Severe toxicity to capecitabine due to a new variant at a donor splicing site in the dihydropyrimidine dehydrogenase (DPYD) gene

Xandra García-González,1,* Sara López-Tarruella,2,* María Isabel García,1 Eva González-Haba,1 Carolina Blanco,1 Sara Salvador-Martin,1 Yolanda Jerez,2 Fabienne Thomas,3 María Jarama,1 María Sanjurjo Sáez,1 Miguel Martín,2 Luis Andrés López-Fernández1 1Pharmacy Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; 2Medical Oncology Service, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; 3Department of Pharmacology, Institut Claudius-Regaud, CRCT, Université de Toulouse, Inserm, UPS, Toulouse, France *These authors contributed equally to this work Abstract: Severe, life-threatening adverse reactions to capecitabine sometimes occur in the treatment of solid tumors. Screening for dihydropyrimidine dehydrogenase (DPYD) deficiency is encouraged before start of treatment, but the genetic variants that are commonly analyzed often fail to explain toxicities seen in clinical practice. Here we describe the case of a 79-year-old Caucasian female with breast cancer who presented with life-threatening, rapidly increasing toxicity after 1 week of treatment with capecitabine and for whom routine genetic DPYD test resulted negative. DPYD exon sequencing found variant c.2242+1G>T at the donor splicing site of exon 19. This variant is responsible for skipping of exon 19 and subsequent generation of a non-functional DPYD enzyme. This variant has not been described previously but was found in three other members of the patient’s family. With this case, we show that exon sequencing of DPYD in patients who experience marked toxicity to fluoropyrimidines and test negative for commonly evaluated variants can prove extremely useful for identifying new genetic variants and better explain adverse reactions causality. Keywords: pharmacogenetics, adverse drug reaction, fluoropyrimidine, breast cancer