UGT1A and TYMS genetic variants predict toxicity and response of colorectal cancer patients treated with first-line irinotecan and fluorouracil combination therapy
Por:
Martinez-Balibrea, E, Abad, A, Martinez-Cardus, A, Gines, A, Valladares, M, Navarro, M, Aranda, E, Marcuello, E, Benavides, M, Massuti, B, Carrato, A, Layos, L, Manzano, JL, Moreno, V
Publicada:
10 ago 2010
Resumen:
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. British Journal of Cancer (2010) 103, 581-589. doi:10.1038/sj.bjc.6605776 www.bjcancer.com Published online 13 July 2010 (C) 2010 Cancer Research UK
Filiaciones:
Martinez-Balibrea, E:
Hosp Badalona Germans Trias & Pujol, Inst Catala Oncol, Med Oncol Serv, Barcelona 08916, Spain
Fundacio Inst Invest Ciencies Salut Germans Trias, Barcelona 08916, Spain
Abad, A:
Hosp Badalona Germans Trias & Pujol, Inst Catala Oncol, Med Oncol Serv, Barcelona 08916, Spain
Fundacio Inst Invest Ciencies Salut Germans Trias, Barcelona 08916, Spain
Martinez-Cardus, A:
Fundacio Inst Invest Ciencies Salut Germans Trias, Barcelona 08916, Spain
Gines, A:
Fundacio Inst Invest Ciencies Salut Germans Trias, Barcelona 08916, Spain
Valladares, M:
Complejo Hosp Univ Juan Canalejo, Med Oncol Serv, La Coruna 15006, Spain
Navarro, M:
Hosp Duran & Reynals, Inst Catala Oncol, Med Oncol Serv, Lhospitalet De Llobregat 08907, Spain
Hosp Duran & Reynals, Inst Catala Oncol, Biostat & Bioinformat Unit, Lhospitalet De Llobregat 08907, Spain
Aranda, E:
Hosp Univ Reina Sofia, Med Oncol Serv, Cordoba 14004, Spain
Marcuello, E:
Hosp Santa Creu & Sant Pau, Med Oncol Serv, Barcelona 08025, Spain
Benavides, M:
Hosp Carlos Haya, Med Oncol Serv, Malaga 29010, Spain
Massuti, B:
Hosp Gen Univ Alicante, Med Oncol Serv, Alicante 03010, Spain
Carrato, A:
Hosp Gen Univ Elche, Med Oncol Serv, Elche 03203, Spain
Layos, L:
Hosp Badalona Germans Trias & Pujol, Inst Catala Oncol, Med Oncol Serv, Barcelona 08916, Spain
Manzano, JL:
Hosp Badalona Germans Trias & Pujol, Inst Catala Oncol, Med Oncol Serv, Barcelona 08916, Spain
Moreno, V:
Hosp Duran & Reynals, Inst Catala Oncol, Biostat & Bioinformat Unit, Lhospitalet De Llobregat 08907, Spain
Inst Invest Bellvitge, Lhospitalet De Llobregat 08907, Spain
Univ Barcelona, Dept Clin Sci, Lhospitalet De Llobregat 08907, Spain
Green Accepted, Green Published
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