Abstract 1869: Severe toxicities in patients undergoing gemcitabine, ARA-C, capecitabine, or azacytidine treatments: Is deregulated cytidine deaminase the bad guy

Abstract

Abstract Background: Nucleoside analogs are anticancer drugs widely used both in adults and in children. Genetic polymorphisms leading to impaired ability to detoxify drugs in the liver are a major issue in clinical oncology. Cytidine deaminase (CDA) is a ubiquituous enzyme responsible for the metabolism of several pyrimidine derivatives. CDA is involved in the activation pattern of capecitabine, but conversely is responsible for the liver catabolism of most other nucleosidic analogs. So far, downregulated CDA is considered as an issue with gemcitabine, but little is known about the impact of deregulated CDA on the clinical outcome with other pyrimidine analogs. Methods: A retrospective study was perfomed as a proof-of-concept for the implication of CDA in severe toxicities with several pyrimidine analogs. Phenotypic and genotypic investigations were performed in a subset of patients presenting with severe toxicities soon after being treated for the first time with a pyrimidine derivative. CDA status was evaluated on a phenotypic basis using a surrogate enzymatic test. Additionally, polymorphisms associated with loss of CDA activity (i.e. 79A>C, 435 T>C, 208 G>A mutations) or conversely with increased expression (i.e. rs532545 deletion) were screened. Toxicities were monitored following the standard CTC 4.0 grading. Results & Discussion: We followed five patients (4 adults, 1 child), all presenting with extremely severe toxicities soon after being treated with a nucleoside analog (i.e. capecitabine, gemcitabine, azacytidine and ara-C, respectively). Two patients treated with capecitabine underwent severe toxicities, including a lethal one. Both patients were phenotyped as CDA ultra-metabolizer (UM: CDA > 6 U/mg). The rs532545 deletion in the CDA promoter region was found in the patient with lethal outcome. This suggests that CDA UM status triggers toxicities through an increased activation of capecitabine towards its toxics metabolites. Conversely, poor metabolizer (PM) profile (i.e. CDA < 2 U/mg) was evidenced in the 3 other patients with severe toxicities upon gemcitabine, azacytidine and Ara-C intake. Of note, one of the patient exhibited the double 79A>C and rs532545 polymorphisms, which have opposite impacts on CDA levels eventually. In this case, phenotypic determination proved to be critical to picture the CDA status, and confirmed her PM phenotype. Our observations suggest that CDA deficiency makes patients administered with gemcitabine, azacytidine and ara-C at risk of early severe toxicities alike. Conclusions: Deregulated CDA (i.e. PM or UM patients) proved to be associated with a serial of severe/lethal toxicities in patients treated with nucleoside analogs frequently administered in clinical oncology. Overall, this POC study warrants the identification of CDA status in patients prior to starting pyrimidine-based treatments. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1869. doi:1538-7445.AM2012-1869