Gemcitabine pathway genotype analysis to predict toxicity in phase II gemcitabine monotherapy in heavily pre-treated metastatic breast cancer

Abstract

2066 Background: We evaluated the efficacy and tolerability of gemcitabine monotherapy in heavily pretreated breast cancer patients, and the polymorphism of gemcitabine-related genes to elucidate the association with toxicity. We detected the polymorphism of deoxycytidine kinase (dCK), deoxycytidine deaminase (dCDA), and ribonucleotide reductase (RNR). Methods: A weekly infusion of gemcitabine at 850mg/m2 for 3 of every 4 weeks was introduced in patients who had failed previous doxorubicin and taxane. Treatment was delayed until leukopenia was recovered with G-CSF support without dose modification. The known polymorphism site of 3 genes were evaluated by CEQ™ 8000 Genetic Analysis System (Beckman): dCK(GG->GT), dCDA(AA->AG), RNR(CC-> CT, TT->TC) with genomic DNA of peripheral lymphocytes. Results: Of 51 enrolled patients, 47 were evaluable. Total 208 cycles were administered and the relative dose intensity was 89%. The response rate was 20%. Median response duration and overall survival were 8 and 12 months, respectively. The toxicity was mild with 14% of grade III neutropenia and 6% of grade III/IV thrombocytopenia. Polymorphism was found in 13% of dCK, 11% of dCDA. 42% of the 1st RNR, 38% of the 2nd RNR and 18% of both RNR sites. By Gibbs sampling-based algorithm, AGCT was the most frequent type (0.6226) with 3 genes, and CT was the most common haplotype in RNR (0.6909). When we evaluated the association of the 4 polymorphic sites from 3 genes with maximum leukopenia, AGTC type polymorphism showed the correlation with leukopenia. Moreover, the number of polymorphism in RNR and the polymorphism of the second site in RNR showed the significant correlation with leukopenia. Subsequently, patients with more number of polymorphism in 3 genes or polymorphism in RNR gene required more numbers of G-CSF rescue without gemcitabine dose reduction. Finally, patients with AGCT type showed a less response to treatment. Conclusions: Gemcitabine monotherapy is effective as salvage treatment and dose adjustment can be done effectively by pharmacogenomic association study in heavily pretreated, breast cancer patients. No significant financial relationships to disclose.