title: DLL4 expression is a prognostic marker and may predict gemcitabine benefit in resected pancreatic cancer.
abstract: BACKGROUND
  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).
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Low DLL4 abundance in tumour cells may predict the benefit from adjuvant gemcitabine therapy after PDAC resection.
authors.affiliation: Department of Gastroenterology and Digestive Oncology, University Hospital of Dijon, Dijon, France.|Digestive Cancer Registry of Burgundy, INSERM U866, University Hospital of Dijon, Dijon, France.
authors.forename: A
authors.initials: A
authors.lastname: Drouillard
authors.affiliation: Department of Gastroenterology and Digestive Oncology, Erasme Hospital, Brussels, Belgium.
authors.forename: F
authors.initials: F
authors.lastname: Puleo
authors.affiliation: Department of Hepatogastroenterology, Pitié Salpêtrière Hospital, APHP, Paris, France.
authors.forename: J B
authors.initials: JB
authors.lastname: Bachet
authors.affiliation: Department of Gastroenterology and Digestive Oncology, Erasme Hospital, Brussels, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: Ouazzani
authors.affiliation: Department of Gastroenterology and Digestive Oncology, Erasme Hospital, Brussels, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Calomme
authors.affiliation: Department of Pathology, Erasme Hospital, Brussels, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Demetter
authors.affiliation: Department of Gastroenterology and Digestive Oncology, Erasme Hospital, Brussels, Belgium.
authors.forename: G
authors.initials: G
authors.lastname: Verset
authors.affiliation: Department of Gastroenterology and Digestive Oncology, Erasme Hospital, Brussels, Belgium.
authors.forename: J L
authors.initials: JL
authors.lastname: Van Laethem
authors.affiliation: Department of Gastroenterology and Digestive Oncology, Erasme Hospital, Brussels, Belgium.|Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: R
authors.initials: R
authors.lastname: Maréchal
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002135:Calcium-Binding Proteins; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017024:Chemotherapy, Adjuvant / Q000379:methods; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D051881:Receptor, Notch1 / Q000378:metabolism; D000071656:Receptor, Notch3 / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D051881:Receptor, Notch1; D000071656:Receptor, Notch3; D003841:Deoxycytidine; D000093542:Gemcitabine