Fluorouracil Toxicity and DPYD
5-Fluorouracil (5FU) is a fluorinated pyrimidine analogue commonly used in combination chemotherapy regimens for patients with breast, colorectal, lung, and other malignancies. Dihydropyrimidine dehydrogenase (DPD), an enzyme encoded by the DPYD gene, is the rate-limiting step in pyrimidine catabolism and deactivates more than 80% of standard doses of 5FU and the oral 5FU prodrug capecitabine.
True deficiency of DPD affects approximately 5% of the overall population. In these patients, the lack of enzymatic activity increases the half-life of the drug, resulting in excess drug accumulation and toxicity.1 In addition, 3% to 5% of the population has a partial DPD deficiency due to sequence variations in DPYD gene, which potentially limits their ability to fully metabolize the drug, thereby resulting in toxicity.2
The IVS14+1G>A mutation in intron 14 coupled with exon 14 deletion (known as DPYD*2A) is the most well known variant resulting in partial DPD deficiency and 5FU toxicity.1 Other recognized variants associated with toxicity include 496A>G in exon 6; 2846A>T in exon 22;3,4 and T1679G (DPYD*13) in exon 13,5 although multiple other mutations have been detected in individual families and via full gene sequences.
Clinical Implications of the Genetic Mutation
Patients with DPD deficiency who are treated with 5FU or capecitabine are at significantly increased risk of developing severe (grade III/IV) and potentially fatal neutropenia, mucositis, diarrhea.2,3,4,6 As noted in their respective product labels, both 5FU and capecitabine are therefore contraindicated in patients with known DPD deficiency.
By contrast, the clinical effects of DPYD variants and partial DPD deficiency are unclear. Different series have demonstrated increased toxicity to varying degrees,3,4 but mutations in DPYD have, for the most part, been unable to account for the magnitude of toxicity seen in the general population. Some groups have begun to evaluate the contribution of mutations in other candidate genes,4 but the effects of these and other genetic and nongenetic factors will remain unknown until there is clear elucidation of all of the pathways involved in 5FU/capecitabine metabolism.7
Based on what is known to date about the role of DPD in 5FU/capecitabine metabolism, patients with known DPD deficiency and/or a family history of known mutations should avoid therapy with 5FU/capecitabine. For the general population, because true DPD deficiency is rare and because the clinical implications of partial deficiency are still unclear, screening for mutations prior to initiating therapy is not warranted.2,7 In addition, even if a partial deficiency is detected, there are no guidelines on how to tailor therapy to minimize toxicity, so the clinical utility of testing for DPYD variants remains unclear.
Until such time that guidelines are available, patients with known or suspected partial DPD deficiency who might be at greater risk for fluorouracil toxicity can be managed per the dose modification guidelines outlined in the capecitabine product label. In this rare situation, alternative non-5FU containing treatment regimens (if available) may also be considered.
Testing for the Genetic Mutation
Enzymatic activity in patients with suspected DPD deficiency can be determined via RNA extracted from peripheral blood mononuclear cells and measurement of DPD mRNA copy number. High-throughput genetic analysis using denaturing high performance liquid chromatography (DHPLC) can be used if the patient is severely neutropenic.8
Testing for DPD deficiency and the IVS14+1G>A DPYD variant (DPYD*2A) is available; testing for other variants is not currently available.