Early Development of Atherosclerotic Plaques in the Coronary Arteries after Radiotherapy for Breast Cancer (BACCARAT Study).

Background-Radiotherapy (RT) for breast cancer (BC) can lead to an increased risk of coronary artery disease several years after RT. The aim of this study was to evaluate the development of overall, non-calcified and calcified atherosclerotic plaques over 2 years after BC for RT and associations with cardiac exposure. Methods-The study included 101 left- or right-sided BC patients treated with RT without chemotherapy. A coronary CT angiography was performed before and 2 years after RT. Plaque development thorough the entire coronary network was defined as an increased number of plaques. Cardiac exposure was quantified with mean doses to the heart, left ventricle, and coronary arteries. Logistic regression models were used to assess association with doses. Results-At inclusion, 37% of patients had plaques, increasing to 42% two years after RT. Overall plaque development was observed in seven patients: five with calcified plaque development and four with non-calcified plaque development. The risk of overall plaque development was significantly associated with doses to the Left Main and Circumflex coronary arteries (OR at 1 Gy = 2.32, p = 0.03 and OR at 1 Gy = 2.27, p = 0.03, respectively). Specific analyses for calcified and non-calcified plaque development showed similar results. Conclusion-Our study suggests an association between coronary arteries exposure and the risk of developing both calcified and non-calcified atherosclerotic plaques over 2 years after BC RT. Trial registration number: NCT02605512.

Early Coronary Artery Calcification Progression over Two Years in Breast Cancer Patients Treated with Radiation Therapy: Association with Cardiac Exposure (BACCARAT Study).

Background: Radiotherapy (RT) for breast cancer (BC) can induce coronary artery disease many years after RT. At an earlier stage, during the first two years after RT, we aimed to evaluate the occurrence of increased coronary artery calcium (CAC) and its association with cardiac exposure. Methods: This prospective study included 101 BC patients treated with RT without chemotherapy. Based on CAC CT scans performed before and two years after RT, the event 'CAC progression' was defined by an increase in overall CAC score (CAC RT+ two years­CAC before RT > 0). Dosimetry was evaluated for whole heart, left ventricle (LV), and coronary arteries. Multivariable logistic regression models were used to assess association with doses. Results: Two years after RT, 28 patients presented the event 'CAC progression', explained in 93% of cases by a higher CAC score in the left anterior descending coronary (LAD). A dose−response relationship was observed with LV exposure (for Dmean LV: OR = 1.15, p = 0.04). LAD exposure marginally explained increased CAC in the LAD (for D2 LV: OR =1.03, p = 0.07). Conclusion: The risk of early CAC progression may be associated with LV exposure. This progression might primarily be a consequence of CAC increase in the LAD and its exposure.

Association Between Cardiac Radiation Exposure and the Risk of Arrhythmia in Breast Cancer Patients Treated With Radiotherapy: A Case-Control Study.

Background: Previous studies suggested that radiation therapy (RT) for breast cancer (BC) can induce cardiac arrhythmias and conduction disorders. However, the association with mean heart dose and specific cardiac substructures doses was less studied. Materials and Methods: We conducted a nested case-control study based on French BC patients, enrolled in the European MEDIRAD-BRACE study (https://clinicaltrials.gov, Identifier: NCT03211442), who underwent three-dimensional conformal radiation therapy (3D-CRT) between 2009 and 2013 and were retrospectively followed until 2019. Cases were incident cases of cardiac arrhythmia. Controls without arrhythmia were selected with propensity-scored matching by age, duration of follow-up, chemotherapy, hypertension, and diabetes (ratio 1:4 or 5). Doses to the whole heart (WH), left and right atria (LA and RA), and left and right ventricles (LV and RV) were obtained after delineation with multi-atlas-based automatic segmentation. Results: The study included 116 patients (21 cases and 95 controls). Mean age at RT was 64 ± 10 years, mean follow-up was 7.0 ± 1.3 years, and mean interval from RT to arrhythmia was 4.3 ± 2.1 years. None of the results on association between arrhythmia and cardiac doses reached statistical significance. However, the proportion of right-sided BC was higher among patients with arrhythmia than among controls (57% vs. 51%, OR = 1.18, p = 0.73). Neither mean WH dose, nor LV, RV, and LA doses were associated with an increased risk of arrhythmia (OR = 1.00, p > 0.90). In contrast, the RA dose was slightly higher for cases compared to controls [interquartile range (0.61-1.46 Gy) vs. (0.49-1.31 Gy), p = 0.44], and a non-significant trend toward a potentially higher risk of arrhythmia with increasing RA dose was observed (OR = 1.19, p = 0.60). Subanalysis according to BC laterality showed that the association with RA dose was reinforced specifically for left-sided BC (OR = 1.76, p = 0.75), while for right-sided BC, the ratio of mean RA/WH doses may better predict arrhythmia (OR = 2.39, p = 0.35). Conclusion: Despite non-significant results, our exploratory investigation on BC patients treated with RT is the first study to suggest that right-sided BC patients and the right atrium irradiation may require special attention regarding the risk of cardiac arrhythmia and conduction disorders. Further studies are needed to expand on this topic.

Myocardial deformation after radiotherapy: a layer-specific and territorial longitudinal strain analysis in a cohort of left-sided breast cancer patients (BACCARAT study).

BACKGROUND: Radiotherapy for breast cancer (BC) and its resulting cardiac exposure are associated with subclinical left ventricular dysfunction characterized by early decrease of global longitudinal strain (LS) measurement based on 2D speckle-tracking echocardiography. Recent software allows multi-layer and segmental analysis of strain, which may be of interest to quantify and locate the impact of cardiac exposure on myocardial function and potentially increase the early detection of radiation-induced cardiotoxicity. The aim of the study was to evaluate whether decrease in LS 6 months after radiotherapy is layer-specific and if it varies according to the left ventricular regional level and the coronary arterial territories. METHODS: LS was measured at baseline before radiotherapy and 6 months post-radiotherapy. The LS was obtained for each myocardial layer (endocardial, mid-myocardial, epicardial), left ventricular regional level (basal, mid, apical) and coronary artery territory (left anterior descending artery (LAD), circumflex artery, right coronary artery). RESULTS: The study included 64 left-sided BC patients. Mean age was 58 years, mean doses to the heart, the left ventricle and the LAD were respectively 3.0, 6.7 and 16.4 Gy. The absolute decrease of LS was significant for the three layers (endocardial: - 20.0 ± 3.2% to - 18.8 ± 3.8%; mid-myocardial: - 16.0 ± 2.7% to - 15.0 ± 3.1%; epicardial: - 12.3 ± 2.5% to - 11.4 ± 2.8%, all p = 0.02), but only the relative decrease of LS in the endocardial layer was close to be significant (- 4.7%, p = 0.05). More precisely, the LS of the endocardial layer was significantly decreased for the most exposed parts of the left ventricle corresponding to the apical level (- 26.3 ± 6.0% vs. -24.2 ± 7.1%, p = 0.03) and LAD territory (- 22.8 ± 4.0% vs. -21.4 ± 4.8%, p = 0.03). CONCLUSION: Six months post-radiotherapy, LS decreased predominantly in the endocardial layer of the most exposed part of the left ventricle. For precise evaluation of radiotherapy-induced cardiotoxicity and early left ventricular dysfunction, the endocardial layer-based LS might be the most sensitive parameter. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02605512 , Registered 6 November 2015 - Retrospectively registered.

Early detection of subclinical left ventricular dysfunction after breast cancer radiation therapy using speckle-tracking echocardiography: association between cardiac exposure and longitudinal strain reduction (BACCARAT study).

BACKGROUND: Breast cancer (BC) radiotherapy (RT) can induce cardiotoxicity, with adverse events often observed many years after BC RT. Subclinical left ventricular (LV) dysfunction can be detected early after BC RT with global longitudinal strain (GLS) measurement based on 2D speckle-tracking echocardiography. This 6-month follow-up analysis from the BACCARAT prospective study aimed to investigate the association between cardiac radiation doses and subclinical LV dysfunction based on GLS reduction. METHODS: The patient study group consisted of 79 BC patients (64 left-sided BC, 15 right-sided BC) treated with RT without chemotherapy. Echocardiographic parameters, including GLS, were measured before RT and 6 months post-RT. The association between subclinical LV dysfunction, defined as GLS reduction > 10%, and radiation doses to whole heart and the LV were performed based on logistic regressions. Non-radiation factors associated with subclinical LV dysfunction including age, BMI, hypertension, hypercholesterolemia and endocrine therapy were considered for multivariate analyses. RESULTS: A mean decrease of 6% in GLS was observed (- 15.1% ± 3.2% at 6 months vs. - 16.1% ± 2.7% before RT, p = 0.01). For left-sided patients, mean heart and LV doses were 3.1 ± 1.3 Gy and 6.7 ± 3.4 Gy respectively. For right-sided patients, mean heart dose was 0.7 ± 0.5 Gy and median LV dose was 0.1 Gy. Associations between GLS reduction > 10% (37 patients) and mean doses to the heart and the LV as well as the V20 were observed in univariate analysis (Odds Ratio = 1.37[1.01-1.86], p = 0.04 for Dmean Heart; OR = 1.14 [1.01-1.28], p = 0.03 for Dmean LV; OR = 1.08 [1.01-1.14], p = 0.02 for LV V20). In multivariate analysis, these associations did not remain significant after adjustment for non-radiation factors. Further exploratory analysis allowed identifying a subgroup of patients (LV V20 > 15%) for whom a significant association with subclinical LV dysfunction was found (adjusted OR = 3.97 [1.01-15.70], p = 0.048). CONCLUSIONS: This analysis indicated that subclinical LV dysfunction defined as a GLS decrease > 10% is associated with cardiac doses, but adjustment for non-radiation factors such as endocrine therapy lead to no longer statistically significant relationships. However, LV dosimetry may be promising to identify high-risk subpopulations. Larger and longer follow-up studies are required to further investigate these associations. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02605512, Registered 6 November 2015 - Retrospectively registered.

Is mean heart dose a relevant surrogate parameter of left ventricle and coronary arteries exposure during breast cancer radiotherapy: a dosimetric evaluation based on individually-determined radiation dose (BACCARAT study).

BACKGROUND: Intra-individual heterogeneity of cardiac exposure is an issue in breast cancer (BC) radiotherapy that was poorly considered in previous cardiotoxicity studies mainly based on mean heart dose (MHD). This dosimetric study analyzes the distribution of individually-determined radiation doses to the heart and its substructures including coronary arteries and evaluate whether MHD is a relevant surrogate parameter of dose for these substructures. METHODS: Data were collected from the BACCARAT prospective study that included left or right unilateral BC patients treated with 3D-Conformal Radiotherapy (RT) between 2015 and 2017 and followed-up for 2 years with repeated cardiac imaging examinations. A coronary computed tomography angiography (CCTA) was performed before RT for all patients. Registration of the planning CT and CCTA images allowed delineation of the coronary arteries on the planning CT images. Using the 3D dose matrix generated during treatment planning and the added coronary contours, dose distributions were generated for whole heart and the following substructures: left ventricle (LV), left main coronary artery (LMCA), left anterior descending artery (LAD), left circumflex artery (LCX) and right coronary artery (RCA). A descriptive analysis of the physical doses in Gray (Gy) was performed, Dmean was the volume-weighted mean dose. RESULTS: Dose distributions were generated for 89 left-sided BC patients (MHD = 2.9 ± 1.5 Gy, Dmean_LAD = 15.7 ± 3.1 Gy) and 15 right-sided BC patients (MHD = 0.5 ± 0.1 Gy; Dmean_RCA = 1.2 ± 0.4 Gy). For left-sided BC patients, the ratio Dmean_LAD/MHD was around 5. Pearson correlation coefficients between MHD and Dmean for delineated substructures were all statistically significant. However, for all substructures, the coefficient of determination R2 indicated that the proportion of the variance in Dmean of the substructure predictable from MHD was moderate to low (in particular R2 = 0.45 for LAD). Among left-sided BC patients with MHD < 3Gy, 56% of patients could nevertheless receive LAD doses above 40Gy (V40 > 0). CONCLUSION: Our study illustrates that MHD is not enough to predict with confidence individual patient dose to the LV and coronary arteries, in particular the LAD. For precise radiotherapy-induced cardiotoxicity studies it would be necessary to consider the distribution of doses within these cardiac substructures rather than just the MHD. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02605512 , Registered 6 November 2015 - Retrospectively registered.

Early detection and prediction of cardiotoxicity after radiation therapy for breast cancer: the BACCARAT prospective cohort study.

BACKGROUND: Radiotherapy (RT) for breast cancer presents a benefit in terms of reducing local recurrence and deaths resulting from breast cancer but it can lead to secondary effects due to the presence of neighboring cardiac normal tissues within the irradiation field. Breast RT has been shown to be associated with long-term increased risk of heart failure, coronary artery disease, myocardial infarction and finally cardiovascular death more than 10 years after RT. However, there is still a lack of knowledge for early cardiotoxicity induced by breast RT that can appear long before the onset of clinically significant cardiac events. Based on a 2-year follow-up prospective cohort of patients treated with breast RT, the BACCARAT (BreAst Cancer and CArdiotoxicity Induced by RAdioTherapy) study aims to enhance knowledge on detection and prediction of early subclinical cardiac dysfunction and lesions induced by breast RT and on biological mechanisms potentially involved, based on functional and anatomical cardiac imaging combined with simultaneous assessment of multiple circulating biomarkers and accurate heart dosimetry. METHODS/DESIGN: BACCARAT study consists in a monocentric prospective cohort study that will finally include 120 women treated with adjuvant 3D CRT for breast cancer, and followed for 2 years after RT. Women aged 50 to 70 years, treated for breast cancer and for whom adjuvant 3D CRT is indicated, without chemotherapy are eligible for the study. Baseline (before RT) and follow-up data include measurements of functional myocardial dysfunction including strain and strain rate based on 2D-speckle tracking echocardiography, anatomical coronary lesions including description of plaques in segments of coronary arteries based on Coronary computed tomography angiography, and a wide panel of circulating biomarkers. The absorbed dose is evaluated for the whole heart and its substructures, in particular the coronary arteries. Analysis on occurrence and evolution of subclinical cardiac lesions and biomarkers will be performed and completed with dose-response relationship. Multivariate model of normal tissue complication probability (NTCP) will also be proposed. DISCUSSION: Tools and results developed in the BACCARAT study should allow improving prediction and prevention of potential lesions to cardiac normal tissues surrounding tumors and ultimately enhance patients' care and quality of life. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02605512.