Page 27 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Prospective DPYD genotyping: ready for prime time
Case: fatal toxicity following treatment with capecitabine
A 52-year-old woman with human epidermal growth factor receptor 2 (HER2)-positive metastasised breast cancer was treated with capecitabine 1,250 mg/m2 twice daily, for 14 2 days every three weeks, plus intravenous trastuzumab on day 1. The first cycle was fully completed; at day 18 of treatment mild diarrhoea and a herpes zoster infection located
at her mouth were noticed during routine outpatient visit. Due to low haematological laboratory values (leucocytes, neutrophils CTC-AE grade 2, and thrombocytes CTC-AE grade
3), the second cycle was planned to be deferred by one week. However, three days later she returned to the hospital with now severe diarrhoea (CTC-AE grade 4), sepsis, neutropenic
fever, severe leucopenia and life-threatening thrombocytopenia and mucositis, for which she
was admitted to the intensive care unit. A long and intensive hospitalisation period followed,
but despite optimal treatment and supportive care, the patient did not recover from severe toxicity and deteriorated even further. At day 34 of admission the patient deceased as a result of this severe toxicity. Genetic testing revealed that the patient was heterozygous for DPYD*2A, a variant allele known to result in dihydropyrimidine dehydrogenase deficiency.1
In case screening would have been performed prior to start of therapy, capecitabine dosage
could have been reduced by 50%, thereby possibly preventing fatal capecitabine-induced toxicity.2
Introduction
5-Fluorouracil (5-FU) and its oral pro-drug capecitabine belong to the group of the fluoropyrimidine drugs, and are among the most frequently used anticancer drugs in the treatment of common cancer types such as colorectal, stomach, breast, head and neck and skin cancer.3-7 5-FU has a relatively narrow therapeutic index and, depending on type of treatment regimen, around 15–30% of patients suffer from severe toxicity such as diarrhoea, nausea, mucositis, stomatitis, myelosuppression, neurotoxicity and hand-foot syndrome.4,8-12 These side-effects lead to mortality in approximately 0.5–1% of patients using 5-FU and capecitabine.4,13
The enzyme dihydropyrimidine dehydrogenase (DPD) plays a key role in the catabolism of
5-FU. It is the rate limiting enzyme degrading over 80% of the drug to its inactive metabolite
5-fluoro-5,6-dihydrouracil.9,14,15 Because of this, DPD is an important factor for efficacy,16,17 as
well as the development of toxicity.10 DPD is encoded by the gene DPYD, which consists of 23
exons on chromosome 1p22.18 More than 160 single nucleotide polymorphisms (SNPs) are
known within this gene, some resulting in altered enzyme activity.19 Eighty DPYD variants
were experimentally tested for their enzyme activity20 and DPYD variants may result in an
absolute or a partial DPD-deficiency (0.5% versus 3–5% of the population, respectively).21,22
About 30–50% of the patients treated with a fluoropyrimidine drug who suffer from severe
or life-threatening toxicity (grade 3–5) have no or decreased DPD enzyme activity, and 50–
88% of patients carrying a variant in DPYD suffer from grade ≥3 fluoropyrimidine-related toxicity.6,10,11,21,23-25
Although pharmacogenomic tests in general have the potential to improve clinical outcome by increasing efficacy and decreasing toxicity, and the potential to decrease the cost of healthcare, their use in routine clinical practice is still limited.26 This also holds true
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