Page 217 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Evaluating the implementation of prospective DPYD genotyping
Introduction
Fluoropyrimidines such as 5-fluorouracil (5-FU) and its oral prodrug capecitabine are the cornerstone anticancer drugs for several types of cancer such as colorectal cancer, head–
neck cancer and breast cancer. Approximately 10–30% of the patients receiving 5-FU or capecitabine experience severe (grade ≥3) toxicity, such as diarrhea, mucositis and hand-foot syndrome.1 5-FU is extensively metabolized (>80%) by the liver enzyme dihydropyrimidine dehydrogenase (DPD). DPD is encoded by the gene DPYD for which more than 160 genetic variants are known, some of them being pathogenic by reducing enzyme function.2,3 There
is a strong correlation between reduced DPD activity and increased risk for severe and potentially lethal toxicity following treatment with a normal dose of 5-FU.4-7 Toxicity occurred
in 73% of DPYD*2A carriers, compared with 23% of wild-types.8 Several meta-analyses
have consistently shown that DPYD*2A, c.2846A>T, DPYD*13 and c.1236C>G/HapB3 are associated with toxicity.1,6,9 Although the sensitivity of DPYD genotyping is low (<14.5% for DPYD*2A and c.2846A>T combined), prospective screening for genetic variants in DPYD
is a well-known strategy to detect patients who have reduced DPD enzyme activity (DPD deficient).8,10,11 Patients with no or reduced DPD enzyme activity can be treated more safely
when applying a 25–50% dose reduction of 5-FU or capecitabine, or using an alternative 8 drug.10,12,13 Recently it was shown that prospective screening for DPYD*2A followed by a 50%
dose reduction significantly reduces the number of severe toxicities and is cost-effective.8 Several pharmacogenetic guidelines are available that provide dose recommendations when a reduced function DPYD variant is present. The pharmacogenetic guidelines of the Dutch Pharmacogenetic Working Group (DPWG), recommend a 25–50% dose reduction of 5-FU or capecitabine for the first treatment cycle followed by dose titration guided upon toxicity during subsequent cycles for patients with a variant in DPYD (DPYD*2A, DPYD*13, c.2846A>T or c.1236G>A). A minimum of 50% reduction or alternative therapy is advised for homozygous patients, depending on the variant.14 The Clinical Pharmacogenetics Implementation Consortium (CPIC)15,16 recommends a 50% dose reduction of 5-FU or capecitabine for patients with DPYD*2A, DPYD*13 and c.2846A>T and alternative therapy for patients who are homozygous for these variants. While these guidelines are very useful for dose adjustments in patients with a genetic variant, they do not advocate prospective DPYD testing prior to initiation of therapy.
At Leiden University Medical Center (LUMC; Leiden, The Netherlands), a routine DPYD screening program prior to prescribing 5-FU or capecitabine was initiated in April 2013. In this retrospective study we evaluated the physician’s acceptance of prospective DPYD screening for patients who were prescribed 5-FU or capecitabine in LUMC and the adherence of the recommended dose reduction.
Methods
Setting
At LUMC all patients with an indication for a fluoropyrimidine containing therapy were routinely screened for DPYD variants by the laboratory of the department of Clinical Pharmacy and Toxicology (CPT) using two independent techniques (TaqMan® Genotyping SNP assay from Thermo Fisher Scientific [MA USA], and a home-brew pyrosequencing (PSQ),
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