UGT1A and TYMS genetic variants predict toxicity and response of colorectal cancer patients treated with first-line irinotecan and fluorouracil combination therapy

• Published in: British journal of cancer Vol. 103; no. 4; pp. 581 - 589
• Main Authors: Martinez-Balibrea, E, Abad, A, Martínez-Cardús, A, Ginés, A, Valladares, M, Navarro, M, Aranda, E, Marcuello, E, Benavides, M, Massutí, B, Carrato, A, Layos, L, Manzano, J L, Moreno, V
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.08.2010; Nature Publishing Group; Cancer Research UK
• Subjects: 631/154/53/2423; 692/699/67/1504/1885; 692/700/565/1436/1437; Aged; Algorithms; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomedical and Life Sciences; Biomedicine; Camptothecin - administration & dosage; Camptothecin - analogs & derivatives; Cancer Research; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - secondary; Càncer colorectal; Drug Resistance; Drug toxicity; Drug-Related Side Effects and Adverse Reactions - genetics; Epidemiology; Female; Fluorouracil - administration & dosage; Gene Frequency; Genetics & Genomics; genetics-and-genomics; Genotype; Germ-Line Mutation; Glucuronosyltransferase - genetics; Humans; Male; Middle Aged; Molecular Medicine; Oncology; Patient Selection; Polymorphism, Genetic; Survival Analysis; Thymidylate Synthase - genetics; Toxicitat dels medicaments; Treatment Outcome; toxicity; irinotecan; 5FU; colorectal; polymorphisms
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6605776

Background: The impact of thymidylate synthase (TYMS) and UDP-glucoronosyltransferase 1A (UGT1A) germline polymorphisms on the outcome of colorectal cancer (CRC) patients treated with irinotecan plus 5-fluorouracil (irinotecan/5FU) is still controversial. Our objective was to define a genetic-based algorithm to select patients to be treated with irinotecan/5FU. Methods: Genotyping of TYMS (5′TRP and 3′UTR), UGT1A1 * 28, UGT1A9 * 22 and UGT1A7 * 3 was performed in 149 metastatic CRC patients treated with irinotecan/5FU as first-line chemotherapy enrolled in a randomised phase 3 study. Their association with response, toxicity and survival was investigated by univariate and multivariate statistical analysis. Results: TYMS 3TRP/3TRP genotype was the only independent predictor of tumour response (OR=5.87, 95% confidence interval (CI)=1.68–20.45; P =0.005). UGT1A1 * 28/ * 28 was predictive for haematologic toxicity (OR=6.27, 95% CI=1.09–36.12; P =0.04), specifically for neutropenia alone (OR=6.40, 95% CI=1.11–37.03; P =0.038) or together with diarrhoea (OR=18.87, 95% CI=2.14–166.67; P =0.008). UGT1A9 * 1/ * 1 was associated with non-haematologic toxicity (OR=2.70, 95% CI=1.07–6.82; P =0.035). Haplotype VII (all non-favourable alleles) was associated with non-haematologic toxicity (OR=2.11, 95% CI=1.12–3.98; P =0.02). Conclusion: TYMS and UGT1A polymorphisms influence on tumour response and toxicities derived from irinotecan/5FU treatment in CRC patients. A genetic-based algorithm to optimise treatment individualisation is proposed.