

Radiology 2015 Nov 23;277(2):527-37. Epub 2015 Jun 23.

From the Julius Center for Health Sciences and Primary Care (M.J.E., M.F.B., P.H.M.P., E.M.M., C.H.v.G.) and Department of Radiology (R.M.P., M.A.A.J.v.d.B., W.P.Th.M.M., W.B.V.), Stratenum 6.131, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, the Netherlands; Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, London, United Kingdom (P.H.M.P.); Department of Radiology, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands (C.E.L.); Department of Radiology, Radboud University Medical Center, Nijmegen, the Netherlands (R.M.M., N.K.); Department of Radiology, Jeroen Bosch Hospital, 's-Hertogenbosch, the Netherlands (M.D.F.d.J.); Department of Radiology, Albert Schweitzer Hospital, Dordrecht, the Netherlands (R.H.C.B.); Department of Radiology, Hospital Group Twente (ZGT), Almelo and Hengelo, the Netherlands (J.V.); Department of Radiology, VU University Medical Center, Amsterdam, the Netherlands (K.M.D.); Department of Radiology, Maastricht University Medical Center, Maastricht, the Netherlands (M.B.I.L.); Dutch Reference Centre for Screening, Nijmegen, the Netherlands (R.M.P.); and Department of Public Health, Erasmus Medical Center, Rotterdam, the Netherlands (H.J.d.K.).

Women with extremely dense breasts have an increased risk of breast cancer and lower mammographic tumor detectability. Nevertheless, in most countries, these women are currently screened with mammography only. Magnetic resonance (MR) imaging has the potential to improve breast cancer detection at an early stage because of its higher sensitivity. However, MR imaging is more expensive and is expected to be accompanied by an increase in the number of false-positive results and, possibly, an increase in overdiagnosis. To study the additional value of MR imaging, a randomized controlled trial (RCT) design is needed in which one group undergoes mammography and the other group undergoes mammography and MR imaging. With this design, it is possible to determine the proportion of interval cancers within each study arm. For this to be an effective screening strategy, the additional cancers detected at MR imaging screening must be accompanied by a subsequent reduction in interval cancers. The Dense Tissue and Early Breast Neoplasm Screening, or DENSE, trial is a multicenter RCT performed in the Dutch biennial population-based screening program (subject age range, 50-75 years). The study was approved by the Dutch Minister of Health, Welfare and Sport. In this study, mammographic density is measured by using a fully automated volumetric method. Participants with extremely dense breasts (American College of Radiology breast density category 4) and a negative result at mammography (Breast Imaging Recording and Data System category 1 or 2) are randomly assigned to undergo additional MR imaging (n = 7237) or to be treated according to current practice (n = 28 948). Participants provide written informed consent before the MR imaging examination, which consists of dynamic breast MR imaging with gadolinium-based contrast medium and is intended to be performed for three consecutive screening rounds. The primary outcome is the difference in the proportions of interval cancers between the study arms. Secondary outcomes are the number of MR imaging screening-detected cancers, proportions of false-positive results, diagnostic yield of MR imaging, tumor characteristics, quality of life, and cost effectiveness.
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http://dx.doi.org/10.1148/radiol.2015141827DOI Listing
November 2015

A treelet transform analysis to relate nutrient patterns to the risk of hormonal receptor-defined breast cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC).

Public Health Nutr 2016 Feb 23;19(2):242-54. Epub 2015 Feb 23.

31Molecular and Nutritional Epidemiology Unit,Cancer Research and Prevention Institute - ISPO,Florence,Italy.

Objective: Pattern analysis has emerged as a tool to depict the role of multiple nutrients/foods in relation to health outcomes. The present study aimed at extracting nutrient patterns with respect to breast cancer (BC) aetiology.

Design: Nutrient patterns were derived with treelet transform (TT) and related to BC risk. TT was applied to twenty-three log-transformed nutrient densities from dietary questionnaires. Hazard ratios (HR) and 95 % confidence intervals computed using Cox proportional hazards models quantified the association between quintiles of nutrient pattern scores and risk of overall BC, and by hormonal receptor and menopausal status. Principal component analysis was applied for comparison.

Setting: The European Prospective Investigation into Cancer and Nutrition (EPIC).

Subjects: Women (n 334 850) from the EPIC study.

Results: The first TT component (TC1) highlighted a pattern rich in nutrients found in animal foods loading on cholesterol, protein, retinol, vitamins B12 and D, while the second TT component (TC2) reflected a diet rich in β-carotene, riboflavin, thiamin, vitamins C and B6, fibre, Fe, Ca, K, Mg, P and folate. While TC1 was not associated with BC risk, TC2 was inversely associated with BC risk overall (HRQ5 v. Q1=0·89, 95 % CI 0·83, 0·95, P trend<0·01) and showed a significantly lower risk in oestrogen receptor-positive (HRQ5 v. Q1=0·89, 95 % CI 0·81, 0·98, P trend=0·02) and progesterone receptor-positive tumours (HRQ5 v. Q1=0·87, 95 % CI 0·77, 0·98, P trend<0·01).

Conclusions: TT produces readily interpretable sparse components explaining similar amounts of variation as principal component analysis. Our results suggest that participants with a nutrient pattern high in micronutrients found in vegetables, fruits and cereals had a lower risk of BC.
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http://dx.doi.org/10.1017/S1368980015000294DOI Listing
February 2016

Degree of urbanization and mammographic density in Dutch breast cancer screening participants: results from the EPIC-NL cohort.

Breast Cancer Res Treat 2014 Dec 16;148(3):655-63. Epub 2014 Nov 16.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Stratenum 6.131, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands.

It has been observed that women living in urban areas have a higher mammographic density (MD) compared to women living in rural areas. This association might be explained by regional differences in reproductive and lifestyle factors or perhaps by variation in exposure to ambient air pollution as air pollution particles have been described to show estrogenic activity. We investigated the association between degree of urbanization and MD, and aimed to unravel the underlying etiology. 2,543 EPIC-NL participants were studied, and general linear models were used. Urbanization was categorized into five categories according to the number of addresses/km(2). Information on reproductive and lifestyle factors was obtained from the recruitment questionnaire. Air pollution exposure was estimated using land-use regression models. MD was expressed as percent density (PD) and dense area (DA), and was quantified using Cumulus. Women living in extremely urbanized areas had a higher PD (21.4%, 95% confidence interval (CI) 20.5-22.3%) compared to women living in not urbanized areas (16.1, 95% CI 14.5-17.8%, P trend < 0.01).The association persisted after adjustment for reproductive and lifestyle factors as well as for individual exposure to air pollution (adjusted PDextremely_urbanized = 22.1%, 95% CI 18.0-26.5% versus adjusted PDnot_urbanized = 16.9%, 95% CI 13.0-21.2, P trend < 0.01).The results for DA showed close similarity to the results for PD. We found evidence that degree of urbanization is associated with MD. The association could not be explained by differences in reproductive and lifestyle factors or by variation in air pollution exposure.
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http://dx.doi.org/10.1007/s10549-014-3205-2DOI Listing
December 2014

Plasma carotenoids, vitamin C, retinol and tocopherols levels and pancreatic cancer risk within the European Prospective Investigation into Cancer and Nutrition: a nested case-control study: plasma micronutrients and pancreatic cancer risk.

Int J Cancer 2015 Mar 17;136(6):E665-76. Epub 2014 Sep 17.

Department of Gastroenterology and Hepatology, University Medical Center Utrecht, the Netherlands; National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.

Evidence of a protective effect of several antioxidants and other nutrients on pancreatic cancer risk is inconsistent. The aim of this study was to investigate the association for prediagnostic plasma levels of carotenoids, vitamin C, retinol and tocopherols with risk of pancreatic cancer in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). 446 incident exocrine pancreatic cancer cases were matched to 446 controls by age at blood collection, study center, sex, date and time of blood collection, fasting status and hormone use. Plasma carotenoids (α- and β-carotene, lycopene, β-cryptoxanthin, canthaxanthin, zeaxanthin and lutein), α- and γ-tocopherol and retinol were measured by reverse phase high-performance liquid chromatography and plasma vitamin C by a colorimetric assay. Incidence rate ratios (IRRs) with 95% confidence intervals (95%CIs) for pancreatic cancer risk were estimated using a conditional logistic regression analysis, adjusted for smoking status, smoking duration and intensity, waist circumference, cotinine levels and diabetes status. Inverse associations with pancreatic cancer risk were found for plasma β-carotene (IRR highest vs. lowest quartile 0.52, 95%CI 0.31-0.88, p for trend = 0.02), zeaxanthin (IRR highest vs. lowest quartile 0.53, 95%CI 0.30-0.94, p for trend = 0.06) and α-tocopherol (IRR highest vs. lowest quartile 0.62, 95%CI 0.39-0.99, p for trend = 0.08. For α- and β-carotene, lutein, sum of carotenoids and γ-tocopherol, heterogeneity between geographical regions was observed. In conclusion, our results show that higher plasma concentrations of β-carotene, zeaxanthin and α-tocopherol may be inversely associated with risk of pancreatic cancer, but further studies are warranted.
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http://dx.doi.org/10.1002/ijc.29175DOI Listing
March 2015

Mammographic density phenotypes and risk of breast cancer: a meta-analysis.

J Natl Cancer Inst 2014 May 10;106(5). Epub 2014 May 10.

Affiliations of authors: Department of Epidemiology (AP, REG, RMT), and Department of Biostatistics (BAR), Harvard School of Public Health, Boston, MA; Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway (GU); Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA (GU); Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK (IdSS); Section of Environment and Radiation, International Agency for Research on Cancer, Lyon, France (VM); Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia (LB, GGG, KK); Centre for Molecular, Environmental, Genetic and Analytical Epidemiology, University of Melbourne, Melbourne, Australia (LB, GGG, JLH, KK, JS); Division of Epidemiology (CV) and Division of Biomedical Statistics and Informatics (CS), Department of Health Sciences Research, Mayo Clinic, Rochester, MN; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands (MFB, CHvG); Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia (GGG); Saw Swee Hock School of Public Health (KSC, MH, CSW), and Department of Surgery, Yong Loo Lin School of Medicine (MH), National University of Singapore, National University Health System, Singapore, Singapore; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (KC, LE, PH, MH); Department of Radiology, Addenbrooke's Hospital, Cambridge, UK (RMLW); School of Population and Public Health, University of British Columbia, Vancouver, BC , Canada (GH); Prevention and Cancer Control, Cancer Care, Toronto, ON, Canada (AMC); Human Genetics, Genome Institute of Singapore, Singapore, Singapore (JL); Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, ON, Canada (QL, NFB); University of Hawaii Cancer Center, Honolu

Background: Fibroglandular breast tissue appears dense on mammogram, whereas fat appears nondense. It is unclear whether absolute or percentage dense area more strongly predicts breast cancer risk and whether absolute nondense area is independently associated with risk.

Methods: We conducted a meta-analysis of 13 case-control studies providing results from logistic regressions for associations between one standard deviation (SD) increments in mammographic density phenotypes and breast cancer risk. We used random-effects models to calculate pooled odds ratios and 95% confidence intervals (CIs). All tests were two-sided with P less than .05 considered to be statistically significant.

Results: Among premenopausal women (n = 1776 case patients; n = 2834 control subjects), summary odds ratios were 1.37 (95% CI = 1.29 to 1.47) for absolute dense area, 0.78 (95% CI = 0.71 to 0.86) for absolute nondense area, and 1.52 (95% CI = 1.39 to 1.66) for percentage dense area when pooling estimates adjusted for age, body mass index, and parity. Corresponding odds ratios among postmenopausal women (n = 6643 case patients; n = 11187 control subjects) were 1.38 (95% CI = 1.31 to 1.44), 0.79 (95% CI = 0.73 to 0.85), and 1.53 (95% CI = 1.44 to 1.64). After additional adjustment for absolute dense area, associations between absolute nondense area and breast cancer became attenuated or null in several studies and summary odds ratios became 0.82 (95% CI = 0.71 to 0.94; P heterogeneity = .02) for premenopausal and 0.85 (95% CI = 0.75 to 0.96; P heterogeneity < .01) for postmenopausal women.

Conclusions: The results suggest that percentage dense area is a stronger breast cancer risk factor than absolute dense area. Absolute nondense area was inversely associated with breast cancer risk, but it is unclear whether the association is independent of absolute dense area.
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http://dx.doi.org/10.1093/jnci/dju078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568991PMC
May 2014

Weight change in middle adulthood and breast cancer risk in the EPIC-PANACEA study.

Int J Cancer 2014 Dec 16;135(12):2887-99. Epub 2014 May 16.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.

Long-term weight gain (i.e., weight gain since age 20) has been related to higher risk of postmenopausal breast cancer, but a lower risk of premenopausal breast cancer. The effect of weight change in middle adulthood is unclear. We investigated the association between weight change in middle adulthood (i.e., women aged 40-50 years) and the risk of breast cancer before and after the age of 50. We included female participants of the European Prospective Investigation into Cancer and Nutrition cohort, with information on anthropometric measures at recruitment and after a median follow-up of 4.3 years. Annual weight change was categorized using quintiles taking quintile 2 and 3 as the reference category (-0.44 to 0.36 kg/year). Multivariable Cox proportional hazards regression analysis was used to examine the association. 205,723 women were included and 4,663 incident breast cancer cases were diagnosed during a median follow-up of 7.5 years (from second weight assessment onward). High weight gain (Q5: 0.83-4.98 kg/year) was related to a slightly, but significantly higher breast cancer risk (HRQ5_versus_Q2/3 : 1.09, 95% CI: 1.01-1.18). The association was more pronounced for breast cancer diagnosed before or at age 50 (HRQ5_versus_Q2/3 : 1.37, 95% CI: 1.02-1.85). Weight loss was not associated with breast cancer risk. There was no evidence for heterogeneity by hormone receptor status. In conclusion, high weight gain in middle adulthood increases the risk of breast cancer. The association seems to be more pronounced for breast cancer diagnosed before or at age 50. Our results illustrate the importance of avoiding weight gain in middle adulthood.
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http://dx.doi.org/10.1002/ijc.28926DOI Listing
December 2014

Plasma and dietary carotenoids and vitamins A, C and E and risk of colon and rectal cancer in the European Prospective Investigation into Cancer and Nutrition.

Int J Cancer 2014 Dec 14;135(12):2930-9. Epub 2014 May 14.

Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands; Institute for Risk Assessment Sciences, Utrecht University, the Netherlands.

Carotenoids and vitamins A, C and E are possibly associated with a reduced colorectal cancer (CRC) risk through antioxidative properties. The association of prediagnostic plasma concentrations and dietary consumption of carotenoids and vitamins A, C and E with the risk of colon and rectal cancer was examined in this case-control study, nested within the European Prospective Investigation into Cancer and Nutrition study. Plasma concentrations of carotenoids (α- and β-carotene, canthaxanthin, β-cryptoxanthin, lutein, lycopene, zeaxanthin) and vitamins A (retinol), C and E (α-, β- and γ- and δ-tocopherol) and dietary consumption of β-carotene and vitamins A, C and E were determined in 898 colon cancer cases, 501 rectal cancer cases and 1,399 matched controls. Multivariable conditional logistic regression models were performed to estimate incidence rate ratios (IRR) and corresponding 95% confidence intervals (CIs). An association was observed between higher prediagnostic plasma retinol concentration and a lower risk of colon cancer (IRR for highest quartile = 0.63, 95% CI: 0.46, 0.87, p for trend = 0.01), most notably proximal colon cancer (IRR for highest quartile = 0.46, 95% CI: 0.27, 0.77, p for trend = 0.01). Additionally, inverse associations for dietary β-carotene and dietary vitamins C and E with (distal) colon cancer were observed. Although other associations were suggested, there seems little evidence for a role of these selected compounds in preventing CRC through their antioxidative properties.
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http://dx.doi.org/10.1002/ijc.28938DOI Listing
December 2014

Plasma 25-hydroxyvitamin D and the risk of breast cancer in the European prospective investigation into cancer and nutrition: a nested case-control study.

Int J Cancer 2013 Oct 22;133(7):1689-700. Epub 2013 Apr 22.

Division of Cancer Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 581, Heidelberg, Germany.

Experimental evidence suggests that vitamin D might play a role in the development of breast cancer. Although the results of case-control studies indicate that circulating 25-hydroxyvitamin D [25(OH)D] is inversely associated with the risk of breast cancer, the results of prospective studies are inconsistent. A case-control study embedded in the European Prospective Investigation into Cancer and Nutrition (EPIC) was carried out comprising 1,391 incident breast cancer cases and 1,391 controls. Multivariable conditional logistic regression models did not reveal a significant overall association between season-standardized 25(OH)D levels and the risk of breast cancer (ORQ4-Q1 [95% CI]: 1.07 [0.85-1.36], ptrend = 0.67). Moreover, 25(OH)D levels were not related to the risks of estrogen receptor positive tumors (ORQ4-Q1 [95% CI]: 0.97 [0.67-1.38], ptrend = 0.90) and estrogen receptor negative tumors (ORQ4-Q1 [95% CI]: 0.97 [0.66-1.42], ptrend = 0.98). In hormone replacement therapy (HRT) users, 25(OH)D was significantly inversely associated with incident breast cancer (ORlog2 [95% CI]: 0.62 [0.42-0.90], p = 0.01), whereas no significant association was found in HRT nonusers (ORlog2 [95% CI]: 1.14 [0.80-1.62], p = 0.48). Further, a nonsignificant inverse association was found in women with body mass indices (BMI) < 25 kg/m(2) (ORlog2 [95% CI]: 0.83 [0.67-1.03], p = 0.09), as opposed to a borderline significant positive association in women with BMI ≥ 25 kg/m(2) (ORlog2 [95% CI]: 1.30 [1.0-1.69], p = 0.05). Overall, prediagnostic levels of circulating 25(OH)D were not related to the risk of breast cancer in the EPIC study. This result is in line with findings in the majority of prospective studies and does not support a role of vitamin D in the development of breast cancer.
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http://dx.doi.org/10.1002/ijc.28172DOI Listing
October 2013

Dietary fiber intake and risk of hormonal receptor-defined breast cancer in the European Prospective Investigation into Cancer and Nutrition study.

Am J Clin Nutr 2013 Feb 26;97(2):344-53. Epub 2012 Dec 26.

International Agency for Research on Cancer, Lyon, France.

Background: Limited scientific evidence has characterized the association between dietary fiber intake and risk of breast cancer (BC) by menopausal status and hormone receptor expression in tumors.

Objective: We investigated the relation between total dietary fiber and its main food sources (vegetables, fruit, cereals, and legumes) and BC risk by using data from the European Prospective Investigation into Cancer and Nutrition (EPIC).

Design: A total of 11,576 invasive BC cases in 334,849 EPIC women mostly aged 35-70 y at baseline were identified over a median follow-up of 11.5 y. Dietary fiber was estimated from country-specific dietary questionnaires. Multivariable Cox proportional hazards regression models were used to quantify the association between dietary variables and BC risk with energy adjustment by using the residual method. Subgroup analyses were performed by menopausal status and estrogen receptor (ER) and progesterone receptor (PR) expression in tumors.

Results: BC risk was inversely associated with intakes of total dietary fiber [hazard ratio comparing fifth quintile to first quintile (HR(Q5-Q1)): 0.95; 95% CI: 0.89, 1.01; P-trend = 0.03] and fiber from vegetables (0.90; 0.84, 0.96; P-trend < 0.01) but not with fiber from fruit, cereals, or legumes. Overall, associations were homogeneous by menopausal status and ER and PR expression in tumors. For vegetable fiber, stronger associations were observed for estrogen receptor-negative and progesterone receptor-negative (HR(Q5-Q1):0.74; 95% CI: 0.59, 0.93; P-trend = 0.01) than for estrogen receptor-positive and progesterone receptor-positive tumors (0.92: 0.81, 1.03; P-trend = 0.05), with P-heterogeneity = 0.09.

Conclusion: Diets rich in dietary fiber and, particularly, fiber from vegetables may be associated with a small reduction in risk of BC, independently of menopausal status.
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http://dx.doi.org/10.3945/ajcn.112.034025DOI Listing
February 2013

Increase of body mass index in a tight controlled methotrexate-based strategy with prednisone in early rheumatoid arthritis: side effect of the prednisone or better control of disease activity?

Arthritis Care Res (Hoboken) 2013 Jan;65(1):88-93

University Medical Center Utrecht, Utrecht, The Netherlands.

Objective: To clarify whether increase of body weight in patients with early rheumatoid arthritis (RA) upon administration of prednisone is a side effect of prednisone or a result of better control of disease activity, we examined the association of prednisone and disease activity with a subsequent change in body mass index (BMI).

Methods: In the Computer Assisted Management in Early Rheumatoid Arthritis Trial-II, patients ages ≥18 years with early RA (disease duration <1 year and no prior use of disease-modifying antirheumatic drugs) had been randomized to a methotrexate (MTX)-based tight control strategy with either 10 mg of prednisone (MTX + prednisone) or placebo (MTX + placebo). The MTX + prednisone group had lower disease activity, but gained more weight than the MTX + placebo group (mean ± SD 2.9 ± 4.2 kg versus 1.3 ± 5.3 kg; P = 0.03). Data from patients with monthly measurements of disease activity (Disease Activity Score in 28 joints [DAS28]) and BMI were analyzed with a longitudinal regression (mixed model) analysis with BMI as the dependent variable and treatment strategy and DAS28 as the independent variables, correcting for baseline BMI and possible confounders (sex, age, and rheumatoid factor status).

Results: There was no independent association of glucocorticoid therapy with a change in BMI, but a lower DAS28 was associated with an increased BMI 6 months later. The association of the DAS28 with BMI was most strongly present in postmenopausal women. Clinical cutoff points showed a clear association between DAS28 level and the change in BMI 6 months later.

Conclusion: Weight gain during treatment with prednisone seems attributable to a reduction of disease activity and is probably, at least partly, regained weight.
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http://dx.doi.org/10.1002/acr.21797DOI Listing
January 2013

Performance of a multi-biomarker score measuring rheumatoid arthritis disease activity in the CAMERA tight control study.

Ann Rheum Dis 2012 Oct 17;71(10):1692-7. Epub 2012 May 17.

Correspondence to Marije F Bakker, UMC Utrecht, Department of Rheumatology & Clinical Immunology, Utrecht PO BOX 85500, The Netherlands.

Objectives: To evaluate the performance of individual biomarkers and a multi-biomarker disease activity (MBDA) score in the early rheumatoid arthritis (RA) patient population from the computer assisted management in early rheumatoid arthritis (CAMERA) study.

Methods: Twenty biomarkers were measured in the CAMERA cohort, in which patients were treated with either intensive or conventional methotrexate-based treatment strategies. The MBDA score was calculated using the concentrations of 12 biomarkers (SAA, IL-6, TNF-RI, VEGF-A, MMP-1, YKL-40, MMP-3, EGF, VCAM-1, leptin, resistin and CRP) according to a previously trained algorithm. The performance of the scores was evaluated relative to clinical disease activity assessments. Change in MBDA score over time was assessed by paired Wilcoxon rank sum test. Logistic regression was used to evaluate the ability of disease activity measures to predict radiographic progression.

Results: The MBDA score had a significant correlation with the disease activity score based on 28 joints-C reactive protein (DAS28-CRP) (r=0.72; p<0.001) and an area under the receiver operating characteristic curve for distinguishing remission/low from moderate/high disease activity of 0.86 (p<0.001) using a DAS28-CRP cut-off of 2.7. In multivariate analysis the MBDA score, but not CRP, was an independent predictor of disease activity measures. Additionally, mean (SD) MBDA score decreased from 53 (18) at baseline to 39 (16) at 6 months in response to study therapy (p<0.0001). Neither MBDA score nor clinical variables were predictive of radiographic progression.

Conclusions: This multi-biomarker test performed well in the assessment of disease activity in RA patients in the CAMERA study. Upon further validation, this test could be used to complement currently available disease activity measures and improve patient care and outcomes.
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http://dx.doi.org/10.1136/annrheumdis-2011-200963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3439649PMC
October 2012
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