Effect of cytidine deaminase (CDA)–related biomarkers on overall survival in patients with advanced pancreatic cancer receiving gemcitabine (GEM) monotherapy.

Abstract

e14645 Background: CDA metabolizes GEM to an inactive metabolite, 2’,2’-difluorodeoxyuridine (dFdU). We have already reported the impact of CDA-related biomarkers on GEM-induced toxicities (Sugiyama, J Clin Oncol. 2007; and Ueno, Br J Cancer. 2009). This study was intended to clarify the effects of CDA-related phenotypic and genetic biomarkers on the overall survival of advanced pancreatic cancer pts treated with GEM monotherapy. Methods: Using advanced pancreatic cancer (stage IV) pts enrolled in the first study (n=73) and the second study (n=98) who received a 30-minute intravenous GEM infusion at a dose of 1,000 mg/m2, the overall survival was analyzed for associations with the pharmacokinetic parameters of GEM and dFdU, plasma CDA activity and nonsynonymous SNPs of CDA {79A>C (CDA*2) and 208G>A (CDA*3) } as well as the pts’ background factors. Results: In the first study, overall survival was significantly longer in pts with longer mean residence time (MRT) of GEM and lower plasma concentration of dFdU at 0.5hr (C0.5) than in pts with a shorter GEM MRT and higher dFdU C0.5 (p=0.0138 and p=0.0011, respectively). Low plasma CDA activity and heterozygous CDA*3 were also significantly associated with prolonged overall survival (p=0.0062 and p=0.0247, respectively). After adjusting with the pts’ background factors, CDA related biomarkers were still significantly associated with overall survival in the multivariate Cox proportional hazard models. Association of low plasma CDA activity with prolonged overall survival was also confirmed by the second study (p=0.0061). Conclusions: In GEM monotherapy, reduced CDA activity correlated well with prolonged survival of advanced pancreatic cancer pts. CDA*3 is one of the factors that reduced the CDA activity in Japanese pts. 1st study 2nd study No. of pts MST P value No. of pts MST P value Plasma CDA activity High 18 5.3 mo 0.0062 42 5.1 mo 0.0061 Low 16 8.1 mo 37 8.6 mo CDA*2 Negative 44 6.1 mo 0.2546 56 7.1 mo 0.3819 Positive 26 4.5 mo 30 7.2 mo CDA*3 Negative 65 5.4 mo 0.0247 81 6.9 mo 0.1771 Positive 5 17.3 mo 5 11.7 mo