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

There are no validated predictive biomarkers for antiangiogenic treatments. Serum lactate dehydrogenase (LDH) isoenzymes were measured in patients with advanced colorectal cancer receiving chemotherapy with bevacizumab or cediranib. Patients with high hypoxic-related LDH isoenzymes had poorer prognosis, and a trend of benefit from cediranib vs. bevacizumab. LDH isoenzymes should be further investigated as predictive for benefit from small-molecule antiangiogenic inhibitors vs. bevacizumab. Introduction: 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. Materials and 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. Conclusion: 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. (C) 2014 Elsevier Inc. All rights reserved.