title: A Novel Biomarker Panel Examining Response to Gemcitabine with or without Erlotinib for Pancreatic Cancer Therapy in NCIC Clinical Trials Group PA.3.
abstract: OBJECTIVE
  NCIC Clinical Trials Group PA.3 was a randomized control trial that demonstrated improved overall survival (OS) in patients receiving erlotinib in addition to gemcitabine for locally advanced or metastatic pancreatic cancer. Prior to therapy, patients had plasma samples drawn for future study. We sought to identify biomarkers within these samples.
  
  
  METHODS
  Using the proximity ligation assay (PLA), a probe panel was built from commercially available antibodies for 35 key proteins selected from a global genetic analysis of pancreatic cancers, and used to quantify protein levels in 20 uL of patient plasma. To determine if any of these proteins levels independently associated with OS, univariate and mulitbaraible Cox models were used. In addition, we examined the associations between biomarker expression and disease stage at diagnosis using Fisher's exact test. The correlation between Erlotinib sensitivity and each biomarkers was assessed using a test of interaction between treatment and biomarker.
  
  
  CONCLUSIONS
  Of the 569 eligible patients, 480 had samples available for study. Samples were randomly allocated into training (251) and validation sets (229). Among all patients, elevated levels of interleukin-8 (IL-8), carcinoembryonic antigen (CEA), hypoxia-inducible factor 1-alpha (HIF-1 alpha), and interleukin-6 were independently associated with lower OS, while IL-8, CEA, platelet-derived growth factor receptor alpha and mucin-1 were associated with metastatic disease. Patients with elevated levels of receptor tyrosine-protein kinase erbB-2 (HER2) expression had improved OS when treated with erlotinib compared to placebo. In conclusion, PLA is a powerful tool for identifying biomarkers from archived, small volume serum samples. These data may be useful to stratify patient outcomes regardless of therapeutic intervention.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00040183.
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: David B
authors.initials: DB
authors.lastname: Shultz
authors.affiliation: School of Medicine, University of California San Francisco, San Francisco, United States of America.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Pai
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: Wayland
authors.initials: W
authors.lastname: Chiu
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: Kendall
authors.initials: K
authors.lastname: Ng
authors.affiliation: Kaiser Permanente Medical Center, San Francisco, United States of America.
authors.forename: Madeline G
authors.initials: MG
authors.lastname: Hellendag
authors.affiliation: Moores Cancer Center, University of California San Diego, La Jolla, CA, United States of America.
authors.forename: Gregory
authors.initials: G
authors.lastname: Heestand
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Chang
authors.affiliation: NCIC Clinical Trials Group, Queen's University, Kingston, Canada.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Tu
authors.affiliation: British Columbia Cancer Agency, Vancouver, British Columbia, CA, United States of America.
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: Moore
authors.affiliation: NCIC Clinical Trials Group, Queen's University, Kingston, Canada.
authors.forename: Wendy R
authors.initials: WR
authors.lastname: Parulekar
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Koong
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004311:Double-Blind Method; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D010919:Placebos; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D010919:Placebos; D003841:Deoxycytidine; D000069347:Erlotinib Hydrochloride; D000093542:Gemcitabine