Abstract
We evaluated the prognostic and predictive use of circulating VEGF-A levels in phase III trials of bevacizumab in colorectal cancer, lung cancer, and renal cell carcinoma. Baseline plasma samples from 1,816 patients were analyzed for VEGF-A using an ELISA, which recognizes the major isoforms with equivalent sensitivity. HR and 95% confidence intervals (CI) for study end points were estimated using Cox regression analysis. A subset of matched archival tumor samples was analyzed for VEGF-A expression using in situ hybridization. Higher VEGF-A levels showed trends toward adverse prognostic significance in the control arms of multiple trials, reaching statistical significance for overall survival (OS) in AVF2107 (highest vs. lowest 50%: HR = 1.76; 95% CI, 1.28-2.41), AVAiL (HR = 1.52; 95% CI, 1.16-2.00), and AVOREN (HR = 1.67; 95% CI, 1.18-2.36). In predictive analyses, the HRs for progression-free survival were similar across low and high VEGF-A subgroups and favored bevacizumab-containing treatment. In the low VEGF-A subgroups, HRs (95% CIs) were 0.61 (0.43-0.87) in AVF2107, 0.71 (0.43-1.16) in E4599, 0.74 (0.59-0.94) in AVAiL (low-dose), 0.89 (0.70-1.13) in AVAiL (high-dose), and 0.56 (0.40-0.78) in AVOREN. Analyses of OS data have shown similar results. No correlation between primary tumor VEGF-A expression and plasma VEGF-A levels was observed. In this comprehensive evaluation, pretreatment total circulating VEGF-A was prognostic for outcome in metastatic colorectal, lung, and renal cell cancers, but it was not predictive for bevacizumab-based treatment benefit.
Highlights
VEGF-A, which exists in humans in multiple isoforms [1], is a proangiogenic ligand that is upregulated in a large proportion of primary malignancies [2]
No correlation between primary tumor VEGF-A expression and plasma VEGF-A levels was observed. In this comprehensive evaluation, pretreatment total circulating VEGF-A was prognostic for outcome in metastatic colorectal, lung, and renal cell cancers, but it was not predictive for bevacizumabbased treatment benefit
Tumor expression levels of VEGF-A have been correlated with vascularization, pathologic stage, metastasis, and poor outcome in patients with metastatic colorectal cancer, non–small cell lung cancer (NSCLC), and metastatic renal cell carcinoma
Summary
VEGF-A, which exists in humans in multiple isoforms [1], is a proangiogenic ligand that is upregulated in a large proportion of primary malignancies [2]. Tumor expression levels of VEGF-A have been correlated with vascularization, pathologic stage, metastasis, and poor outcome in patients with metastatic colorectal cancer (mCRC), non–small cell lung cancer (NSCLC), and metastatic renal cell carcinoma Circulating VEGF-A levels are elevated in a proportion of patients with carcinomas, Authors' Affiliations: Departments of 1Oncology Biomarkers, 2Pathology, 3Biostatistics, 4Biochemical and Cellular Pharmacology, 5BioAnalytical Sciences, and 6Oncology Early Clinical Development, Genentech, Inc., South San Francisco, California; and 7F. The monoclonal antibody bevacizumab, which selectively inhibits VEGF-A signaling, has been extensively examined across multiple tumor types in both combination and single-agent trials. Positive data from clinical trials of multitargeted agents that inhibit VEGF-A signaling, such as the tyrosine kinase inhibitors sunitinib [17] and sorafenib [18], further underscore the value of antiangiogenic strategies in cancer treatment
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