ESTRO 2024 - Abstract Book

S5409

Radiobiology - Tumour biology

ESTRO 2024

1 University of Antwerp, Antwerp Research in Radiation Oncology (AReRO), Center for Oncological Research (CORE), Antwerp, Belgium. 2 Iridium Netwerk, Radiation Oncology, Antwerp, Belgium. 3 University, Antwerp Research in Radiation Oncology (AReRO), Center for Oncological Research (CORE), Antwerp, Belgium

Purpose/Objective:

Breast cancer is the leading cause of cancer death in women. Every year in Belgium 10 000 women are diagnosed with breast cancer, and approximately 70% of them are treated with radiotherapy. Nevertheless, radiotherapy can be limited by its side effects to surrounding healthy organs (lung, heart, skin, healthy breast) that can generate debilitating effects, which limit the dose escalation sometimes needed to treat very aggressive tumors like triple negative breast cancers (TNBC). Ultra-high dose rate “FLASH” radiotherapy (FLASH-RT) has been described as a technique able to limit normal tissue toxicities while keeping iso-efficacy in tumor control compared to conventional dose rate radiotherapy (CONV-RT). In this study, we investigated for the first time the effect of FLASH-RT on TNBC in terms of tumor cure, cellular and molecular effects.

Material/Methods:

A well-described syngeneic model of TNBC was used in this study. murine 4T1 TNBC cells were injected subcutaneously or in the mammary fat pad of BALB/c mice and irradiated with a single dose of 14 or 20 Gy at conventional dose rate (0.1 Gy/s) or FLASH-RT (>10 6 Gy/s) using the ElectronFLASH linac (SIT Sordina). Tumor growth was followed and tumors were harvested 24h or 5 days post-irradiation, or kept until humane endpoints were reached. Ki67 score, DNA damage, vasculature structure and stemness were quantified at all timepoints. Correlation between FLASH-response marker GADD45 expression and tumor growth was investigated. RNAseq was performed to identify potential differences in gene expression. Fractionation schedule are under investigation.

Results:

While 20 Gy was necessary to induce significant tumor growth delay in irradiated groups compared to controls, FLASH RT showed similar tumor growth delay compared to conventional dose rate RT in all tested conditions. This correlates with our results showing the high expression of previously described GADD45 FLASH response marker. The majority of GADD45 high tumors correlated with good response to FLASH-RT. The structure of tumor vessels was partly preserved after FLASH-RT compared to CONV-RT, while proliferation and stemness was increased at late time points in both treatments groups compared to control. Results on early time points, DNA damage and RNA seq are currently being analyzed.

Conclusion:

In conclusion, the first results or our study show that FLASH-RT is as efficient as CONV-RT to delay the growth of aggressive TNBC in mice, necessitating the use of very high treatment doses. While FLASH-RT relatively preserves the tumor vasculature compared to CONV-RT, it does not further increase tumor stem cells, as it could have been expected according to the preservation of normal stem cell by FLASH-RT in normal tissues. Moreover, we partly confirmed that GADD45 could be used as a marker of response to FLASH-RT. Further results on DNA damage and RNA seq are currently being analyzed. Investigation on human TNBC cell lines xenografted in mice will also be performed to confirm these results.