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).

Dose-Dependent Association between UGT1A1*28 Genotype and Irinotecan-Induced Neutropenia: Low Doses Also Increase Risk

“…Association between UGT1A1*28 and neutropenia (UGT1A1*28/*28 versus UGT1A1*1/*1 or UGT1A1*1/*28) Relevant data for the comparison of the risk of neutropenia between UGT1A1*28/*28 patients and those with a UGT1A1*1/*1 or UGT1A1*1/*28 genotype were available in 15 included trials (3)(4)(5)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). Considering the individual subgroup, there was no evidence of publication bias according to either Begg's test or Egger's test (Table 3).…”

“…UGT1A1*28 has been shown to be associated with decreased SN-38 glucuronidation in humans (3)(4)(5)(6)(7)(8)(9)(10)(11). The association between the UGT1A1*28 genotype and irinotecan-induced neutropenia has been extensively studied (3)(4)(5)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). Seven of these studies found that UGT1A1*28/*28 patients had an elevated risk of neutropenia compared with those carrying UGT1A1*1 allele(s) (refs.…”

Combinations of Polymorphisms in Genes Involved in the 5-Fluorouracil Metabolism Pathway Are Associated with Gastrointestinal Toxicity in Chemotherapy-Treated Colorectal Cancer Patients

“…Previous studies have shown contradicting results with regard to the role of MTHFR in toxicity in relation to 5-FU chemotherapy (6,13,17,(33)(34)(35). The contradictory results may reflect that the MTHFR 677C>T and MTHFR 1298A>C SNPs were not combined according to phenotypic effects, differences in treatment regimens, and inadequate statistical analyses.…”

Clinical usefulness of testing for UDP glucuronosyltransferase 1 family, polypeptide A1 polymorphism prior to the inititation of irinotecan-based chemotherapy

“…In East Asian populations, including the Japanese, the association between UGT1A1 * 28 and * 6 polymorphisms and irinotecan-induced toxicities was previously investigated (3,5,6). In colorectal cancer, irinotecan-induced grade 3/4 neutropenia occurs more frequently in patients with the homozygous UGT1A1 * (7)(8)(9). These findings were similar for Japanese patients (9,10) and individuals with low enzyme activity constitute ~10% of the Japanese population (10,11).…”