Pharmacogenetic prediction of clinical outcome in advanced colorectal cancer patients receiving oxaliplatin/5-fluorouracil as first-line chemotherapy.
To determine whether molecular parameters could be partly responsible for resistance or sensitivity to oxaliplatin (OX)-based chemotherapy used as first-line treatment in advanced colorectal cancer (CRC). We studied the usefulness of the excision repair cross-complementing 1 (ERCC1), xeroderma pigmentosum group D (XPD), XRCC1 and GSTP1 polymorphisms as predictors of clinical outcome in these patients. We treated 126 CRC patients with a first-line OX/5-fluorouracil chemotherapeutic regimen. Genetic polymorphisms were determined by real-time PCR on an ABI PRISM 7000, using DNA from peripheral blood. Clinical response (CR), progression-free survival (PFS) and overall survival (OS) were evaluated according to each genotype. In the univariate analysis for CR, ERCC1-118 and XPD 751 polymorphisms were significant (P=0.02 and P=0.05, respectively). After adjustment for the most relevant clinical variables, only ERCC1-118 retained significance (P=0.008). In the univariate analysis for PFS, ERCC1-118 and XPD 751 were significant (P=0.003 and P=0.009, respectively). In the multivariant analysis, only the XPD 751 was significant for PFS (P=0.02). Finally, ERCC1-118 and XPD 751 polymorphisms were significant in the univariate analysis for OS (P=0.006 and P=0.015, respectively). Both genetic variables remained significant in the multivariate Cox survival analysis (P=0.022 and P=0.03). Our data support the hypothesis that enhanced DNA repair diminishes the benefit of platinum-based treatments.
Paré
L
L
Department of Genetics, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona [corrected] Barcelona 08025, Spain.
Marcuello
E
E
Altés
A
A
del Río
E
E
Sedano
L
L
Salazar
J
J
Cortés
A
A
Barnadas
A
A
Baiget
M
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics; D018572:Disease-Free Survival; D004720:Endonucleases / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D010597:Pharmacogenetics; D016133:Polymerase Chain Reaction; D016896:Treatment Outcome; D000076105:X-ray Repair Cross Complementing Protein 1
D004268:DNA-Binding Proteins; D009944:Organoplatinum Compounds; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D000077150:Oxaliplatin; D005982:Glutathione Transferase; C071447:ERCC1 protein, human; D004720:Endonucleases; D005472:Fluorouracil
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