• Cunningham, David
• Starling, Naureen
• Li, Su
• Razzaq, Muhammad Bilal
• Gonzalez-Exposito, Reyes
• Chau, Ian
• Hubank, Michael
• Katifi, Hannah
• Rao, Sheela
• Fribbens, Charlotte
• Hernandez, Monica Arenas
• Macklin-Doherty, Aislinn
• Watkins, David
• Cortez, Lillian
• Arouri, Faten
• Fong, Caroline
• Lau, David K.

Abstract

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Dihydropyrimidine dehydrogenase (DPD) is a key enzyme in the metabolism of fluoropyrimidines. Variations in the encoding <jats:italic>DPYD</jats:italic> gene are associated with severe fluoropyrimidine toxicity and up-front dose reductions are recommended. We conducted a retrospective study to evaluate the impact of implementing <jats:italic>DPYD</jats:italic> variant testing for patients with gastrointestinal cancers in routine clinical practice in a high volume cancer centre in London, United Kingdom.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Patients receiving fluoropyrimidine chemotherapy for gastrointestinal cancer prior to, and following the implementation of <jats:italic>DPYD</jats:italic> testing were identified retrospectively. After November 2018, patients were tested for <jats:italic>DPYD</jats:italic> variants c.1905+1G&gt;A (<jats:italic>DPYD</jats:italic>*2A), c.2846A&gt;T (<jats:italic>DPYD</jats:italic> rs67376798), c.1679T&gt;G (<jats:italic>DPYD</jats:italic>*13), c.1236G&gt;A (<jats:italic>DPYD</jats:italic> rs56038477), c.1601G&gt;A (<jats:italic>DPYD</jats:italic>*4) prior to commencing fluoropyrimidines alone or in combination with other cytotoxics and/or radiotherapy. Patients with a <jats:italic>DPYD</jats:italic> heterozygous variant received an initial dose reduction of 25–50%. Toxicity by CTCAE v4.03 criteria was compared between <jats:italic>DPYD</jats:italic> heterozygous variant and wild type carriers.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Between 1<jats:sup>st</jats:sup> December 2018 and 31<jats:sup>st</jats:sup> July 2019, 370 patients who were fluoropyrimidine naïve underwent a <jats:italic>DPYD</jats:italic> genotyping test prior to receiving a capecitabine (<jats:italic>n</jats:italic> = 236, 63.8%) or 5FU (<jats:italic>n</jats:italic> = 134, 36.2%) containing chemotherapy regimen. 33 patients (8.8%) were heterozygous <jats:italic>DPYD</jats:italic> variant carriers and 337 (91.2%) were wild type. The most prevalent variants were c.1601G &gt; A (<jats:italic>n</jats:italic> = 16) and c.1236G &gt; A (<jats:italic>n</jats:italic> = 9). Mean relative dose intensity for the first dose was 54.2% (range 37.5–75%) for <jats:italic>DPYD</jats:italic> heterozygous carriers and 93.2% (42.9–100%) for <jats:italic>DPYD</jats:italic> wild type carriers. Overall grade 3 or worse toxicity was similar in <jats:italic>DPYD</jats:italic> variant carriers (4/33, 12.1%) as compared to wild-type carriers (89/337, 25.7%; <jats:italic>P</jats:italic> = 0.0924).</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Our study demonstrates successful routine <jats:italic>DPYD</jats:italic> mutation testing prior to the initiation of fluoropyrimidine chemotherapy with high uptake. In patients with <jats:italic>DPYD</jats:italic> heterozygous variants with pre-emptive dose reductions, high incidence of severe toxicity was not observed. Our data supports routine <jats:italic>DPYD</jats:italic> genotype testing prior to commencement of fluoropyrimidine chemotherapy.</jats:p></jats:sec>

Topics

• impedance spectroscopy
• toxicity
• size-exclusion chromatography
• dissipative particle dynamics