Adjuvant radiotherapy is a standard treatment for early stage breast cancer. Radiotherapy reduced the 10-year risk of any first recurrence from 35.0% to 19.3% and reduced the 15-year risk of breast cancer death from 25.2% to 21.4% (1), however there is potential for cardiac and pulmonary toxicity (2). Darby et al. recorded in 2013 that the rate of major coronary events increased linearly with the mean dose to the heart by 7.4% per gray in patients with left-sided breast cancer. Cardiovascular events could occur within the first 5 years after radiotherapy (RT) completion and continue up to 30 years after treatment (3). Damage to cardiac micro and macro-vasculature is the pathophysiological cause of radiation-related heart disease, with a predominance of ischaemic heart disease (4). This indicates that the coronary arteries, and the left anterior descending artery (LAD), may be a critical structure for the development of late radiation-induced heart morbidity. The risk of radiation-induced cardiotoxicity may be increased by baseline patient cardiac risk factors and systemic therapies (5,6), such as anthracyclines, trastuzumab, taxanes, tamoxifen (7,8). Furthermore, serum biomarkers may play an important role in the detection of heart damage after radiotherapy. Cardiac biomarkers have been applied for early identification, evaluation, and monitoring cardiotoxicity during chemotherapy (9).

High-sensitivity cardiac troponin T (Hs-cTnT) is a biomarker of myocardial damage and may have a predictive value in patients who underwent radiotherapy for left sided breast cancer (10,11). Cardiac troponins (cTn) are structural proteins that bind to the actin complexes in myofilaments and regulate muscle contraction by interacting with calcium ions and inhibiting the ATPase activity of actinomyosin. cTn represents a complex composed of three subunits: troponin T (cTnT), troponin I (cTnI), and troponin C (cTnC) (12). cTn have high specificities and high sensitivity for myocardial injury and are used in the diagnosis and risk stratification of acute coronary syndromes.

The aim of this study was to evaluate the early effect of left whole breast radiotherapy (WB-RT) on serum Hs-cTnT levels and to correlate them with radiation dose, to the whole heart, to its substructures and to patients’ clinical features.

Population. We conducted a prospective observational study between December 2017 and May 2018. A total of 45 consecutive patients with early stage left-sided breast cancer or ductal carcinoma in situ (DCIS) were analyzed. Exclusion criteria were: age over 75 years, previous chemotherapy treatment, pre-existing heart disease, severe lung disease, kidney failure, and autoimmune disease. Patients with pharmacologically treated hypertension were included. The main cardiovascular risk factors were recorded. All patients were treated with adjuvant conformal 3D RT after surgery in the supine position using “wing board” with arms above heads, computed tomography scan was performed with 2.5 mm thickness, without intravenous contrast. Conformal treatment plans were obtained using the Pinnacle treatment planning system (Phillips Medical Systems, Andover, MA, USA) and were delivered using an Elekta Precise linear accelerator. Treatment was given to a total dose of 42.5 Gy in 16 fractions over 3 weeks with eventually an additional boost to tumor bed.

High sensitivity cardiac troponin (Hs-cTnT) was analyzed in serum samples taken before RT (T0), weekly during the first, (T1), the second (T2) and the third week (T3) and one week after the end of the treatment (T4). Blood sampling was carried out in the timeslot between 8:00 and 9:00 am, since diurnal variation of troponin were observed with a decline in values of 0.8% per hour from 8:30 am to 2:30 pm (13).

Considering the physiological variations of serum levels, a significant increase in Hs-cTnT levels during RT was predefined to exceed 30% from baseline value in this protocol. Dose volume histograms (DVHs) were used to provide a quantitative analysis. The maximum dose and the mean dose and dose-volume parameters V5, V10, V15, V20, V25, and V30 were evaluated for the whole heart, left ventricle, and LAD. A comprehensive echocardiography study and 12-lead electrocardiogram (ECG) were performed at the baseline and at the end of RT. The study was approved by the local Ethics Committee and written consent was obtained for all patients.

Statistical analysis. Data are expressed as means±standard deviation (SD) for normally distribute continuous variables and as medians with inter-quartile range (IQR) for variables with non-normal distribution.

Statistical analyses were performed using MedCalc for Windows, version 17.9.6 (Medcalc Software, Ostend, Belgium). The χ² test was performed for the correlation between ∆Hs-cTnT and clinical and dosimetric variables. Multivariate analysis was performed using binary logistic regression. Statistical significance was set at p<0.05.

Baseline characteristics of the patients are presented in Table I. Median Hs-cTnT for the whole study population was 3.1 ng/l before RT (IQR=3.0-5.7), 3.4 ng/l at 1 week (IQR=3-6), 4.8 ng/l at 2 weeks (IQR=3.0-6.0), 5.1 ng/l at 3 weeks (IQR=3.2-7.0) and 5.5 ng/l after RT (IQR=3.3-7.5). Hs-cTnT increased over 30% from the baseline value in 12/45 (26%) patients.

In these 12 patients, median Hs-cTnT was 3.1 ng/l before RT (IQR=3.0-5.3), 5.0 ng/l at 1week (IQR=3.3-6.8), 3.5 at 2 weeks (IQR=3.0-5.0), 7.4 at 3 weeks (IQR=4.1-10.2), 6.3 after RT (IQR=4.3-8.1) (Figure 1A). An increase in Hs-cTnt was not accompanied by early clinical changes in ECG or echocardiography. Finally, for the remaining 33 patients, median values at the same time points were: 4 ng/l (IQR=3.0-6.5), 3.8 ng/l (IQR=3.0-6.7), 4.2 ng/l (IQR=3.0-6.3), 3.6 ng/l (IQR=3.0-6.3), and 3.8 ng/l (IQR=3.0-6.7), respectively (Figure 1B).

Dose-volumes parameters are shown in Table II. The following maximum and average dose values [median (IQR)] were recorded for LAD: 33.7 Gy (IQR=14.4-42.1) and 6.4 Gy (IQR=3.3-11.7). For the maximum and average doses, the following values for the left ventricle were recorded [median (IQR)]: 40.2 Gy (IQR=17.5-42.3) and 2.2 Gy (IQR=1.4-3.5).

Univariate analysis (Table III) revealed that ∆Hs-cTnT is strongly associated with heart V5 (p=0.05) and pre-existing hypertension (p=0.05). Multivariate analysis confirmed the correlation between heart V5 and ∆Hs-cTnT (HR=3.75, 95%CI=0.9-14,8; p<0.005).

Several studies have shown the correlation between heart exposure to irradiation and an increased risk of heart disease (14). Although morbidity of radiation induced heart disease (RIHD) has been reduced by optimizing treatment plan and techniques, recent studies have shown that modern technology does not eliminate the risk of RIHD (15,16).

Specifically, patients with left side breast cancer clearly present higher risk for developing cardiac events in comparison with right –sided one’s (3). The early detection of radiation –induced cardiac toxicity may potentially indicate patients that will develop late toxicity among breast cancer survivors. The cardiac troponin has been extensively studied as early detector of cardiac toxicity resulting from anticancer therapies (17). Several studies have evaluated the increased levels of this biomarker after radiotherapy and suggested that the cardiac troponin could be a potential marker of early radiation-induced heart damage. Cramer et al. found a correlation between irradiation doses to cardiac tissue and Hs-cTnT (18). In patients with increased levels of this biomarker, the mean heart dose and mean LV were significantly higher (18). In our observational prospective study, we analyzed Hs-cTnT before, during, and after radiotherapy in chemotherapy–naive breast cancer patients.

The Hs-cTnT is a well-established biomarker of acute myocardial infarction (AMI) (19,20). In addition, elevated Hs-cTnT levels can be detected in chronic heart failure (21) and LV hypertrophy (22,23). The values of Hs-cTnT in healthy individuals show variations in the different published studies; the 99th percentile differs from 12 ng/l (24) to 20 ng/l (25) and it has been shown that these values are influenced by patient age, sex and comorbidities (26). Excluding patients with known heart diseases, it is estimated that the median Hs-cTnT in women aged 55 to 75 years is 3 ng /l (26). Based on these data and considering the physiological weekly and diurnal changes in Hs-cTnT, an increase more than 30% from baseline value was interpreted as significant (17). In our series, 12/45 (26%) patients recorded an increase in the levels of this biomarker, mainly during the last week of RT; however, during a median of 3 years follow-up, no cardiac event was recorded. To correlate the rise in troponin levels with the risk of long-term cardiovascular morbidity and mortality, a longer follow-up is needed, since the cardiotoxic effects of RT tend to increase even after long periods of irradiation (3).

Moreover, a correlation with hearth V5 was also observed. This suggests that V5 and its correlation with a serum biomarker could represent a potential tool to predict myocardial damage leading to an appropriate stratification of patients at greater risk for long-term cardiac toxicity. A prolonged follow-up seems mandatory to obtain long-term results.

The Authors declare that they have no competing interests in relation to this study.

All Authors participated in the study design and coordination and discussed the outcome during the study.