Prediction of irinotecan and 5-fluorouracil toxicity and response in patients with advanced colorectal cancer

Abstract

Irinotecan and 5-fluorouracil (5-FU) are used to treat metastatic colorectal cancer. Irinotecan's active metabolite is inactivated by UDP-glucuronosyltransferase 1A1 (UGT1A1), which is deficient in Gilbert's syndrome. Irinotecan and metabolites are transported by P-glycoprotein, encoded by ABCB1. 5-FU targets folate metabolism through inhibition of thymidylate synthase (TYMS). Methylenetetrahydrofolate reductase (MTHFR) generates active folate necessary for haematopoiesis. We retrospectively genotyped 140 Swedish and Norwegian irinotecan and 5-FU-treated colorectal cancer patients from the Nordic VI clinical trial for selected variants of UGT1A1, ABCB1, TYMS and MTHFR. We found an increased risk of clinically relevant early toxicity in patients carrying the ABCB1 3435 T/T genotype, Odds ratio (OR)=3.79 (95% confidence interval (CI)=1.09-13.2), and in patients carrying the UGT1A1(*)28/(*)28 genotype, OR=4.43 (95% CI=1.30-15.2). Patients with UGT1A1(*)28/(*)28 had an especially high risk of neutropenia, OR=6.87 (95% CI=1.70-27.7). Patients who had reacted with toxicity during the first two cycles were in total treated with fewer cycles (P<0.001), and less often responded to treatment (P<0.001). Genetic variation in ABCB1 was associated with both early toxicity and lower response to treatment. Carriers of the ABCB1 1236T-2677T-3435T haplotype responded to treatment less frequently (43 vs 67%, P=0.027), and survived shorter time, OR=1.56 (95% CI=1.01-2.45).

Figure 1

Odds ratios with 95% confidence limits for clinically relevant toxicity by genotype. (a) Outcome A: Grade 3–4 toxicity after cycle 1 or 2, delay or dose reductions of cycle 2 or 3. (b) Outcome B: Worst grade 3–4 toxicity, all cycles.

Figure 2

(a) Odds ratios with 95% confidence limits for non-response (SD+PD) by genotype. (b) Hazard ratios with 95% confidence limits for the risk of progression or death by genotype. (c) Hazard ratios with 95% confidence limits for the risk death by genotype.

Figure 3

Kaplan–Meier survival curves showing the probability of survival for different ABCB1 genotypes. (a) ABCB1 1236C>T. (b) ABCB1 2677G>T/A. (c) ABCB1 3435C>T.