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: Shaveta Mehta, Nick P Hughes, Sonia Li, Adrian Jubb, Rosie Adams, Simon Lord, Lefteris Koumakis, Ruud van Stiphout, Anwar Padhani, Andreas Makris, Francesca M Buffa, Adrian L Harris
• Journal: EBioMedicine (EBioMedicine) Vol. 10 Pg. 109-16 (Aug 2016) ISSN: 2352-3964 [Electronic] Netherlands
• PMID: 27474395 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• Biomarkers, Tumor
• Vascular Endothelial Growth Factor A

Topics

• Angiogenesis Inhibitors (administration & dosage, pharmacokinetics, therapeutic use)
• Antineoplastic Agents (administration & dosage, pharmacokinetics, therapeutic use)
• Biomarkers, Tumor
• Breast Neoplasms (diagnosis, drug therapy, genetics)
• Cell Proliferation (drug effects)
• Cluster Analysis
• Drug Resistance, Neoplasm (genetics)
• Energy Metabolism (genetics)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Immunomodulation (genetics)
• Magnetic Resonance Imaging (methods)
• Neovascularization, Pathologic (diagnosis, drug therapy, genetics)
• Signal Transduction (drug effects)
• Transcriptome
• Treatment Outcome
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, genetics, metabolism)