Genomic profiling as predictor of toxicity in patients with advanced colorectal cancer treated with platinum-based chemotherapy

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Abstract
3627 Background: We had previously shown an association between functional polymorphisms in genes involved in drug metabolism and DNA-repair, and outcome to platinum-based chemotherapy in advanced colorectal cancer. We are currently conducting a confirmatory prospective study. Here in, we report the association between relevant genomic polymorphisms and toxicity to platinum-based chemotherapy. Methods: As of December 2003, 168 patients with advanced refractory colorectal cancer have been enrolled. Patients received 5-FU 200 mg/m2/day as continuous infusion and oxaliplatin 130 mg/m2, in three week cycles. The first 130 patients with sufficient follow-up time were included in the analysis. Polymorphisms in genes involved in drug metabolism, DNA-repair, sodium channel, angiogenesis, and drug targets (XPD, TS, ERCC1, GST, COX2, R19K sodium channel) were determined and their potential associations with gastrointestinal (GI) and neurological toxicities assessed. Results: Our cohort of 130 patients comprised 68 males and 62 females, with a median age of 60 (25–87). The median number of cycles received was 4. Sixty-two percent (72/123) of patients experienced G3+ overall toxicity, 42% (52/123) GI toxicity, and 9% (11/123) neurotoxicity. Female patients were at a higher risk for experiencing G3+ overall and GI toxicity (RR=2.07 and 2.41, log-rank pVal105Val polymorphisms were associated with mucositis (G1+) (RR=1.73, p=0.049; RR=3.88, pGln751Gln and G3+ overall (RR=2.19; p=0.017) and GI toxicity (RR=2.65; p=0.019) were found. Conclusion: Genomic polymorphisms in XPD, GSTP1, TS, and COX2 promoter may predict toxicity to 5-FU/oxaliplatin chemotherapy. Further studies are needed to delineate clear mechanistic explanations for the reported association.

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