Abstract
No validated biological markers (or biomarkers) currently exist for appropriately selecting patients with cancer for antiangiogenic therapy. Nor are there biomarkers identifying escape pathways that should be targeted after tumors develop resistance to a given antiangiogenic agent. A number of potential systemic, circulating, tissue and imaging biomarkers have emerged from recently completed phase I–III studies. Some of these are measured at baseline (for example VEGF polymorphisms), others are measured during treatment (such as hypertension, MRI-measured Ktrans, circulating angiogenic molecules or collagen IV), and all are mechanistically based. Some of these biomarkers might be pharmacodynamic (for example, increase in circulating VEGF, placental growth factor) while others have potential for predicting clinical benefit or identifying the escape pathways (for example, stromal-cell-derived factor 1α, interleukin-6). Most biomarkers are disease and/or agent specific and all of them need to be validated prospectively. We discuss the current challenges in establishing biomarkers of antiangiogenic therapy, define systemic, circulating, tissue and imaging biomarkers and their advantages and disadvantages, and comment on the future opportunities for validating biomarkers of antiangiogenic therapy.
Key Points
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There are no validated biomarkers for selecting patients who will respond to antiangiogenic therapy; however, a number of systemic, circulating, tissue and imaging biomarkers are emerging and need to be prospectively validated
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Antiangiogenic therapy can prune tumor vessels and 'normalize' the remaining vasculature, which decreases vessel diameter, vascular basement membrane thickness, vascular permeability, interstitial fluid pressure and increases pericyte coverage
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A 'vascular normalization index' is associated with increased overall survival in patients with recurrent glioblastoma treated with cediranib, a pan-VEGFR tyrosine kinase inhibitor
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Baseline levels of VEGF in tumors or the circulation seem to correlate with the outcome for some disease-agent combinations (bevacizumab with chemotherapy in metastatic breast cancer) but not others (metastatic colorectal cancer)
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The most prevalent toxic effect of antiangiogenic therapy is hypertension, which when severe might be associated with certain genotypes but also with a better outcome in patients with metastatic breast cancer
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VEGF and placental growth factor levels increase after anti-angiogenic treatment, but other biomarkers are associated with poor outcome, which suggests that these pathways have a role in resistance to anti-VEGF therapies
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Acknowledgements
The authors thank the members of the Steele Lab, especially M. Ancukiewicz, Y. Boucher, E. di Tomaso, and L. Xu and M. Buyse, H. Chen, A. Grothey, C. Hudis, R. Horvitz, and A. Marshall for their helpful comments on this manuscript. The authors' work is supported by grants from the National Cancer institute P01-CA80124, P41-rr14075, R01-CA115767, R01-CA85140, R01CA126642, R21-CA99237, R21-CA117079, R01-CA129371, R01CA57683, K24-CA125440, Federal share/NCI Proton Beam Program income, M01-RR-01066, Harvard Clinical and Translational Science Center (CTSC) grant; the National Foundation for Cancer research; the Richard and Nancy Simches Endowment for Brain Tumor Research; the Montesi Family Fund; and MIND institute.
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R. K. Jain declares he is a Consultant for AstraZenenca, Dyax, Millenium and SynDevRx. He is on the Speakers' Bureau for Pfizer and Roche, and receives grant/research support from AstraZenenca and Dyax. He is a stockholder for SynDevRx. C. G. Willett is on the Speakers' Bureau for Genentech. A. X. Zhu declares he is a consultant for Bayer and Genentech. T. T. Batchelor declares he is a consultant for Exelixis, EMD-Serono, Genentech and ImClone Systems. He receives grant/research support from AstraZeneca and Millenium, and is on the Speakers Bureau for Schering–Plough. A. G. Sorensen declares he is a consultant for AstraZeneca, Genentech and Millenium and also receives grant/research support from AstraZeneca, Genentech, Exelixis, Millenium, Novartis and Schering–Plough. The others authors declare no competing interests.
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Jain, R., Duda, D., Willett, C. et al. Biomarkers of response and resistance to antiangiogenic therapy. Nat Rev Clin Oncol 6, 327–338 (2009). https://doi.org/10.1038/nrclinonc.2009.63
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DOI: https://doi.org/10.1038/nrclinonc.2009.63
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