Epidermal Growth Factor–like Domain 7 Predicts Response to First-Line Chemotherapy and Bevacizumab in Patients with Metastatic Colorectal Cancer

Abstract

The number of approved antiangiogenic drugs is constantly growing and emphasizes the need for predictive biomarkers. The aim of this study was to analyze the predictive value of epidermal growth factor-like domain 7 (EGFL7) and microRNA-126 (miR126) to first-line chemotherapy combined with bevacizumab, in patients with metastatic colorectal cancer (mCRC). A total of 158 patients from two different, but comparable, cohorts were included. Analyses were performed on tumor tissue from the primary tumor either based on a whole-tumor resection or an endoscopic biopsy. EGFL7 was analyzed by immunohistochemistry (IHC) and miR126 by in situ hybridization (ISH). Both biomarkers were quantified by image-guided analyses. Endpoints were response rate (RR) and progression-free survival (PFS). The EGFL7 vessel area (VA) in tumor resections was closely related to treatment response with a median EGFL7 VA in responding patients of 4 [95% confidence interval (CI), 4-6] compared with 8.5 (95% CI, 7-11) in nonresponders, P ¼ 0.0008. This difference translated into a borderline significant difference in PFS (P ¼ 0.06). Furthermore, a significant relationship between high EGFL7 VA and KRAS mutation was detected (P ¼ 0.049). The results showed no significant relationship between the miR126 VA and the clinical endpoints. Our study suggests a predictive value of EGFL7 in regard to first-line chemotherapy and bevacizumab in patients with mCRC and supports the mechanism of a dual blocking of the vascular endothelial growth factor-A and EGFL7 axis in this setting. Mol Cancer Ther; 13(9); 2238-45. Ó2014 AACR.

Prognostic importance of circulating epidermal growth factor-like domain 7 in patients with metastatic colorectal cancer treated with chemotherapy and bevacizumab

“…In reference to previously published data on this cohort 12 we found no relationship between tumor expression of EGFL7 and the present cir-EGFL7 data. These comparisons across data furthermore indicate that tumors from patients with the rs9411215 GG genotype presented with a lower EGFL7 tumor expression but this is based on a rather small subsample (N = 40).…”

“…This is especially the case considering our previous studies demonstrating a relationship between RR and EGFL7 tumor tissue expression levels 11, 12 . In addition to multiple methodological differences (formalin fixed paraffin embedded tissue versus serum, immunohistochemistry versus enzyme-linked immunosorbent assay (ELISA), subjective/semi-quantitative versus quantitative assessment, etc.)…”

“…Recent studies have indicated that high tumor expression levels of EGFL7 may be associated with poor prognosis in several different malignancies 12–16 . Furthermore, we have previously shown a relationship between high expression levels of EGFL7 in CRC tissue and reduced response rate (RR) in the metastatic setting 11, 12 , and antibodies targeting EGFL7 have demonstrated efficacy in early phases of clinical testing 17 .…”

“…Furthermore, we have previously shown a relationship between high expression levels of EGFL7 in CRC tissue and reduced response rate (RR) in the metastatic setting 11, 12 , and antibodies targeting EGFL7 have demonstrated efficacy in early phases of clinical testing 17 . In order to further characterize the clinical value of EGFL7 it is necessary to address it in the circulation and investigate how this pro-angiogenic protein is influenced by disease and treatment.…”

“…In the extracellular matrix, EGFL7 supports EC adhesion and migration 7, 9 , protects the ECs from apoptosis 10 , and is important for tube formation 7 and guiding of endothelial sprouts 9 . Recent studies have suggested a relationship between efficacy of first line treatment and tumor expression of EGFL7 11, 12 , but the role of circulating EGFL7 (cir-EGFL7) in this context has so far not been explored. The possible influence of variations in the EGFL7 gene also calls for elucidation.…”