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

• DCE-MRI two weeks post-treatment of primary breast cancer shows heterogeneity of initial response to bevacizumab.
• Gene expression shows heterogeneous changes but an overall decrease in angiogenic factors ESM1 and FLT1, and proliferation.
• Increased PI3K-Akt and immune checkpoint signaling suggests combination of Bevacizumab with inhibitors of these pathways.
• Increased PI3K-Akt and immune checkpoint signaling suggests combination of Bevacizumab with inhibitors of these pathways.Available evidence is that the anti-angiogenic treatment Bevacizumab currently has a limited range of indications in breast cancer compared to other cancers. Here, we show that multimodality dynamic monitoring of treatment response allow classification of patient's response as early as two weeks after treatment, and reveals new mechanisms associated with resistance. The implications, are that the role of bevacizumab in neoadjuvant breast cancer needs to be re-evaluated using early classification of resistant patients, but more generally that trials need to be designed prospectively, taking into account dynamic monitoring to be able to rapidly adapt available new agents for combination.

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 2 weeks 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 Ktrans, 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 Ktrans, 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.