Dihydropyrimidine enzyme activity and its effect on chemotherapy toxicity: importance of genetic testing

Patients with partial or complete DPD deficiency have decreased capacity to degrade fluorouracil and are at risk of developing toxicity, which can be even life-threatening.

A 43-year-old man with moderately differentiated rectal adenocarcinoma on capecitabine presented to the emergency department with complaints of nausea, vomiting, diarrhea, weakness, and lower abdominal pain for several days. Laboratory findings include grade 4 neutropenia (ANC 10) and thrombocytopenia (platelets 36,000). Capecitabine is used as a component of first-line adjuvant therapy by approximately 2 million patients worldwide each year. Capecitabine is metabolized to fluorouracil via the enzyme dihydropyrimidine dehydrogenase (DPD). With worsening pancytopenia and diarrhea, genetic testing for DPD deficiency was sent. Prompt treatment with uridine triacetate was initiated for presumed DPD deficiency. Unfortunately, he passed away from an infectious complication and was later confirmed to have a heterozygous DPYD*2A mutation.

Our case demonstrates uneven testing guidelines for DPD prior to initiating 5-FU chemotherapy, appropriateness of treating with uridine triacetate, and analysis of next-generation sequencing (NGS) on tumor samples and co-incidentally obtaining germline DPD deficiency status. Our case also highlights the severe clinical impact of having DPD deficiency even with early uridine triacetate therapy.

It is our recommendation to perform DPD deficiency in curative intent cancer treatment and this information can increasingly be obtained in standard tumor NGS profiling, a growing norm in medical oncology.