Running title : Complete DPD deficiency caused by a novel DPYD genotype Article category : Cancer therapy and prevention Metadata : Word count : 2122

word count: 250; max 250) Fluoropyrimidines are frequently used anti-cancer drugs. It is known that patients with reduced activity of dihydropyrimidine dehydrogenase (DPD), the key metabolic enzyme in fluoropyrimidine inactivation, are at increased risk of developing severe fluoropyrimidine-related toxicity. Upfront screening for DPD deficiency and dose reduction in patients with partial DPD deficiency is recommended and improves patient safety. For patients with complete DPD deficiency, fluoropyrimidine-treatment has generally been discouraged. During routine pretreatment screening, we identified a 59-year old patient with a sigmoid adenocarcinoma who proved to have a complete DPD deficiency. Genetic analyses showed that this complete absence of DPD activity was likely to be caused by a novel DPYD genotype, consisting of a combination of amplification of exon 17 and 18 of DPYD and heterozygosity for DPYD*2A. Despite absence of DPD activity, the patient was treated with capecitabine-based chemotherapy, but capecitabine dose was drastically reduced to 150 mg once every five days (0.8% of original dose). Pharmacokinetic analyses showed that the area under the concentration-time curve (AUC) and half-life of 5-fluorouracil were respectively ten-fold and four-fold higher compared to control values of patients receiving capecitabine 850 mg/m 2 . When extrapolating from the dosing schedule of once every five days to twice daily, the AUC of 5-fluorouracil was comparable to controls. Treatment was tolerated well for Page 4 of 23 John Wiley & Sons, Inc. International Journal of Cancer This article is protected by copyright. All rights reserved.