David Kerr, Professor of Cancer Medicine at University of Oxford, United Kingdom, and past President of ESMO, wrote about an article published in the Journal of Clinical Oncology by Lambrechts and colleagues, which looked at predictive markers for the antiangiogenic drug bevacizumab.
All of us understand the impact that bevacizumab has had across a range of metastatic tumor types on slowing the progression of disease. This drug is widely used around the world. One of the "holy grails" has involved finding markers that would allow us to select and identify patients who will benefit most. A huge amount of work has been performed to find such markers, and in this article the author has managed to distill the research to give us an idea about which of these many markers may be most successful in the clinic. The candidates actually turn out to be quite a small number of markers.
When we consider circulating markers, then short-form VEGF-A (vascular endothelial growth factor-A) looks as though it may be a likely candidate. When we look at the tumor tissue itself, expression of VEGFR-1 -- the vascular endothelial growth factor type 1 receptor -- if it is expressed at low levels, is a marker of greater likelihood of response and clinical benefit from treatment with bevacizumab. Similarly, tumor expression of low levels of neuropilin-1 has the same effect.
Some genetic work looking at the germline response is consistent with this. A set of SNPs, single nucleotide polymorphisms, in the genes encodes VEGFR-1. Those SNPs, which are associated with relatively high levels of expression of the receptor, are associated with a lower chance of response to bevacizumab. Thus, we see an internal consistency. Not only are these the markers that have been statistically identified as being those most likely to help us select patients who will benefit most, but there is also an entirely plausible underlying biology that stretches all the way from preclinical studies through to the clinic that supports use of these markers.
At the moment, these markers are not validated because no prospective study has stratified or selected patients on the basis of these markers. These authors propose to undertake a study, which they call MERiDiAN, in patients with metastatic breast cancer in which they will stratify patients on the basis of circulating levels of short VEGF-A. This will be the proof of the pudding and may at last shed some interesting light on what has proven an elusive concept: the ability to identify markers for a drug like bevacizumab, which functions at the interface between the tumor and the stroma and therefore affects those cells that are most easy to manipulate -- cancer cells, whether cell lines, explants, and so on. The answer does not lie entirely there, hence the relative difficulty.
Nevertheless, this is a masterful review. The authors collected the data beautifully and, best of all, tell us what we need to do next in order to be able to validate these findings and take a further step toward clinically validating a useful marker for this important drug.
References
Lambrechts D, Lenz HJ, de Haas S, et al. Markers of response for the antiangiogenic agent bevacizumab. J Clin Oncol. 2013;31:1219-1230.
Biomarkers of Antiangiogenic Therapy: How Do We Move From Candidate Biomarkers to Valid Biomarkers?
http://cancerfocus.org/forum/showthread.php?t=3372