Abstract
3075 Background: Pharmacogenetic determinants of the disposition of the topoisomerase I (TOP1) poison, irinotecan, appear to predict patient (pt) risk of developing severe toxicity, but do not explain all reported cases of toxicity or tumor response to irinotecan treatment. Proteins encoded by the TOP1, ADPRT, TDP1, CDC45L, NFKB1 and XRCC1 genes abate the cytotoxic action of camptothecins in vitro. Methods: Genetic variation in the drug target, TOP1, and downstream effectors may influence pt outcomes to irinotecan therapy. A retrospective haplotype-association study was undertaken to investigate the hypothesis. The association between common haplotypes of the 6 candidate genes and severe adverse events (Grade 3/4 diarrhea, neutropenia) and tumor response (objective response, overall survival) was examined in 107 advanced colorectal cancer pts treated with irinotecan-based regimens. Haplotype tags (htSNPs) were selected from haplotype cladograms of each gene. Patient DNA was typed for htSNPs using pyrosequencing and haplotype identities estimated using PHASE v.0.9. Results: Genotype frequencies were in Hardy-Weinberg equilibrium. TOP1 IVS4+61 was related to neutropenia incidence (GG<AG<AA, p<0.05) and TDP1 IVS12+79 to objective response (TT<TG<GG, p<0.05). TOP1 IVS4+61 AG+GG survived longer (24.9 months) than AA pts (7.8 months; p<0.005) and ADPRT +852 (A284A) CT+TT pts longer than CCs (p<0.05). More pts with the XRCC1 3/3 diplotype (83%) had an objective response to therapy than pts with other diplotypes (30%, p<0.05). There was a trend towards more ADPRT 2/2s (33%) experiencing severe neutropenia than pts with other diplotypes (13%, p=0.08). No genetic variant influenced diarrhea incidence. Conclusions: This is the first pharmacogenetic investigation of irinotecan pharmacodynamic factors. Our results suggest TOP1 and ADPRT variants may alter a patient’s risk of experiencing neutropenia and TOP1, TDP1, ADPRT and XRCC1 variants may influence tumor response to irinotecan-based therapies. [Table: see text]
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