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

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 p<0.001). COX2 promoter C-allele and GSTP1 Val105Val polymorphisms were associated with mucositis (G1+) (RR=1.73, p=0.049; RR=3.88, p<0.001). A trend for neurotoxicity (G2+) was seen for TS 5' GC (SNP) in patients homozygous for the C allele (RR=2.35, p=0.08). After stratification by gender, significant associations between XPD Gln751Gln 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. [Table: see text].