MMR+ AND AVASTIN BENEFIT

Hello. I am David Kerr, Professor of Cancer Medicine at the University of Oxford and past President of the European Society for Medical Oncology. Today I would like to talk about a very interesting study from the Journal of the National Cancer Institute ^[1] that has furthered our search for the holy grail, a biomarker that may allow us to select patients who would benefit most from bevacizumab. This is the National Surgical Adjuvant Breast and Bowel Project (NSABP) adjuvant colorectal study C-08. Michael O'Connell and colleagues had looked at the addition of 1 year of bevacizumab to conventional adjuvant chemotherapy with FOLFOX.^[2] The results of that trial were negative. However, what they have done here is a post hoc analysis, a subset analysis looking at molecular markers, to see if they can find any correlations between the genotype of the cancer and patients who might respond best to bevacizumab. It is a well-conducted study. They identified 12.5% of MMR-deficient tumors that seem to give a significantly better survival benefit with bevacizumab compared with the majority of those with MMR-proficient tumors. It was an immunohistochemical study using well-recognized techniques, and the laboratory stuff is very sound indeed. The statistical analysis using the Cox proportional hazards model was entirely appropriate. It showed a hazard ratio of 0.52 for patients with MMR-deficient tumors, a P value of .02, and a reasonably wide confidence interval compared with the hazard ratio of almost exactly 1 for patients with MMR-proficient tumors.

This comes with all the data, warning that it is a post hoc analysis. It is a fishing exercise. It wasn't preplanned, but the results are very interesting. Is it biologically plausible? It could be. We know that MMR-deficient tumors are hypermutated from the Cancer Genome Atlas. These tumors are very highly immunogenic, and there does seem to be a role for vascular endothelial growth factor E (VEGFE) in avoiding or escaping somewhat from immune surveillance. The authors presented a plausible biological rationale for how the combination of bevacizumab and chemotherapy could reduce a number of circulating regulatory T cells. Therefore, this might be the group of patients that would benefit most from bevacizumab in the adjuvant setting for colon cancer.

This is a very interesting and provocative study, but of course it requires confirmation from larger studies, so watch this space. This is possibly one step forward in the search for the holy grail of a bevacizumab marker, but further work needs to be done.