Abstract
4116 Background: To test the predictive value of germinal gene polymorphisms potentially related to fluorouracil (FU) and oxaliplatin (Oxa) pharmacodynamics on toxicity, response rate, progression-free and overall survival. Methods: As part of a phase II OPTIMOX 2 trial by the GERCOR group, 117 patients were enrolled in a prospective pharmacogenetic study conducted in patients with advanced colorectal cancer, all receiving a modified FOLFOX7 therapy (65 men, 52 women, mean age 64.7, range 31–80). The maximum observed toxicity (NCI-CTCAE) for each toxic pattern, along with the best response (RECIST) were recorded. Median follow-up was 19.7 months. Gene polymorphisms relevant for FU: thymidylate synthase (TS, 28 bp repeats including the G>C mutation + 6 bp deletion in 3’UTR) and MTHFR (677C>T + 1298A>C), as well as for Oxa: GSTπ (105Ile>Val + 114Ala>Val), ERCC1 (118AAT>AAC) and ERCC2 (XPD, 751Lys>Gln) were determined (blood mononuclear cells). Results: None of the gene polymorphisms were predictive of toxicity, considered either as the maximum observed grade, or as a score equal to the sum of each toxicity pattern grade. The best response was complete response (CR) in 2 patients, partial response (PR) in 64 patients, stable disease in 47 patients and progression for 4 patients. Both the 677C>T (p = 0.022) and 1298A>C (p = 0.004) MTHFR genotypes were linked to clinical responsiveness (CR+PR, 56.4 %), with the rare allele theoretically favoring elevated reduced folate concentrations, linked to improved responsiveness. Importantly, the number of favorable MTHFR alleles (i.e. 677T and 1298C) revealed response rates of 37.1%, 53.3%, 66.1% and 80.0% in patients bearing 0, 1, 2 or 3 favorable alleles (N = 35, 15, 56 and 10), respectively (P = 0.018). None of the other genotypes were linked to treatment responsiveness. In addition, none of the analyzed polymorphisms were related to progression-free or overall survival. Conclusions: These results establish the role of MTHFR germinal polymorphism as a strong predictor of response for FOLFOX therapy in patients with advanced colorectal cancer. No significant financial relationships to disclose.
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