title: Serum protein profiling reveals baseline and pharmacodynamic biomarker signatures associated with clinical outcome in mCRC patients treated with chemotherapy ± cediranib.
abstract: BACKGROUND
  This study evaluated soluble serum proteins as biomarkers to subset patients with metastatic colorectal cancer (mCRC) treated with chemotherapy±cediranib, a vascular endothelial growth factor (VEGF) signalling inhibitor (VEGFi). Exploring biomarkers at pre- and on-treatment may identify patient subgroups showing clinical benefit on cediranib combination.
  
  
  METHODS
  Two hundred and seven serum proteins were analysed in 588 mCRC patients at pre- and on-treatment with chemotherapy (FOLFOX/CAPOX)±cediranib 20 mg. Patients were enrolled in the phase III trial HORIZON II. We correlated baseline biomarker signatures and pharmacodynamic (PD) biomarkers with PFS and OS.
  
  
  RESULTS
  We identified a baseline signature (BS) of 47 biomarkers that included VEGFA, VEGFD, VEGFR2, VEGFR3 and TIE-2, which defined two distinct subgroups of patients. Patients treated with chemotherapy plus cediranib who had 'high' BS had shorter PFS (HR=1.82, P=0.003) than patients with 'low' BS. This BS did not correlate with PFS of the patients treated with chemotherapy plus placebo. In addition, we identified a profile of 16 PD proteins on treatment associated with PFS (HR=0.58, P<0.001) and OS (HR=0.52, P<0.001) in patients treated with chemotherapy plus cediranib. This PD profile did not correlate with PFS and OS in patients treated with chemotherapy plus placebo.
  
  
  CONCLUSIONS
  Serum proteins may represent relevant biomarkers to predict the outcome of patients treated with VEGFi-based therapies. We report a BS and PD biomarkers that may identify mCRC patients showing increased benefit of combining cediranib with chemotherapy. These exploratory findings need to be validated in future prospective studies.
authors.affiliation: AstraZeneca, Oncology iMED, Alderley Park, Macclesfield SK10 4TG, UK.
authors.forename: A J C
authors.initials: AJ
authors.lastname: Pommier
authors.affiliation: AstraZeneca, Oncology iMED, Alderley Park, Macclesfield SK10 4TG, UK.
authors.forename: R
authors.initials: R
authors.lastname: Shaw
authors.affiliation: AstraZeneca, Oncology iMED, Alderley Park, Macclesfield SK10 4TG, UK.
authors.forename: S K M
authors.initials: SK
authors.lastname: Spencer
authors.affiliation: AstraZeneca, Oncology iMED, Alderley Park, Macclesfield SK10 4TG, UK.
authors.forename: S R
authors.initials: SR
authors.lastname: Morgan
authors.affiliation: 1] Instituto do Cancer do Estado de São Paulo, Universidade de São Paulo, São Paulo, Brazil [2] Centro de Oncologia, Hospital Sírio Libanês, São Paulo, Brazil.
authors.forename: P M
authors.initials: PM
authors.lastname: Hoff
authors.affiliation: AstraZeneca, Oncology iMED, Alderley Park, Macclesfield SK10 4TG, UK.
authors.forename: J D
authors.initials: JD
authors.lastname: Robertson
authors.affiliation: AstraZeneca, Oncology iMED, Alderley Park, Macclesfield SK10 4TG, UK.
authors.forename: S T
authors.initials: ST
authors.lastname: Barry
authors.affiliation: 1] AstraZeneca, Oncology iMED, Alderley Park, Macclesfield SK10 4TG, UK [2] Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Jürgensmeier
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D001798:Blood Proteins / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D011799:Quinazolines / Q000627:therapeutic use*; D016896:Treatment Outcome; D007211:Indoles
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D001798:Blood Proteins; D011799:Quinazolines; C500926:cediranib; D007211:Indoles