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Effectiveness and safety of reduced‐dose fluoropyrimidine therapy in patients carrying the DPYD *2A variant: A matched pair analysis
Author(s) -
Henricks Linda M.,
Merendonk Lisanne N.,
Meulendijks Didier,
Deenen Maarten J.,
Beijnen Jos H.,
Boer Anthonius,
Cats Annemieke,
Schellens Jan H.M.
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32022
Subject(s) - dpyd , medicine , toxicity , oncology , dihydropyrimidine dehydrogenase , dosing , gastroenterology , chemotherapy , pharmacology , cohort , genotype , pharmacogenetics , surgery , fluorouracil , biology , genetics , thymidylate synthase , gene
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.