P-0268 Notch and DLL4 Expression in Colon Cancer Patients Treated with Bevacizumab

Abstract

ABSTRACT Introduction Delta-like 4 ligand (DLL4)-mediated Notch signalling has emerged as an attractive target for angiogenesis-based cancer therapies, given that DLL4 is an important component of Notch-mediated stem cell self-renewal and vascular development. DLL4-induced Notch signalling mediates tumour-resistance to anti-VEGF therapy by inducing the formation of large vessels and activating multiple pathways in tumours. To investigate mechanisms of resistance to angiogenesis inhibitors, we correlated DLL4 and Notch expression with response and survival in a series of bevacizumab treated colon cancer patients. Methods Notch and DLL4 expression was evaluated by immunohistochemistry (IHC) on 35 primary colon cancer patients enrolled within randomized clinical trials assessing first-line bevacizumab plus chemotherapy. Results Notch positivity was localized to the cytoplasm of malignant epithelial cells. In all, 3 out of 33 (9%) evaluable primary tumours had a high Notch expression and 2 of these (67%) had progressive disease (PD) compared with 2/30 (7%) of Notch negative cases. High levels of membranous and/or cytoplasmic DLL4 immunoreactivity of tumour vessels was observed in 14/31 (45%) evaluable colon cancers. High DLL4 expression was observed in 3/4 cases who had PD. Patients with low levels of DLL4 expression showed a median progression-free survival (PFS) of 10.97 months compared with 8.97 months for patients with high levels. Conclusion Clinical trials investigating the therapeutic efficacy of bevacizumab in colon cancer did not explore the impact of DLL4-Notch pathway on response and clinical outcome. Notwithstanding the limited power of the present analysis, these data seem to suggest that high Notch and DLL4 expression might be involved in tumour resistance to bevacizumab.