Treatment failure upon gemcitabine intake: Is cytidine deaminase extensivity the ideal culprit?

Abstract

e14558 Background: Gemcitabine is a mainstay for treating various solid tumors, including pancreatic and lung cancers, as well as sarcomas. Gemcitabine metabolism in the body is dependent primarily upon a detoxification step in the liver driven by cytidine deaminase (CDA). Activity in CDA is highly variable among patients, with possible impact on drug disposition and subsequent clinical outcome. The aim of this work was to investigate whether extensivity in CDA could be at the origin of treatment failure with gemcitabine. Methods: Forty patients (19F, 21 M, mean age 61 years) mostly treated with gemcitabine alone (23 patients) or associated with oxaliplatin, capecitabine, erlotinib or a biotherapy (7 patients) for pancreatic or biliary cancers were retrospectively studied. CDA status was evaluated both upon a phenotypic (CDA residual activity in serum) and a genotypic (search for the 79A>C polymorphism) basis. Extensive Metabolizer (EM) phenotype was defined as a CDA activity above 6 U/mg (e.g., 50% above the mean value of a reference adult population). Results: Median CDA activity was 3.4 U/mg (range: 0.8-17.4). No genotype to phenotype relationship was evidenced. Eight out of 40 patients (20%) displayed CDA values associated with the EM phenotype (range: 6-17.4). A statistical difference (p < 0.001, Mann-Whitney Rank Sum Test) was observed in response between EM and non-EM patients. In the EM subset, 75% of the patients had progressive disease (PD), the remaining 25% patients displaying equally Objective Response and Stable Disease. Conversely, Progressive disease was observed in 15.5% patients with normal/low CDA activities, whereas 84.5% had controlled disease. Conclusions: Our data suggest that EM with CDA could be a predictive marker for treatment failure with gemcitabine. Complementary data from patients with sarcoma are currently evaluated and should be presented. Overall, our data suggest that CDA-based adaptive dosing strategies could improve clinical outcome with gemcitabine, one of the most prescribed anticancer drug worldwide. No significant financial relationships to disclose.