title: Correlation of lactate dehydrogenase isoenzyme profile with outcome in patients with advanced colorectal cancer treated with chemotherapy and bevacizumab or cediranib: Retrospective analysis of the HORIZON I study.
abstract: BACKGROUND
  Bevacizumab improves outcome for patients with advanced colorectal cancer (CRC) when added to chemotherapy. The HORIZON I trial resulted in similar outcome with bevacizumab or cediranib, a small-molecule tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF) receptor, as treatment of advanced CRC. The spectrum of lactate dehydrogenase (LDH) isoenzyme expression was examined in serum samples of HORIZON I participants to identify biomarkers predictive of efficacy of VEGF pathway inhibitors.
  
  
  METHODS
  Total LDH levels, as well as LDH isoenzyme levels in frozen baseline serum samples, were retrospectively evaluated. Total LDH serum levels measured during the study, progression-free survival (PFS), and overall survival (OS) were available from the HORIZON I study data.
  
  
  RESULTS
  Total LDH levels measured in the frozen serum samples correlated with those measured in fresh samples. The expected reciprocal correlation was found between hypoxic and oxic LDH isoenzymes. High total LDH correlated with shorter PFS, and high hypoxia-related LDH isoenzymes correlated with shorter PFS and OS. The difference in outcome of the cediranib-treated patients vs. those treated with bevacizumab was not substantially different in the various LDH isoform expression subgroups. In patients with a hypoxic LDH pattern of expression, there was a nonsignificant trend of better outcome in cediranib-treated patients.
  
  
  CONCLUSIONS
  Evaluation of total LDH and its isoforms in frozen serum samples is feasible. High total LDH and high hypoxic LDH isoenzymes were associated with poor prognosis. Further studies are needed to evaluate the predictive value of LDH isoenzyme expression pattern for VEGF-pathway inhibition efficacy.
authors.affiliation: Institute of Oncology, Sheba Medical Center, Tel-Hashomer, Israel; Division of Medical Oncology, Department of Medicine, University of Ottawa, Canada. Electronic address: bar.jair@gmail.com.
authors.forename: Jair
authors.initials: J
authors.lastname: Bar
authors.affiliation: AstraZeneca, Alderley Park, United Kingdom.
authors.forename: Stuart
authors.initials: S
authors.lastname: Spencer
authors.affiliation: AstraZeneca, Alderley Park, United Kingdom.
authors.forename: Shethah
authors.initials: S
authors.lastname: Morgan
authors.affiliation: AstraZeneca, Alderley Park, United Kingdom.
authors.forename: Laura
authors.initials: L
authors.lastname: Brooks
authors.affiliation: The Royal Marsden NHS Foundation Trust, London, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Cunningham
authors.affiliation: AstraZeneca, Alderley Park, United Kingdom.
authors.forename: Jane
authors.initials: J
authors.lastname: Robertson
authors.affiliation: AstraZeneca, Alderley Park, United Kingdom; Yale School of Medicine, Department of Medical Oncology, New Haven, CT.
authors.forename: Juliane M
authors.initials: JM
authors.lastname: Jürgensmeier
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Ottawa, Canada.
authors.forename: Glenwood D
authors.initials: GD
authors.lastname: Goss
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000401:mortality; D005472:Fluorouracil; D006801:Humans; D007527:Isoenzymes / Q000097:blood; D053208:Kaplan-Meier Estimate; D007770:L-Lactate Dehydrogenase / Q000097:blood*; D002955:Leucovorin; D009944:Organoplatinum Compounds; D011379:Prognosis; D011799:Quinazolines / Q000008:administration & dosage; D012189:Retrospective Studies; D016896:Treatment Outcome; D007211:Indoles
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D005472:Fluorouracil; D007527:Isoenzymes; D007770:L-Lactate Dehydrogenase; D002955:Leucovorin; D009944:Organoplatinum Compounds; D011799:Quinazolines; C500926:cediranib; D007211:Indoles
keywords: Angiogenesis inhibitors; FOLFOX regimen; Hypoxia; LDH; Predictive biomarkers