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An Observational Study of First-Line Bevacizumab (Avastin) With Fluoropyrimidine-Based Chemotherapy in Participants With Metastatic Colorectal Cancer

ABSTRACT: This multicenter observational study will evaluate the efficacy and safety of first-line bevacizumab (Avastin) in combination with fluoropyrimidine-based chemotherapy in participants with metastatic colorectal cancer (mCRC). Participants for whom the treating physician has decided to initiate first-line fluoropyrimidine based chemotherapy in combination with bevacizumab will be observed for approximately 4 years.

DISEASE(S): Colorectal Cancer,Colorectal Neoplasms

PROVIDER: 2134002 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Objective: Insights about differences in tumor vasculature and how it reacts to VEGF inhibition is limited, but nevertheless of major relevance to anti-angiogenic therapy. In this study we therefore characterize the effect of bevacizumab combined with chemoradiotherapy (CRT), and explore molecular and genetic markers for response prediction to this combination treatment. Material and Methods: In an academic multicentric randomized phase II study, patients with advanced rectal cancer have been treated with bevacizumab (5mg/kg) in combination with capecitabine (1650mg/m2/day) and radiotherapy (45Gy; 1.8Gy/day) with (50mg/m2) or without oxaliplatin prior to surgery. Of 59 patients, tumor tissue and blood samples were collected before treatment and after the first loading dose of bevacizumab but before CRT (week 3). First, cDNA micro-arrays were performed on the biopsies to investigate differences in gene expression of tumors from patients with and without a pathological complete response (pCR) before start of treatment and to identify biological processes affected by bevacizumab delivery. The paraffin embedded tissue was stained for blood vessels (CD31/CD34) combined with α-SMA (pericytes) and CA-IX (hypoxia). To explore candidate blood-based biomarkers ELISA’s were performed for PDGF-AA, PDGF-BB, THBS-1, IL-8, CYR61 and Ang-2. The expression of all markers was correlated with the pathological response of the patients. Results: Differences in tumoral gene expression are observed between patients with and without a pCR, with the first response group presenting a more angiogenic phenotype before start of treatment and changes in angiogenic processes after bevacizumab delivery. One dose of bevacizumab leads to a decrease in the number of pericyte covered blood vessels, a decrease in circulating PDGF-AA, PDGF-BB and Thrombospondin-1. Patients showing a pCR having less pericyte covered blood vessels, more hypoxia, and less circulating PDGF-BB compared to patients who did not have a pCR after bevacizumab treatment with chemoradiation and bevacizumab. Conclusions: The translational data demonstrate that tumors with an angiogenic expression profile respond better to bevacizumab combined with CRT and points towards a possible role for PDGF, CA-IX and pericyte covered blood vessels for the early response prediction to this treatment. Our findings suggest a role for mural cell recruitment and vessel maturation for the susceptibility of the tumor vasculature to bevacizumab treatment. Further validation of our biological observations and hypothesis generating data in randomized trials is needed.

Dataset Information

An Observational Study of First-Line Bevacizumab (Avastin) With Fluoropyrimidine-Based Chemotherapy in Participants With Metastatic Colorectal Cancer

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