Determinants of the interindividual variability in serum cytidine deaminase activity of patients with solid tumours

Abstract

AIMSCytidine deaminase (CDA) activity in cancer patients' serum has been proposed as a predictive biomarker for efficacy and toxicity of nucleoside analogues. However, discrepant results about its predictive value have been reported due to the high interindividual variability in CDA activity. This study aimed at identifying determinants of this interindividual variability. METHODSFrom December 2014 to November 2015, 183 patients were prospectively included. Serum CDA activity, biological and clinical characteristics as well as five common single nucleotide polymorphisms (SNPs) in the CDA gene (c.-451C > T, c.-92A > G, c.-33_-31delC, c.79A > C, c.435 T > C) were analysed. Associations between clinical characteristics, pharmacogenetic variants and CDA activity were univariately tested. P < 0.1-candidate variables were analysed through a multivariate analysis. The association between CDA activity and toxicity was assessed for the 56 gemcitabine-treated patients. Intraindividual variability in CDA activity was explored in six pancreatic cancer patients treated with gemcitabine. RESULTSMedian CDA activity was 3.97 U mg -1 (range 1.53-15.49 U mg -1 ). A univariate analysis showed that CDA activity was statistically associated with Eastern Cooperative Oncology Group performance status, mild or severe malnutrition, inflammatory syndrome, leucocyte count, neutrophil count, albumin, C-reactive protein and -c.-33_-31delC single nucleotide polymorphism. A multivariate analysis identified that only neutrophil count (P < 0.0001) and severe malnutrition (P = 0.0278) were independently associated with CDA activity. Low CDA activity (<2 U mg -1 ) was not statistically associated with severe gemcitabine-related British Journal of Clinical Pharmacology Br toxicities (P = 0.16). A decrease in CDA activity was observed during the longitudinal follow-up of six pancreatic cancer patients treated with gemcitabine (P = 0.03). CONCLUSIONSThese results suggest that neutrophil count and malnutrition should be considered for the interpretation of pretherapeutic CDA activity. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Serum cytidine deaminase (CDA) activity in cancer patients is a potential biomarker for the efficacy and toxicity of nucleoside analogues. • Discrepant results have been reported due to the high interindividual variability of CDA activity. WHAT THIS STUDY ADDS• This study shows for the first time that elevated neutrophil count and malnutrition are significantly correlated with increased serum CDA activity in cancer patients. • Our work suggests that serum CDA activity should be interpreted along with the inflammation and malnutrition status. CDA serum activity in cancer patientsBr

Can cytidine deaminase be used as predictive biomarker for gemcitabine toxicity and response?

“…Certain polymorphisms (such as CDA Lys27Gln) are associated with a decreased red blood cell CDA activity, but there was a large overlap in enzyme activities. In their paper, Cohen et al showed that the c.‐33_‐31delC SNP contributed only 4.1% to the variation in CDA activity. Although significant, this does not seem relevant considering the much larger contribution of, eg, neutrophil count (24.8%).…”

“…Because the variation induced by inflammation may be larger than that caused by a genotype, a phenotypic assay measuring enzyme activity to evaluate fluctuations in CDA activity would be preferable over a genomic assay. Cohen et al described an independent cross‐validation of a phenotypic assay, earlier developed by Ciccolini et al…”

“…The strength of the paper by Cohen et al is that they applied the simplified CDA assay outside the EORTC‐PAMM framework and investigated a number of additional potential variables. The data confirmed the robustness of the assay in an independent laboratory, and they observed a similar variation in CDA enzyme activity, as described earlier through the Marseille‐Amsterdam‐Nice collaboration .…”

“…The Cohen paper also identified a number of important aspects which need validation in a larger prospective study. They demonstrated the importance of malnutrition and of inflammation by showing a relation with neutrophil count in samples of patients, before and during treatment.…”

Association between the use of antibiotics and efficacy of gemcitabine plus nab-paclitaxel in advanced pancreatic cancer

“…[ 25 ] Therefore, we speculate that CDD is related to the efficacy and toxicity of gemcitabine. In clinical settings, neutrophil count and malnutrition are associated with serum CDD activity, [ 26 ] and serum CDD is a prognostic marker for gemcitabine/platinum-treated advanced nonsmall cell lung cancer. [ 27 ]…”