Abstract Purpose Radiotherapy (RT) of early breast cancer is associated with cardiovascular morbidity. Transforming growth factor beta 1 (TGFβ-1) is a pro-fibrotic cytokine that also has a role in immunological activation and epithelial proliferation, but its clinical role remains unclear. Endoglin, matrix metalloproteinase 9 (MMP-9), platelet derived growth factor (PDGF), and oxidative stress are involved in regulation of TGFβ-1. 8-isoprostane is a biomarker of oxidative stress. The aim of our study was to evaluate the behavior of these fibrosis-associated biomarkers during adjuvant RT of early breast cancer. Materials and methods The study included 67 patients with early breast cancer or ductal carcinoma in situ (DCIS) receiving adjuvant RT, but no chemotherapy. The dose of RT was either 42.56 Gy in 2.66 Gy fractions or 50 Gy in 2 Gy fractions with or without boost of 10 or 16 Gy. TGFβ-1 (ng/ml), endoglin (ng/ml), PDGF (ng/ml), MMP-9 (ng/ml) and 8-isoprostane (pg/ml) were measured by enzyme-linked immunoassay (ELISA) from serum samples acquired before starting RT, 2 weeks (for 42.56 Gy) or 3 week (for 50 Gy) into RT and at the end of RT. Results Adjuvant RT induced significant decreases in the levels of TGFβ-1 (p=0.002), MMP-9 (p=0.017) and PDGF (p<0.001) from before RT to after RT (Table 1). Whereas, the levels of endoglin and 8-isoprostane remained stable. For the first 2 or 3 weeks of RT, TGFβ-1 remained stable and then decreased significantly by the end of RT (p=0.022). The decrease in MMP-9 was significant only from before RT to after RT (p=0.017). On the other hand, PDGF also decreased significantly during the first 2 or 3 weeks (p=0.016) and from 2-3 weeks to after RT (p=0.038). Although, endoglin remained stable throughout the whole RT, the decrease during first 2-3 weeks was significant (p=0.002). Table 1 Change in biomarkers during RT Before RT2-3 weeksAfter RTp1p2p3TGFβ-1, Md (IQR)25.2 (21.1-30.7)25.5 (21.0-31.1)23.8 (19.6-26.9)0.2080.0220.002endoglin, Md (IQR)26.7 (22.9-29.7)25.3 (21.7-29.2)26.5 (22.4-29.4)0.0020.2490.098MMP-9, Md (IQR)334 (249-485)330 (217-475)289 (209-384)0.1690.1670.017PDGF, Md (IQR)18.7 (13.7-23.5)16.7 (13.0-22.6)16.1 (12.8-19.8)0.0160.038<0.0018-isoprostane, Md (IQR)85.9 (53.0-134.3)72.8 (36.2-120.5)80.8 (45.7-134.3)0.2460.3470.841Md median, IQR interquartile range, 1Wilcoxon signed ranks test for change from before RT to 2-3 weeks into RT, 2Wilcoxon signed ranks test for change from 2-3 weeks into RT to after RT, 3 Wilcoxon signed ranks test for change from before RT to after RT Conclusion This study demonstrates the behavior of TGFβ-1, endoglin, MMP-9, PDGF and 8-isoprostane during adjuvant RT of early breast cancer. Although the role TGFβ-1 as profibrotic cytokine is widely accepted, it has not been extensively studied in radiotherapy of breast cancer. The fibrotic effects of RT take years to manifest, including increased cardiovascular morbidity. More extensive studies, with longer follow-up, are needed to determine whether the changes in TGFβ-1 and its modulators are associated with clinical, RT related, cardiovascular complications in breast cancer patients. Citation Format: Aula H, Skyttä T, Luukkaala T, Hämäläinen M, Moilanen E, Kellokumpu-Lehtinen P-L. Adjuvant radiotherapy of early breast cancer induces a decrease in levels of TGFβ-1, MMP-9 and PDGF [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-11-15.
Transforming growth factor beta 1 (TGF-β1) and platelet-derived growth factor (PDGF) are cytokines involved in fibrotic processes causing radiotherapy (RT)-induced cardiovascular changes. We aimed to investigate the associations between TGF-β1 and PDGF and the echocardiographic changes that occur during RT and during three-year follow-up. The study included 63 women receiving adjuvant RT for early-stage breast cancer or ductal carcinoma in situ. Serum TGF-β1 (ng/ml) and PDGF (ng/ml) levels were measured by enzyme-linked immunoassay and echocardiographic examination was performed before RT, after RT and at 3 years. Patients were grouped by biomarker behavior by a trajectory analysis. TGF-β1 decreased from 19.2 (IQR 17.1–22.3) before RT to 18.8 (14.5–22.0) after RT (p = 0.003) and the decrease persisted at 17.2 (13.7–21.2) 3 years after RT (p = 0.101). PDGF decreased from 15.4 (12.6–19.1) before RT to 13.8 (11.7–16.2) after RT, p = 0.001, and persisted at 15.6 (10.4–18.4) at 3 years, p = 0.661. The TGF-β1 level before RT (Spearman's rho 0.441, p < 0.001) and the three-year change in TGF-β1 (rho = − 0.302, p = 0.018) correlated with global longitudinal strain (GLS) in echocardiography at 3 years. In trajectory analysis, two TGF-β1 behavior groups were found. Group 1 had significantly higher TGF-β1 levels before RT, 25.6 (22.3–28.6), than group 2, 17.8 (15.9–19.9), p < 0.001. In multivariable analysis, TGF-β1 trajectory group 1 (β = 0.27, p = 0.013), left-sided breast cancer (β = 0.39, p = 0.001) and the use of aromatase inhibitors (β = 0.29, p = 0.011) were significantly associated with a worsening in GLS from before RT to 3 years. An elevated pretreatment TGF-β1 may predict RT-associated changes in echocardiography.
Aim: To identify patients with breast cancer at risk for cardiotoxicity, we evaluated homoarginine (HA) behavior during adjuvant treatment. Patients and Methods: Eighty-one patients received radiotherapy (RT) with or without endocrine treatment, and 19 received chemotherapy, RT and endocrine therapy. Serum HA, asymmetric dimethylarginine (ADMA) and high-sensitivity cardiac troponin T (hscTnT) were measured and echocardiography was performed before chemotherapy, and before and after RT. Results: In chemo-naïve tamoxifen users HA increased during RT from a median (IQR) of 2.47 (1.61-3.35) to 2.86 (1.93-4.23) μM (p=0.028) and remained stable in patients with aromatase inhibitor and in those without endocrine therapy. Tamoxifen users were mostly spared from echocardiographic changes. In chemotherapy-treated patients, HA decreased during chemotherapy (p=0.001) from 1.46 (1.01-2.18) to 0.91 (0.71-1.29) μM, and increased (p=0.004) to 1.19 (0.83-1.63) μM during RT, remaining lower than at baseline (p=0.014). Echocardiographic changes were observed during chemotherapy. Conclusion: HA decrease during chemotherapy could indicate an increased risk of cardiovascular morbidity. Additionally, HA increase in tamoxifen users may reflect a cardioprotective effect of tamoxifen.
Radiotherapy (RT) induces late changes in all cardiac structures. Most studies of early changes focus on individual parameters.Data from eighty early-stage breast cancer patients at baseline, post-RT and three-year follow-up visit were assessed prospectively. Changes in ten cardiac parameters were collected including electrocardiogram (ECG), echocardiography, and biomarkers. A percentage of abnormal changes was calculated.The mean heart radiation dose (Dmean) was independently associated with the increased incidence of changes post-RT (β=0.403, p<0.001) and at the three-year follow-up (β=0.353, p=0.001). Each 1-Gray increase in Dmean increased the cardiac changes by 3.7% (95%CI=1.9-5.6%) after RT and 3.1% (95%CI=1.3, 4.9%) at the three-year follow-up.A higher cardiac radiation dose was independently associated with a higher incidence of changes in cardiac parameters. Multiparameter changes imply that the early phase after RT is already characterized by several overlapping cardiac changes.
To search for biomarkers of RT-induced cardiotoxicity, we studied the behavior of ST2 during RT and three years after RT, and the associations with echocardiographic changes.We measured soluble ST2 (ng/ml) in serum samples from 63 patients receiving RT for early breast cancer. Sampling and echocardiography were performed at baseline, after RT and at the three-year follow-up. Patients were grouped by >15% (group 1) and ≤15% (group 2) relative worsening in global longitudinal strain (GLS).ST2 levels tended to increase during RT, from a median (interquartile range; IQR) of 17.9 (12.4-22.4) at baseline to 18.2 (14.1-23.5) after RT (p = 0.075). By the three-year follow up, ST2 levels increased to 18.7 (15.8-24.2), p = 0.018. The increase in ST2 level was associated with worsening cardiac systolic function at three-year follow-up, GLS (rho = 0.272, p = 0.034) and left ventricular ejection fraction (LVEF) (rho = ─0.343, p = 0.006). Group 1 (n = 14) had a significant increase in ST2 levels from 17.8 (12.3-22.5) at baseline to 18.4 (15.6-22.6) after RT, p = 0.035 and to 19.9 (16.0-25.1) three years after RT, p = 0.005. ST2 levels were stable in group 2 (n = 47): 17.8 (12.3-22.0) at baseline, 17.7 (12.6-23.5) after RT and 18.0 (15.5-22.4) at three years.ST2 may be useful for determining which patients are at risk for long-term cardiovascular toxicity following adjuvant breast cancer RT, but prospective clinical studies are needed to confirm this hypothesis.
Radiation-induced heart disease is mainly caused by activation of the fibrotic process. Transforming growth factor-beta 1 (TGF-β1) and platelet-derived growth factor (PDGF) are pro-fibrotic mediators. The aim of our study was to evaluate the behavior of TGF-β1 and PDGF during adjuvant radiotherapy (RT) for breast cancer and the association of these cytokines with echocardiographic changes.Our study included 73 women with early-stage breast cancer or ductal carcinoma in situ (DCIS) receiving post-operative RT but not chemotherapy. TGF-β1 and PDGF levels in serum samples taken before and on the last day of RT were measured by an enzyme-linked immunosorbent assay. Echocardiography was also performed at same time points. Patients were grouped according to a ≥ 15% worsening in tricuspid annular plane systolic excursion (TAPSE) and pericardium calibrated integrated backscatter (cIBS).In all patients, the median TGF-β1 decreased from 25.0 (IQR 21.1-30.3) ng/ml to 23.6 (IQR 19.6-26.8) ng/ml (p = 0.003), and the median PDGF decreased from 18.0 (IQR 13.7-22.7) ng/ml to 15.6 (IQR 12.7-19.5) ng/ml (p < 0.001). The baseline TGF-β1, 30.7 (IQR 26.0-35.9) ng/l vs. 23.4 (IQR 20.1-27.3) ng/l (p < 0.001), and PDGF, 21.5. (IQR 15.7-31.2) ng/l vs. 16.9. (IQR 13.0-21.2) ng/ml, were higher in patients with a ≥ 15% decrease in TAPSE than in patients with a < 15% decrease. In patients with a ≥ 15% decrease in TAPSE, the median TGF-β1 decreased to 24.7 (IQR 20.0-29.8) ng/ml (p < 0.001), and the median PDGF decreased to 16.7 (IQR 12.9-20.9) ng/ml (p < 0.001). The patients with a < 15% decrease had stable TGF-β1 (p = 0.104), but PDGF decreased to 15.1 (IQR 12.5-18.6), p = 0.005. The patients with a ≥ 15% increase in cIBS exhibited a decrease in TGF-β1 from 26.0 (IQR 21.7-29.7) to 22.5 (IQR 16.6.-26.7) ng/ml, p < 0.001, and a decrease in PDGF from 19.8 (IQR 14.6-25.9) to 15.7 (IQR 12.8-20.2) ng/ml, p < 0.001. In patients with a < 15% increase, TGF-β1 and PDGF did not change significantly, p = 0.149 and p = 0.053, respectively.We observed a decrease in TGF-β1 and PDGF levels during adjuvant RT for breast cancer. Echocardiographic changes, namely, in TAPSE and cIBS, were associated with a greater decrease in TGF-β1 and PDGF levels. Longer follow-up times will show whether these changes observed during RT translate into increased cardiovascular morbidity.
Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): State research funding (Finland) Heart Hospital funding (Tampere, Finland) Aims Breast cancer radiotherapy (RT) increases the incidence of heart failure with preserved ejection fraction with long latency. The prevalence and the early phases of this process are not well characterized. The aims of our study were to evaluate changes in diastology and left atrial function after breast cancer RT in a prospective manner. Methods 31 patients with early stage left-sided breast cancer were studied prior to RT, immediately after RT and three and six years after RT. Biomarkers were measured and echocardiography, including left atrial strain, was performed at each visit. Cardiac magnetic resonance imaging (CMR) was performed at the six-year follow-up (FU). Results At baseline, the median diastology gradus was 1 with 5 patients displaying diastology gradus greater than 2. At six-year follow-up the median diastology gradus had increased to 2 (p = 0.012) with 13 patients in diastology gradus 3-4. Additionally, proBNP increased progressively from baseline level of 63 [37, 124] ng/l to post-RT level of 84 [40, 154] ng/l (p = 0.031), to 90 [46, 132] ng/l at the three-year follow-up (p = 0.021) and to 98 [50, 176] ng/l at the six-year follow-up (p = 0.010). Left atrial strain initially increased from 23.2 ± 4.9% at baseline to 25.5 ± 6.7% post-RT (p = 0.199) and thereafter decreased to 21.2 ± 6.0% (p = 0.002) at six-year follow-up. There was no correlation in left atrial strain between 2D-echocardiography and CMR. Age (mean 62.2 years) had no correlation with changes in diastology or left atrial strain. Furthermore, left atrial strain rate (SR) increased progressively from 2.14 [1.83, 2.50]1/s at baseline to 2.35 [1.95, 2.96]1/s at the three-year follow-up (p = 0.040) and thereafter declined to 1.92 [1.62, 2.59]1/s (p = 0.014). The change in left atrial SR (from RT to the six-year control) was independently correlated with body mass index (BMI) (p = 0.044, β=0.472). The changes in diastology had no independent predictors. Conclusions RT induced a gradual worsening in diastology gradus, which was initially compensated with an increase in left atrial function. However, at the six-year follow-up, 43.7% of the patients had restrictive or pseudonormal diastology and a significant decline in left atrial strain and SR were detected. A lower BMI had a negative influence on the left atrial function. Abstract Figure. Changes in diastoly during six-year FU
