Abstract P1-10-02: FLASH-RT, ultra-high dose rate rate radiotherapy, is as effective as conventional dose rate radiotherapy in eradicating tumor in a preclinical model of breast cancer
Authors: Dirbas Frederick , Melemenidis Stavros , Loo Bill , Horst Kathleen , Graves Edward E. , Dutt Suparna , Viswanathan Vignesh , Lau Brianna , Yu Amy 
Published: March 2023

Abstract
Problem Statement: Radiation therapy (RT) for breast cancer (BC) can induce skin and soft tissue fibrosis, raises concerns over cardiac and pulmonary injury, is associated with higher rates of lymphedema and shoulder dysfunction with regional nodal irradiation, and significantly increases complication rates in women undergoing implant-based reconstruction due to radiation toxicity. Although these toxicities are not generally associated with higher mortality, in general, they can represent significant setbacks with respect to quality of life. These toxicities dissuade some patients from breast conservation leading to unnecessary mastectomy and can lead patients to omit reconstruction after mastectomy or choose more extensive autologous breast reconstruction. Women with implant-based reconstruction and radiotherapy have known higher rates of reconstruction failure. Purpose: Ultra-high dose rate radiation (FLASH) has been shown to induce less normal tissue toxicity, therefore if tumor control of FLASH-RT would be comparable to conventional radiotherapy (CONV) then it has the potential to lower morbidity associated with radiotherapy for breast cancer and allow overall improved outcomes. At first, we aimed to determine the effectiveness of FLASH-RT compared to CONV in eradicating small breast tumors in an orthotopic BC model using single-fraction 20 or 30Gy RT to compare effectiveness of FLASH-RT vs CONV. Methods: Radiation sensitive, syngeneic mammary tumor cell line Py117, that efficiently forms non-metastatic orthotopic tumors in C57BL/6 mice, were injected (106 cells) into the left 4th mammary fat pad. 30mm3 tumors or a range of greater volumes (200-800mm3) were irradiated with single-fraction 20 or 30Gy with a 2x2cm radiation field (~17MeV beams), exposing only 5mm of the surrounding tissue. FLASH RT was delivered with 2Gy per pulse at dose rate ~200Gy/s compared to CONV dose rate of 0.13Gy/s Results: Single-fraction 20Gy suppressed 30mm3 tumor growth until ~day 15 post-RT then regrew for both FLASH and CONV, while 30mm3 tumors were eradicated with both FLASH and CONV at 30Gy. Larger tumors irradiated with 30Gy regressed until ~day 12 post-RT then regrew for both FLASH and CONV. There was no significant difference in growth suppression or tumor eradication between FLASH and CONV in any cohort. Conclusion: In this murine model of breast cancer, FLASH is as effective as CONV in controlling tumor growth. Future studies will extend the evaluation of the tumor control using clinically relevant fractionated dose schedules to be followed by comparisons of tumor control in xenograft models. Additional studies will assess normal tissue toxicity of FLASH vs CONV in murine models of implant-based breast reconstruction. We have established collaborations to understand differences in molecular pathways activated by FLASH vs CONV in tumor and normal tissue to explain the observed experimental differences in normal tissue, tumor, and cancer stem cells.
Citation Format: Frederick Dirbas, Stavros Melemenidis, Bill Loo, Kathleen Horst, Edward E. Graves, Suparna Dutt, Vignesh Viswanathan, Brianna Lau, Amy Yu. FLASH-RT, ultra-high dose rate rate radiotherapy, is as effective as conventional dose rate radiotherapy in eradicating tumor in a preclinical model of breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-10-02.