Abstract
This study intends to identify biomarkers that could refine the selection of patients with metastatic colorectal cancer (mCRC) for bevacizumab treatment. Pretreatment 36 plasma cytokines and angiogenic factors (CAFs) were first measured by protein microarray analysis in patients who received first-line bevacizumab-containing therapies (discovery cohort, n = 64), and further evaluated by enzyme-linked immunosorbent assay in patients treated on regimens with or without bevacizumab (validation cohort, n = 186). Factor levels were correlated with clinical outcomes, predictive values were assessed using a treatment by marker interaction term in the Cox model. Patients with lower pretreatment levels of hepatocyte growth factor (HGF) or VEGF-A121 gain much more benefit from bevacizumab treatment as measured by progression-free survival (PFS) and overall survival (OS), while angiopoietin-like 4 (ANGPTL4) levels negatively correlated with PFS and response rate following bevacizumab (all adjusted interaction P < 0.05). A baseline CAF signature combining these three markers has greater predictive ability than individual markers. Signature-negative patients showed impaired survival following bevacizumab treatment (PFS, 7.3 vs 7.0 months; hazard ratio [HR] 1.03; OS, 29.9 vs 21.1 months, HR 1.33) compared with signature-positive patients (PFS, 6.5 vs 11.9 months, HR 0.52; OS, 28.0 vs 55.3 months, HR 0.67). These promising results warrant further prospective studies.
Highlights
The identification of predictive biomarkers will be urgently required in achieving the full therapeutic potential of bevacizumab
To overcome some of the deficiencies of earlier investigations, we simultaneously assessed a series of cytokines and angiogenic factors (CAFs) with a commercially available protein microarray which incorporated various markers known to be associated with the effect of bevacizumab in previous studies, first in pretreatment plasma of patients who received first-line bevacizumab-containing therapies from a single-center registry study, and in patients treated on a regimen with or without bevacizumab
This study aims to search for circulating biomarkers that could identify patients likely to benefit from bevacizumab
Summary
The identification of predictive biomarkers will be urgently required in achieving the full therapeutic potential of bevacizumab. Possible baseline predictors of bevacizumab included circulating short VEGF-A isoforms and expression of VEGF receptors (VEGF receptor-1 [VEGFR1] or neuropilin 1 [NRP1]), either in plasma or in tumor tissues[13,14]. The single-arm study design was unable to distinguish between markers associated with general prognosis for the cytotoxic chemotherapy component of the regimen and markers that predict for benefit afforded by bevacizumab. To overcome some of the deficiencies of earlier investigations, we simultaneously assessed a series of cytokines and angiogenic factors (CAFs) with a commercially available protein microarray which incorporated various markers known to be associated with the effect of bevacizumab in previous studies, first in pretreatment plasma of patients who received first-line bevacizumab-containing therapies from a single-center registry study, and in patients treated on a regimen with or without bevacizumab. We explored a “CAF index” that combined individual markers to better serve as a signature for predicting benefit from bevacizumab
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