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Pharmacokinetics and pharmacodynamics
PKP-007 Dpyd snps and disease free survival after capecitabine based adjuvant treatment in colorectal cancer
  1. X García-González1,
  2. M Pellicer1,
  3. MI García1,
  4. P García-Alfonso1,
  5. C Grávalos2,
  6. V Pachón3,
  7. V Martinez4,
  8. P Martinez-Ortega1,
  9. M Sanjurjo1,
  10. LA López-Fernández1
  1. 1Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón IiSGM, Pharmacy Department, Madrid, Spain
  2. 2Hospital Universitario Doce de Octubre-Instituto de Investigación Sanitaria Hospital Doce de Octubre, Oncology Department, Madrid, Spain
  3. 3Hospital Universitario Ramón y Cajal-Instituto Ramón y Cajal de Investigación Sanitaria, Oncology Department, Madrid, Spain
  4. 4Hospital Universitario La Paz-Instituto de Investigación Hospital Universitario La Paz, Oncology Department, Madrid, Spain

Abstract

Background DPYD has a key role in fluoropyrimidines metabolism. The relationship between enzyme activity and drug efficacy and toxicity has been widely studied, but the predictive value of the most accepted variants is still poor. Hence the search for new biomarkers is needed.

Purpose To analyse if single nucleotide polymorphisms (SNPs) in the DPYD exon regions have an influence on disease free survival (DFS) in colorectal cancer patients treated with capecitabine based adjuvant chemotherapy.

Material and methods The study design was observational, ambispective and multicentric. The study population included 138 adult patients with stages II and III colorectal cancer that received capecitabine based adjuvant chemotherapy. DNA was isolated from peripheral blood samples and seven polymorphisms (rs12119882, rs1801158, rs1801159, rs291592, rs291593, rs44221623, rs6668296) in the DPYD exon regions were genotyped through OpenArray technology. DFS was estimated by the Kaplan–Meier method. The relationship between polymorphisms and DFS was explored using the Cox regression model with tumour stage, treatment and hospital as co-variables.

Results 76.8% of patients received capecitabine in combination with oxaliplatin (XELOX regimen), and the remaining 23.2% monotherapy. Median follow-up time was 30.1 months (range 7–171.9). At the cut-off date, 35 patients had relapsed (25.4%). Patients harbouring the DPYD rs291593 GG genotype had a worse DFS than those carriers of the GA/AA variants (HR 2.15; 95% CI 1.10–4.23; p=0.026). Patients with the TT homozygous genotype in DPYD rs1801159 also showed a trend to shorter DFS than heterozygous or homozygous carriers of the C allele when analysed by Kaplan–Meier (p=0.019). In multivariate analysis, differences remained in the limit of the statistical significance (HR 2.16; 95% CI 1.00–4.67; p=0.051). No statistically significant association was found between DFS and the other polymorphisms that were studied.

Conclusion Genotyping of exonic genetic variants in DPYD are related to DFS after capecitabine based adjuvant chemotherapy in CRC patients and could be a successful approach to find new pharmacogenetic predictors of tumour relapse. However, more studies in larger cohorts with a longer follow-up are needed.

No conflict of interest

https://doi.org/10.1136/ejhpharm-2017-000640.435

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