Pharmacogenetic prediction of clinical outcome in advanced colorectal cancer patients receiving 5-fluorouracil (FU)/oxaliplatin (OX) as first-line chemotherapy

Abstract

2509 Background: Chemotherapy using oxaliplatin, 5-fluorouracil is known to be effective in the treatment of CRC patients. Optimization of this therapy is complicated due to wide variability in drug response that may be due to functional genomic polymorphisms in genes related to the drug target, to the metabolizing or to the DNA repair. We report the evaluation of polymorphisms in the TS, MTHFR (drug target) ERCC1, XPD and GSTP1 (repair enzymes) genes. Methods: We treated 109 CRC patients with a first line oxaliplatin/5-FU chemotherapeutic regimen. Genetic polymorphisms were determined by PCR based RFLP or by Real-Time PCR on an ABI PRISM 7000, using DNA from peripheral blood. The investigated polymorphisms were: TS (VNTR in the 5’ UTR, the 3R G>C SNP and the 1494del6), ERCC1 (Asn118Asn, 8092C>A, 19716 G>C), GSTP1 (Ile105Val) and XPD (Lys751Gln). Clinical response (CR), progression free survival (PFS) and overall survival (OS) were evaluated according to each genotype. Results: The patients were classified according to the clinical risk assessment (CRA) defined by EORTC in three groups with different DFS (12, 9, 7 months; P= 0.008) and different OS (41,19,11 months; P= 0.0002). In the univariate analysis for CR, ERCC1 and XPD polymorphisms were significant (P=0.03, P= 0.047, respectively). After adjustment for the mentioned clinical risk assessment, only ERCC1 retained significance (P=0.037; HR: 4.2, C/C vs T/T). In the univariate analysis for PFS, only ERCC1 polymorphism was significant (P=0.034). After adjustment for the clinical risk, this genotype did not retained its significance (P=0.37). Finally, TS, ERCC1 and XPD polymorphisms were significant in the univariate analysis for overall survival, (P=0.032, P=0.003, P=0.016 respectively). Following the adjustement for the clinical risk, all three genotype variables retained significance (P=0.019, P=0.002, P= 0.024, respectively). Conclusions: i) The EORTC risk assessment classification was a very useful predictor of DFS and OS in our group of patients; ii) Germline genetic polymorphism of ERCC1 predicted response to FU/OX in CRC patients and iii) Polymorphisms in the TS, ERCC1 and XPD genes were good predictors of overall survival. No significant financial relationships to disclose.