The Impact of Synchrotron Microbeam Radiation Therapy Combined With Broad Beam in a Preclinical Breast Cancer Model

Abstract

Purpose: Both local tumor control and distant metastasis are important indicators of the efficacy of radiation therapy treatment. Synchrotron microbeam radiation therapy (MRT), spatially fractionated radiation delivered at ultrahigh dose rates, shows remarkable normal tissue sparing with excellent local control in some models. Some MRT regimens trigger an antitumor immune response that contributes not only to the local but also to systemic treatment efficacy. Despite recent advances in the treatment of primary breast cancer, metastatic disease is still the major cause of treatment failure in the clinic. Here, in an aggressive preclinical triple-negative breast cancer model, we compared local tumor response and metastasis following different MRT treatment programs. Methods and Materials: 4T1.2 mouse mammary tumors were treated with 300 Gy peak/7 Gy valley dose MRT and/or 8 Gy broad beam (BB) radiation, all delivered as daily fractionated programs (3 consecutive daily sessions of either MRT or BB or 1 MRT combined with 2 BB sessions, the first or last of the 3 fractions). The mice were euthanized on day 9 post last irradiation, when unirradiated control animals reached an ethical endpoint. Primary tumors were collected to evaluate immune cell prevalence, while lungs, spinal cords, and locoregional lymph nodes were collected to measure metastatic burden. In parallel, local tumor growth and survival were monitored. Results: The combined MRT/BB treatment shifted the balance between pro- and antitumorigenic macrophages toward the accumulation of antitumorigenic macrophages in the tumor. Monitoring of the tumor volume and animal health indicated the benefit of the combined MRT/BB treatment for local control and treatment tolerance, while animal survival was only marginally longer for one combined schedule. The metastatic burden was similar for all 4 treatment schedules. Conclusions: The addition of a single MRT to BB treatment improved the primary tumor response. This provides a basis for future experiments incorporating adjuvant immunotherapy or chemotherapy to improve local and systemic treatment outcomes.