UGT1A1,A7 and A9 genotyping and pharmacokinetics of irinotecan-containing chemotherapy in patients with advanced cancer

Abstract

e14563 Background: To the best of our knowledge only one previous report in asian lung cancer patients (pts) assesed UGT1A1, A7 and A9 genotypes along with irinotecan pharmacokinetics (Han et al. JCO 2006; 24: 2237–44). We set out to evaluate UGT1A1, A7 and A9 genotypes in caucasian cancer patients and their relationship with both irinotecan toxicity and irinotecan pharmacokinetics. Methods: UGT1A1, A7 and A9 genotypes were obtained from blood genomic DNA by direct sequencing. The area under the time-concentration curve (AUC) of SN-38 and SN-38G were calculated. The ratio between these AUCs (AUC SN-38G /AUC SN-38) was also calculated. Associations between pharmacokinetics parameters and the UGT1A genotypes were assessed by univariate analysis. Toxicity was collected using standard NCI grading criteria. Statistical correlation between presence of grade III and IV toxicity and UGT1A1,A7 and A9 genotypes was done by Pearson's Chi square. At least 80 patients (with both genotype and pharmacokinetics) are needed to achieve enough statistical power. Results: At the time of writing this abstract, complete genotyping and toxicity data from 59 patients were available. Sex (females 17, males 42). Median age 60 (range 25–88). Pathology (no. pts): lung (26), colon (17), others (16). 21 pts. (35.59%) had received previous chemotherapy. All but 5 pts received doses of irinotecan between 120 and 150 mg/m2. Median no. of cycles 6 (range 1–15). The frequencies of the different UGT1A1, A7 and A9 genotypes are similar to those previously reported. At least one episode of grade III or IV leukopenia was present in 19 pts. (32.2%), and grade III diarrea in 11 pts (18.6%). No statistically significant correlation was found between presence of leukopenia grades III and IV, and the genotypes UGT1A1,A7, and A9 (P=0.687, P=0.156 and P=0.476, respectively). Diarrea grade III was not statistically significantly associated with UGT1A1 (P=0.318), A7 (P=0.318) and A9 (P=0.158). 21 out of 59 pts. had pharmacokinetics (PK) data available. In genotype-PK association analysis, UGT1A1,A7 and A9 were not statistically associated with AUC SN-38G / AUC SN-38 ratios (P=0.844, P=0.911, P=0.431, respectively). Conclusions: Patients are still being accrued to achieve the targeted size. No significant financial relationships to disclose.