The value of lactate dehydrogenase serum levels as a prognostic and predictive factor for advanced pancreatic cancer patients receiving sorafenib

Luca Faloppi,Silvia Fanello,Valter Torri,Kalliopi Andrikou,Michela Cinquini,Rossana Berardi,Alessandro Bittoni,Enrico Aitini,Stefano Cascinu,Roberto Labianca,Daris Ferrari,Alberto Zaniboni,Sandro Barni,Riccardo Giampieri,Mario Scartozzi,Francesco Caprioni,Maristella Bianconi,S Mosconi ,C Boni ,Alberto F Sobrero

doi:10.18632/oncotarget.5197

Abstract

Although lactate dehydrogenase (LDH) serum levels, indirect markers of angiogenesis, are associated with a worse outcome in several tumours, their prognostic value is not defined in pancreatic cancer. Moreover, high levels are associated even with a lack of efficacy of tyrosine kinase inhibitors, contributing to explain negative results in clinical trials. We assessed the role of LDH in advanced pancreatic cancer receiving sorafenib. Seventy-one of 114 patients included in the randomised phase II trial MAPS (chemotherapy plus or not sorafenib) and with available serum LDH levels, were included in this analysis. Patients were categorized according to serum LDH levels (LDH ≤ vs.> upper normal rate). A significant difference was found in progression free survival (PFS) and in overall survival (OS) between patients with LDH values under or above the cut-off (PFS: 5.2 vs. 2.7 months, p = 0.0287; OS: 10.7 vs. 5.9 months, p = 0.0021). After stratification according to LDH serum levels and sorafenib treatment, patients with low LDH serum levels treated with sorafenib showed an advantage in PFS (p = 0.05) and OS (p = 0.0012). LDH appears to be a reliable parameter to assess the prognosis of advanced pancreatic cancer patients, and it may be a predictive parameter to select patients candidate to receive sorafenib.

Highlights

A growing body of evidence indicates that hypoxia may promote cancer development and it is involved in the resistance to treatment of cancer cells via the formation of new blood vessels.Lactate dehydrogenase (LDH), is a key enzyme in the conversion of pyruvate to lactate under anaerobic conditions [1, 2]
A statistically significant difference was found in progression free survival (PFS) (Figure 2a) and in overall survival (OS) (Figure 2b) between patients with lactate dehydrogenase (LDH) values under (58 patients, 82%), or above (13 patients, 18%) the cut-off
Stratifying the study population according to LDH serum levels and treatment, patients with low LDH serum levels receiving sorafenib showed an advantage in PFS (Figure 3a; sorafenib and LDH ≤ upper normal rate (UNR): 31 patients, 44%, 7.6 months; sorafenib and LDH > UNR: 6 patients, 8%, 2.8 months; no sorafenib and LDH ≤ UNR: 27 patients, 38%, 3.3 months; no sorafenib and LDH > UNR: 7 patients, 10%, 2.2 months; p = 0.05) and OS (Figure 3b; sorafenib and LDH ≤ UNR: 12.7 months; sorafenib and LDH > UNR: 5.9 months; no sorafenib and LDH ≤ UNR: 8.6 months; no sorafenib and LDH > UNR: 5.2 months; p = 0.0012) (Table 2)

Summary

Introduction

Lactate dehydrogenase (LDH), is a key enzyme in the conversion of pyruvate to lactate under anaerobic conditions [1, 2]. The biological link between hypoxia, LDH levels and the tumor-driven angiogenesis pathway through the abnormal activation of the hypoxia inducible factor 1 (HIF-1) is well established. HIF-1α is an essential factor that up-regulates a series of genes involved in glycolytic energy metabolism, angiogenesis, erythropoiesis and cell survival [4]. Hypoxia in the tumor microenvironment is sufficient to activate HIF-dependent expression of several down-regulated genes [5]. These include genes encoding for vascular endothelial growth factor, erythropoietin and many enzymes involved in glucose, iron, and nucleotide metabolism [6]

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Results

Conclusion