Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre

Abstract

AbstractBackgroundDihydropyrimidine dehydrogenase (DPD) is a key enzyme in the metabolism of fluoropyrimidines. Variations in the encodingDPYDgene are associated with severe fluoropyrimidine toxicity and up-front dose reductions are recommended. We conducted a retrospective study to evaluate the impact of implementingDPYDvariant testing for patients with gastrointestinal cancers in routine clinical practice in a high volume cancer centre in London, United Kingdom.MethodsPatients receiving fluoropyrimidine chemotherapy for gastrointestinal cancer prior to, and following the implementation ofDPYDtesting were identified retrospectively. After November 2018, patients were tested forDPYDvariants c.1905+1G>A (DPYD*2A), c.2846A>T (DPYDrs67376798), c.1679T>G (DPYD*13), c.1236G>A (DPYDrs56038477), c.1601G>A (DPYD*4) prior to commencing fluoropyrimidines alone or in combination with other cytotoxics and/or radiotherapy. Patients with aDPYDheterozygous variant received an initial dose reduction of 25–50%. Toxicity by CTCAE v4.03 criteria was compared betweenDPYDheterozygous variant and wild type carriers.ResultsBetween 1stDecember 2018 and 31stJuly 2019, 370 patients who were fluoropyrimidine naïve underwent aDPYDgenotyping test prior to receiving a capecitabine (n = 236, 63.8%) or 5FU (n = 134, 36.2%) containing chemotherapy regimen. 33 patients (8.8%) were heterozygousDPYDvariant carriers and 337 (91.2%) were wild type. The most prevalent variants were c.1601G > A (n = 16) and c.1236G > A (n = 9). Mean relative dose intensity for the first dose was 54.2% (range 37.5–75%) forDPYDheterozygous carriers and 93.2% (42.9–100%) forDPYDwild type carriers. Overall grade 3 or worse toxicity was similar inDPYDvariant carriers (4/33, 12.1%) as compared to wild-type carriers (89/337, 25.7%;P = 0.0924).ConclusionsOur study demonstrates successful routineDPYDmutation testing prior to the initiation of fluoropyrimidine chemotherapy with high uptake. In patients withDPYDheterozygous variants with pre-emptive dose reductions, high incidence of severe toxicity was not observed. Our data supports routineDPYDgenotype testing prior to commencement of fluoropyrimidine chemotherapy.