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. The Oncologist 2010;15:577-583

Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation

“…We and others have demonstrated that anti-VEGFR therapy is invariably associated with increases in PlGF and decreases in plasma sVEGFR2 across different anti-VEGF tyrosine kinase inhibitors (e.g. cediranib, sorafenib, vandetanib, sunitinib) and different cancers (10,(31)(32)(33)(34)(35)(36). Thus, data from our study support the notion that PlGF and sVEGFR2 should be further explored as pharmacodynamic biomarkers (i.e., surrogate biomarkers of biological activity).…”

“…Furthermore, consistent with the results from a study of cediranib in rGBM (10), we detected an association between sVEGFR1 levels after 4 wk of treatment and PFS after cediranib/chemoradiation in nGBM. We previously proposed that sVEGFR1-a negative regulator of the VEGF pathway-is a potential resistance biomarker to anti-VEGF therapy (31). However, because cediranib significantly decreases sVEGFR1 levels in circulation, future studies should determine if the associations observed are because of the biological effects of sVEGFR1 or because of "pharmacodynamic" changes in its level as a result of treatment.…”

A phase II trial of thalidomide in patients with refractory uterine carcinosarcoma and correlation with biomarkers of angiogenesis: A Gynecologic Oncology Group study

“…This correlation is consistent with the reported anti-angiogenic activity of sVEGFR-2 and inhibition of xenograft tumor growth by gene therapy with soluble sVEGFR-1, -2, and -3 [24][25][26]. While some studies reported correlations of high sVEGFR status with poorer prognosis of cancer patients [27][28][29], studies which evaluated the ratio of sVEGFR-1 to sVEGF reported that low sVEGFR-1 associated with high VEGF was associated with poorer prognosis [30,31]. The association of high IGFBP1 levels with worse survival is consistent with published studies of mortality in older adults [32,33].…”

Growing tumor vessels: More than one way to skin a cat – Implications for angiogenesis targeted cancer therapies

“…In metastatic breast cancer, genetic polymorphisms of the VEGFR1 and VEGFR2 may be associated with the clinical prognosis (Schneider et al, 2008). In rectal cancer, the circulating soluble VEGFR1 (sVEGFR1) is suggested to be a predictor of survival performance in neoadjuvant treatment with bevacizumab-containing radiochemotherapy (Duda et al, 2010). Furthermore, some evidence exists concerning a prognostic significance of circulating endothelial cells reflecting active angiogenesis (Ronzoni et al, 2010).…”