title: Radiogenomics Monitoring in Breast Cancer Identifies Metabolism and Immune Checkpoints as Early Actionable Mechanisms of Resistance to Anti-angiogenic Treatment.
abstract: 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.
authors.affiliation: Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: Shaveta
authors.initials: S
authors.lastname: Mehta
authors.affiliation: Department of Engineering, University of Oxford, Oxford, UK.
authors.forename: Nick P
authors.initials: NP
authors.lastname: Hughes
authors.affiliation: Paul Strickland Scanner Centre, Northwood, Middlesex, UK.
authors.forename: Sonia
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: Adrian
authors.initials: A
authors.lastname: Jubb
authors.affiliation: Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: Rosie
authors.initials: R
authors.lastname: Adams
authors.affiliation: Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Lord
authors.affiliation: Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: Lefteris
authors.initials: L
authors.lastname: Koumakis
authors.affiliation: Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: Ruud
authors.initials: R
authors.lastname: van Stiphout
authors.affiliation: Mount Vernon Cancer Centre, Northwood, Middlesex, UK.
authors.forename: Anwar
authors.initials: A
authors.lastname: Padhani
authors.affiliation: Paul Strickland Scanner Centre, Northwood, Middlesex, UK.
authors.forename: Andreas
authors.initials: A
authors.lastname: Makris
authors.affiliation: Department of Oncology, University of Oxford, Oxford, UK. Electronic address: francesca.buffa@oncology.ox.ac.uk.
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Buffa
authors.affiliation: Department of Oncology, University of Oxford, Oxford, UK. Electronic address: adrian.harris@oncology.ox.ac.uk.
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D016000:Cluster Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004734:Energy Metabolism / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D056747:Immunomodulation / Q000235:genetics*; D008279:Magnetic Resonance Imaging / Q000379:methods; D009389:Neovascularization, Pathologic / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D059467:Transcriptome; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D042461:Vascular Endothelial Growth Factor A
keywords: Anti-angiogenic treatment; Breast cancer; DCE-MRI; Radiogenomics; Resistance