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Anti-VEGF antibody bevacizumab has prolonged progression-free survival in several cancer types, however acquired resistance is common. Adaption has been observed pre-clinically, but no human study has shown timing and genes involved, enabling formulation of new clinical paradigms. In a window-of-opportunity study in 35 ductal breast cancer patients for 2weeks prior to neoadjuvant chemotherapy, we monitored bevacizumab response by Dynamic Contrast-Enhanced Magnetic Resonance [DCE-MRI], transcriptomic and pathology. Initial treatment response showed significant overall decrease in DCE-MRI median K(trans), angiogenic factors such ESM1 and FLT1, and proliferation. However, it also revealed great heterogeneity, spanning from downregulation of blood vessel density and central necrosis to continued growth with new vasculature. Crucially, significantly upregulated pathways leading to resistance included glycolysis and pH adaptation, PI3K-Akt and immune checkpoint signaling, for which inhibitors exist, making a strong case to investigate such combinations. These findings support that anti-angiogenesis trials should incorporate initial enrichment of patients with high K(trans), and a range of targeted therapeutic options to meet potential early resistance pathways. Multi-arm adaptive trials are ongoing using molecular markers for targeted agents, but our results suggest this needs to be further modified by much earlier adaptation when using drugs affecting the tumor microenvironment.

Original publication

DOI

10.1016/j.ebiom.2016.07.017

Type

Journal article

Journal

EBioMedicine

Publication Date

08/2016

Volume

10

Pages

109 - 116

Keywords

Anti-angiogenic treatment, Breast cancer, DCE-MRI, Radiogenomics, Resistance, Angiogenesis Inhibitors, Antineoplastic Agents, Biomarkers, Tumor, Breast Neoplasms, Cell Proliferation, Cluster Analysis, Drug Resistance, Neoplasm, Energy Metabolism, Female, Gene Expression Regulation, Neoplastic, Humans, Immunomodulation, Magnetic Resonance Imaging, Neovascularization, Pathologic, Signal Transduction, Transcriptome, Treatment Outcome, Vascular Endothelial Growth Factor A