Pharmacogenetic analysis of TS and UGT1A polymorphisms predictive for response and toxicity in Spanish patients with advanced colorectal cancer treated with first-line irinotecan and 5-fluorouracil
4066 Background: The possible role of uridine diphosphate-glucuronosyltransferase 1A (UGT1A) and Thymidylate Synthase (TS) gene polymorphisms in predicting toxicity and outcomes in irinotecan/ 5-Fluorouracil (5FU)-treated patients is still controversial. The aim of this work was to determine whether UGT1A1, UGT1A7, and UGT1A9 as well as TS polymorphisms affect toxicities and/or outcomes of Spanish patients with advanced colorectal cancer (mCRC) Methods: A total of 149 patients with mCRC were treated either with weekly irinotecan plus high-dose 5FU (FUIRI) or biweekly irinotecan plus 5FU/Leucovorin (FOLFIRI) as first-line chemotherapy (Aranda E; Ann Oncol. 2008 Aug 20). Genomic DNA was extracted from peripheral blood and genotyped using allelic discrimination and direct sequencing. Chi-square test, Fisher's exact test and logistic regression were used to study the association of genotypes with toxicity and response. Log rank and cox regression were used in survival analysis. All statistical tests were two-sided. Results: According to TS 5’TRP genotypes, 79.3% of the 2R/2R patients responded to therapy while only 52.5% of 2R/3R or 3R/3R patients do so (HR=3.5; 95% CI=1.3- 9.1; p=0.009). TS genotypes were not associated with toxicity. UGT1A1*28 TA7/TA7 genotype was clearly associated with severe toxicity (HR=12.7; 95% CI=3.1–51.3; p=0.001) and diarrhea (HR=4; 95% CI=1.3–12; p=0.016) when compared to TA6/TA7 and TA6/TA6 genotypes. These patients also experienced more severe neutropenia (40% vs. 18.8%, p=0.087) and more frequent dose reductions (53.3% vs. 38.1%, p=ns). UGT1A7*3/*3 and UGT1A9–118(dT)9/9 were associated with severe diarrhea (50% vs. 27% p=0.032 and 43% vs. 23% p=0.012). When all non-favourable genotypes (TA7/TA7, *3/*3 and 9/9) were taken into account, there was a statistically significant association with severe diarrhea (HR=4.5; 95% CI 1.3–16.3; p=0.021), neutropenia (HR=3.5; 95% CI=1–12.7; p=0.047) and both (HR=12.4; 95% CI=2.8–54.2; p=0.001). Conclusions: Our data clearly link UGT1A genotypes with irinotecan-related severe toxicity. TS 5’TRP genotypes are predictive of response to irinotecan/5FU first-line chemotherapy. No significant financial relationships to disclose.