Dihydropyrimidine dehydrogenase (DPD) is the main enzyme for the degradation of 5-fluorouracil (5-FU) and capecitabine. The fluoropyrimidine 5-FU and its oral formulation capectitabine are widely used chemotherapeutic agents for the treatment of a variety of solid tumors, including colorectal cancer. About 10-40% of all patients treated with 5-FU or capecitabine patients develop severe and in about 1% of cases life-threatening toxicity [1] (neutropenia, nausea, vomiting, diarrhea, mucositis, myelosuppression, hand-foot disease). This may be due to reduced DPYD activity. Normally, more than 80% of the administered 5-FU is metabolized within a short period of time; in patients with reduced DPD activity, the 5-FU plasma levels are greatly increased.
Around 7% of the European population are at least heterozygous carriers of a DPYD mutation and therefore have an increased risk of 5-FU intolerance [2]. Homozygous carriers of DPYD mutations or carriers of 2 heterozygous mutations are very rare. 5-FU therapy is contraindicated in these groups of people. In a genetic test for 5-FU incompatibility, at least the four most important DPYD mutations are examined: c.1905 + 1G>A (rs3918290, also known as DPYD*2A, DPYD:IVS14 + 1G>A), c.1679T>G (rs55886062, DPYD *13, p.I560S), c.2846A>T (rs67376798, p.D949V), and c.1129-5923C>G (rs75017182, HapB3) [2]. It should be noted that rarer DPYD variants are not detected by genetic analysis. If no variants are detectable, the genotype is reported as DPYD*1/*1, but DPYD deficiency cannot be excluded with absolute certainty.
- Prior to initiation of 5-FU/Capecitabine therapy for risk assessment and dose adjustment, if necessary.
- To clarify the molecular cause of any 5-FU/capecitabine toxicity that has occurred.
In heterozygous mutation carriers, a 25-50% reduced 5-FU dose should be initially administered according to the obtained activity score. In homozygous carriers, 5-FU therapy is contraindicated.
[1] Caudle KE, Thorn CF and Klein TE, "Clinical Pharmacogenetics Implementation Consortium Guidelines for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing - Supplemental Material [review]," Clinical Pharmacology and Therapeutics, 9 2013. [2] Amstutz U, Henricks LM and Offer SM, "Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update," Clinical Pharmacology and Therapeutics, vol. 103, no. 2, pp. 210-216, 3 2018. [3] Henricks LM, Lunenburg CTC and de Man FM, "DYPD genotype-guided dose individualization of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis," The Lancet Oncology, vol. 19, pp. 1459-1467, 12 2018.
