DLL4 expression is a prognostic marker and may predict gemcitabine benefit in resected pancreatic cancer

• Published in: British journal of cancer Vol. 115; no. 10; pp. 1245 - 1252
• Main Authors: Drouillard, A, Puleo, F, Bachet, J B, Ouazzani, S, Calomme, A, Demetter, P, Verset, G, Van Laethem, J L, Maréchal, R
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 08.11.2016; Cancer Research UK
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic - therapeutic use; Biomarkers, Tumor - metabolism; Cancer; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Chemotherapy, Adjuvant - methods; Deoxycytidine - analogs & derivatives; Deoxycytidine - therapeutic use; Disease-Free Survival; Female; Humans; Immunohistochemistry - methods; Intercellular Signaling Peptides and Proteins - metabolism; Kaplan-Meier Estimate; Life Sciences; Male; Middle Aged; Molecular Diagnostics; Multivariate Analysis; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Prognosis; Receptor, Notch1 - metabolism; Receptor, Notch3 - metabolism; Immunohistochemistry; Anti-Dll4; Biomarker; Chemoresistance; Blockade; Pancreatic Cancer; Cells; Vasculature; Dll4; Poor-Prognosis; Angiogenesis; Contributes; Notch1; Notch3; Inhibits Tumor-Growth; Differentiation
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2016.319

There is an increasing interest for Notch signalling pathway and particularly Delta-like ligand 4 (DLL4) as potential therapeutic target to improve outcome for patients with pancreatic ductal adenocarcinoma (PDAC). Using immunohistochemistry (IHC) and tissue microarray (TMA), we assessed the expression patterns of DLL4, Notch1 and Notch3 in 151 patients from two independent cohorts of resected PDAC. We investigated the prognostic and the predictive significance of these proteins. High IHC DLL4 expression in cancer cells was associated with worse overall survival (OS) and disease-free survival (DFS) than low DLL4 expression (median OS: 12.9 vs 30.4 months, P=0.004 and median DFS: 8.8 vs 17.4 months, P=0.02). High DLL4 expression remained a significant negative prognostic factor in multivariate analysis (HR for OS: 2.1, P=0.02 and HR for DFS: 2.0, P=0.02). Low DLL4 abundance was associated with a longer OS-only for patients who received an adjuvant gemcitabine-based chemotherapy (P<0.001) but not for patients who did not receive gemcitabine (P=0.72). Furthermore, the interaction test for adjuvant gemcitabine therapy was statistically significant (P<0.001). The validating cohort recapitulated the findings of the training cohort. Low DLL4 abundance in tumour cells may predict the benefit from adjuvant gemcitabine therapy after PDAC resection.