DPYD single nucleotide polymorphisms (SNPs) and haplotypes in patients (pts) with metastatic colorectal cancer and toxicity of capecitabine.

Abstract

3099 Background: Capecitabine is the oral prodrug of 5-FU, which is inactivated for 85% by dihydropyrimidine dehydrogenase (DPD, DPYD). The aim of this study was to determine the effect of DPYD SNPs and haplotypes on toxicity and efficacy of capecitabine. Methods: Toxicity and survival were determined in 568 previously untreated pts with metastatic colorectal cancer participating in the CAIRO2 trial and randomly assigned to capecitabine, oxaliplatin, bevacizumab ± cetuximab (Tol et al, NEJM 2009). The entire DPYD coding region was sequenced in 50 pts that presented with grade ≥3 capecitabine-related toxicity within the first 2 treatment cycles. SNP frequencies were compared to those in 100 pts randomly drawn from the entire population. SNPs that appeared of clinical relevance from this nested case-cohort part were analyzed in all 568 pts. DPYD SNPs and haplotypes were correlated with toxicity, dose modifications of capecita-bine, and survival. Results: 29 SNPs were detected in the case-cohort population, 8 of which were analyzed in all 568 pts. IVS14+1G>A, 2846A>T, 1236>A, 2194G>A and 496A>G were associated with diarrhea grade 3-4 with positive predictive values of 0.71, 0.63, 0.50, 0.41 and 0.33, respectively (p<0.05). All 7 pts polymorphic for IVS14+1G>A developed any grade 3-4 toxicity with one chemotherapy-induced death. Due to toxicity, mean dose reductions of capecitabine of 50% and 25% were applied in IVS14+1G>A or 2846A>T variant allele carriers, respectively (p<0.005). SNPs were not associated with survival. Pts were categorized in 6 haplotype groups (HP1-6). HP3 (heterozygous for 85T>C and wild type for other SNPs) pts had a decreased risk for diarrhea grade 3-4 (p=0.002). Pts with 2 variant haplotype alleles and pts heterozygous for rare (<3%) haplotypes (HP5) showed increased risks for diarrhea grade 3-4 (p=0.01). HP5 was associated with increased overall survival (p=0.03). Conclusions: DPYD IVS14+1G>A and 2846A>T are predictive markers for severe toxicity requiring strong dose reductions. DPYD haplotypes could assist in selecting pts at risk for toxicity to capecitabine. The predictive value of DPYD SNPs and haplotypes for survival appears to be limited. No significant financial relationships to disclose.