Capecitabine is an orally administered prodrug of the pyrimidine analog 5-flourouracil (5-FU), which is used frequently in the treatment of metastatic breast cancer. Capecitabine is enzymatically converted to 5-FU, and inhibits DNA synthesis within tumors, thereby slowing growth. Dihydropyrimidine dehydrogenase (DPD), an enzyme encoded by DPYD, is the rate-limiting step in pyrimidine catabolism and deactivates more than 80% of standard doses of 5-FU and the oral 5-FU prodrug capecitabine (). Up to 5% of the population lacks the DPD enzyme, and this has been associated with excess drug accumulation and toxicity (). Additionally, an estimated 3% to 5% of the population has sequence variations in DPYD, and these pharmacogenetic variants may be linked with 5-FU toxicity. Multiple DPYD variants have been identified, including well-known non-synonymous and splice site variations within the coding regions of the gene, and more novel variations within noncoding regions (), and their association with 5-FU toxicity has been replicated in multiple studies. Future metabolic profiling of patients and comprehensive genetic screening of DPYD has been proposed to further refine the understanding of relative contribution of individual DPYD variants to the risk of severe 5-FU-related toxicity ().
While variants in several genes encoding for tamoxifen metabolizing enzymes have been correlated with tamoxifen-associated outcomes (). Variable activity of the pertinent cytochrome P450 enzymes (CYP), brought about by genetic polymorphisms and drug interactions, may alter the balance of tamoxifen metabolites, thereby altering its effects. While there are several genes of interest in tamoxifen’s metabolism, the one that has generated the most press has been CYP2D6, which encodes the enzyme responsible for metabolism of N-desmethyl-tamoxifen to endoxifen. CYP2D6 is a polymorphic gene with more than 100 reported allelic variants, often due to SNPs (). Common allelic variants in this gene are associated with the extent of N-desmethyl-tamoxifen metabolism and subsequently with in vivo concentrations of endoxifen. This observation has led to the hypothesis that allelic variation may predict responsiveness to therapy with tamoxifen. This theory has generated great interest, studies and even practice changes over the last decade. In general, patients have been classified as extensive, intermediate or poor metabolizers based upon their CYP2D6 allelic variants.
The anthracyclines doxorubicin and epirubicin have been widely used in breast cancer treatment for several decades. This class of drugs inhibits topoisomerase II and thereby induces apoptosis of cells. Pharmacogenetic variations have been observed in genes encoding for anthracycline-metabolizing enzymes, drug transporters, and enzymes influencing oxidative stress and apoptosis (). Approximately 50% of infused doxorubicin is eliminated in its intact form. The metabolism of remainder of doxorubicin is complex and involves a variety of enzymes, principally aldoketoreductase (AKR1A1), carbonyl reductases (CBR1 and CBR3), NADH dehydrogenase (NQO1), and nitric oxide synthases (NOS1, NOS2 and NOS3).