The Queen Elizabeth Hospital and University of Adelaide, Woodville, Australia
Timothy Jay Price , Amanda Rose Townsend , Maressa Bruhn , Chee Lee , Joe Wrin , Aravind Shivasami , Georgia Arentz , Niall C. Tebbutt , David Cunningham , Jenny Hardingham
Background: There remains a need for predictive biomarkers in mCRC to better identify patients who clinically benefit from anti-VEGF therapy, in particular bevacizumab (BEV). The AGITG MAX trial compared capecitabine (C) with capecitabine (+/- mitomycin C (M)) and BEV and PFS was superior in the CB+/-M arm. Here we have taken a panel of pro-angiogenic proteins to assess whether there is a signal for a predictive factor for bevacizumab outcome in the MAX trial tissue population (TTP). Methods: Protein was isolated from FFPE tumour tissue and assayed using custom Bio-plex arrays to assess the expression levels of candidate tumour biomarkers IL-6, IL-8, bFGF, PDGF-BB and VEGF-A. As there are no accepted cutoff points for these analytes we chose the medians of distribution of each of these biomarkers as cutoff points for dichotomization into “high” v “low”. We then correlated levels of the biomarkers with objective response rate, disease-free and overall survival. Results: Total protein was isolated from FFPE tumour sections from 41.5% of patients (n=196) recruited into the MAX clinical trial and assayed for the proteins using a multiplex platform. Patients were generally balanced, tumour tissue population v intention to treat. Median follow up time is 30.2 mths. For patients receiving BEV there was no relationship between the level of IL-6, IL-8, bFGF, PDGF-BB and VEGF-A and PFS and OS. In patients treated with BEV/C vs. C alone, low tumor VEGF-A was predictive of better ORR as compared to those with a high level (ORR 53% vs 38%, p = 0.03). Multivariate analyses showed low VEGF-A expression level was a significant prognostic factor for longer progression free survival (median PFS 9.3 months low VEGF-A v 7.2 months high VEGF-A, multivariate adjusted HR 1.55 (95% CI 1.12-2.13), p = 0.008). Conclusions: We have shown that the chosen panel of pro-angiogenic proteins was not predictive for PFS or OS outcomes when B is added to C in mCRC. However low VEGF-A level did predict for higher ORR and was an independent prognostic marker for PFS in this cohort.
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