Bragatston study protocol: a multicentre cohort study on automated quantification of cardiovascular calcifications on radiotherapy planning CT scans for cardiovascular risk prediction in patients with breast cancer

Introduction Cardiovascular disease (CVD) is an important cause of death in breast cancer survivors. Some breast cancer treatments including anthracyclines, trastuzumab and radiotherapy can increase the risk of CVD, especially for patients with pre-existing CVD risk factors. Early identification of patients at increased CVD risk may allow switching to less cardiotoxic treatments, active surveillance or treatment of CVD risk factors. One of the strongest independent CVD risk factors is the presence and extent of coronary artery calcifications (CAC). In clinical practice, CAC are generally quantified on ECGtriggered cardiac CT scans. Patients with breast cancer treated with radiotherapy routinely undergo radiotherapy planning CT scans of the chest, and those scans could provide the opportunity to routinely assess CAC before a potentially cardiotoxic treatment. The Bragatston study aims to investigate the association between calcifications in the coronary arteries, aorta and heart valves (hereinafter called ‘cardiovascular calcifications’) measured automatically on planning CT scans of patients with breast cancer and CVD risk. Methods and analysis In a first step, we will optimise and validate a deep learning algorithm for automated quantification of cardiovascular calcifications on planning CT scans of patients with breast cancer. Then, in a multicentre cohort study (University Medical Center Utrecht, Utrecht, Erasmus MC Cancer Institute, Rotterdam and Radboudumc, Nijmegen, The Netherlands), the association between cardiovascular calcifications measured on planning CT scans of patients with breast cancer (n≈16 000) and incident (non-)fatal CVD events will be evaluated. To assess the added predictive value of these calcifications over traditional CVD risk factors and treatment characteristics, a case-cohort analysis will be performed among all cohort members diagnosed with a CVD event during follow-up (n≈200) and a random sample of the baseline cohort (n≈600). Ethics and dissemination The Institutional Review Boards of the participating hospitals decided that the Medical R

Etiology and early detection of breast cancer : Biomarkers, lifestyle and mammographic density

In the Netherlands, one in seven women will develop breast cancer at some point during her lifetime. Although breast cancer mortality has declined, still 23% of the breast cancer patients dies from the disease within 10 years after initial diagnosis. This emphasizes the importance of research on breast cancer prevention and screening. This thesis aims to find clues for primary (part I) and secondary (part II) prevention of breast cancer. To design primary prevention strategies, knowledge on the etiology is required. In part I, studies on the association between estrogen metabolites, lifestyle factors and (subtype-defined) breast cancer risk are described. We observe that high urinary estrogen and estrogen metabolite concentrations are associated with higher postmenopausal breast cancer risk. Besides on the exploration of the underlying pathway, this thesis zooms in on the effects of weight changes later in life and the consumption of vegetables and fruits on subtype-defined breast cancer risk. We observe that high vegetable intake is associated with lower overall breast cancer risk. The inverse association is most apparent for hormone receptor-negative breast cancer. Furthermore, we find evidence that a high weight gain in middle adulthood is associated with slightly higher breast cancer risk. The association seems to be more pronounced for breast cancer diagnosed before age 50. In part II, we focus on the early detection of breast cancer within the scope of the national population-based screening program. In the Netherlands, women between the ages of 50 and 75 years are screened for breast cancer every two years using mammography. In women with high mammographic density (i.e. high amount of fibroglandular tissue and low amount of fat tissue in the breast) the sensitivity of mammography is reduced and these women have a higher breast cancer risk. This dual effect makes mammographic density a promising key determinant in the evaluation and personalization of the national screening program. In this thesis, we investigate whether regional variation in mammographic density is present within the population-based screening program. We find evidence that women living in urban areas have a higher mammographic density compared to women living in nonurbanized areas. As we observe regional variation in mammographic density, we conclude that mammographic density is an important parameter to incorporate into the evaluation of screening performance. Furthermore, this thesis describes the rationale and design of the DENSE trial. The DENSE trial is a multicenter parallel-group randomized trial that investigates the (cost-)effectiveness of screening with mammography and MRI, compared to mammography alone in Dutch breast cancer screening participants with extremely dense breasts. In conclusion, the results of part I underline that nutrition, weight and hormones play a role in the etiology of breast cancer. It is important to take tumor subtype into account when studying (the etiology of) breast cancer. Based on part II, we advise to incorporate mammographic density as a parameter for monitoring the quality of the national screening program. The question whether screening participants with extremely dense breasts benefit from additional screening with MRI will be answered in the coming years

Etiology and early detection of breast cancer : Biomarkers, lifestyle and mammographic density

In the Netherlands, one in seven women will develop breast cancer at some point during her lifetime. Although breast cancer mortality has declined, still 23% of the breast cancer patients dies from the disease within 10 years after initial diagnosis. This emphasizes the importance of research on breast cancer prevention and screening. This thesis aims to find clues for primary (part I) and secondary (part II) prevention of breast cancer. To design primary prevention strategies, knowledge on the etiology is required. In part I, studies on the association between estrogen metabolites, lifestyle factors and (subtype-defined) breast cancer risk are described. We observe that high urinary estrogen and estrogen metabolite concentrations are associated with higher postmenopausal breast cancer risk. Besides on the exploration of the underlying pathway, this thesis zooms in on the effects of weight changes later in life and the consumption of vegetables and fruits on subtype-defined breast cancer risk. We observe that high vegetable intake is associated with lower overall breast cancer risk. The inverse association is most apparent for hormone receptor-negative breast cancer. Furthermore, we find evidence that a high weight gain in middle adulthood is associated with slightly higher breast cancer risk. The association seems to be more pronounced for breast cancer diagnosed before age 50. In part II, we focus on the early detection of breast cancer within the scope of the national population-based screening program. In the Netherlands, women between the ages of 50 and 75 years are screened for breast cancer every two years using mammography. In women with high mammographic density (i.e. high amount of fibroglandular tissue and low amount of fat tissue in the breast) the sensitivity of mammography is reduced and these women have a higher breast cancer risk. This dual effect makes mammographic density a promising key determinant in the evaluation and personalization of the national screening program. In this thesis, we investigate whether regional variation in mammographic density is present within the population-based screening program. We find evidence that women living in urban areas have a higher mammographic density compared to women living in nonurbanized areas. As we observe regional variation in mammographic density, we conclude that mammographic density is an important parameter to incorporate into the evaluation of screening performance. Furthermore, this thesis describes the rationale and design of the DENSE trial. The DENSE trial is a multicenter parallel-group randomized trial that investigates the (cost-)effectiveness of screening with mammography and MRI, compared to mammography alone in Dutch breast cancer screening participants with extremely dense breasts. In conclusion, the results of part I underline that nutrition, weight and hormones play a role in the etiology of breast cancer. It is important to take tumor subtype into account when studying (the etiology of) breast cancer. Based on part II, we advise to incorporate mammographic density as a parameter for monitoring the quality of the national screening program. The question whether screening participants with extremely dense breasts benefit from additional screening with MRI will be answered in the coming years

Risk of death from cardiovascular disease following breast cancer: a systematic review

10.1007/s10549-017-4282-9Breast Cancer Research and Treatment1643537-555BCTR

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

Contains fulltext : 152266.pdf (publisher's version ) (Open Access)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

Coronary artery calcifications on breast cancer radiotherapy planning CT scans and cardiovascular risk: What do patients want to know?

Background: Coronary artery calcifications (CAC) is a strong predictor of cardiovascular disease (CVD), which can be automatically quantified on routine breast radiotherapy planning computed tomography (CT) scans. Around 8% of patients have (very) high CAC scores and corresponding increased risks of CVD. Aim: This study explores whether, how, and under what conditions women with breast cancer want to be informed about their CAC-based CVD risk. Methods: A cross-sectional survey study was conducted in a random sample of UMBRELLA, a prospective breast cancer cohort. Participants (n = 79) filled out a questionnaire about their knowledge on the CVD risk following breast cancer, their interest in being informed about their CVD risk based on CAC score, and preferences on how they would want to receive this information. Results: Most participants (66%) were not aware that the presence of CAC indicates an increased CVD risk. Participants indicated that they were not or only slightly aware of the risk of treatment-induced cardiotoxicity (48%), and that the risk of cardiotoxicity was higher in patients with pre-existing CVD risk factors (82%). The vast majority (90%) indicated that they want to be informed about in increased CAC-based CVD risk. Conclusions: The majority of patients with breast cancer wants to be informed about their CAC-based CVD risk. With the majority of patients with breast cancer undergoing radiotherapy, and with low cost and automated options for accurate CAC measurement in planning CT scans, it is important to develop strategies to manage patients with an increased CAC-based risk of CVD

Bragatston study protocol: a multicentre cohort study on automated quantification of cardiovascular calcifications on radiotherapy planning CT scans for cardiovascular risk prediction in patients with breast cancer

Contains fulltext : 208554.pdf (publisher's version ) (Open Access)INTRODUCTION: Cardiovascular disease (CVD) is an important cause of death in breast cancer survivors. Some breast cancer treatments including anthracyclines, trastuzumab and radiotherapy can increase the risk of CVD, especially for patients with pre-existing CVD risk factors. Early identification of patients at increased CVD risk may allow switching to less cardiotoxic treatments, active surveillance or treatment of CVD risk factors. One of the strongest independent CVD risk factors is the presence and extent of coronary artery calcifications (CAC). In clinical practice, CAC are generally quantified on ECG-triggered cardiac CT scans. Patients with breast cancer treated with radiotherapy routinely undergo radiotherapy planning CT scans of the chest, and those scans could provide the opportunity to routinely assess CAC before a potentially cardiotoxic treatment. The Bragatston study aims to investigate the association between calcifications in the coronary arteries, aorta and heart valves (hereinafter called 'cardiovascular calcifications') measured automatically on planning CT scans of patients with breast cancer and CVD risk. METHODS AND ANALYSIS: In a first step, we will optimise and validate a deep learning algorithm for automated quantification of cardiovascular calcifications on planning CT scans of patients with breast cancer. Then, in a multicentre cohort study (University Medical Center Utrecht, Utrecht, Erasmus MC Cancer Institute, Rotterdam and Radboudumc, Nijmegen, The Netherlands), the association between cardiovascular calcifications measured on planning CT scans of patients with breast cancer (n approximately 16 000) and incident (non-)fatal CVD events will be evaluated. To assess the added predictive value of these calcifications over traditional CVD risk factors and treatment characteristics, a case-cohort analysis will be performed among all cohort members diagnosed with a CVD event during follow-up (n approximately 200) and a random sample of the baseline cohort (n approximately 600). ETHICS AND DISSEMINATION: The Institutional Review Boards of the participating hospitals decided that the Medical Research Involving Human Subjects Act does not apply. Findings will be published in peer-reviewed journals and presented at conferences. TRIAL REGISTRATION NUMBER: NCT03206333

Identification of Risk of Cardiovascular Disease by Automatic Quantification of Coronary Artery Calcifications on Radiotherapy Planning CT Scans in Patients With Breast Cancer

Importance: Cardiovascular disease (CVD) is common in patients treated for breast cancer, especially in patients treated with systemic treatment and radiotherapy and in those with preexisting CVD risk factors. Coronary artery calcium (CAC), a strong independent CVD risk factor, can be automatically quantified on radiotherapy planning computed tomography (CT) scans and may help identify patients at increased CVD risk. Objective: To evaluate the association of CAC with CVD and coronary artery disease (CAD) in patients with breast cancer. Design, Setting, and Participants: In this multicenter cohort study of 15915 patients with breast cancer receiving radiotherapy between 2005 and 2016 who were followed until December 31, 2018, age, calendar year, and treatment-adjusted Cox proportional hazard models were used to evaluate the association of CAC with CVD and CAD. Exposures: Overall CAC scores were automatically extracted from planning CT scans using a deep learning algorithm. Patients were classified into Agatston risk categories (0, 1-10, 11-100, 101-399, >400 units). Main Outcomes and Measures: Occurrence of fatal and nonfatal CVD and CAD were obtained from national registries. Results: Of the 15915 participants included in this study, the mean (SD) age at CT scan was 59.0 (11.2; range, 22-95) years, and 15879 (99.8%) were women. Seventy percent (n = 11179) had no CAC. Coronary artery calcium scores of 1 to 10, 11 to 100, 101 to 400, and greater than 400 were present in 10.0% (n = 1584), 11.5% (n = 1825), 5.2% (n = 830), and 3.1% (n = 497) respectively. After a median follow-up of 51.2 months, CVD risks increased from 5.2% in patients with no CAC to 28.2% in patients with CAC scores higher than 400. After adjustment, CVD risk increased with higher CAC score (hazard ratio [HR]CAC = 1-10 = 1.1; 95% CI, 0.9-1.4; HRCAC = 11-100 = 1.8; 95% CI, 1.5-2.1; HRCAC = 101-400 = 2.1; 95% CI, 1.7-2.6; and HRCAC>400 = 3.4; 95% CI, 2.8-4.2). Coronary artery calcium was particularly strongly associated with CAD (HRCAC>400 = 7.8; 95% CI, 5.5-11.2). The association between CAC and CVD was strongest in patients treated with anthracyclines (HRCAC>400 = 5.8; 95% CI, 3.0-11.4) and patients who received a radiation boost (HRCAC>400 = 6.1; 95% CI, 3.8-9.7). Conclusions and Relevance: This cohort study found that coronary artery calcium on breast cancer radiotherapy planning CT scan results was associated with CVD, especially CAD. Automated CAC scoring on radiotherapy planning CT scans may be used as a fast and low-cost tool to identify patients with breast cancer at increased risk of CVD, allowing implementing CVD risk-mitigating strategies with the aim to reduce the risk of CVD burden after breast cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT03206333

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

Item does not contain fulltextWomen 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. ((c)) RSNA, 2015