Trial Information

Multicentric Pilot Study of Dihydropyrimidine Dehydrogenase (DPD) Deficiency for Predicting Capecitabine Toxicity in Breast Cancer Patients

OBJECTIVES:

Primary

- To determine the sensitivity, specificity, and positive and negative predictive values
of dihydrouracil/uracil (UH_2/U) ratio measured before starting treatment on grade 3-4
capecitabine-related toxicity in women with metastatic breast cancer.

Secondary

- To prospectively test the value of the germinal genotype of thymidylate synthase (TS)
and methylenetetrahydrofolate reductase (MTHFR) as predictors of resistance to
capecitabine.

- To evaluate the practical feasibility of such pre-therapeutic screening.

- To determine the sensitivity, specificity, and positive and negative predictive values
of dihydropyrimidine dehydrogenase genotyping on grade 3-4 capecitabine-related
toxicity in the first and second courses.

- To evaluate the predictive gain provided by genotyping relative to phenotyping alone.

- To evaluate the influence of TS and MTHFR gene polymorphisms on clinical response and
duration of response.

- To evaluate the pharmacokinetics of capecitabine and its metabolites and their
relationship with UH_2/U and genotype.

- To evaluate the total cost of pre-therapeutic phenotyping alone and the combination of
phenotyping and genotyping.

- To exhaustively analyze the 23 exons of the dihydropyrimidine dehydrogenase (DPYD) gene
in patients who developed toxicity.

OUTLINE: This is a multicenter study.

Patients receive oral capecitabine twice daily on days 1-14. Treatment repeats every 21 days
in the absence of disease progression or unacceptable toxicity.

Blood samples are collected 8-15 days before the start of treatment and periodically on the
first day of treatment for dihydropyrimidine dehydrogenase phenotyping (dihydrouracil/uracil
ratio and high performance liquid chromatography analysis), genotyping (4 most relevant
single nucleotide polymorphisms), and pharmacokinetic analysis.