Demonstrating FLASH effectiveness against CONV dose rates, on eradication of orthotopic breast cancer tumor model

Purpose: Post-lumpectomy radiotherapy (RT) reduces in-breast tumor recurrence by eradicating residual mm size breast cancer (BC) tumors. However, RT can often induce skin fibrosis due to radiation toxicity and limit options of implant-based breast reconstruction. This possibility can dissuade patients from breast conservation leading to unnecessary mastectomy, while also causing significant difficulties for women who have implant-based reconstruction and require post-mastectomy radiotherapy. Ultra-high dose rate (FLASH) radiation is known to induce less normal tissue toxicity compared to conventional (CONV) RT, therefore if tumor control of FLASH-RT would be as effective to CONV-RT then it has the potential to be an alternative less toxic therapy for BC treatment that allows overall improved outcome. At first, we aimed to determine the effectiveness of FLASH compared to CONV-RT in eradicating small tumors in an orthotopic BC model using single-fraction 20, 25 or 30 Gy RT.

Methodology: Radiation sensitive 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. 30 mm3 tumors or a range of greater volumes (200 – 800 mm3) were irradiated with single fraction 20, 25 or 30 Gy by positioning in a 3D printed jig exposing only 5 mm of the surrounding tissue when placed on a 2 x 2 cm radiation shield that shapes the beam that comes from underneath the assembly. The energy of both beams is ~16 MeV beams. FLASH-RT was delivered with 1 or 2 Gy per pulse at dose rate ~100 or 200 Gy/s compared to CONV-RT dose rate of 0.13 Gy/s.

Results: Small 30 mm3 tumors regressed until ~ day 15 after 20 Gy single fraction RT then regrew for both FLASH and CONV. 30 mm3 tumors were eradicated with both FLASH and CONV at 30 Gy with no regrowth up to day 35 post-RT. Larger tumors irradiated with 30 Gy regressed until ~ day 12 post-RT then regrew for both FLASH and CONV. There was no significant difference in growth delay or tumor eradication between FLASH and CONV in any cohort.

Conclusions: FLASH was as effective as CONV in controlling growth and eradicating murine BC. Based on other preclinical studies, single-fraction doses between 20 and 30 Gy, as well as hypofractioned RT schedules, may identify FLASH doses that achieve comparable tumor control with less toxicity than CONV. Such findings would encourage clinical trials of FLASH in human BC.

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