Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy.
The primary end point of the study was the analysis of associations between polymorphisms with putative influence on 5-fluorouracil/irinotecan activity and progression-free survival (PFS) of patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy. Peripheral blood samples from 146 prospectively enrolled patients were used for genotyping polymorphisms in thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), excision repair cross-complementation group-1 (ERCC 1) xeroderma pigmentosum group-D (XPD), X-ray cross-complementing-1 (XRCC 1), X-ray cross-complementing-3 (XRCC 3) and uridine diphosphate-glucuronosyltransferases-A1 (UGT1 A1). TS 3'-UTR 6+/6+ and XRCC3-241 C/C genotypes were associated with adverse PFS. Hazard ratio for PFS achieved 2.89 (95% confidence interval=1.56-5.80; P=0.002) in 30 patients (20%) with both risk genotypes. Risk for Grade III-IV neutropenia was significantly associated with UGT1A1*28 7/7 genotype. These promising findings deserve further investigations and their validation in independent prospective studies.
Ruzzo
A
A
Institute of Biochemistry G Fornaini, University of Urbino, Urbino, Italy.
Graziano
F
F
Loupakis
F
F
Santini
D
D
Catalano
V
V
Bisonni
R
R
Ficarelli
R
R
Fontana
A
A
Andreoni
F
F
Falcone
A
A
Canestrari
E
E
Tonini
G
G
Mari
D
D
Lippe
P
P
Pizzagalli
F
F
Schiavon
G
G
Alessandroni
P
P
Giustini
L
L
Maltese
P
P
Testa
E
E
Menichetti
E T
ET
Magnani
M
M
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use; D020869:Gene Expression Profiling / Q000379:methods*; D005838:Genotype; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods; D011110:Polymorphism, Genetic / Q000187:drug effects / Q000235:genetics; D011446:Prospective Studies
D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin