title: 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).
authors.affiliation: Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Uppsala, Sweden.
authors.forename: B
authors.initials: B
authors.lastname: Glimelius
authors.forename: H
authors.initials: H
authors.lastname: Garmo
authors.forename: A
authors.initials: A
authors.lastname: Berglund
authors.forename: L A
authors.initials: LA
authors.lastname: Fredriksson
authors.forename: M
authors.initials: M
authors.lastname: Berglund
authors.forename: H
authors.initials: H
authors.lastname: Kohnke
authors.forename: P
authors.initials: P
authors.lastname: Byström
authors.forename: H
authors.initials: H
authors.lastname: Sørbye
authors.forename: M
authors.initials: M
authors.lastname: Wadelius
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006239:Haplotypes; D006801:Humans; D000077146:Irinotecan; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced / Q000235:genetics; D012189:Retrospective Studies; D015996:Survival Rate; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome; D000099148:UGT1A1 Enzyme
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002166:Camptothecin; D005472:Fluorouracil; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase; D000099148:UGT1A1 Enzyme