Implementing DPYD*2A genotyping in clinical practice, the Quebec experience.

Abstract

650 Background: Fluoropyrimidines (FU) are part of chemotherapy combinations for multiple gastrointestinal cancers. Deficient dihydropyrimidine deshydrogenase (DPD) activity can lead to severe life-threatening toxicities in 3-5% of populations tested. The DPYD*2A polymorphism leading to deficient DPD activity is one of the most studied variants. Methods: We retrospectively performed chart reviews of all patients that tested positive for a heterozygous or homozygous DPYD*2A mutation in samples obtained from patients throughout the province of Quebec (Canada). The study objective was to document the impact of implementing this test in routine clinical practice, including the effects on treatment types, delays and toxicities. Results: 2,617 patients were tested by PCR for the presence of DPYD*2A in a period of 17 months: 25 patients tested positive. All were Caucasian. 24 of the 25 patients were heterozygous (0.92%) and one was homozygous (0.038%). A chart review was available for 20 patients: 15 were tested upfront while five were performed following severe toxicities on the first cycle of FU-based chemotherapy. Of the five patients identified following toxicities, all had grade 4 cytopenias, 80% grade ≥ 3 mucositis, 20% grade 3 rash and 20% grade 3 diarrhea, with an average of 15 days of hospitalisations due to febrile neutropenia. Seven of the 13 patients identified upfront received FU-based chemotherapy at reduced initial doses ranging from 25 to 50%. The average dose during the course of chemotherapy was 50% and two patients reached 100% dosage. No grade ≥ 3 toxicities were observed. DPYD*2A test results were available in an average of 6 days, causing no significant delays in treatment initiation according to 99% of queried physicians. Conclusions: Upfront genotyping before FU-based treatment is feasible in clinical practice. It may prevent severe toxicities and hospitalisations without delaying treatment initiation. The administration of chemotherapy at reduced doses appears to be safe in patients heterozygous for DPYD*2A.