title: Contribution of CXCR4 and SMAD4 in predicting disease progression pattern and benefit from adjuvant chemotherapy in resected pancreatic adenocarcinoma.
abstract: BACKGROUND
  Prognosis of patients with pancreatic adenocarcinoma is poor. Many prognostic biomarkers have been tested, but most studies included heterogeneous patients. We aimed to investigate the prognostic and/or predictive values of four relevant biomarkers in a multicentric cohort of patients.
  
  
  METHODS
  A total of 471 patients who had resected pancreatic adenocarcinoma were included. Using tissue microarray, we assessed the relationship of biomarker expressions with the overall survival: Smad4, type II TGF-β receptor, CXCR4, and LKB1.
  
  
  RESULTS
  High CXCR4 expression was found to be the only independent negative prognostic biomarker [hazard ratio (HR) = 1.74; P < 0.0001]. In addition, it was significantly associated with a distant relapse pattern (HR = 2.19; P < 0.0001) and was the strongest prognostic factor compared with clinicopathological factors. In patients who did not received adjuvant treatment, there was a trend toward decrease in the overall survival for negative Smad4 expression. Loss of Smad4 expression was not correlated with recurrence pattern but was shown to be predictive for adjuvant chemotherapy (CT) benefit (HR = 0.59; P = 0.002).
  
  
  CONCLUSIONS
  CXCR4 is a strong independent prognostic biomarker associated with distant metastatic recurrence and appears as an attractive target to be evaluated in pancreatic adenocarcinoma. Negative SMAD4 expression should be considered as a potential predictor of adjuvant CT benefit.
authors.affiliation: Medical University Pierre et Marie Curie, UFR Paris VI, Paris; EA4340 "Epidémiologie et oncogènes des tumeurs digestives", Versailles Saint-Quentin-en-Yvelines University, Versailles; Department of Hepato-Gastroenterology, Pitié-Salpêtrière Hospital, APHP, Paris, France; Department of Gastroenterology, Gastrointestinal cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Brussels. Electronic address: jean-baptiste.bachet@psl.aphp.fr.
authors.forename: J B
authors.initials: JB
authors.lastname: Bachet
authors.affiliation: Department of Gastroenterology, Gastrointestinal cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Brussels.
authors.forename: R
authors.initials: R
authors.lastname: Maréchal
authors.affiliation: Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, and DiaPath, Brussels, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Demetter
authors.affiliation: Department of Biostatistic and Epidemiology (EA 4184), Georges François Leclerc Center, Dijon.
authors.forename: F
authors.initials: F
authors.lastname: Bonnetain
authors.affiliation: Department of Pathology, Beaujon Hospital, APHP, Clichy.
authors.forename: A
authors.initials: A
authors.lastname: Couvelard
authors.affiliation: Medical University Pierre et Marie Curie, UFR Paris VI, Paris; Department of Pathology, Saint Antoine Hospital, APHP, Paris.
authors.forename: M
authors.initials: M
authors.lastname: Svrcek
authors.affiliation: Medical University Pierre et Marie Curie, UFR Paris VI, Paris; Department of Pathology, Pitié-Salpêtrière Hospital, APHP, Paris.
authors.forename: A
authors.initials: A
authors.lastname: Bardier-Dupas
authors.affiliation: Department of Gastroenterology, Beaujon Hospital, APHP, Clichy.
authors.forename: P
authors.initials: P
authors.lastname: Hammel
authors.affiliation: Department of Surgery, Beaujon Hospital, APHP, Clichy.
authors.forename: A
authors.initials: A
authors.lastname: Sauvanet
authors.affiliation: Medical University Pierre et Marie Curie, UFR Paris VI, Paris; Department of Oncology, Saint Antoine Hospital, APHP, Paris; Department of Oncology, Institut Mutualiste Montsouris, Paris.
authors.forename: C
authors.initials: C
authors.lastname: Louvet
authors.affiliation: Medical University Pierre et Marie Curie, UFR Paris VI, Paris; Department of Surgery, Saint Antoine Hospital, APHP, Paris.
authors.forename: F
authors.initials: F
authors.lastname: Paye
authors.affiliation: EA4340 "Epidémiologie et oncogènes des tumeurs digestives", Versailles Saint-Quentin-en-Yvelines University, Versailles; Department of Digestive Oncology, European Georges Pompidou Hospital, APHP, Paris.
authors.forename: P
authors.initials: P
authors.lastname: Rougier
authors.affiliation: EA4340 "Epidémiologie et oncogènes des tumeurs digestives", Versailles Saint-Quentin-en-Yvelines University, Versailles; Department of Surgery, Ambroise Paré Hospital, APHP, Boulogne-Billancourt.
authors.forename: C
authors.initials: C
authors.lastname: Penna
authors.affiliation: Medical University Pierre et Marie Curie, UFR Paris VI, Paris; Department of Surgery, Pitié-Salpêtrière Hospital, APHP, Paris, France.
authors.forename: J C
authors.initials: JC
authors.lastname: Vaillant
authors.affiliation: Medical University Pierre et Marie Curie, UFR Paris VI, Paris; Department of Hepato-Gastroenterology, Pitié-Salpêtrière Hospital, APHP, Paris, France.
authors.forename: T
authors.initials: T
authors.lastname: André
authors.affiliation: Department of Surgery, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Closset
authors.affiliation: Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, and DiaPath, Brussels, Belgium.
authors.forename: I
authors.initials: I
authors.lastname: Salmon
authors.affiliation: EA4340 "Epidémiologie et oncogènes des tumeurs digestives", Versailles Saint-Quentin-en-Yvelines University, Versailles; Department of Pathology, Ambroise Paré Hospital, APHP, Boulogne-Billancourt, France.
authors.forename: J F
authors.initials: JF
authors.lastname: Emile
authors.affiliation: Department of Gastroenterology, Gastrointestinal cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Brussels.
authors.forename: J L
authors.initials: JL
authors.lastname: Van Laethem
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000556:secondary / Q000628:therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D017024:Chemotherapy, Adjuvant; D018450:Disease Progression; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D016016:Proportional Hazards Models; D011446:Prospective Studies; D019718:Receptors, CXCR4 / Q000378:metabolism*; D051901:Smad4 Protein / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; C527276:CXCR4 protein, human; D019718:Receptors, CXCR4; C497796:SMAD4 protein, human; D051901:Smad4 Protein