Toxic death case in a patient undergoing gemcitabine-based chemotherapy in relation with cytidine deaminase downregulation

Abstract

Gemcitabine is an antimetabolite drug used in the treatment of various solid tumours, including lung, pancreatic or gynaecological cancers. Innovative combinational strategies (e.g. gemcitabine+capecitabine or gemcitabine+oxaliplatin) make gemcitabine an extensively prescribed drug now. Gemcitabine is characterized by a narrow therapeutic index, and its liver elimination depends upon a key enzymatic step, driven by cytidine deaminase (CDA). CDA is prone to gene polymorphism, including the 208A>G mutation, which can result in marked enzymatic deficiency with subsequent impact on drug exposure levels and related toxicities. We have developed a simple and inexpensive method to determine phenotypically CDA status in cancer patients, as an attempt to detect those at risk upon gemcitabine intake. Conjointly to genotypic investigations, this method was used to phenotype, in a retrospective setting, a female patient displaying extremely severe, and eventually lethal, toxicities after administration of a standard gemcitabine/carboplatin protocol. Phenotypic investigation showed a marked CDA deficiency (-75%) in this patient when compared with a reference, nontoxic population. Genetic studies undertaken next to screen mutations, possibly at the origin of this deficiency, showed heterozygosity for the 79A>C single-point mutation, whereas surprisingly the canonical CDA 208A>G polymorphism was not found. Taken together, this case report demonstrates, for the first time, that CDA downregulation can lead to toxic-death in patients exposed to gemcitabine. Besides, we showed here that our cost-effective and simple phenotypic approach should enable, in the future, the detection of deficient patients at risk upon gemcitabine administration.

Cytidine deaminase single-nucleotide polymorphism is predictive of toxicity from gemcitabine in patients with pancreatic cancer: RTOG 9704

“…25 In a follow-up study on one patient with several gemcitabine toxicity studied by the same group, marked CDA deficiency was associated with heterozygosity for the CDA Lys 27 Gln polymorphism, whereas surprisingly the CDA Ala 70 Thr polymorphism was not found. 26 This observation was felt to be consistent with other observations describing controversies regarding genotype to phenotype associations with CDA. 20,25 In a small clinical study among non-small cell lung cancer patients treated with cisplatin plus gemcitabine, the homozygous wild-type CDA Lys 27 Lys genotype predicted a better clinical benefit, grade 3 or higher neutropenia or thrombocytopenia, longer time to progression and overall survival than the other CDA genotypes (Table 5).…”

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).…”