Abstract
Novel predictive biomarkers are needed to improve patient selection and optimize the use of bevacizumab (B) in metastatic colorectal cancer. We analyzed the potential of five circulating biomarkers to predict B efficacy and monitor response. Peripheral blood samples collected at baseline, at the first clinical evaluation and at progression were available for 129 patients enrolled in the prospective multicentric ITACa trial and randomized to receive FOLFOX4/FOLFIRI (CT) with (64 patients) or without B (65 patients). VEGF-A, eNOS, EPHB4, COX2 and HIF-1α mRNA levels were measured by qRT-PCR. Baseline marker expression levels and their modulation during therapy were analyzed in relation to objective response, progression-free survival and overall survival (OS). VEGF and eNOS expression was significantly correlated in both groups (Spearman’s correlation coefficient = 0.80; P < 0.0001 and 0.75; P < 0.0001, respectively). B-treated patients with >30% reduction in eNOS and VEGF levels from baseline to the first clinical evaluation showed better OS than the others (median OS 31.6 months, 95% CI 21.3–49.5 months and median OS 14.4 months, 95% CI 9.0–22.7 months, respectively, HR 0.38, 95% CI 0.19–0.78, P = 0.008). A reduction in eNOS and VEGF expression from baseline to the first clinical evaluation may indicate a response to B.
Highlights
Bevacizumab (B), a humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF-A), has proven clinical efficacy when used in first- or second-line treatment in association with fluorouracil-based chemotherapy (CT) in metastatic colorectal cancer patients[1,2,3]
We found that baseline circulating levels of biomarkers were not associated with clinical outcome, whereas >30% reduction in endothelial nitric oxide synthase (eNOS) or VEGF levels from baseline to the first evaluation was associated with longer overall survival (OS) than in patients with
With regard to the 3 other biomarkers analyzed (HIF-1α, ephrin type-B receptor 4 (EPHB4) and COX-2), no significant correlations were seen between their variations during treatment and patient outcome
Summary
Bevacizumab (B), a humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF-A), has proven clinical efficacy when used in first- or second-line treatment in association with fluorouracil-based chemotherapy (CT) in metastatic colorectal cancer patients (mCRC)[1,2,3]. An increase in serum VEGF-A concentration after an initial decrease has been proposed as a predictive marker of poor response and of reactive resistance to chemotherapy plus B10. We previously described the role of endothelial nitric oxide synthase (eNOS) polymorphisms as possible predictive biomarkers of B efficacy[11] in patients enrolled in the ITACa (Italian Trial in Advanced Colorectal Cancer) trial, a prospective randomized phase III multicentric study designed to investigate the role of B treatment in mCRC patients[12]. EPHB4 belongs to a large family of receptor tyrosine kinases and mediates arteriovenous differentiation during embryonic development, regulating induction and maturation of newly forming vessels in the adult in both physiological and pathological conditions[15,16,17]
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