Radiogenomics Monitoring in Breast Cancer Identifies Metabolism and Immune Checkpoints as Early Actionable Mechanisms of Resistance to Anti-angiogenic Treatment.

Autor:	Mehta S; Department of Oncology, University of Oxford, Oxford, UK., Hughes NP; Department of Engineering, University of Oxford, Oxford, UK., Li S; Paul Strickland Scanner Centre, Northwood, Middlesex, UK., Jubb A; Department of Oncology, University of Oxford, Oxford, UK., Adams R; Department of Oncology, University of Oxford, Oxford, UK., Lord S; Department of Oncology, University of Oxford, Oxford, UK., Koumakis L; Department of Oncology, University of Oxford, Oxford, UK., van Stiphout R; Department of Oncology, University of Oxford, Oxford, UK., Padhani A; Mount Vernon Cancer Centre, Northwood, Middlesex, UK., Makris A; Paul Strickland Scanner Centre, Northwood, Middlesex, UK., Buffa FM; Department of Oncology, University of Oxford, Oxford, UK. Electronic address: francesca.buffa@oncology.ox.ac.uk., Harris AL; Department of Oncology, University of Oxford, Oxford, UK. Electronic address: adrian.harris@oncology.ox.ac.uk.
Jazyk:	angličtina
Zdroj:	EBioMedicine [EBioMedicine] 2016 Aug; Vol. 10, pp. 109-16. Date of Electronic Publication: 2016 Jul 16.
DOI:	10.1016/j.ebiom.2016.07.017
Abstrakt:	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. (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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