Capecitabine Therapy and Genotype

Capecitabine (brand name Xeloda) is a chemotherapy agent that belongs to the drug class of fluoropyrimidines. It is widely used in the treatment of several malignancies including colon cancer, metastatic colorectal cancer, and metastatic breast cancer. Capecitabine is a prodrug that is enzymatically converted to its active form, fluorouracil (also called 5-fluorouracil), which acts as an antimetabolite to slow tumor growth. The gene encodes dihydropyrimidine dehydrogenase (DPD), an enzyme that catalyzes the rate-limiting step in fluorouracil metabolism. Dihydropyrimidine dehydrogenase inactivates 80–90% of 5-fluorouracil (5-FU) into 5,6-dihydro-fluorouracil. Genetic variants in the gene can lead to enzymes with reduced or absent activity. Individuals who have at least one copy of a nonfunctional variant (for example, c.1905+1G>A (formerly *2A; rs3918290) or c.1679T>G (p.I560S; formerly *13; rs55886062)) will not be able to metabolize fluorouracil at normal rates. Consequently, these individuals are at risk of potentially life-threatening fluorouracil toxicity, such as bone marrow suppression, gastrointestinal toxicity and, rarely, neurotoxicity. The prevalence of DPD partial deficiency varies in different populations but is approximately 3–5%. There is an FDA-approved antidote for 5-FU overdose: uridine triacetate. Overdose can occur in individuals with partial DPD deficiency taking either capecitabine or 5-FU. The FDA-approved drug label for capecitabine states that no capecitabine dose has been proven safe in individuals with absent DPD activity, and that there is insufficient data to recommend a specific dose in individuals with partial DPD activity as measured by any specific test (Table 1) (1). The Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) have published dosing recommendations for fluoropyrimidines (capecitabine and fluorouracil) based on genotype (Tables 2 and 3). Both recommendations include dose reductions for intermediate metabolizers (with reduced enzyme activity), and avoiding fluorouracil and choosing an alternative agent for poor metabolizers (with absent enzyme activity) (2, 3, 4).