Lactate dehydrogenase-5 is an independent prognostic factor in colorectal cancer: implications for future therapies


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S Yeluri1, P Prasad3, B Madhok1, H Thorpe4, SL Perry2, TA Hughes2, KR Prasad1, P Quirke2, DG Jayne1

1Leeds Institute of Molecular Medicine, University of Leeds & St. James's University Hospital, Leeds, UK, 2Leeds Institute of Molecular Medicine, University of Leeds, UK, 3St.James's University Hospital, Leeds, UK, 4Clinical Trials Research Unit, University of Leeds, UK

Abstract

Proffered paper presentation

Background
Recent evidence suggests that cancers undergoing a high level of aerobic glycolysis (Warburgs effect) behave in a more aggressive fashion, with implications for selectively targeting cancer bioenergetics. Lactate dehydrogenase 5 (LDH-5) plays an important role in the control of aerobic glycolysis by regulating the transformation of pyruvate to lactate. This study aimed to investigate the prognostic relevance of LDH-5 in a large clinical series of colorectal cancers, to identify the impact of Warburgs effect on tumour biology and its potential implications for anti-cancer chemotherapy.

Method
Immunohistochemistry (IHC) for LDH-5 was performed on tissue micro arrays incorporating 280 colorectal cancers from the MRC- CLASICC trial. Immunoreactivity was scored semi-quantitatively by two independent assessors. Correlations between LDH-5 expression and clinicopathological variables including prospectively collected 5-year survival data were examined.

Results
LDH-5 expression was both cytoplasmic and nuclear. 167 (61%) cases showed high LDH-5 expression. Kappa score on agreement between the two scorers was 0.58. High LDH-5 expression significantly correlated with biological aggressiveness- lymph node involvement (p= 0.012), extramural vascular invasion (p= 0.014), and worsening TNM and Dukes staging (p= 0.008). LDH-5 expression was not significantly different between left and right sided colonic tumours or between colonic and rectal tumours. Patients with high LDH-5 had worse 5-year disease-free survival (47% vs. 66%, p=0.002) as compared to patients with low LDH-5. On multivariate analysis, high LDH-5 expression was an independent predictor of poor disease-free survival (p=0.034, HR 1.6: 95% CI: 1.04, 2.5).

Conclusion
Colorectal cancers demonstrating high LDH-5 expression had worse disease-free survival supporting a link between aerobic glycolysis and aggressive cancer biology. This was seen for both colonic and rectal tumours. LDH-5 may enable the selection of patients for treatment with drugs targeting cancer bio-energetics such as dichloroacetate, glufosfamide, etc.