Bevacizumab induces acute hypoxia and cancer progression in patients with refractory breast cancer: Multimodal functional imaging and multiplex cytokine analysis

Purpose: Bevacizumab, an antibody against endothelial growth factor, is a key but controversial drug in the treatment of metastatic breast cancer. We, therefore, aimed to determine the intrinsic resistance to bevacizumab at the physiological and molecular levels in advanced breast cancer using positron emission tomography (PET), dynamic contrast-enhanced MRI, diffuse optical spectroscopic imaging (DOSI), and multiplex cytokine assays.<br />Experimental Design: In total, 28 patients diagnosed with stage III/IV advanced breast cancer receiving single-agent bevacizumab for 1 week followed by paclitaxel combined with bevacizumab underwent ¹⁸F-fluorodeoxyglucose (FDG)-PET, ¹⁸F-fluoromisonidazole (FMISO)-PET, and MRI at both baseline and two courses after treatment initiation. Hemodynamic measurement using DOSI and blood sample collection were performed at baseline and multiple times during the first week after the initiation of single-agent bevacizumab. We distinguished non-responders from responders by serial FDG-PET based on their glycolytic changes to chemotherapy.<br />Results: Non-responders showed significantly higher hypoxic activity on FMISO-PET and less tumor shrinkage than responders. Hemodynamic parameters showed higher tumor blood volume and a remarkable decrease in the tissue oxygen level in non-responders compared with responders after the infusion of single-agent bevacizumab. Multiplex cytokine assays revealed increased plasma levels of both pro-angiogenic and hypoxia-related inflammatory cytokines in non-responders and decreased levels in responders. <br />Conclusions: Non-responders exhibited a higher degree of angiogenesis with more severe hypoxia than responders during bevacizumab treatment. These findings demonstrated that the addition of bevacizumab to paclitaxel treatment under hypoxic conditions could be ineffective and may result in acute hypoxia and increased cytokine secretion associated with cancer progression.

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