Transforming growth factor beta 1 levels predict echocardiographic changes at three years after adjuvant radiotherapy for breast cancer

Hanna Aula,Eeva Moilanen,Vesa Virtanen,Tanja Skyttä,Mari Hämäläinen,Suvi Tuohinen,Pirkko-Liisa Kellokumpu-Lehtinen,Pekka Raatikainen,Tiina Luukkaala

doi:10.1186/s13014-019-1366-1

Abstract

BackgroundTransforming 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.MethodsThe 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.ResultsTGF-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.ConclusionAn elevated pretreatment TGF-β1 may predict RT-associated changes in echocardiography.

Highlights

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
The trajectory group 1 remained a significant factor in predicting global longitudinal strain (GLS) worsening during the 3 years in addition to aromatase inhibitors (AI) use and left-sided breast cancer, which we have reported in earlier to affect echocardiographic parameters [12, 13]
Changes in TGF-β1 levels Earlier, we reported that TGF-β1 and PDGF decrease during RT [10], but this study shows that TGF-β1 remains at a lower level at 3 years compared to before RT

Summary

Introduction

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. Transforming growth factor beta 1 (TGF-β1) is involved in the process responsible for the long-term fibrotic effects of RT, including cardiovascular changes and morbidity [2]. In a radiation fibrosis model, the production of profibrotic cytokines, such as TGF-β1 and platelet-derived growth factor (PDGF), is thought to be induced by radiation, which in turn activates fibroblasts. TGF-β1 is released following myocardial injury, exerting profibrotic actions on the myocardium This process is involved in the pathogenesis of different myocardial diseases [3]. Mutations in genes determining TGF-β1 levels may be responsible for susceptibility to radiation injury, such as breast fibrosis or increased cardiovascular morbidity [6, 7]

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