Abstract P2-09-28: Integrated Gene Expression and MRI Analysis To Assess Early Therapeutic Response to Bevacizumab in Primary Breast Cancer
Authors: Mehta S , Buffa FM , Li SP , Hughes NP , Adams RF , Adwani A , Taylor NJ , Levitt NC , Padhani AR , Makris A , Harris AL. 
Published: April 2011

Background: Bevacizumab is an approved drug for advanced breast cancer alongside chemotherapy. To date there is no biomarker proven to be effective in patient stratification. To address this, a window of opportunity study was designed where bevacizumab is administered as a short-term first line treatment with a detailed pharmacodynamic assessment to identify the patients who are most likely to benefit from this therapy. This assessment consisted of Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) and gene expression analysis.

Method: This is an on going two-centre, Phase II, non-randomised study. 43 locally advanced breast cancer patients aged &gt;18 years, with performance status 0-1 who have adequate bone marrow, renal and liver functions have been enrolled. A single infusion of bevacizumab (15mg/kg) was given prior to commencement of neoadjuvant chemotherapy. DCE-MRI and core biopsies for exon gene array analysis were performed both at baseline and 2 weeks after bevacizumab. Pharmacokinetic modelling of DCE-MRI was used to quantify the volume transfer constant Ktrans, the rate constant kep, and the fractional volume of the extra-vascular extracellular space ve. The median pharmacokinetic parameter values over the tumour volumes of interest were then computed both pre-and post-bevacizumab.

Results: Our initial gene expression analysis from 21 patients showed a high variability in the response. This was true for both single gene analysis and pathway signatures. In particular the expression fold changes of hypoxia and proliferation signatures after bevacizumab ranged from a minimum of 0.6 fold decrease to a maximum of 4.3 fold increase. Interestingly, fold changes in both these signatures were significantly positively correlated (Spearman rho=0.81, P&lt;0.001). Changes in the proliferation signature were significantly inversely correlated with changes in mean and median ve (rho=-0.57, P&lt;0.01 in both cases). Changes in the hypoxia signature were significantly inversely correlated with changes in mean and median kep (rho=-0.48, p=0.03 and rho=-0.58, p=0.007 respectively). Significantly over-represented pathways amongst genes up-regulated after bevacizumab were T-cell activation, inflammation, PDGF and apoptosis signalling. Discussion: Our initial results provide several potentially important avenues for further research, which may be useful in the identification of new therapeutic approaches. For example, the unexpected correlation of induction of hypoxia and proliferation in the same tumours has important implications for combination therapy. Furthermore, patients whose tumours showed the largest reduction in kep, a measure of vascular leakiness, also showed the greatest increase in hypoxia. In addition, patients who experienced the largest reduction in ve showed the highest fold change in proliferation. Although these results are preliminary and will need to be confirmed at study completion, they illustrate how the integrated analysis of DCE-MRI pharmacokinetic parameters and the corresponding gene expression profiles may enable an improved understanding of the mechanisms governing response and resistance to bevacizumab.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-28.