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Purpose: Breast cancer (BC) treatment can induce adverse events, such as cardiovascular disease (CVD). Defective DNA repair, as in carriers of BRCA1/2 pathogenic variants (BRCA1/2pv), may contribute to CVD risk. We aimed to study if female BRCA1/2pv carriers are more sensitive to develop CVD after BC treatment than BC patients without a known BRCA1/2pv., Methods: In a hospital-based cohort of 17,300 female BC patients, we identified 509 BRCA1/2pv carriers. Cardiovascular morbidity and mortality were assessed through hospital charts and general practitioner questionnaires. We performed Cox regression analyses comparing BRCA1/2pv carriers with all other BC patients, adjusting for age, radiotherapy regimen, chemotherapy regimen, and smoking status., Results: Median follow-up time since BC treatment was 14 years. In total, 1108 women experienced ischemic heart disease (IHD), of whom 20 (1.8%) were BRCA1/2pv carriers. Heart failure (HF) was diagnosed in 638 women, of whom 10 (1.6%) were BRCA1/2pv carriers. BRCA1/2pv carriership was associated with a slight not statistically significant increase of IHD (adjHR 1.51, 95%CI 0.93; 2.42), but not with risk of HF (adjHR 0.86, 95%CI 0.44; 1.69). The association between radiotherapy and IHD risk was not significantly different between BRCA1/2pv carriers [HR 2.30 (95%CI 0.79; 6.66)] and other BC patients (HR 1.50, 95%CI 1.30; 1.73). Associations between anthracycline-based chemotherapy and HF risk also did not differ between carriers and other BC patients (HRs of 4.02 (95%CI 1.02; 15.77) and 2.31 (95%CI 1.77; 3.01), respectively)., Conclusions: In BRCA1/2pv BC patients, we found no evidence for a higher risk of BC treatment-related CVD than in other BC patients., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Purpose: The COVID-19 pandemic resulted in an accelerated recommendation to use five-fraction radiotherapy schedules, according to the FAST- and FAST-Forward trial. In this study, trends in the use of different radiotherapy schedules in the Netherlands were studied, as well as the likelihood of receiving five fractions., Materials and Methods: Data from the NABON Breast Cancer Audit-Radiotherapy and Netherlands Cancer Registry was used. Women receiving radiotherapy for their primary invasive breast cancer or DCIS between 01-01-2020 and 31-12-2021 were included. Logistic regression was used to investigate the association between patient-, tumour-, treatment-, and radiotherapy institution-related characteristics and the likelihood of receiving five fractions in tumours meeting the FAST and FAST-Forward criteria., Results: Detailed information about radiotherapy treatment was available for 9,392 tumours. Shortly after the start of the COVID-19 pandemic, i.e. April 2020, 19% of the tumours being treated with radiotherapy received five fractions of 5.2 or 5.7 Gray (Gy). While only 3% of the tumours received five fractions in March 2020. The usage of five fractions increased to 26% in December 2021. Partial breast irradiation, compared to whole breast irradiation, was significantly associated with the administration of five fractions, as well as radiotherapy delivered in an academic radiotherapy institution compared to an independent institution., Conclusion: The start of the COVID-19 pandemic was associated with the early use of ultra-hypofractionated radiotherapy schedules. After publication of the trials, and mainly after the recommendation by the national radiotherapy society, the implementation further increased. These schedules were not yet used in all patients meeting the eligibility criteria for the FAST- or FAST-Forward trial., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Background and Purpose: To evaluate the performance of automated surface-guided gating for left-sided breast cancer with DIBH and VMAT., Materials and Methods: Patients treated in the first year after introduction of DIBH with VMAT were retrospectively considered for analysis. With automated surface-guided gating the beam automatically switches on/off, if the surface region of interest moved in/out the gating tolerance (±3 mm, ±3°). Patients were coached to hold their breath as long as comfortably possible. Depending on the patient's preference, patients received audio instructions during treatment delivery. Real-time positional variations of the breast/chest wall surface with respect to the reference surface were collected, for all three orthogonal directions. The durations and number of DIBHs needed to complete dose delivery, and DIBH position variations were determined. To evaluate an optimal gating window threshold, smaller tolerances of ±2.5 mm, ±2.0 mm, and ±1.5 mm were simulated., Results: 525 fractions from 33 patients showed that median DIBH duration was 51 s (range: 30-121 s), and median 4 DIBHs per fraction were needed to complete VMAT dose delivery. Median intra-DIBH stability and intrafractional DIBH reproducibility approximated 1.0 mm in each direction. No large differences were found between patients who preferred to perform the DIBH procedure with (n = 21) and without audio-coaching (n = 12). Simulations demonstrated that gating window tolerances could be reduced from ±3.0 mm to ±2.0 mm, without affecting beam-on status., Conclusion: Independent of the use of audio-coaching, this study demonstrates that automated surface-guided gating with DIBH and VMAT proved highly efficient. Patients' DIBH performance far exceeded our expectations compared to earlier experiences and literature. Furthermore, gating window tolerances could be reduced., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Radiation-induced secondary breast cancer (BC) may be a concern after radiation therapy (RT) for primary breast cancer (PBC), especially in young patients with germline (g)BRCA-associated BC who already have high contralateral BC (CBC) risk and potentially increased genetic susceptibility to radiation. We sought to investigate whether adjuvant RT for PBC increases the risk of CBC in patients with gBRCA1/2-associated BC., Methods: The gBRCA1/2 pathogenic variant carriers diagnosed with PBC were selected from the prospective International BRCA1/2 Carrier Cohort Study. We used multivariable Cox proportional hazards models to investigate the association between RT (yes vs no) and CBC risk. We further stratified for BRCA status and age at PBC diagnosis (<40 and >40 years). Statistical significance tests were 2-sided., Results: Of 3602 eligible patients, 2297 (64%) received adjuvant RT. Median follow-up was 9.6 years. The RT group had more patients with stage III PBC than the non-RT group (15% vs 3%, P < .001), received chemotherapy more often (81% vs 70%, P < .001), and received endocrine therapy more often (50% vs 35%, P < .001). The RT group had an increased CBC risk compared with the non-RT group (adjusted hazard ratio [HR] = 1.44; 95% confidence interval [CI] = 1.12 to 1.86). Statistical significance was observed in gBRCA2 (HR = 1.77; 95% CI = 1.13 to 2.77) but not in gBRCA1 pathogenic variant carriers (HR = 1.29; 95% CI = 0.93 to 1.77; P = .39 for interaction). In the combined gBRCA1/2 group, patients irradiated when they were younger than or older than 40 years of age at PBC diagnosis showed similar risks (HR = 1.38; 95% CI = 0.93 to 2.04 and HR = 1.56; 95% CI = 1.11 to 2.19, respectively)., Conclusions: RT regimens minimizing contralateral breast dose should be considered in gBRCA1/2 pathogenic variant carriers., (© The Author(s) 2023. Published by Oxford University Press.)

Breast cancer survival is significantly improved over the past decades due to major improvements in anti-tumor therapies and the implementation of regular screening, which leads to early detection of breast cancer. Therefore, it is of utmost importance to prevent patients from long-term side effects, including radiotherapy-induced cardiotoxicity. Radiotherapy may contribute to damage of myocardial structures on the cellular level, which eventually could result in various types of cardiovascular problems, including coronary artery disease and (non-)ischemic cardiomyopathy, leading to heart failure. These cardiac complications of radiotherapy are preceded by alterations in myocardial perfusion and blood flow. Therefore, early detection of these alterations is important to prevent the progression of these pathophysiological processes. Several radionuclide imaging techniques may contribute to the early detection of these changes. Single-Photon Emission Computed Tomography (SPECT) cameras can be used to create Multigated Acquisition scans in order to assess the left ventricular systolic and diastolic function. Furthermore, SPECT cameras are used for myocardial perfusion imaging with radiopharmaceuticals such as 99m Tc-sestamibi and 99m Tc-tetrofosmin. Accurate quantitative measurement of myocardial blood flow (MBF), can be performed by Positron Emission Tomography (PET), as the uptake of some of the tracers used for PET-based MBF measurement almost creates a linear relationship with MBF, resulting in very accurate blood flow quantification. Furthermore, there are PET and SPECT tracers that can assess inflammation and denervation of the cardiac sympathetic nervous system. Research over the past decades has mainly focused on the long-term development of left ventricular impairment and perfusion defects. Considering laterality of the breast cancer, some early studies have shown that women irradiated for left-sided breast cancer are more prone to cardiotoxic side effects than women irradiated for right-sided breast cancer. The left-sided radiation field in these trials, which predominantly used older radiotherapy techniques without heart-sparing techniques, included a larger volume of the heart and left ventricle, leading to increased unavoidable radiation exposure to the heart due to the close proximity of the radiation treatment volume. Although radiotherapy for breast cancer exposes the heart to incidental radiation, several improvements and technical developments over the last decades resulted in continuous reduction of radiation dose and volume exposure to the heart. In addition, radiotherapy reduces loco-regional tumor recurrences and death from breast cancer and improves survival. Therefore, in the majority of patients, the benefits of radiotherapy outweigh the potential very low risk of cardiovascular adverse events after radiotherapy. This review addresses existing nuclear imaging techniques, which can be used to evaluate (long-term) effects of radiotherapy-induced mechanical cardiac dysfunction and discusses the potential use of more novel nuclear imaging techniques, which are promising in the assessment of early signs of cardiac dysfunction in selected irradiated breast cancer patients., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Proton therapy is a radiation technique that yields less dose in normal tissues than photon therapy. In the Netherlands, proton therapy is reimbursed if the reduced dose to normal tissues is predicted to translate into a prespecified reduction in toxicity, based on nationally approved validated models. The aim of this paper is to present the development of a national indication protocol for proton therapy (NIPP) for model-based selection of breast cancer patients and to report on first clinical experiences., Materials and Methods: A national proton therapy working group for breast cancer (PWG-BC) screened the literature for prognostic models able to estimate the individual risk of specific radiation-induced side-effects. After critical appraisal and selection of suitable models, a NIPP for breast cancer was written and subjected to comments by all stakeholders. The approved NIPP was subsequently introduced to select breast cancer patients who would benefit most from proton therapy., Results: The model of Darby et al. (N Engl J Med 2013; 368:987-82) was the only model fulfilling the criteria prespecified by the PWG-BC. The model estimates the relative risk of an acute coronary event (ACE) based on the mean heart dose. The absolute lifetime risk of ACE <80 years was calculated by applying this model to the Dutch absolute incidence of ACE for female and male patients, between 40 and 70 years at breast cancer radiotherapy, with/without cardiovascular risk factors. The NIPP was approved for reimbursement in January 2019. Based on a threshold value of a 2% absolute lower risk on ACE for proton therapy compared with photons, 268 breast cancer patients have been treated in the Netherlands with proton therapy between February 2019 and January 2021., Conclusion: The NIPP includes a model that allows the estimation of the absolute risk on ACE <80 years based on mean heart dose. In the first 2 years, 268 breast cancer patients have been treated with proton therapy in The Netherlands., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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 15 915 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 15 915 participants included in this study, the mean (SD) age at CT scan was 59.0 (11.2; range, 22-95) years, and 15 879 (99.8%) were women. Seventy percent (n = 11 179) 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.

Purpose: To investigate the dosimetric impact of breathing motion on robustly optimized proton therapy treatment plans for left-sided breast cancer patients with an indication for locoregional irradiation., Materials and Methods: Clinical Target Volumes (CTVs) (left-sided breast, level 1 to 4 axillary lymph nodes, interpectoral and internal mammary lymph node regions) and organs at risk were delineated on 4 D-CTs of ten female patients. After treatment planning to a prescribed dose of 40.05 Gy(RBE) in 15 fractions on the time-averaged CT, the dose was calculated on all ten phases of the breathing cycle. Robustness to setup (5 mm) and range errors (3%) was evaluated for those ten phases. Correlations were evaluated between the phases of the breathing cycle and the D98% of the CTV and the D mean of the heart., Results: Correlations coefficients were between -0.12 and 0.29. At the most extreme values of the 28 robustness scenarios, the clinical goals were met for all but two patients. The mean heart dose was 0.41 Gy(RBE) with a standard deviation of 0.31 Gy(RBE) of proton therapy plans., Conclusion: The effect of breathing motion on the robustness of proton therapy treatment plans for this patient group is minor and not of clinical significance. Based on this patient group, a deep-inspiration breath hold seems to be unnecessary to improve robustness for these patients.

Background and Aim: Patient decision aids for oncological treatment options, provide information on the effect on recurrence rates and/or survival benefit, and on side-effects and/or burden of different treatment options. However, often uncertainty exists around the probability estimates for recurrence/survival and side-effects which is too relevant to be ignored. Evidence is lacking on the best way to communicate these uncertainties. The aim of this study is to develop a method to incorporate uncertainties in a patient decision aid for breast cancer patients to support their decision on radiotherapy., Methods: Firstly, qualitative interviews were held with patients and health care professionals. Secondly, in the development phase, thinking aloud sessions were organized with four patients and 12 health care professionals, individual and group-wise., Results: Consensus was reached on a pictograph illustrating the whole range of uncertainty for local recurrence risks, in combination with textual explanation that a more exact personalized risk would be given by their own physician. The pictograph consisted of 100 female icons in a 10 x 10 array. Icons with a stepwise gradient color indicated the uncertainty margin. The prevalence and severity of possible side-effects were explained using verbal labels., Conclusions: We developed a novel way of visualizing uncertainties in recurrence rates in a patient decision aid. The effect of this way of communicating risk uncertainty is currently being tested in the BRASA study (NCT03375801)., Competing Interests: Declaration of competing interest All authors declare to have no conflict of interest., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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≈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 Research Involving Human Subjects Act does not apply. Findings will be published in peer-reviewed journals and presented at conferences., Trial Registration Number: NCT03206333., Competing Interests: Competing interests: II: disclosures not related to the present article: II received research grants from 1) PIE Medical Imaging BV; 2) the Netherlands Organization for Health Research and Development (ZonMw) with participation of PIE Medical Imaging BV; 3) the Dutch Technology Foundation (STW) within Deep Learning for Medical Image Analysis (DLMedIA) with participation of PIE Medical Imaging BV and Philips Healthcare; 4) Dutch Technology Foundation (STW) with participation of PIE Medical Imaging BV and 3mensio Medical Imaging. In addition, II has a patent, US Patent Application Number 15/933854, with royalties paid and she is scientific founder and a shareholder of Quantib-U BV. JP: disclosures not related to the present article: JP received grants from 1) Accuray, Sunnyvale, California, USA; 2) Elekta AB,Stockholm, Sweden., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: After the diagnosis and treatment of disease, a major barrier to research on psychosexual functioning is the lack of a consistent estimate for the prevalence of female sexual dysfunction in the general population., Aim: To clarify the prevalence of age-related female sexual functioning in the general population., Methods: A sample was compiled by random selection of women from the general population in the northern part of the Netherlands and was categorized by age. Women completed the Female Sexual Function Index (FSFI), personal medical items and daily activities, the Body Image Scale, the SF-36 Health Survey, the Hospital Anxiety and Depression Scale, and the Multidimensional Fatigue Inventory. Participants' representativeness was assessed by comparing their characteristics with data from the Dutch Central Agency for Statistics and the Dutch Health Monitor. General health, fatigue, and well-being were compared with national or international data., Outcomes: Age-related total and domain scores of the FSFI., Results: We evaluated female sexual functioning of 521 sexually active women. For women 20 to 80 years old, sexual functioning showed wide variance and was poor in 28% of all sexually active women, with FSFI scores being below the defined clinical cutoff (FSFI score < 26.55). Although sexual activity and functioning significantly decreased with increasing age, sexual satisfaction decreased only non-significantly., Clinical Implications: This study provides valuable age-specific ranges for female sexual functioning in the general population and can inform upcoming clinical studies., Strengths and Limitations: This is the largest study on female sexual function in a representative Dutch population using internationally validated tools and described by age categories, providing valuable information that can help in the understanding of how female sexual function changes with age. The FSFI has been criticized for not assessing personal distress related to sexual problems, so the lack of the Female Sexual Distress Scale in our study is an unfortunate shortcoming. The high rate of sexual inactivity (31%) resulted in fewer women being available to evaluate sexual functioning, but this could reflect the actual level of sexual (in)activity among women in a general population., Conclusion: FSFI total and domain scores showed wide variation across all age categories, but overall, one in four sexually active women scored below the diagnostic cutoff score. Sexual activity and functioning also decreased with age, whereas sexual satisfaction decreased only slightly. Lammerink EAG, de Bock GH, Pascal A, et al. A Survey of Female Sexual Functioning in the General Dutch Population. J Sex Med 2017;42:937-949., (Copyright © 2017. Published by Elsevier Inc.)