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


CONCLUSIONS
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.
Martinez-Balibrea
E
E
Medical Oncology Service, Institut Català d'Oncologia, Hospital Germans Trias I Pujol. C/Ctra. Canyet s/n, Badalona 08916, Spain.
Abad
A
A
Martínez-Cardús
A
A
Ginés
A
A
Valladares
M
M
Navarro
M
M
Aranda
E
E
Marcuello
E
E
Benavides
M
M
Massutí
B
B
Carrato
A
A
Layos
L
L
Manzano
J L
JL
Moreno
V
V
D000368:Aged; D000465:Algorithms; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000556:secondary; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005787:Gene Frequency; D005838:Genotype; D018095:Germ-Line Mutation; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D018579:Patient Selection; D011110:Polymorphism, Genetic; D016019:Survival Analysis; D013940:Thymidylate Synthase / Q000235:genetics*; D016896:Treatment Outcome; D000099148:UGT1A1 Enzyme
D002166:Camptothecin; D005472:Fluorouracil; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D013940:Thymidylate Synthase; D000099148:UGT1A1 Enzyme