Uridine diphosphate glucuronosyl transferase 1A1 promoter polymorphism predicts the risk of gastrointestinal toxicity and fatigue induced by irinotecan-based chemotherapy.
BACKGROUND
In the current Phase II study, the authors evaluated the association between genomic polymorphic variants in uridine diphosphate glucuronosyl transferase (UGT1A1), methylenetetrahydrofolate reductase (MTHFR), and thymidylate synthase (TS) genes, and the incidence of the adverse effects of irinotecan and raltitrexed in previously heavily treated patients with metastatic colorectal carcinoma.


METHODS
Fifty-six patients received irinotecan (at a dose of 80 mg/m(2) on Days 1, 8, 15, and 22 every 5 wks), combined with raltitrexed (at a dose of 3 mg/m(2) every 3 wks). Genotyping for the MTHFR C677T polymorphism, the TATA box region in the UGT1A1 promoter, and tandem repeats in the TS promoter was performed on genomic DNA extracted from blood. Nineteen variables related to patient, disease, and treatment characteristics, together with genotypes, were analyzed using a binary logistic regression model with stepwise selection to evaluate their correlation with adverse reactions.


RESULTS
Toxicities (determined according to the National Cancer Institute Common Toxicity Criteria) were evaluated in 169 cycles. Grade 3/4 neutropenia was reported to occur in 2% of cycles, Grade 2-4 nausea was reported to occur in 19% of cycles, Grade 2-4 emesis was reported to occur in 9% of cycles, Grade 2-4 diarrhea was reported to occur in 20% of cycles, Grade 2/3 fatigue was reported to occur in 11% of cycles, and Grade 3/4 hepatic toxicity was reported to occur in 7% of cycles. Homozygosis for six TA repeats in the promoter region of the UGT1A1 gene was found to be the main predictive factor for diarrhea (P < 0.00005), emesis (P = 0.0001), and fatigue (P = 0.007). Homozygosis for two tandem repeats in the TS promoter was found to be predictive of a reduced incidence of fatigue (P = 0.044). MTHFR C677T polymorphism was not found to be associated with any adverse reaction.


CONCLUSIONS
In the current study, UGT1A1 promoter polymorphism was found to be predictive of the risk of diarrhea, emesis, and fatigue caused by chemotherapy with irinotecan and raltitrexed. Screening for UGT1A1 promoter polymorphism may be clinically useful for identifying patients at a higher risk of developing a severe or potentially life-threatening toxicity after irinotecan-based chemotherapy.
Massacesi
Cristian
C
Department of Oncology and Radiotherapy, Ospedali Riuniti, Ancona, Italy. c.massacesi@ao-umbertoprimo.marche.it
Terrazzino
Salvatore
S
Marcucci
Fabiana
F
Rocchi
Marco B
MB
Lippe
Paolo
P
Bisonni
Renato
R
Lombardo
Marco
M
Pilone
Alberta
A
Mattioli
Rodolfo
R
Leon
Alberta
A
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D019731:Carbon-Nitrogen Ligases / Q000235:genetics / Q000378:metabolism; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D003967:Diarrhea / Q000139:chemically induced*; D005221:Fatigue / Q000139:chemically induced*; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D011401:Promoter Regions, Genetic; D011799:Quinazolines / Q000009:adverse effects; D013876:Thiophenes / Q000009:adverse effects; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism; D014839:Vomiting / Q000139:chemically induced*; D000099148:UGT1A1 Enzyme
D002166:Camptothecin; D019731:Carbon-Nitrogen Ligases; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D011799:Quinazolines; D013876:Thiophenes; D013940:Thymidylate Synthase; D000099148:UGT1A1 Enzyme; C021557:5,10-methenyltetrahydrofolate synthetase; C068874:raltitrexed