This prospective study was designed to determine whether plasma vascular endothelial growth factor-A short isoforms (pVEGF-Asi) could predict responsiveness to bevacizumab (BV) and to investigate additional circulating biomarkers in metastatic colorectal cancer (mCRC) patients receiving modified FOLFOX6/XELOX in combination with BV (mFOLFOX6/XELOX + BV). Plasma samples obtained before treatment initiation were collected from 100 mCRC patients treated with first-line mFOLFOX6/XELOX + BV. Levels of 11 angiogenesis-related circulating proteins, including pVEGF-Asi, together with 22 cancer-related gene mutations identified in circulating tumor DNA, were evaluated. For the primary endpoint, the hazard ratio (HR) for progression-free survival (PFS), estimated using a Cox proportional hazards model, was prespecified to be <1.15 when comparing patients classified as having high versus low pVEGF-Asi levels based on the median value. The median pVEGF-Asi concentration was 37 pg/ml (range 6.5–262). Comparison of high and low pVEGF-Asi groups yielded an HR for PFS of 1.3 [95% confidence interval (CI) 0.8–2.1; log-rank, P = 0.25], exceeding the predefined criterion of 1.15. Multivariate analysis identified significant associations between PFS and plasma intercellular adhesion molecule-1 (pICAM-1) (≥190.0 versus <190.0 ng/ml; HR 2.1; 95% CI 1.3–3.5), RAS mutation status (mutant versus wild type; HR 2.5; 95% CI 1.5–4.3), and FBXW7 mutation status (mutant versus wild type; HR 2.8; 95% CI 1.2–6.8). Overall survival was significantly correlated with pICAM-1 (HR 2.0; 95% CI 1.1–3.7) and RAS mutations (HR 2.6; 95% CI 1.5–4.6). BV administration did not mitigate the unfavorable PFS associated with elevated pVEGF-Asi levels, indicating that pVEGF-Asi is unlikely to serve as an effective predictive biomarker for mFOLFOX6/XELOX + BV treatment. Additional studies are required to clarify the clinical relevance of circulating ICAM-1 levels and mutations in RAS and FBXW7.
