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 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.

Integrated Pharmacodynamic Analysis Identifies Two Metabolic Adaption Pathways to Metformin in Breast Cancer

“…Non-parametric rank product (R package and version) was used to discover the genes with consistent statistically significant fold change (probability of false positive < 0.05) between pre- and post-metformin treatment, among all patients were selected. This approach was preferred with respect to EdgeR ( Anders and Huber, 2010 ) and Deseq ( McCarthy et al., 2012 , Robinson et al., 2010 ) as in datasets with high variability and paired samples (pre and post- treatment) non parametric methods tend to work better in our previous studies ( Mehta et al., 2016 ); however analysis with EdgeR (version 3.16.5) and Deseq (version 1.26.0) was also done and did not change the main conclusions.…”

Non-invasive tumor genotyping using radiogenomic biomarkers, a systematic review and oncology-wide pathway analysis

“…To increase insight into underlying genomics of MR-perfusion parameters a study associated gene expression profiles with a heterogeneous centripetal perfusion phenotype [ 116 ] and another study associated perfusion parameters with regulatory non-coding transcripts of RNA associated with early metastasis [ 126 ]. Radiogenomics was applied for monitoring of anti-VEGF treatment by measuring pre- and post-treatment perfusion and associated differential gene expression [ 119 ]. Additionally, a qualitative imaging model including tumor heterogeneity and enhancement predicted expression of immune-response genes [ 114 ].…”

Role of MRI to Assess Response to Neoadjuvant Therapy for Breast Cancer

“…A study of DCE-MRI performed before and after a dose of bevacizumab, an antibody that inhibits angiogenesis, showed that the K trans of the tumor on pretreatment MRI was the strongest predictor of response to therapy, and that tumors with good response had downregulation of angiogenesis gene signatures. 128 A study of DCE-MRI in locally advanced breast cancer patients found that the centripetal enhancement pattern is associated with increased expression of PARP6. 129 FIGURE 14: A 52-year-old woman with triple-positive (ER, PR, and HER2-positive) high-grade invasive ductal carcinoma evaluated with breast MRI before and after four cycles neoadjuvant chemotherapy (a: first postcontrast subtraction, b: T 2 -weighted).…”