Cytidine Deaminase Residual Activity in Serum Is a Predictive Marker of Early Severe Toxicities in Adults After Gemcitabine-Based Chemotherapies

Abstract

PURPOSE Anticipating toxicities with gemcitabine is an ongoing story, and deregulation in cytidine deaminase (CDA) could be associated with increased risk of developing early severe toxicities on drug exposure. PATIENTS AND METHODS A simple test to evaluate CDA phenotypic status was first validated in an animal model investigating relationships between CDA activity and gemcitabine-related toxicities. Next, relevance of this test as a marker for toxicities was retrospectively tested in a first subset of 64 adult patients treated with gemcitabine alone, then it was tested in a larger group of 130 patients who received gemcitabine either alone or combined with other drugs and in 20 children. Additionally, search for the 435 T>C, 208 G>A and 79 A>C mutations on the CDA gene was performed. Results In mice, CDA deficiency impacted on gemcitabine pharmacokinetics and had subsequent lethal toxicities. In human, 12% of adult patients experienced early severe toxicities after gemcitabine administration. A significant difference in CDA activities was observed between patients with and without toxicities (1.2 +/- 0.8 U/mg v 4 +/- 2.6 U/mg; P < .01). Conversely, no genotype-to-phenotype relationships were found. Of note, the patients who displayed particularly reduced CDA activity all experienced strong toxicities. Gemcitabine was well tolerated in children, and no CDA deficiency was evidenced. CONCLUSION Our data suggest that CDA functional testing could be a simple and easy marker to discriminate adult patients at risk of developing severe toxicities with gemcitabine. Particularly, this study demonstrates that CDA deficiency, found in 7% of adult patients, is associated with a maximum risk of developing early severe toxicities with gemcitabine.

Pyrimidine pool imbalance induced by BLM helicase deficiency contributes to genetic instability in Bloom syndrome

“…This study also demonstrates that CDA downregulation in BLM-expressing cells leads to a significant increase in SCE frequency and replication stress, potentially conferring a predisposition to cancer. A previous French study reported that 7% of adult patients with cancer treated with gemcitabine (5′-azacytidine, 2′,2′-difluorodeoxycytidine), a CDA substrate, had very low levels of CDA activity, rendering gemcitabine highly toxic 23 .…”

Severe acute toxicity following gemcitabine administration: A report of four cases with cytidine deaminase polymorphisms evaluation

“…Severe GCB toxicity in NSCLC patients was reported in cases with heterozygous c.437CT variant and, to a lesser degree, in those with homozygous c.435TT variant (25,26). Interestingly, the latter was also found to be related to better response to GCB treatment, owing to reduced serum CDA concentration and higher exposure to active GCB metabolites (27,28). Heterozygous c.79A>C polymorphism was reported to cause severe leukopenia and neutropenia (14,(19)(20)(21)(22).…”

“…Data on the relationship between CDA polymorphisms and GCB toxicity are inconsistent (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Severe GCB toxicity in NSCLC patients was reported in cases with heterozygous c.437CT variant and, to a lesser degree, in those with homozygous c.435TT variant (25,26).…”

“…Previous studies suggested that CDA deficiency associated with CDA gene polymorphisms may affect more patients treated with GCB, but the lack of population data does not allow for the estimation of real CDA polymorphisms frequency. In patients with decreased CDA activity in the serum, the risk of serious side effects is in the range of 5-10% for GCB alone and 15-30% for GCB combinations (27,28). The evaluation of gene polymorphisms is relatively simple and non-invasive (swabbing the inner site of the cheek), yet currently there are no recommendations for routine pretreatment assessment of CDA polymorphisms or CDA serum level (18,40,41).…”

“…Data regarding toxicity related to CDA polymorphisms are inconsistent (16)(17)(18). Nevertheless, several studies demonstrated that single nucleotide polymorphism (SNP) of CDA c.79 A>C, c.208 G>A and c.435C>T, with resulting decreased serum CDA concentration, may lead to severe toxicity induced by GCB (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31).…”