Pharmacogenetic study in patients (pts) with metastatic breast (BC) and colorectal cancer (CRC) treated with Capecitabine (C)

Abstract

2005 Background: Different polymorphisms (P) of the enzymes involved in C metabolism could be responsible of the different efficacy and toxicity in patients treated with C. Carboxylesterase (CES) and Cytidine Deaminase (CDD) are involved in hepatic transformation of C to 5’dFUrd. Thymidilate Synthase (TS) and Dihydropyrimidine Dehydrogenase (DPD) P have been related to 5FU efficacy and toxicity. Our objective was to correlate the efficacy and grade 3–4 toxicity of C with genetic P of CES, CDD, TS and DPD. CES and CDD P have not been previously studied. Methods: Metastatic BC and CRC pts treated with C 1250 mg/m2 PO bid d1–14 every 3 weeks, with evaluable or measurable disease, no dermatological disease and normal hepatic function were prospectively included. PCR and sequencing methods were used to analyze CES exon 3 (5841 G>A, 6046 G>A, 6174 G>A, 6320 G>A); CES UTR (823 C>G, 854 G>C); CDD (575 C>T, 771 C>G, 794 G>A, 942 C>G, 943 insC, 1052 A>C); TS genotype (2R/2R, 2R/3R, 3R/3R) and DPD (IVS14+1 G>A). Fisher’s exact test was used for comparisons. Results: 93 pts (45 BC/48 CRC) previously treated were included, median age 67 yrs (38–90). 31 pts experienced grade 3–4 toxicity: hand-foot syndrome (HFS) 15%, asthenia 6.4%, diarrhea 4.3%, vomiting 3.2%, mucositis 2% and anorexia 2%. Nearly significant correlation was detected between heterozygous (HT) and homozygous (HM) P of CDD gene (943 insC) and greater incidence of HFS than in the wild type (WT) (21.3%, 14.2% and 3.5% respectively) (p=0.055), and HM P of CES exon 3 (6046 G>A) and greater diarrhea rate than in the HT or WT (100%, 0% and 3.4% respectively) (p=0.08). 56 pts were evaluable for response (1 CR/23 PR/14 SD/18 PD). 92% of pts with HT and 100% with HM CES UTR (823 C>G) P obtained clinical benefit (CR+PR+EE) compared with 58% of patients with WT (p=0.04). 60% of pts with 2R/2R variant of TS and 87% with 2R/3R had clinical benefit compared with 47% of 3R/3R form (p=0.01). Conclusions: The occurrence of a single nucleotide P in CES UTR gene and some TS variants are associated with improved efficacy of C and can be useful to select patients for this treatment. The lack of statistical significance for grade 3–4 toxicity may be due to the low number of events. The study is ongoing No significant financial relationships to disclose.