Abstract P2-11-15: Adjuvant radiotherapy of early breast cancer induces a decrease in levels of TGFβ-1, MMP-9 and PDGF
Authors: Aula H , Skyttä T , Luukkaala T , Hämäläinen M , Moilanen E , Kellokumpu-Lehtinen P-L 
Published: February 2018

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&lt;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&lt;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.