Plasma soluble VEGFR-1 is a potential dual biomarker of response and toxicity for bevacizumab with chemoradiation in locally advanced rectal cancer

Abstract

We explored plasma and urinary concentrations of two members of the vascular endothelial growth factor (VEGF) family and their receptors as potential response and toxicity biomarkers of bevacizumab with neoadjuvant chemoradiation in patients with localized rectal cancer. The concentrations of VEGF, placental growth factor (PlGF), soluble VEGF receptor 1 (sVEGFR-1), and sVEGFR-2 were measured in plasma and urine at baseline and during treatment. Pretreatment values and changes over time were analyzed as potential biomarkers of pathological response to treatment as well as for acute toxicity in patients with locally advanced rectal cancer treated prospectively in 2002-2008 with neoadjuvant bevacizumab, 5-fluorouracil, radiation therapy, and surgery in a phase I/II trial. Of all biomarkers, pretreatment plasma sVEGFR-1-an endogenous blocker of VEGF and PlGF, and a factor linked with "vascular normalization"-was associated with both primary tumor regression and the development of adverse events after neoadjuvant bevacizumab and chemoradiation. Based on the findings in this exploratory study, we propose that plasma sVEGFR-1 should be further studied as a potential biomarker to stratify patients in future studies of bevacizumab and/or cytotoxics in the neoadjuvant setting.

Figure 1.

Correlation of baseline soluble vascular endothelial growth factor receptor 1 (sVEGFR-1) concentration with pathological downstaging in rectal cancer after bevacizumab with chemoradiation. Shown are relationships between baseline sVEGFR-1 and the probabilities of complete pathological response (ypT₀) and stage T3 residual disease (ypT₃). The nonlinear curve was estimated by fitting logistic regression with restricted cubic splines, after double-log transformation of sVEGFR-1 concentration. The superimposed rectangles depict the distribution of ypT grade of residual disease by tertile groups of sVEGFR-1 (i.e., <84 pg/ml, 84–154 pg/ml, and >154 pg/ml). Points and triangles represent sVEGFR-1 measurements from patients who had a less than complete (ypT_1–3) and complete (ypT₀) pathological response, respectively (one measurement of >6 ng/ml not shown).

Figure 2.

Correlation of soluble vascular endothelial growth factor receptor 1 (sVEGFR-1) concentration with grade 3 adverse events (AEs) in rectal cancer patients after bevacizumab with chemoradiation. (A, B): Relationships between baseline sVEGFR-1 and mean number of adverse events per patient reported during chemoradiation treatment (A) and the probability of occurrence of grade 3 toxicities (B). The nonlinear curve was estimated by Poisson regression (A) or by fitting logistic regression (B) with restricted cubic splines, after double-log transformation of sVEGFR-1 concentration.