Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFOX-4 chemotherapy.
OBJECTIVE
The objective is to investigate whether polymorphisms with putative influence on fluorouracil/oxaliplatin activity are associated with clinical outcomes of patients with advanced colorectal cancer treated with first-line oxaliplatin, folinic acid, and fluorouracil palliative chemotherapy.


METHODS
Consecutive patients were prospectively enrolled onto medical oncology units in Central Italy. Patients were required to have cytologically/histologically confirmed metastatic disease with at least one measurable lesion. Peripheral blood samples were used for genotyping 12 polymorphisms in thymidylate synthase, methylenetetrahydrofolate reductase, xeroderma pigmentosum group D (XPD), excision repair cross complementing group 1 (ERCC1), x-ray cross complementing group 1, x-ray cross complementing protein 3, glutathione S-transferases (GSTs) genes. The primary end point of the study was to investigate the association between genotypes and progression-free survival (PFS).


RESULTS
In 166 patients, ERCC1-118 T/T, XPD-751 A/C, and XPD-751 C/C genotypes were independently associated with adverse PFS. The presence of two risk genotypes (ERCC1-118 T/T combined with either XPD-751 A/C or XPD-751 C/C) occurred in 50 patients (31%). This profiling showed an independent role for unfavorable PFS with a hazard ratio of 2.84% and 95% CI of 1.47 to 5.45 (P = .002). Neurotoxicity was significantly associated with GSTP1-105 A/G. Carriers of the GSTP1-105 G/G genotype were more prone to suffer from grade 3 neurotoxicity than carriers of GSTP1-105 A/G and GSTP1-105 A/A genotypes.


CONCLUSIONS
A pharmacogenetic approach may be an innovative strategy for optimizing palliative chemotherapy in patients with advanced colorectal cancer. These findings deserve confirmation in additional prospective studies.
Ruzzo
Annamaria
A
Institute of Biochemistry G Fornaini, University of Urbino, Urbino, Italy.
Graziano
Francesco
F
Loupakis
Fotios
F
Rulli
Eliana
E
Canestrari
Emanuele
E
Santini
Daniele
D
Catalano
Vincenzo
V
Ficarelli
Rita
R
Maltese
Paolo
P
Bisonni
Renato
R
Masi
Gianluca
G
Schiavon
Gaia
G
Giordani
Paolo
P
Giustini
Lucio
L
Falcone
Alfredo
A
Tonini
Giuseppe
G
Silva
Rosarita
R
Mattioli
Rodolfo
R
Floriani
Irene
I
Magnani
Mauro
M
D020121:5' Untranslated Regions; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D004268:DNA-Binding Proteins / Q000235:genetics; D004720:Endonucleases / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005838:Genotype; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D000077150:Oxaliplatin; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D013940:Thymidylate Synthase / Q000235:genetics
D020121:5' Untranslated Regions; D004268:DNA-Binding Proteins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase; C071447:ERCC1 protein, human; D004720:Endonucleases; D002955:Leucovorin; D005472:Fluorouracil