Use of plasma angiome to predict PFS in patients with metastatic colorectal cancer (mCRC) treated with capecitabine, oxaliplatin, and bevacizumab (XELOX-A)

Abstract

Background: Biomarkers that predict benefit and define mechanisms of resistance to VEGF inhibitors are urgently needed. Methods: Plasma samples from patients (pts) treated on a phase II trial of XELOX-A in mCRC were analyzed via a multiplex ELISA platform (SearchLight; Aushon Biosystems, Inc.) for 44 factors related to tumor growth, angiogenesis, and inflammation. This platform was extensively optimized for use in cancer patients and nearly all factors had coefficients of variation between 10-20%. Patterns of expression were analyzed at baseline and on-treatment (day 28). Baseline and percent change from baseline (PCFB) values were correlated with progression free survival (PFS) using univariate Cox proportional hazard regression models and multivariate Cox models with leave-one-out cross validation. Results: 38 pts were evaluable at both baseline and on-treatment. Spearman's rank correlation coefficients were calculated for all pairs of analytes at both baseline and PCFB. Unsupervised hierarchical clustering of analytes was also performed to produce dendrogram plots. Data indicate that several analyte clusters reflect known biological categories. Predictors of PFS found to be significant using univariate models included: baseline analytes - von Willebrand Factor (p=0.001), angiopoietin-2 (p=0.034), VEGF-C (p=0.075); and PCFB analytes - TGFb2 (p=0.011), osteopontin (p=0.013), TGFb1 (p=0.0149), and IGF-1 (p=0.05). Leave-one-out cross validation analysis was performed to identify potential baseline and PCFB signatures for PFS. Kaplan-Meier plots and log-rank tests were also used to assess how well the set of analytes predicted the outcome of interest. Conclusions: Multiplex angiome analysis defines biologically and clinically informative patterns of expression. The current analysis has identified a profile that may predict for clinical benefit for mCRC patients treated with the VEGF inhibitor, bevacizumab. Confirmatory studies from separate datasets are now in progress.