Pharmacogenetic analysis of UGT1A1, UGT1A6, UGT1A7 and thymidylate synthase in a phase II study of capecitabine plus irinotecan in patients with metastatic colorectal cancer

Abstract

3623 Background: Capecitabine (CAP) and irinotecan (IR) are used in the treatment of colorectal cancer (CRC). SN-38, the active metabolite of IR, is metabolized by several UDP-glucuronosyltransferases including UGT1A1, UGT1A6, and UGT1A7. Although UGT1A1 genotype has previously been correlated with IR toxicity, the association between other UGT genotypes and IR response or toxicity has not been determined. CAP is a prodrug of 5-fluorouracil (5FU) that inhibits thymidylate synthase (TS). Although genetic polymorphisms in TS have been associated with antitumor response to 5FU, such relationships are not well established with CAP. The objective of this study was to evaluate the impact of genetic polymorphisms in UGT1A1, UGT1A6, UGT1A7, and TS on response and toxicity in patients with CRC treated with CAP/IR. Methods: 67 chemotherapy-naïve patients (pts) with measurable metastatic CRC were treated with IR (100–125 mg/m2 intravenously on days 1 and 8), plus CAP (orally 900-1000 mg/m2 twice daily on days 2–15). DNA was genotyped using Pyrosequencing, dye terminator sequencing, and GeneScan technologies. Results: The overall response rate was 42% (RECIST Criteria). 26 pts (39%) had CTC grade 3–4 diarrhea, and 7 pts had grade 3–4 neutropenia (10%). Low activity UGT1A7 genotypes, UGT1A7*2/*2 (6 pts) and *3/*3 (7 pts), were significantly associated with antitumor response (p=.005, 11 of 13 patients) and lack of toxicity (p=0.01, only 1 of 13 patients exhibited severe toxicity). There were no statistically significant associations between UGT1A1, UGT1A6 or TS genotypes and toxicity or antitumor response. Conclusions: These data suggest, for the first time, that UGT1A7 genotype may be a useful predictor of response and toxicity in patients with CRC treated with irinotecan-based therapy. Specifically, patients with genotypes associated with low metabolic capacity may be particularly likely to exhibit an antitumor response with little toxicity. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Labs Roche Labs Roche Labs Roche Labs Roche Labs