Early Radiation Therapy Response Assessment Using Multi‐Scale Photoacoustic Imaging

ABSTRACT There is a critical unmet clinical need to identify biomarkers that predict and detect radiation therapy (RT) response in cancer. Using the unique capabilities of multi‐scale photoacoustic imaging (PAI) to depict tumor oxygenation and vasculature in vivo, we identified surrogate biomarkers of RT response in two human breast cancer xenograft models (MCF7 and MDA‐MB‐231), comparing hypofractionated delivery with an ablative single‐dose scheme. Mesoscopic and multispectral tomographic PAI were performed 24h pre‐RT, 24h post‐RT and at endpoint and were supported by ex vivo immunohistochemistry. MCF7 xenografts, which exhibited a denser and more mature vasculature, showed improved response to both RT schemes than MDA‐MB‐231, in terms of oxygenation, volume control and proliferation. Higher pre‐RT oxygenation and oxygen‐diffusion capacity were associated with improved outcome, consistent with the oxygen‐enhancement effect. PAI further revealed regimen‐specific vascular effects: ablative RT produced early pruning of looping vessels and superficial blood volume, while only hypofractionated RT led to a rise in intratumoral oxygenation at the endpoint in radiosensitive MCF7, indicative of reduced oxygen consumption in damaged tumor cells. We showed that PAI could capture early RT response and inform on radioresistance, thus demonstrating PAI as a promising tool to monitor the tumor vascular response to RT.