Page 62 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 4
addition it also includes a list of the DPYD variants associated with toxicity and the method developed by DPWG for local translation of assay results into the gene activity score. This information may be useful for laboratories to select and design a DPYD genotyping assay and subsequently determine the patients’ predicted phenotype based on the genotype results. Consequently, the literature review supporting the DPYD-fluoropyrimidine interaction is described and the DPWG guideline is presented. A summary of all references identified by the systematic review which were subsequently used to develop this guideline, can be found in Supplementary Tables 1 and 2. The recommendations provided in this manuscript can be used in combination with a patients’ predicted phenotype to optimize starting dose of fluoropyrimidines, thereby decreasing the risk of severe and potentially fatal toxicity.
Drugs: fluoropyrimidines (5-fluorouracil, capecitabine and tegafur with DPD-inhibitors)
Fluoropyrimidines are antimetabolite drugs widely used in the treatment of colorectal, breast, stomach and skin cancer. Each year, over two million patients worldwide receive treatment with fluoropyrimidines. This includes 5-FU and its oral pro-drugs capecitabine and tegafur. Up to 30% of patients experience severe toxicity (common terminology criteria for adverse events, CTC-AE, grade ≥3), including diarrhoea, hand-foot syndrome, mucositis and myelosuppression. For ~1% of patients toxicity is fatal.8,9 Toxicity may occur within the first treatment cycle (early onset), supporting the importance of optimizing the starting dose of fluoropyrimidine pharmacotherapy on a personalized basis, before initiating therapy.10
Capecitabine is metabolised into 5-FU in three consecutive steps. Capecitabine is firstly metabolised to 5’-deoxy-5-fluorocytidine (5’-DFCR) by carboxylesterase, subsequently, 5’- DFCR is converted into 5’-deoxy-5-fluorouridine (5’-DFUR) by cytidine deaminase, and to 5-FU by thymidine phosphorylase. 5-FU is metabolised in tissues to 5-fluoro-2’-deoxyuridine and then to 5-fluoro-2’-deoxyuridine-5’-monophosphate, the active metabolite of the drug. The active metabolite inhibits the enzyme thymidylate synthase, resulting in inhibition of DNA synthesis and repair, inducing cell apoptosis and thus, its effect. Additionally, toxic effects resulting from partial incorporation of 5-FU and its metabolites in DNA and RNA contribute to the drug’s mechanism of action.11
Tegafur is metabolised into 5-FU and into the less cytotoxic metabolites 3-hydroxytegafur, 4-hydroxytegafur and dihydrotegafur by CYP2A6. The less toxic metabolites are renally cleared. Tegafur was combined with the DPD inhibitor uracil and is now combined with the DPD inhibitor gimeracil and the orotate phoshoribosyltransferase (OPRT) inhibitor oteracil. Oteracil diminishes the activity of 5-FU in normal gastrointestinal mucosa. The DPD inhibitors diminish the formation of functionally inactive metabolites of 5-FU that contribute to adverse events like stomatitis and mucositis. Both uracil and gimeracil inhibit DPD activity reversibly and have a shorter elimination half-life and thus shorter period of action than tegafur. For this reason, genetic variants influencing DPD enzyme activity are clinically relevant for tegafur in combination with DPD inhibitors.
Gene: dihydropyrimidine dehydrogenase (DPYD)
The DPYD gene encodes the enzyme DPD. DPYD is located on chromosome 1p21.3, and transcription variant 1 (NM_000110.3) has 26 exons, spanning approximately 900 kb.12
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