Effectiveness and safety of reduced‐dose fluoropyrimidine therapy in patients carrying the DPYD2A variant: A matched pair analysis

Carriers of the genetic DPYD*2A variant, resulting in dihydropyrimidine dehydrogenase deficiency, are at significantly increased risk of developing severe fluoropyrimidine‐associated toxicity. Upfront DPYD*2A genotype‐based dose reductions improve patient safety, but uncertainty exists whether this...

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Bibliographic Details
Published in:International journal of cancer 2019-05, Vol.144 (9), p.2347-2354
Main Authors: Henricks, Linda M., Merendonk, Lisanne N., Meulendijks, Didier, Deenen, Maarten J., Beijnen, Jos H., Boer, Anthonius, Cats, Annemieke, Schellens, Jan H.M.
Format: Article
Language:English
Subjects:
5‐fluorouracil
Cancer
capecitabine
Chemotherapy
dihydropyrimidine dehydrogenase
Dosage
DPYD
fluoropyrimidines
Genetic analysis
Genotype & phenotype
Genotypes
Medical research
Patient safety
Patients
Safety
Survival
Toxicity
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Summary:Carriers of the genetic DPYD*2A variant, resulting in dihydropyrimidine dehydrogenase deficiency, are at significantly increased risk of developing severe fluoropyrimidine‐associated toxicity. Upfront DPYD*2A genotype‐based dose reductions improve patient safety, but uncertainty exists whether this has a negative impact on treatment effectiveness. Therefore, our study investigated effectiveness and safety of DPYD*2A genotype‐guided dosing. A cohort of 40 prospectively identified heterozygous DPYD*2A carriers, treated with a ~50% reduced fluoropyrimidine dose, was identified. For effectiveness analysis, a matched pair‐analysis was performed in which for each DPYD*2A carrier a matched DPYD*2A wild‐type patient was identified. Overall survival and progression‐free survival were compared between the matched groups. The frequency of severe (grade ≥ 3) treatment‐related toxicity was compared to 1] a cohort of 1606 wild‐type patients treated with full dose and 2] a cohort of historical controls derived from literature, i.e. 86 DPYD*2A variant carriers who received a full fluoropyrimidine dose. For 37 out of 40 DPYD*2A carriers, a matched control could be identified. Compared to matched controls, reduced doses did not negatively affect overall survival (median 27 months versus 24 months, p = 0.47) nor progression‐free survival (median 14 months versus 10 months, p = 0.54). Risk of severe fluoropyrimidine‐related toxicity in DPYD*2A carriers treated with reduced dose was 18%, comparable to wild‐type patients (23%, p = 0.57) and significantly lower than the risk of 77% in DPYD*2A carriers treated with full dose (p < 0.001). Our study is the first to show that DPYD*2A genotype‐guided dosing appears to have no negative effect on effectiveness of fluoropyrimidine‐based chemotherapy, while resulting in significantly improved patient safety. What's new? Genetic variants in the dihydropyrimidine dehydrogenase gene (DPYD) enhance toxicity associated with fluoropyrimidine‐based chemotherapies and a 50% reduction in drug dosing in affected carriers. Here the authors addressed the fear of “underdosing” by retrospectively matching cancer patients with mutant or wild‐type DPYD status. No significant difference was seen in overall survival, progression‐free survival or disease control between the two groups affirming current clinical guidelines.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.32022